Reviews

Off-label prescribing (OLP) refers to the practice of using medications for indications outside of those approved by the FDA, or in dosages, dose forms, or patient populations that have not been approved by the FDA.¹ OLP is common, occurring in many practice settings and nearly every medical specialty. In a 2006 review, Radley et al² found OLP accounted for 21% of the overall use of 160 common medications. The frequency of OLP varies between medication classes. Off-label use of anticonvulsants, antidepressants, and antipsychotics tends to be higher than that of other medications.^3,4 OLP is often more common in patient populations unlikely to be included in clinical trials due to ethical or logistical difficulties, such as pediatric patients and individuals who are pregnant. The Box summarizes several components that contribute to the prevalence of OLP and explains why this practice is often necessary for treating certain substance-related and addictive disorders.

Box

Several important medicolegal and ethical considerations surround OLP. The FDA prohibits off-label promotion, in which manufacturers advertise the use of a medication for off-label use.⁵ However, regulations allow physicians to use their best clinical judgment when prescribing medications for off-label use. When considering off-label use of any medication, physicians should review the most up-to-date research, including clinical trials, case reports, and reviews to safely support their decision-making. OLP should be guided by ethical principles such as autonomy, beneficence, nonmaleficence, and justice. Physicians should obtain informed consent by conducting an appropriate discussion of the risks, benefits, and alternatives of off-label medications. This conversation should be clearly documented, and physicians should provide written material regarding off-label options to patients when available. Finally, physicians should verify their patients’ understanding of this discussion, and allow patients to accept or decline off-label medications without pressure.

This article focuses on current and potential future medications available for OLP to treat patients with alcohol use disorder (AUD), gambling disorder (GD), stimulant use disorder, and cannabis use disorder.

Alcohol use disorder

CASE 1

Ms. X, age 67, has a history of severe AUD, mild renal impairment, and migraines. She presents to the outpatient clinic seeking help to drink less alcohol. Ms. X reports drinking 1 to 2 bottles of wine each day. She was previously treated for AUD but was not helped by naltrexone and did not tolerate disulfiram (abstinence was not her goal and she experienced significant adverse effects). Ms. X says she has a medical history of chronic migraines but denies other medical issues. The treatment team discusses alternative pharmacologic options, including acamprosate and topiramate. After outlining the dosing schedule and risks/benefits with Ms. X, you make the joint decision to start topiramate to reduce alcohol cravings and target her migraine symptoms.

Only 3 medications are FDA-approved for treating AUD: disulfiram, naltrexone (oral and injectable formulations), and acamprosate. Off-label options for AUD treatment include gabapentin, topiramate, and baclofen.

Gabapentin is FDA-approved for treating postherpetic neuralgia and partial seizures in patients age ≥3. The exact mechanism of action is unclear, though its effects are possibly related to its activity as a calcium channel ligand. It also carries a structural resemblance to gamma-aminobutyric acid (GABA), though it lacks activity at GABA receptors.

Several randomized controlled trials (RCTs) evaluating the efficacy of gabapentin for AUD produced promising results. In a comparison of gabapentin vs placebo for AUD, Anton et al⁶ found gabapentin led to significant increases in the number of participants with total alcohol abstinence and participants who reported reduced drinking. Notably, the effect was most prominent in those with heavy drinking patterns and pretreatment alcohol withdrawal symptoms. A total of 41% of participants with high alcohol withdrawal scores on pretreatment evaluation achieved total abstinence while taking gabapentin, compared to 1% in the placebo group.⁶ A meta-analysis of gabapentin for AUD by Kranzler et al⁷ included 7 RCTs and 32 effect measures. It found that although all outcome measures favored gabapentin over placebo, only the percentage of heavy drinking days was significantly different.

Gabapentin is dosed between 300 to 600 mg 3 times per day, but 1 study found that a higher dose (1,800 mg/d) was associated with better outcomes.⁸ Common adverse effects include sedation, dizziness, peripheral edema, and ataxia.

Continue to: Topiramate

Topiramate blocks voltage-gated sodium channels and enhances GABA-A receptor activity.⁹ It is indicated for the treatment of seizures, migraine prophylaxis, weight management, and weight loss. Several clinical trials, including RCTs,^10-12 demonstrated that topiramate was superior to placebo in reducing the percentage of heavy drinking days and overall drinking days. Some also showed that topiramate was associated with abstinence and reduced craving levels.^12,13 A meta-analysis by Blodgett et al¹⁴ found that compared to placebo, topiramate lowered the rate of heavy drinking and increased abstinence.

Topiramate is dosed from 50 to 150 mg twice daily, although some studies suggest a lower dose (≤75 mg/d) may be associated with clinical benefits.^15,16 One important clinical consideration: topiramate must follow a slow titration schedule (4 to 6 weeks) to increase tolerability and avoid adverse effects. Common adverse effects include sedation, word-finding difficulty, paresthesia, increased risk for renal calculi, dizziness, anorexia, and alterations in taste.

Baclofen is a GABA-B agonist FDA-approved for the treatment of muscle spasticity related to multiple sclerosis and reversible spasticity related to spinal cord lesions and multiple sclerosis. Of note, it is approved for treatment of AUD in Europe.

In a meta-analysis of 13 RCTs, Pierce et al¹⁷ found a greater likelihood of abstinence and greater time to first lapse of drinking with baclofen compared to placebo. Interestingly, a subgroup analysis found that the positive effects were limited to trials that used 30 to 60 mg/d of baclofen, and not evident in those that used higher doses. Additionally, there was no difference between baclofen and placebo with regard to several important outcomes, including alcohol cravings, anxiety, depression, or number of total abstinent days. A review by Andrade¹⁸ proposed that individualized treatment with high-dose baclofen (30 to 300 mg/d) may be a useful second-line approach in heavy drinkers who wish to reduce their alcohol intake.

Continue to: Before starting baclofen...

Before starting baclofen, patients should be informed about its adverse effects. Common adverse effects include sedation and motor impairment. More serious but less common adverse effects include seizures, respiratory depression with sleep apnea, severe mood disorders (ie, mania, depression, or suicide risk), and mental confusion. Baclofen should be gradually discontinued, because there is some risk of clinical withdrawal symptoms (ie, agitation, confusion, seizures, or delirium).

Among the medications discussed in this section, the evidence for gabapentin and topiramate is moderate to strong, while the evidence for baclofen is overall weaker or mixed. The American Psychiatric Association’s Practice Guideline suggests offering gabapentin or topiramate to patients with moderate to severe AUD whose goal is to achieve abstinence or reduce alcohol use, or those who prefer gabapentin or topiramate or cannot tolerate or have not responded to naltrexone and acamprosate.¹⁹ Clinicians must ensure patients have no contra­indications to the use of these medications. Due to the moderate quality evidence for a significant reduction in heavy drinking and increased abstinence,^14,20 a practice guideline from the US Department of Veterans Affairs and US Department of Defense²¹ recommends topiramate as 1 of 2 first-line treatments (the other is naltrexone). This guideline suggests gabapentin as a second-line treatment for AUD.²¹

Gambling disorder

CASE 2

Mr. P, age 28, seeks treatment for GD and cocaine use disorder. He reports a 7-year history of sports betting that has increasingly impaired his functioning over the past year. He lost his job, savings, and familial relationships due to his impulsive and risky behavior. Mr. P also reports frequent cocaine use, about 2 to 3 days per week, mostly on the weekends. The psychiatrist tells Mr. P there is no FDA-approved pharmacologic treatment for GD or cocaine use disorder. The psychiatrist discusses the option of naltrexone as off-label treatment for GD with the goal of reducing Mr. P’s urges to gamble, and points to possible benefits for cocaine use disorder.

GD impacts approximately 0.5% of the adult US population and is often co-occurring with substance use disorders.²² It is thought to share neurobiological and clinical similarities with substance use disorders.²³ There are currently no FDA-approved medications to treat the disorder. In studies of GD, treatment success with antidepressants and mood stabilizers has not been consistent,^23,24 but some promising results have been published for the opioid receptor antagonist naltrexone^24-29and N-acetylcysteine (NAC).^30-32

Naltrexone is thought to reduce gambling behavior and urges via downstream modulation of mesolimbic dopamine circuitry.²⁴ It is FDA-approved for the treatment of AUD and opioid use disorder. Open-label RCTs have found a reduction in gambling urges and behavior with daily naltrexone.^25-27 Dosing at 50 mg/d appears to be just as efficacious as higher doses such as 100 and 150 mg/d.²⁷ When used as a daily as-needed medication for strong gambling urges or if an individual was planning to gamble, naltrexone 50 mg/d was not effective.²⁸

Continue to: Naltrexone typically is started...

Naltrexone typically is started at 25 mg/d to assess tolerability and quickly titrated to 50 mg/d. When titrating, common adverse effects include nausea, vomiting, and transient elevations in transaminases. Another opioid antagonist, nalmefene, has also been studied in patients with GD. An RCT by Grant et al²⁹ that evaluated 207 patients found that compared with placebo, nalmefene 25 mg/d for 16 weeks was associated with a significant reduction in gambling assessment scores. In Europe, nalmefene is approved for treating AUD but the oral formulation is not currently available in the US.

N-acetylcysteine is thought to potentially reverse neuronal dysfunction seen in addictive disorders by glutamatergic modulation.³⁰ Research investigating NAC for GD is scarce. A pilot study found 16 of 27 patients with GD reduced gambling behavior with a mean dose of 1,476.9 mg/d.³¹ An additional study investigating the addition of NAC to behavioral therapy in nicotine-dependent individuals with pathologic gambling found a reduction in problem gambling after 18 weeks (6 weeks + 3 months follow-up).³² Common but mild adverse effects associated with NAC are nausea, vomiting, and diarrhea.

A meta-analysis by Goslar et al³³ that reviewed 34 studies (1,340 participants) found pharmacologic treatments were associated with large and medium pre-post reductions in global severity, frequency, and financial loss in patients with GD. RCTs studying opioid antagonists and mood stabilizers (combined with a cognitive intervention) as well as lithium for patients with comorbid bipolar disorder and GD demonstrated promising results.³³

Stimulant use disorder

There are no FDA-approved medications for stimulant use disorder. Multiple off-label options have been studied for the treatment of methamphetamine abuse and cocaine abuse.

Methamphetamine use has been expanding over the past decade with a 3.6-fold increase in positive methamphetamine screens in overdose deaths from 2011 to 2016.³⁴ Pharmacologic options studied for OLP of methamphetamine use disorder include mirtazapine, bupropion, naltrexone, and topiramate.

Continue to: Mirtazapine

Mirtazapine is an atypical antidepressant whose mechanism of action includes modulation of the serotonin, norepinephrine, and alpha-2 adrenergic systems. It is FDA-approved for the treatment of major depressive disorder (MDD). In a randomized placebo-controlled study, mirtazapine 30 mg/d at night was found to decrease methamphetamine use for active users and led to decreased sexual risk in men who have sex with men.³⁵ These results were supported by an additional RCT in which mirtazapine 30 mg/d significantly reduced rates of methamphetamine use vs placebo at 24 and 36 weeks despite poor medication adherence.³⁶ Adverse effects to monitor in patients treated with mirtazapine include increased appetite, weight gain, sedation, and constipation.

Bupropion is a norepinephrine dopamine reuptake inhibitor that produces increased neurotransmission of norepinephrine and dopamine in the CNS. It is FDA-approved for the treatment of MDD and as an aid for smoking cessation. Bupropion has been studied for methamphetamine use disorder with mixed results. In a randomized placebo-controlled trial, bupropion sustained release 150 mg twice daily was not more effective than placebo in reducing methamphetamine use.³⁷ However, the extended-release formulation of bupropion 450 mg/d combined with long-acting injectable naltrexone was associated with a reduction in methamphetamine use over 12 weeks.³⁸ Bupropion is generally well tolerated; common adverse effects include insomnia, tremor, headache, and dizziness.

Naltrexone. Data about using oral naltrexone to treat stimulant use disorders are limited. A randomized, placebo-controlled trial by Jayaram-Lindström et al³⁹ found naltrexone 50 mg/d significantly reduced amphetamine use compared to placebo. Additionally, naltrexone 50 and 150 mg/d have been shown to reduce cocaine use over time in combination with therapy for cocaine-dependent patients and those dependent on alcohol and cocaine.^40,41

Topiramate has been studied for the treatment of cocaine use disorder. It is hypothesized that modulation of the mesocorticolimbic dopamine system may contribute to decreased cocaine cravings.⁴² A pilot study by Kampman et al⁴³ found that after an 8-week titration of topiramate to 200 mg/d, individuals were more likely to achieve cocaine abstinence compared to those who receive placebo. In an RCT, Elkashef et al⁴⁴ did not find topiramate assisted with increased abstinence of methamphetamine in active users at a target dose of 200 mg/d. However, it was associated with reduced relapse rates in individuals who were abstinent prior to the study.⁴⁴ At a target dose of 300 mg/d, topiramate also outperformed placebo in decreasing days of cocaine use.⁴² Adverse effects of topiramate included paresthesia, alteration in taste, and difficulty with concentration.

Cannabis use disorder

In recent years, cannabis use in the US has greatly increased⁴⁵ but no medications are FDA-approved for treating cannabis use disorder. Studies of pharmacologic options for cannabis use disorder have had mixed results.⁴⁶ A meta-analysis by Bahji et al⁴⁷ of 24 studies investigating pharmacotherapies for cannabis use disorder highlighted the lack of adequate evidence. In this section, we focus on a few positive trials of NAC and gabapentin.

Continue to: N-acetylcysteine

N-acetylcysteine. Studies investigating NAC 1,200 mg twice daily have been promising in adolescent and adult populations.^48-50 There are some mixed results, however. A large RCT found NAC 1,200 mg twice daily was not better than placebo in helping adults achieve abstinence from cannabis.⁵¹

Gabapentin may be a viable option for treating cannabis use disorder. A pilot study by Mason et al⁵² found gabapentin 1,200 mg/d was more effective than placebo at reducing cannabis use among treatment-seeking adults.

When and how to consider OLP

OLP for addictive disorders is common and often necessary. This is primarily due to limitations of the FDA-approved medications and because there are no FDA-approved medications for many substance-related and addictive disorders (ie, GD, cannabis use disorder, and stimulant use disorder). When assessing pharmacotherapy options, if FDA-approved medications are available for certain diagnoses, clinicians should first consider them. The off-label medications discussed in this article are outlined in the Table.^{6-21,24-28,30-33,35-44,48-52}

The overall level of evidence to support the use of off-label medications is lower than that of FDA-approved medications, which contributes to potential medicolegal concerns of OLP. Off-label medications should be considered when there are no FDA-approved medications available, and the decision to use off-label medications should be based on evidence from the literature and current standard of care. Additionally, OLP is necessary if a patient cannot tolerate FDA-approved medications, is not helped by FDA-approved treatments, or when there are other clinical reasons to choose a particular off-label medication. For example, if a patient has comorbid AUD and obesity (or migraines), using topiramate may be appropriate because it may target alcohol cravings and can be helpful for weight loss (and migraine prophylaxis). Similarly, for patients with AUD and neuropathic pain, using gabapentin can be considered for its dual therapeutic effects.

It is critical for clinicians to understand the landscape of off-label options for treating addictive disorders. Additional research in the form of RCTs is needed to better clarify the efficacy and adverse effects of these treatments.

Continue to: Bottom Line

Off-label prescribing is prevalent in practice, including in the treatment of substance-related and addictive disorders. When considering off-label use of any medication, clinicians should review the most recent research, obtain informed consent from patients, and verify patients’ understanding of the potential risks and adverse effects associated with the particular medication.

Related Resources

• Joshi KG, Frierson RL. Off-label prescribing: how to limit your liability. Current Psychiatry. 2020;19(9):12,39. doi:10.12788/ cp.0035
• Stanciu CN, Gnanasegaram SA. Don’t balk at using medical therapy to manage alcohol use disorder. Current Psychiatry. 2017;16(2):50-52.

Drug Brand Names

Acamprosate • Campral
Baclofen • Ozobax
Bupropion • Wellbutrin, Zyban
Disulfiram • Antabuse
Gabapentin • Neurontin
Lithium • Eskalith, Lithobid
Mirtazapine • Remeron
Naltrexone • ReVia, Vivitrol
Topiramate • Topamax

Off-label prescribing (OLP) refers to the practice of using medications for indications outside of those approved by the FDA, or in dosages, dose forms, or patient populations that have not been approved by the FDA.¹ OLP is common, occurring in many practice settings and nearly every medical specialty. In a 2006 review, Radley et al² found OLP accounted for 21% of the overall use of 160 common medications. The frequency of OLP varies between medication classes. Off-label use of anticonvulsants, antidepressants, and antipsychotics tends to be higher than that of other medications.^3,4 OLP is often more common in patient populations unlikely to be included in clinical trials due to ethical or logistical difficulties, such as pediatric patients and individuals who are pregnant. The Box summarizes several components that contribute to the prevalence of OLP and explains why this practice is often necessary for treating certain substance-related and addictive disorders.

Box

Several important medicolegal and ethical considerations surround OLP. The FDA prohibits off-label promotion, in which manufacturers advertise the use of a medication for off-label use.⁵ However, regulations allow physicians to use their best clinical judgment when prescribing medications for off-label use. When considering off-label use of any medication, physicians should review the most up-to-date research, including clinical trials, case reports, and reviews to safely support their decision-making. OLP should be guided by ethical principles such as autonomy, beneficence, nonmaleficence, and justice. Physicians should obtain informed consent by conducting an appropriate discussion of the risks, benefits, and alternatives of off-label medications. This conversation should be clearly documented, and physicians should provide written material regarding off-label options to patients when available. Finally, physicians should verify their patients’ understanding of this discussion, and allow patients to accept or decline off-label medications without pressure.

This article focuses on current and potential future medications available for OLP to treat patients with alcohol use disorder (AUD), gambling disorder (GD), stimulant use disorder, and cannabis use disorder.

Alcohol use disorder

CASE 1

Ms. X, age 67, has a history of severe AUD, mild renal impairment, and migraines. She presents to the outpatient clinic seeking help to drink less alcohol. Ms. X reports drinking 1 to 2 bottles of wine each day. She was previously treated for AUD but was not helped by naltrexone and did not tolerate disulfiram (abstinence was not her goal and she experienced significant adverse effects). Ms. X says she has a medical history of chronic migraines but denies other medical issues. The treatment team discusses alternative pharmacologic options, including acamprosate and topiramate. After outlining the dosing schedule and risks/benefits with Ms. X, you make the joint decision to start topiramate to reduce alcohol cravings and target her migraine symptoms.

Only 3 medications are FDA-approved for treating AUD: disulfiram, naltrexone (oral and injectable formulations), and acamprosate. Off-label options for AUD treatment include gabapentin, topiramate, and baclofen.

Gabapentin is FDA-approved for treating postherpetic neuralgia and partial seizures in patients age ≥3. The exact mechanism of action is unclear, though its effects are possibly related to its activity as a calcium channel ligand. It also carries a structural resemblance to gamma-aminobutyric acid (GABA), though it lacks activity at GABA receptors.

Several randomized controlled trials (RCTs) evaluating the efficacy of gabapentin for AUD produced promising results. In a comparison of gabapentin vs placebo for AUD, Anton et al⁶ found gabapentin led to significant increases in the number of participants with total alcohol abstinence and participants who reported reduced drinking. Notably, the effect was most prominent in those with heavy drinking patterns and pretreatment alcohol withdrawal symptoms. A total of 41% of participants with high alcohol withdrawal scores on pretreatment evaluation achieved total abstinence while taking gabapentin, compared to 1% in the placebo group.⁶ A meta-analysis of gabapentin for AUD by Kranzler et al⁷ included 7 RCTs and 32 effect measures. It found that although all outcome measures favored gabapentin over placebo, only the percentage of heavy drinking days was significantly different.

Gabapentin is dosed between 300 to 600 mg 3 times per day, but 1 study found that a higher dose (1,800 mg/d) was associated with better outcomes.⁸ Common adverse effects include sedation, dizziness, peripheral edema, and ataxia.

Continue to: Topiramate

Topiramate blocks voltage-gated sodium channels and enhances GABA-A receptor activity.⁹ It is indicated for the treatment of seizures, migraine prophylaxis, weight management, and weight loss. Several clinical trials, including RCTs,^10-12 demonstrated that topiramate was superior to placebo in reducing the percentage of heavy drinking days and overall drinking days. Some also showed that topiramate was associated with abstinence and reduced craving levels.^12,13 A meta-analysis by Blodgett et al¹⁴ found that compared to placebo, topiramate lowered the rate of heavy drinking and increased abstinence.

Topiramate is dosed from 50 to 150 mg twice daily, although some studies suggest a lower dose (≤75 mg/d) may be associated with clinical benefits.^15,16 One important clinical consideration: topiramate must follow a slow titration schedule (4 to 6 weeks) to increase tolerability and avoid adverse effects. Common adverse effects include sedation, word-finding difficulty, paresthesia, increased risk for renal calculi, dizziness, anorexia, and alterations in taste.

Baclofen is a GABA-B agonist FDA-approved for the treatment of muscle spasticity related to multiple sclerosis and reversible spasticity related to spinal cord lesions and multiple sclerosis. Of note, it is approved for treatment of AUD in Europe.

In a meta-analysis of 13 RCTs, Pierce et al¹⁷ found a greater likelihood of abstinence and greater time to first lapse of drinking with baclofen compared to placebo. Interestingly, a subgroup analysis found that the positive effects were limited to trials that used 30 to 60 mg/d of baclofen, and not evident in those that used higher doses. Additionally, there was no difference between baclofen and placebo with regard to several important outcomes, including alcohol cravings, anxiety, depression, or number of total abstinent days. A review by Andrade¹⁸ proposed that individualized treatment with high-dose baclofen (30 to 300 mg/d) may be a useful second-line approach in heavy drinkers who wish to reduce their alcohol intake.

Continue to: Before starting baclofen...

Before starting baclofen, patients should be informed about its adverse effects. Common adverse effects include sedation and motor impairment. More serious but less common adverse effects include seizures, respiratory depression with sleep apnea, severe mood disorders (ie, mania, depression, or suicide risk), and mental confusion. Baclofen should be gradually discontinued, because there is some risk of clinical withdrawal symptoms (ie, agitation, confusion, seizures, or delirium).

Among the medications discussed in this section, the evidence for gabapentin and topiramate is moderate to strong, while the evidence for baclofen is overall weaker or mixed. The American Psychiatric Association’s Practice Guideline suggests offering gabapentin or topiramate to patients with moderate to severe AUD whose goal is to achieve abstinence or reduce alcohol use, or those who prefer gabapentin or topiramate or cannot tolerate or have not responded to naltrexone and acamprosate.¹⁹ Clinicians must ensure patients have no contra­indications to the use of these medications. Due to the moderate quality evidence for a significant reduction in heavy drinking and increased abstinence,^14,20 a practice guideline from the US Department of Veterans Affairs and US Department of Defense²¹ recommends topiramate as 1 of 2 first-line treatments (the other is naltrexone). This guideline suggests gabapentin as a second-line treatment for AUD.²¹

Gambling disorder

CASE 2

Mr. P, age 28, seeks treatment for GD and cocaine use disorder. He reports a 7-year history of sports betting that has increasingly impaired his functioning over the past year. He lost his job, savings, and familial relationships due to his impulsive and risky behavior. Mr. P also reports frequent cocaine use, about 2 to 3 days per week, mostly on the weekends. The psychiatrist tells Mr. P there is no FDA-approved pharmacologic treatment for GD or cocaine use disorder. The psychiatrist discusses the option of naltrexone as off-label treatment for GD with the goal of reducing Mr. P’s urges to gamble, and points to possible benefits for cocaine use disorder.

GD impacts approximately 0.5% of the adult US population and is often co-occurring with substance use disorders.²² It is thought to share neurobiological and clinical similarities with substance use disorders.²³ There are currently no FDA-approved medications to treat the disorder. In studies of GD, treatment success with antidepressants and mood stabilizers has not been consistent,^23,24 but some promising results have been published for the opioid receptor antagonist naltrexone^24-29and N-acetylcysteine (NAC).^30-32

Naltrexone is thought to reduce gambling behavior and urges via downstream modulation of mesolimbic dopamine circuitry.²⁴ It is FDA-approved for the treatment of AUD and opioid use disorder. Open-label RCTs have found a reduction in gambling urges and behavior with daily naltrexone.^25-27 Dosing at 50 mg/d appears to be just as efficacious as higher doses such as 100 and 150 mg/d.²⁷ When used as a daily as-needed medication for strong gambling urges or if an individual was planning to gamble, naltrexone 50 mg/d was not effective.²⁸

Continue to: Naltrexone typically is started...

Naltrexone typically is started at 25 mg/d to assess tolerability and quickly titrated to 50 mg/d. When titrating, common adverse effects include nausea, vomiting, and transient elevations in transaminases. Another opioid antagonist, nalmefene, has also been studied in patients with GD. An RCT by Grant et al²⁹ that evaluated 207 patients found that compared with placebo, nalmefene 25 mg/d for 16 weeks was associated with a significant reduction in gambling assessment scores. In Europe, nalmefene is approved for treating AUD but the oral formulation is not currently available in the US.

N-acetylcysteine is thought to potentially reverse neuronal dysfunction seen in addictive disorders by glutamatergic modulation.³⁰ Research investigating NAC for GD is scarce. A pilot study found 16 of 27 patients with GD reduced gambling behavior with a mean dose of 1,476.9 mg/d.³¹ An additional study investigating the addition of NAC to behavioral therapy in nicotine-dependent individuals with pathologic gambling found a reduction in problem gambling after 18 weeks (6 weeks + 3 months follow-up).³² Common but mild adverse effects associated with NAC are nausea, vomiting, and diarrhea.

A meta-analysis by Goslar et al³³ that reviewed 34 studies (1,340 participants) found pharmacologic treatments were associated with large and medium pre-post reductions in global severity, frequency, and financial loss in patients with GD. RCTs studying opioid antagonists and mood stabilizers (combined with a cognitive intervention) as well as lithium for patients with comorbid bipolar disorder and GD demonstrated promising results.³³

Stimulant use disorder

There are no FDA-approved medications for stimulant use disorder. Multiple off-label options have been studied for the treatment of methamphetamine abuse and cocaine abuse.

Methamphetamine use has been expanding over the past decade with a 3.6-fold increase in positive methamphetamine screens in overdose deaths from 2011 to 2016.³⁴ Pharmacologic options studied for OLP of methamphetamine use disorder include mirtazapine, bupropion, naltrexone, and topiramate.

Continue to: Mirtazapine

Mirtazapine is an atypical antidepressant whose mechanism of action includes modulation of the serotonin, norepinephrine, and alpha-2 adrenergic systems. It is FDA-approved for the treatment of major depressive disorder (MDD). In a randomized placebo-controlled study, mirtazapine 30 mg/d at night was found to decrease methamphetamine use for active users and led to decreased sexual risk in men who have sex with men.³⁵ These results were supported by an additional RCT in which mirtazapine 30 mg/d significantly reduced rates of methamphetamine use vs placebo at 24 and 36 weeks despite poor medication adherence.³⁶ Adverse effects to monitor in patients treated with mirtazapine include increased appetite, weight gain, sedation, and constipation.

Bupropion is a norepinephrine dopamine reuptake inhibitor that produces increased neurotransmission of norepinephrine and dopamine in the CNS. It is FDA-approved for the treatment of MDD and as an aid for smoking cessation. Bupropion has been studied for methamphetamine use disorder with mixed results. In a randomized placebo-controlled trial, bupropion sustained release 150 mg twice daily was not more effective than placebo in reducing methamphetamine use.³⁷ However, the extended-release formulation of bupropion 450 mg/d combined with long-acting injectable naltrexone was associated with a reduction in methamphetamine use over 12 weeks.³⁸ Bupropion is generally well tolerated; common adverse effects include insomnia, tremor, headache, and dizziness.

Naltrexone. Data about using oral naltrexone to treat stimulant use disorders are limited. A randomized, placebo-controlled trial by Jayaram-Lindström et al³⁹ found naltrexone 50 mg/d significantly reduced amphetamine use compared to placebo. Additionally, naltrexone 50 and 150 mg/d have been shown to reduce cocaine use over time in combination with therapy for cocaine-dependent patients and those dependent on alcohol and cocaine.^40,41

Topiramate has been studied for the treatment of cocaine use disorder. It is hypothesized that modulation of the mesocorticolimbic dopamine system may contribute to decreased cocaine cravings.⁴² A pilot study by Kampman et al⁴³ found that after an 8-week titration of topiramate to 200 mg/d, individuals were more likely to achieve cocaine abstinence compared to those who receive placebo. In an RCT, Elkashef et al⁴⁴ did not find topiramate assisted with increased abstinence of methamphetamine in active users at a target dose of 200 mg/d. However, it was associated with reduced relapse rates in individuals who were abstinent prior to the study.⁴⁴ At a target dose of 300 mg/d, topiramate also outperformed placebo in decreasing days of cocaine use.⁴² Adverse effects of topiramate included paresthesia, alteration in taste, and difficulty with concentration.

Cannabis use disorder

In recent years, cannabis use in the US has greatly increased⁴⁵ but no medications are FDA-approved for treating cannabis use disorder. Studies of pharmacologic options for cannabis use disorder have had mixed results.⁴⁶ A meta-analysis by Bahji et al⁴⁷ of 24 studies investigating pharmacotherapies for cannabis use disorder highlighted the lack of adequate evidence. In this section, we focus on a few positive trials of NAC and gabapentin.

Continue to: N-acetylcysteine

N-acetylcysteine. Studies investigating NAC 1,200 mg twice daily have been promising in adolescent and adult populations.^48-50 There are some mixed results, however. A large RCT found NAC 1,200 mg twice daily was not better than placebo in helping adults achieve abstinence from cannabis.⁵¹

Gabapentin may be a viable option for treating cannabis use disorder. A pilot study by Mason et al⁵² found gabapentin 1,200 mg/d was more effective than placebo at reducing cannabis use among treatment-seeking adults.

When and how to consider OLP

OLP for addictive disorders is common and often necessary. This is primarily due to limitations of the FDA-approved medications and because there are no FDA-approved medications for many substance-related and addictive disorders (ie, GD, cannabis use disorder, and stimulant use disorder). When assessing pharmacotherapy options, if FDA-approved medications are available for certain diagnoses, clinicians should first consider them. The off-label medications discussed in this article are outlined in the Table.^{6-21,24-28,30-33,35-44,48-52}

The overall level of evidence to support the use of off-label medications is lower than that of FDA-approved medications, which contributes to potential medicolegal concerns of OLP. Off-label medications should be considered when there are no FDA-approved medications available, and the decision to use off-label medications should be based on evidence from the literature and current standard of care. Additionally, OLP is necessary if a patient cannot tolerate FDA-approved medications, is not helped by FDA-approved treatments, or when there are other clinical reasons to choose a particular off-label medication. For example, if a patient has comorbid AUD and obesity (or migraines), using topiramate may be appropriate because it may target alcohol cravings and can be helpful for weight loss (and migraine prophylaxis). Similarly, for patients with AUD and neuropathic pain, using gabapentin can be considered for its dual therapeutic effects.

It is critical for clinicians to understand the landscape of off-label options for treating addictive disorders. Additional research in the form of RCTs is needed to better clarify the efficacy and adverse effects of these treatments.

Continue to: Bottom Line

Off-label prescribing is prevalent in practice, including in the treatment of substance-related and addictive disorders. When considering off-label use of any medication, clinicians should review the most recent research, obtain informed consent from patients, and verify patients’ understanding of the potential risks and adverse effects associated with the particular medication.

Related Resources

• Joshi KG, Frierson RL. Off-label prescribing: how to limit your liability. Current Psychiatry. 2020;19(9):12,39. doi:10.12788/ cp.0035
• Stanciu CN, Gnanasegaram SA. Don’t balk at using medical therapy to manage alcohol use disorder. Current Psychiatry. 2017;16(2):50-52.

Drug Brand Names

Acamprosate • Campral
Baclofen • Ozobax
Bupropion • Wellbutrin, Zyban
Disulfiram • Antabuse
Gabapentin • Neurontin
Lithium • Eskalith, Lithobid
Mirtazapine • Remeron
Naltrexone • ReVia, Vivitrol
Topiramate • Topamax

Off-label prescribing (OLP) refers to the practice of using medications for indications outside of those approved by the FDA, or in dosages, dose forms, or patient populations that have not been approved by the FDA.¹ OLP is common, occurring in many practice settings and nearly every medical specialty. In a 2006 review, Radley et al² found OLP accounted for 21% of the overall use of 160 common medications. The frequency of OLP varies between medication classes. Off-label use of anticonvulsants, antidepressants, and antipsychotics tends to be higher than that of other medications.^3,4 OLP is often more common in patient populations unlikely to be included in clinical trials due to ethical or logistical difficulties, such as pediatric patients and individuals who are pregnant. The Box summarizes several components that contribute to the prevalence of OLP and explains why this practice is often necessary for treating certain substance-related and addictive disorders.

Box

Several important medicolegal and ethical considerations surround OLP. The FDA prohibits off-label promotion, in which manufacturers advertise the use of a medication for off-label use.⁵ However, regulations allow physicians to use their best clinical judgment when prescribing medications for off-label use. When considering off-label use of any medication, physicians should review the most up-to-date research, including clinical trials, case reports, and reviews to safely support their decision-making. OLP should be guided by ethical principles such as autonomy, beneficence, nonmaleficence, and justice. Physicians should obtain informed consent by conducting an appropriate discussion of the risks, benefits, and alternatives of off-label medications. This conversation should be clearly documented, and physicians should provide written material regarding off-label options to patients when available. Finally, physicians should verify their patients’ understanding of this discussion, and allow patients to accept or decline off-label medications without pressure.

This article focuses on current and potential future medications available for OLP to treat patients with alcohol use disorder (AUD), gambling disorder (GD), stimulant use disorder, and cannabis use disorder.

Alcohol use disorder

CASE 1

Ms. X, age 67, has a history of severe AUD, mild renal impairment, and migraines. She presents to the outpatient clinic seeking help to drink less alcohol. Ms. X reports drinking 1 to 2 bottles of wine each day. She was previously treated for AUD but was not helped by naltrexone and did not tolerate disulfiram (abstinence was not her goal and she experienced significant adverse effects). Ms. X says she has a medical history of chronic migraines but denies other medical issues. The treatment team discusses alternative pharmacologic options, including acamprosate and topiramate. After outlining the dosing schedule and risks/benefits with Ms. X, you make the joint decision to start topiramate to reduce alcohol cravings and target her migraine symptoms.

Only 3 medications are FDA-approved for treating AUD: disulfiram, naltrexone (oral and injectable formulations), and acamprosate. Off-label options for AUD treatment include gabapentin, topiramate, and baclofen.

Gabapentin is FDA-approved for treating postherpetic neuralgia and partial seizures in patients age ≥3. The exact mechanism of action is unclear, though its effects are possibly related to its activity as a calcium channel ligand. It also carries a structural resemblance to gamma-aminobutyric acid (GABA), though it lacks activity at GABA receptors.

Several randomized controlled trials (RCTs) evaluating the efficacy of gabapentin for AUD produced promising results. In a comparison of gabapentin vs placebo for AUD, Anton et al⁶ found gabapentin led to significant increases in the number of participants with total alcohol abstinence and participants who reported reduced drinking. Notably, the effect was most prominent in those with heavy drinking patterns and pretreatment alcohol withdrawal symptoms. A total of 41% of participants with high alcohol withdrawal scores on pretreatment evaluation achieved total abstinence while taking gabapentin, compared to 1% in the placebo group.⁶ A meta-analysis of gabapentin for AUD by Kranzler et al⁷ included 7 RCTs and 32 effect measures. It found that although all outcome measures favored gabapentin over placebo, only the percentage of heavy drinking days was significantly different.

Gabapentin is dosed between 300 to 600 mg 3 times per day, but 1 study found that a higher dose (1,800 mg/d) was associated with better outcomes.⁸ Common adverse effects include sedation, dizziness, peripheral edema, and ataxia.

Continue to: Topiramate

Topiramate blocks voltage-gated sodium channels and enhances GABA-A receptor activity.⁹ It is indicated for the treatment of seizures, migraine prophylaxis, weight management, and weight loss. Several clinical trials, including RCTs,^10-12 demonstrated that topiramate was superior to placebo in reducing the percentage of heavy drinking days and overall drinking days. Some also showed that topiramate was associated with abstinence and reduced craving levels.^12,13 A meta-analysis by Blodgett et al¹⁴ found that compared to placebo, topiramate lowered the rate of heavy drinking and increased abstinence.

Topiramate is dosed from 50 to 150 mg twice daily, although some studies suggest a lower dose (≤75 mg/d) may be associated with clinical benefits.^15,16 One important clinical consideration: topiramate must follow a slow titration schedule (4 to 6 weeks) to increase tolerability and avoid adverse effects. Common adverse effects include sedation, word-finding difficulty, paresthesia, increased risk for renal calculi, dizziness, anorexia, and alterations in taste.

Baclofen is a GABA-B agonist FDA-approved for the treatment of muscle spasticity related to multiple sclerosis and reversible spasticity related to spinal cord lesions and multiple sclerosis. Of note, it is approved for treatment of AUD in Europe.

In a meta-analysis of 13 RCTs, Pierce et al¹⁷ found a greater likelihood of abstinence and greater time to first lapse of drinking with baclofen compared to placebo. Interestingly, a subgroup analysis found that the positive effects were limited to trials that used 30 to 60 mg/d of baclofen, and not evident in those that used higher doses. Additionally, there was no difference between baclofen and placebo with regard to several important outcomes, including alcohol cravings, anxiety, depression, or number of total abstinent days. A review by Andrade¹⁸ proposed that individualized treatment with high-dose baclofen (30 to 300 mg/d) may be a useful second-line approach in heavy drinkers who wish to reduce their alcohol intake.

Continue to: Before starting baclofen...

Before starting baclofen, patients should be informed about its adverse effects. Common adverse effects include sedation and motor impairment. More serious but less common adverse effects include seizures, respiratory depression with sleep apnea, severe mood disorders (ie, mania, depression, or suicide risk), and mental confusion. Baclofen should be gradually discontinued, because there is some risk of clinical withdrawal symptoms (ie, agitation, confusion, seizures, or delirium).

Among the medications discussed in this section, the evidence for gabapentin and topiramate is moderate to strong, while the evidence for baclofen is overall weaker or mixed. The American Psychiatric Association’s Practice Guideline suggests offering gabapentin or topiramate to patients with moderate to severe AUD whose goal is to achieve abstinence or reduce alcohol use, or those who prefer gabapentin or topiramate or cannot tolerate or have not responded to naltrexone and acamprosate.¹⁹ Clinicians must ensure patients have no contra­indications to the use of these medications. Due to the moderate quality evidence for a significant reduction in heavy drinking and increased abstinence,^14,20 a practice guideline from the US Department of Veterans Affairs and US Department of Defense²¹ recommends topiramate as 1 of 2 first-line treatments (the other is naltrexone). This guideline suggests gabapentin as a second-line treatment for AUD.²¹

Gambling disorder

CASE 2

Mr. P, age 28, seeks treatment for GD and cocaine use disorder. He reports a 7-year history of sports betting that has increasingly impaired his functioning over the past year. He lost his job, savings, and familial relationships due to his impulsive and risky behavior. Mr. P also reports frequent cocaine use, about 2 to 3 days per week, mostly on the weekends. The psychiatrist tells Mr. P there is no FDA-approved pharmacologic treatment for GD or cocaine use disorder. The psychiatrist discusses the option of naltrexone as off-label treatment for GD with the goal of reducing Mr. P’s urges to gamble, and points to possible benefits for cocaine use disorder.

GD impacts approximately 0.5% of the adult US population and is often co-occurring with substance use disorders.²² It is thought to share neurobiological and clinical similarities with substance use disorders.²³ There are currently no FDA-approved medications to treat the disorder. In studies of GD, treatment success with antidepressants and mood stabilizers has not been consistent,^23,24 but some promising results have been published for the opioid receptor antagonist naltrexone^24-29and N-acetylcysteine (NAC).^30-32

Naltrexone is thought to reduce gambling behavior and urges via downstream modulation of mesolimbic dopamine circuitry.²⁴ It is FDA-approved for the treatment of AUD and opioid use disorder. Open-label RCTs have found a reduction in gambling urges and behavior with daily naltrexone.^25-27 Dosing at 50 mg/d appears to be just as efficacious as higher doses such as 100 and 150 mg/d.²⁷ When used as a daily as-needed medication for strong gambling urges or if an individual was planning to gamble, naltrexone 50 mg/d was not effective.²⁸

Continue to: Naltrexone typically is started...

Naltrexone typically is started at 25 mg/d to assess tolerability and quickly titrated to 50 mg/d. When titrating, common adverse effects include nausea, vomiting, and transient elevations in transaminases. Another opioid antagonist, nalmefene, has also been studied in patients with GD. An RCT by Grant et al²⁹ that evaluated 207 patients found that compared with placebo, nalmefene 25 mg/d for 16 weeks was associated with a significant reduction in gambling assessment scores. In Europe, nalmefene is approved for treating AUD but the oral formulation is not currently available in the US.

N-acetylcysteine is thought to potentially reverse neuronal dysfunction seen in addictive disorders by glutamatergic modulation.³⁰ Research investigating NAC for GD is scarce. A pilot study found 16 of 27 patients with GD reduced gambling behavior with a mean dose of 1,476.9 mg/d.³¹ An additional study investigating the addition of NAC to behavioral therapy in nicotine-dependent individuals with pathologic gambling found a reduction in problem gambling after 18 weeks (6 weeks + 3 months follow-up).³² Common but mild adverse effects associated with NAC are nausea, vomiting, and diarrhea.

A meta-analysis by Goslar et al³³ that reviewed 34 studies (1,340 participants) found pharmacologic treatments were associated with large and medium pre-post reductions in global severity, frequency, and financial loss in patients with GD. RCTs studying opioid antagonists and mood stabilizers (combined with a cognitive intervention) as well as lithium for patients with comorbid bipolar disorder and GD demonstrated promising results.³³

Stimulant use disorder

There are no FDA-approved medications for stimulant use disorder. Multiple off-label options have been studied for the treatment of methamphetamine abuse and cocaine abuse.

Methamphetamine use has been expanding over the past decade with a 3.6-fold increase in positive methamphetamine screens in overdose deaths from 2011 to 2016.³⁴ Pharmacologic options studied for OLP of methamphetamine use disorder include mirtazapine, bupropion, naltrexone, and topiramate.

Continue to: Mirtazapine

Mirtazapine is an atypical antidepressant whose mechanism of action includes modulation of the serotonin, norepinephrine, and alpha-2 adrenergic systems. It is FDA-approved for the treatment of major depressive disorder (MDD). In a randomized placebo-controlled study, mirtazapine 30 mg/d at night was found to decrease methamphetamine use for active users and led to decreased sexual risk in men who have sex with men.³⁵ These results were supported by an additional RCT in which mirtazapine 30 mg/d significantly reduced rates of methamphetamine use vs placebo at 24 and 36 weeks despite poor medication adherence.³⁶ Adverse effects to monitor in patients treated with mirtazapine include increased appetite, weight gain, sedation, and constipation.

Bupropion is a norepinephrine dopamine reuptake inhibitor that produces increased neurotransmission of norepinephrine and dopamine in the CNS. It is FDA-approved for the treatment of MDD and as an aid for smoking cessation. Bupropion has been studied for methamphetamine use disorder with mixed results. In a randomized placebo-controlled trial, bupropion sustained release 150 mg twice daily was not more effective than placebo in reducing methamphetamine use.³⁷ However, the extended-release formulation of bupropion 450 mg/d combined with long-acting injectable naltrexone was associated with a reduction in methamphetamine use over 12 weeks.³⁸ Bupropion is generally well tolerated; common adverse effects include insomnia, tremor, headache, and dizziness.

Naltrexone. Data about using oral naltrexone to treat stimulant use disorders are limited. A randomized, placebo-controlled trial by Jayaram-Lindström et al³⁹ found naltrexone 50 mg/d significantly reduced amphetamine use compared to placebo. Additionally, naltrexone 50 and 150 mg/d have been shown to reduce cocaine use over time in combination with therapy for cocaine-dependent patients and those dependent on alcohol and cocaine.^40,41

Topiramate has been studied for the treatment of cocaine use disorder. It is hypothesized that modulation of the mesocorticolimbic dopamine system may contribute to decreased cocaine cravings.⁴² A pilot study by Kampman et al⁴³ found that after an 8-week titration of topiramate to 200 mg/d, individuals were more likely to achieve cocaine abstinence compared to those who receive placebo. In an RCT, Elkashef et al⁴⁴ did not find topiramate assisted with increased abstinence of methamphetamine in active users at a target dose of 200 mg/d. However, it was associated with reduced relapse rates in individuals who were abstinent prior to the study.⁴⁴ At a target dose of 300 mg/d, topiramate also outperformed placebo in decreasing days of cocaine use.⁴² Adverse effects of topiramate included paresthesia, alteration in taste, and difficulty with concentration.

Cannabis use disorder

In recent years, cannabis use in the US has greatly increased⁴⁵ but no medications are FDA-approved for treating cannabis use disorder. Studies of pharmacologic options for cannabis use disorder have had mixed results.⁴⁶ A meta-analysis by Bahji et al⁴⁷ of 24 studies investigating pharmacotherapies for cannabis use disorder highlighted the lack of adequate evidence. In this section, we focus on a few positive trials of NAC and gabapentin.

Continue to: N-acetylcysteine

N-acetylcysteine. Studies investigating NAC 1,200 mg twice daily have been promising in adolescent and adult populations.^48-50 There are some mixed results, however. A large RCT found NAC 1,200 mg twice daily was not better than placebo in helping adults achieve abstinence from cannabis.⁵¹

Gabapentin may be a viable option for treating cannabis use disorder. A pilot study by Mason et al⁵² found gabapentin 1,200 mg/d was more effective than placebo at reducing cannabis use among treatment-seeking adults.

When and how to consider OLP

OLP for addictive disorders is common and often necessary. This is primarily due to limitations of the FDA-approved medications and because there are no FDA-approved medications for many substance-related and addictive disorders (ie, GD, cannabis use disorder, and stimulant use disorder). When assessing pharmacotherapy options, if FDA-approved medications are available for certain diagnoses, clinicians should first consider them. The off-label medications discussed in this article are outlined in the Table.^{6-21,24-28,30-33,35-44,48-52}

The overall level of evidence to support the use of off-label medications is lower than that of FDA-approved medications, which contributes to potential medicolegal concerns of OLP. Off-label medications should be considered when there are no FDA-approved medications available, and the decision to use off-label medications should be based on evidence from the literature and current standard of care. Additionally, OLP is necessary if a patient cannot tolerate FDA-approved medications, is not helped by FDA-approved treatments, or when there are other clinical reasons to choose a particular off-label medication. For example, if a patient has comorbid AUD and obesity (or migraines), using topiramate may be appropriate because it may target alcohol cravings and can be helpful for weight loss (and migraine prophylaxis). Similarly, for patients with AUD and neuropathic pain, using gabapentin can be considered for its dual therapeutic effects.

It is critical for clinicians to understand the landscape of off-label options for treating addictive disorders. Additional research in the form of RCTs is needed to better clarify the efficacy and adverse effects of these treatments.

Continue to: Bottom Line

Off-label prescribing is prevalent in practice, including in the treatment of substance-related and addictive disorders. When considering off-label use of any medication, clinicians should review the most recent research, obtain informed consent from patients, and verify patients’ understanding of the potential risks and adverse effects associated with the particular medication.

Related Resources

• Joshi KG, Frierson RL. Off-label prescribing: how to limit your liability. Current Psychiatry. 2020;19(9):12,39. doi:10.12788/ cp.0035
• Stanciu CN, Gnanasegaram SA. Don’t balk at using medical therapy to manage alcohol use disorder. Current Psychiatry. 2017;16(2):50-52.

Drug Brand Names

Acamprosate • Campral
Baclofen • Ozobax
Bupropion • Wellbutrin, Zyban
Disulfiram • Antabuse
Gabapentin • Neurontin
Lithium • Eskalith, Lithobid
Mirtazapine • Remeron
Naltrexone • ReVia, Vivitrol
Topiramate • Topamax

Burnout is an occupational phenomenon and a syndrome resulting from unsuccessfully managed chronic workplace stress. The characteristic features of burnout include feelings of exhaustion, cynicism, and reduced professional efficacy.¹ A career in surgery is associated with demanding and unpredictable work hours in a high-stress environment.^2-8 Research indicates that surgeons are at an elevated risk for developing burnout and mental health problems that can compromise patient care. A survey of the fellows of the American College of Surgeons found that 40% of surgeons experience burnout, 30% experience symptoms of depression, and 28% have a mental quality of life (QOL) score greater than one-half an SD below the population norm.^9,10 Surgeon burnout was also found to compromise the delivery of medical care.^9,10

To prevent serious harm to surgeons and patients, it is critical to understand the causative factors of burnout among surgeons and how they can be addressed. We conducted this systematic review to identify factors linked to burnout across surgical specialties and to suggest ways to mitigate these risk factors.  

Methods

To identify studies of burnout among surgeons, we conducted an electronic search of Ovid MEDLINE, Ovid PsycInfo, SCOPUS, Cochrane Database of Systematic Reviews, and Cochrane Central Register of Controlled Trials. The headings and keywords used are listed in Supplemental Table 1. Studies met the inclusion criteria if they evaluated residents or attendings, used a tool to measure burnout, and examined any surgical specialty. Studies were excluded if they were published before 2010; were conducted outside the United States; were review articles, commentaries, or abstracts without full text articles; evaluated medical school students; were published in a language other than English; did not use a tool to measure burnout; or examined a nonsurgical specialty.  Our analysis was guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)¹¹ and is outlined in the Supplemental Figure.

Results

Surgical specialties and burnout

We identified 56 studies^2-10,12-58 that focused on specific surgical specialties in relation to burnout. Supplemental Table 2^2-10,12-58 lists these studies and the surgical specialties they evaluated.

Work/life balance factors

Fifteen studies^{2-5,14,15,18,19,22,32,34,38,39,47,57} examined the role of work/life balance in burnout. Table 1^{2-5,14,15,18,19,22,32,34,38,39,47,57} lists the work/life factors these studies identified as being linked to burnout. Six studies^{2,4,18,22,32,47} discussed how decreased leisure time was linked to burnout. Eleven studies^{2,4,14,15,19,22,34,38,39,42,57} associated inabilities to meet family commitments with burnout. A lack of time to spend with family and not having adequate time to raise children was more prevalent among women. Seven studies^{2,3,18,22,32,34,47} implicated increased time commitment to work as playing a role in burnout. This increased time commitment was also found to be a compounding variable for other factors, such as limited time for family and leisure.

Work hours

Fifteen studies^{2,7,14,20,21,30,34,41,42,44-46,50,52,56} examined work hours and burnout. Of these, 14^{2,7,14,20,21,30,34,42,44-46,50,52,56} found a correlation between increased work hours and burnout, while only 1 study⁴¹ found no correlation between these factors. 

Medical errors

Six studies^{2,14,18,43,49,52} discussed the role of burnout in medical errors. Of these, 5^{2,14,43,49,52} reported a correlation between burnout and medical errors, while 1 study¹⁸ found no link between burnout and medical errors. The medical errors were self-reported.^14,49 They included actions that resulted in patient harm, sample collection error, and errors in medication orders and laboratory test orders.²

Continue to: Institutional and organizational factors

Eighteen studies^{3,13,14,18,20,22,23,29,30,36-38,44,45,47,54,56,57} examined how different organizational factors play a role in burnout. Four studies^3,13,20,37 discussed administrative/bureaucratic work, 4^20,45,54,57 mentioned electronic medical documentation, 2^22,30 covered duty hour regulations, 3^18,45,57 discussed mistreatment of physicians, and 6^{13,18,23,44,47,56} described the importance of workplace support in addressing burnout.

Physical and mental health factors

Eighteen studies^{6,7,14,15,17,20,26,27,29,34,43,44,48,52,54,57-59} discussed aspects of physical and mental health linked to burnout. Among these, 3^34,43,59 discussed the importance of physical health and focused on how improving physical health can reduce stress and burnout. Three studies^6,17,58 noted the prevalence of suicidal ideation in both residents and attendings experiencing prolonged burnout. Five studies^{26,29,43,44,48} described the systematic barriers that inhibit physicians from getting professional help. Two studies^7,27 reported marital status as a factor for burnout; participants who were single reported higher levels of depression and suicidal ideation. Five studies^{6,14,15,54,57} outlined how depression is associated with burnout.

Strategies to mitigate burnout

Fifteen studies^{2,4,5,14,20,22,33,36,47,51,53,55-58} described strategies physicians use to cope with burnout. Table 2^{2,4,5,14,20,22,33,36,47,51,53,55-58} outlines the strategies postulated and reported by these studies as helpful in reducing burnout. Two studies^2,4 mentioned that physicians may turn to maladaptive behaviors, such as substance abuse, to cope with stress and burnout. Four studies^2,4,53,56 mentioned the importance of social support in fighting burnout and building resilience. Ten studies^{2,5,14,20,22,33,36,47,57,58} described the benefits of institutional interventions, such as what administrators can do to reduce the rate of burnout. Three studies^5,36,53 postulated different adaptive behaviors physicians can implement to reduce burnout.

Take-home points 

Research that focused on work/life balance and burnout found excessive time commitment to work is a major factor associated with poor work/life balance. Residents who worked >80 hours a week had a significantly higher burnout rate.⁵⁶ One study found that 70% of residents reported not getting enough sleep, 30% reported not having enough energy for relationships, and 39% reported that they were not eating or exercising due to time constraints.⁴ A high correlation was found between the number of hours worked per week and rates of burnout, emotional exhaustion, and depersonalization. Emotional exhaustion and depersonalization are aspects of burnout measured by the Maslach Burnout Inventory (MBI).²⁴ The excessive time commitment to work not only contributes to burnout but also prevents physicians from getting professional help. In 1 study, both residents (56%) and attendings (24%) reported that 1 of the biggest barriers to getting help for their burnout symptoms was the inability to take time off.³⁴ Research indicates that the hours worked per week and work/home conflicts were independently associated with burnout and career satisfaction.¹⁵ A decrease of weekly work hours may give physicians time to meet their responsibilities at work and home, allowing for a decrease in burnout and an increase in career satisfaction.

Increased work hours have also been found to be correlated with medical errors. One study found that those who worked 60 hours per week were significantly less likely to report any major medical errors in the previous 3 months compared with those who worked 80 hours per week.⁹ The risk for the number of medical errors has been reported as being 2-fold if surgeons are unable to combat the burnout.⁴⁹ On the other hand, a positive and supportive environment with easy access to resources to combat burnout and burnout prevention programs can reduce the frequency of medical errors, which also can reduce the risk of malpractice, thus further reducing stress and burnout.⁴³

Continue to: In response to resident complaints...

In response to resident complaints about long duty hours, a new rule has been implemented that states residents cannot work >16 hours per shift.³⁰ This rule has been found to increase quality of life and prevent burnout.³⁰

The amount of time spent on electronic medical records and documentation has been a major complaint from doctors and was identified as a factor contributing to burnout.⁴⁵ It can act as a time drain that impedes the physician from providing optimal patient care and cause additional stress. This suggests the need for organizations to find solutions to minimize this strain.

A concerning issue reported as an institutional factor and associated with burnout is mistreatment through discrimination, harassment, and physical or verbal abuse. A recent study found 45% of general and vascular surgeons reported being mistreated in some fashion.⁵⁷ The strategies reported as helpful for institutions to combat mistreatment include resilience training, improved mentorship, and implicit bias training.⁵⁷

Burnout has been positively correlated with anxiety and depression.⁶ A recent study reported that 13% of orthopedic surgery residents screened positive for depression.⁴⁴ Higher levels of burnout and depersonalization have been found to be closely associated with increased rates of suicidal ideation.¹⁷ In a study of vascular surgeons, 8% were found to report suicidal ideation, and this increased to 15% among vascular surgeons who had higher levels of depersonalization and emotional exhaustion,⁵⁸ both of which are associated with burnout. In another study, surgery residents and fellows were found to have lower levels of personal achievement and higher levels of depersonalization, depressive symptoms, alcohol abuse, and suicidal ideation compared to attending physicians and the general population.⁵⁴ These findings spell out the association between burnout and depressive symptoms among surgeons and emphasize the need for institutions to create a culture that supports the mental health needs of their physicians. Without access to supportive resources, residents resort to alternative methods that may be detrimental in the long run. In a recent study, 17% of residents admitted to using alcohol, including binge drinking, to cope with their stress.⁴

Burnout and depression are linked to physical health risks such as cardiovascular disease, diabetes, substance abuse, and male infertility.⁶ Exercise has been shown to be beneficial for stress reduction, which can lead to changes in metabolism, inflammation, coagulation, and autonomic function.⁶ One study of surgeons found aerobic exercise and strength training were associated with lower rates of burnout and a higher quality of life.⁵⁹

Continue to: The amount of burnout physicians...

The amount of burnout physicians experience can be determined by how they respond to adversities. Adaptive behaviors such as socializing, mindfulness, volunteering, and exercising have been found to be protective against burnout.^6,37,54 Resilience training and maintaining low stress at work can decrease burnout.³⁷ These findings highlight the need for physicians to be trained in the appropriate ways to combat their burnout symptoms.

Unfortunately, seeking help by health care professionals to improve mental health has been stigmatized, causing physicians to not seek help and instead resort to other ways to cope with their distress.^26,34 While some of these coping methods may be positive, others—such as substance abuse or stress eating—can be maladaptive, leading to a poor quality of life, and in some cases, suicide.⁵⁴ It is vital that effective mental health services become more accessible and for health care professionals to become aware of their maladaptive behaviors.³⁴

Institutions finding ways to ease the path for their physicians to seek professional help to combat burnout may mitigate its negative impact. One strategy is to embed access to mental health services within regular wellness checks. Institutions can use wellness checks to provide resources to physicians who need it. These interventions have been found to be effective because they give physicians a safe space to seek help and become aware of any factors that could lead to burnout.¹⁸ Apart from these direct attempts to combat burnout, program-sponsored social events would also promote social connectedness with colleagues and contribute to a sense of well-being that could help decrease levels of burnout and depression.¹³ Mentorship has been shown to play a crucial role in decreasing burnout among residents. One study that examined the role of mentorship reported that 55% of residents felt supported, and of these, 96% felt mentorship was critical to their success.¹⁸ The role of institutions in helping to improve the well-being of surgeons is highlighted by the finding that increasing workplace support results in psychological resilience that can mitigate burnout at its roots.²⁹

Bottom Line

Surgeons are at risk for burnout, which can impact their mental health and reduce their professional efficacy. Both institutions and surgeons themselves can take action to prevent burnout and treat burnout early when it occurs.

Related Resources

• Pahal P, Lippmann S. Building a better work/life balance. Current Psychiatry. 2021;20(8):e1-e2. doi:10.12788/cp.0158
• Gibson R, Hategan A. Physician burnout vs depression: recognize the signs. Current Psychiatry. 2019;18(10):41-42.

Burnout is an occupational phenomenon and a syndrome resulting from unsuccessfully managed chronic workplace stress. The characteristic features of burnout include feelings of exhaustion, cynicism, and reduced professional efficacy.¹ A career in surgery is associated with demanding and unpredictable work hours in a high-stress environment.^2-8 Research indicates that surgeons are at an elevated risk for developing burnout and mental health problems that can compromise patient care. A survey of the fellows of the American College of Surgeons found that 40% of surgeons experience burnout, 30% experience symptoms of depression, and 28% have a mental quality of life (QOL) score greater than one-half an SD below the population norm.^9,10 Surgeon burnout was also found to compromise the delivery of medical care.^9,10

To prevent serious harm to surgeons and patients, it is critical to understand the causative factors of burnout among surgeons and how they can be addressed. We conducted this systematic review to identify factors linked to burnout across surgical specialties and to suggest ways to mitigate these risk factors.  

Methods

To identify studies of burnout among surgeons, we conducted an electronic search of Ovid MEDLINE, Ovid PsycInfo, SCOPUS, Cochrane Database of Systematic Reviews, and Cochrane Central Register of Controlled Trials. The headings and keywords used are listed in Supplemental Table 1. Studies met the inclusion criteria if they evaluated residents or attendings, used a tool to measure burnout, and examined any surgical specialty. Studies were excluded if they were published before 2010; were conducted outside the United States; were review articles, commentaries, or abstracts without full text articles; evaluated medical school students; were published in a language other than English; did not use a tool to measure burnout; or examined a nonsurgical specialty.  Our analysis was guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)¹¹ and is outlined in the Supplemental Figure.

Results

Surgical specialties and burnout

We identified 56 studies^2-10,12-58 that focused on specific surgical specialties in relation to burnout. Supplemental Table 2^2-10,12-58 lists these studies and the surgical specialties they evaluated.

Work/life balance factors

Fifteen studies^{2-5,14,15,18,19,22,32,34,38,39,47,57} examined the role of work/life balance in burnout. Table 1^{2-5,14,15,18,19,22,32,34,38,39,47,57} lists the work/life factors these studies identified as being linked to burnout. Six studies^{2,4,18,22,32,47} discussed how decreased leisure time was linked to burnout. Eleven studies^{2,4,14,15,19,22,34,38,39,42,57} associated inabilities to meet family commitments with burnout. A lack of time to spend with family and not having adequate time to raise children was more prevalent among women. Seven studies^{2,3,18,22,32,34,47} implicated increased time commitment to work as playing a role in burnout. This increased time commitment was also found to be a compounding variable for other factors, such as limited time for family and leisure.

Work hours

Fifteen studies^{2,7,14,20,21,30,34,41,42,44-46,50,52,56} examined work hours and burnout. Of these, 14^{2,7,14,20,21,30,34,42,44-46,50,52,56} found a correlation between increased work hours and burnout, while only 1 study⁴¹ found no correlation between these factors. 

Medical errors

Six studies^{2,14,18,43,49,52} discussed the role of burnout in medical errors. Of these, 5^{2,14,43,49,52} reported a correlation between burnout and medical errors, while 1 study¹⁸ found no link between burnout and medical errors. The medical errors were self-reported.^14,49 They included actions that resulted in patient harm, sample collection error, and errors in medication orders and laboratory test orders.²

Continue to: Institutional and organizational factors

Eighteen studies^{3,13,14,18,20,22,23,29,30,36-38,44,45,47,54,56,57} examined how different organizational factors play a role in burnout. Four studies^3,13,20,37 discussed administrative/bureaucratic work, 4^20,45,54,57 mentioned electronic medical documentation, 2^22,30 covered duty hour regulations, 3^18,45,57 discussed mistreatment of physicians, and 6^{13,18,23,44,47,56} described the importance of workplace support in addressing burnout.

Physical and mental health factors

Eighteen studies^{6,7,14,15,17,20,26,27,29,34,43,44,48,52,54,57-59} discussed aspects of physical and mental health linked to burnout. Among these, 3^34,43,59 discussed the importance of physical health and focused on how improving physical health can reduce stress and burnout. Three studies^6,17,58 noted the prevalence of suicidal ideation in both residents and attendings experiencing prolonged burnout. Five studies^{26,29,43,44,48} described the systematic barriers that inhibit physicians from getting professional help. Two studies^7,27 reported marital status as a factor for burnout; participants who were single reported higher levels of depression and suicidal ideation. Five studies^{6,14,15,54,57} outlined how depression is associated with burnout.

Strategies to mitigate burnout

Fifteen studies^{2,4,5,14,20,22,33,36,47,51,53,55-58} described strategies physicians use to cope with burnout. Table 2^{2,4,5,14,20,22,33,36,47,51,53,55-58} outlines the strategies postulated and reported by these studies as helpful in reducing burnout. Two studies^2,4 mentioned that physicians may turn to maladaptive behaviors, such as substance abuse, to cope with stress and burnout. Four studies^2,4,53,56 mentioned the importance of social support in fighting burnout and building resilience. Ten studies^{2,5,14,20,22,33,36,47,57,58} described the benefits of institutional interventions, such as what administrators can do to reduce the rate of burnout. Three studies^5,36,53 postulated different adaptive behaviors physicians can implement to reduce burnout.

Take-home points 

Research that focused on work/life balance and burnout found excessive time commitment to work is a major factor associated with poor work/life balance. Residents who worked >80 hours a week had a significantly higher burnout rate.⁵⁶ One study found that 70% of residents reported not getting enough sleep, 30% reported not having enough energy for relationships, and 39% reported that they were not eating or exercising due to time constraints.⁴ A high correlation was found between the number of hours worked per week and rates of burnout, emotional exhaustion, and depersonalization. Emotional exhaustion and depersonalization are aspects of burnout measured by the Maslach Burnout Inventory (MBI).²⁴ The excessive time commitment to work not only contributes to burnout but also prevents physicians from getting professional help. In 1 study, both residents (56%) and attendings (24%) reported that 1 of the biggest barriers to getting help for their burnout symptoms was the inability to take time off.³⁴ Research indicates that the hours worked per week and work/home conflicts were independently associated with burnout and career satisfaction.¹⁵ A decrease of weekly work hours may give physicians time to meet their responsibilities at work and home, allowing for a decrease in burnout and an increase in career satisfaction.

Increased work hours have also been found to be correlated with medical errors. One study found that those who worked 60 hours per week were significantly less likely to report any major medical errors in the previous 3 months compared with those who worked 80 hours per week.⁹ The risk for the number of medical errors has been reported as being 2-fold if surgeons are unable to combat the burnout.⁴⁹ On the other hand, a positive and supportive environment with easy access to resources to combat burnout and burnout prevention programs can reduce the frequency of medical errors, which also can reduce the risk of malpractice, thus further reducing stress and burnout.⁴³

Continue to: In response to resident complaints...

In response to resident complaints about long duty hours, a new rule has been implemented that states residents cannot work >16 hours per shift.³⁰ This rule has been found to increase quality of life and prevent burnout.³⁰

The amount of time spent on electronic medical records and documentation has been a major complaint from doctors and was identified as a factor contributing to burnout.⁴⁵ It can act as a time drain that impedes the physician from providing optimal patient care and cause additional stress. This suggests the need for organizations to find solutions to minimize this strain.

A concerning issue reported as an institutional factor and associated with burnout is mistreatment through discrimination, harassment, and physical or verbal abuse. A recent study found 45% of general and vascular surgeons reported being mistreated in some fashion.⁵⁷ The strategies reported as helpful for institutions to combat mistreatment include resilience training, improved mentorship, and implicit bias training.⁵⁷

Burnout has been positively correlated with anxiety and depression.⁶ A recent study reported that 13% of orthopedic surgery residents screened positive for depression.⁴⁴ Higher levels of burnout and depersonalization have been found to be closely associated with increased rates of suicidal ideation.¹⁷ In a study of vascular surgeons, 8% were found to report suicidal ideation, and this increased to 15% among vascular surgeons who had higher levels of depersonalization and emotional exhaustion,⁵⁸ both of which are associated with burnout. In another study, surgery residents and fellows were found to have lower levels of personal achievement and higher levels of depersonalization, depressive symptoms, alcohol abuse, and suicidal ideation compared to attending physicians and the general population.⁵⁴ These findings spell out the association between burnout and depressive symptoms among surgeons and emphasize the need for institutions to create a culture that supports the mental health needs of their physicians. Without access to supportive resources, residents resort to alternative methods that may be detrimental in the long run. In a recent study, 17% of residents admitted to using alcohol, including binge drinking, to cope with their stress.⁴

Burnout and depression are linked to physical health risks such as cardiovascular disease, diabetes, substance abuse, and male infertility.⁶ Exercise has been shown to be beneficial for stress reduction, which can lead to changes in metabolism, inflammation, coagulation, and autonomic function.⁶ One study of surgeons found aerobic exercise and strength training were associated with lower rates of burnout and a higher quality of life.⁵⁹

Continue to: The amount of burnout physicians...

The amount of burnout physicians experience can be determined by how they respond to adversities. Adaptive behaviors such as socializing, mindfulness, volunteering, and exercising have been found to be protective against burnout.^6,37,54 Resilience training and maintaining low stress at work can decrease burnout.³⁷ These findings highlight the need for physicians to be trained in the appropriate ways to combat their burnout symptoms.

Unfortunately, seeking help by health care professionals to improve mental health has been stigmatized, causing physicians to not seek help and instead resort to other ways to cope with their distress.^26,34 While some of these coping methods may be positive, others—such as substance abuse or stress eating—can be maladaptive, leading to a poor quality of life, and in some cases, suicide.⁵⁴ It is vital that effective mental health services become more accessible and for health care professionals to become aware of their maladaptive behaviors.³⁴

Institutions finding ways to ease the path for their physicians to seek professional help to combat burnout may mitigate its negative impact. One strategy is to embed access to mental health services within regular wellness checks. Institutions can use wellness checks to provide resources to physicians who need it. These interventions have been found to be effective because they give physicians a safe space to seek help and become aware of any factors that could lead to burnout.¹⁸ Apart from these direct attempts to combat burnout, program-sponsored social events would also promote social connectedness with colleagues and contribute to a sense of well-being that could help decrease levels of burnout and depression.¹³ Mentorship has been shown to play a crucial role in decreasing burnout among residents. One study that examined the role of mentorship reported that 55% of residents felt supported, and of these, 96% felt mentorship was critical to their success.¹⁸ The role of institutions in helping to improve the well-being of surgeons is highlighted by the finding that increasing workplace support results in psychological resilience that can mitigate burnout at its roots.²⁹

Bottom Line

Surgeons are at risk for burnout, which can impact their mental health and reduce their professional efficacy. Both institutions and surgeons themselves can take action to prevent burnout and treat burnout early when it occurs.

Related Resources

• Pahal P, Lippmann S. Building a better work/life balance. Current Psychiatry. 2021;20(8):e1-e2. doi:10.12788/cp.0158
• Gibson R, Hategan A. Physician burnout vs depression: recognize the signs. Current Psychiatry. 2019;18(10):41-42.

Burnout is an occupational phenomenon and a syndrome resulting from unsuccessfully managed chronic workplace stress. The characteristic features of burnout include feelings of exhaustion, cynicism, and reduced professional efficacy.¹ A career in surgery is associated with demanding and unpredictable work hours in a high-stress environment.^2-8 Research indicates that surgeons are at an elevated risk for developing burnout and mental health problems that can compromise patient care. A survey of the fellows of the American College of Surgeons found that 40% of surgeons experience burnout, 30% experience symptoms of depression, and 28% have a mental quality of life (QOL) score greater than one-half an SD below the population norm.^9,10 Surgeon burnout was also found to compromise the delivery of medical care.^9,10

To prevent serious harm to surgeons and patients, it is critical to understand the causative factors of burnout among surgeons and how they can be addressed. We conducted this systematic review to identify factors linked to burnout across surgical specialties and to suggest ways to mitigate these risk factors.  

Methods

To identify studies of burnout among surgeons, we conducted an electronic search of Ovid MEDLINE, Ovid PsycInfo, SCOPUS, Cochrane Database of Systematic Reviews, and Cochrane Central Register of Controlled Trials. The headings and keywords used are listed in Supplemental Table 1. Studies met the inclusion criteria if they evaluated residents or attendings, used a tool to measure burnout, and examined any surgical specialty. Studies were excluded if they were published before 2010; were conducted outside the United States; were review articles, commentaries, or abstracts without full text articles; evaluated medical school students; were published in a language other than English; did not use a tool to measure burnout; or examined a nonsurgical specialty.  Our analysis was guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)¹¹ and is outlined in the Supplemental Figure.

Results

Surgical specialties and burnout

We identified 56 studies^2-10,12-58 that focused on specific surgical specialties in relation to burnout. Supplemental Table 2^2-10,12-58 lists these studies and the surgical specialties they evaluated.

Work/life balance factors

Fifteen studies^{2-5,14,15,18,19,22,32,34,38,39,47,57} examined the role of work/life balance in burnout. Table 1^{2-5,14,15,18,19,22,32,34,38,39,47,57} lists the work/life factors these studies identified as being linked to burnout. Six studies^{2,4,18,22,32,47} discussed how decreased leisure time was linked to burnout. Eleven studies^{2,4,14,15,19,22,34,38,39,42,57} associated inabilities to meet family commitments with burnout. A lack of time to spend with family and not having adequate time to raise children was more prevalent among women. Seven studies^{2,3,18,22,32,34,47} implicated increased time commitment to work as playing a role in burnout. This increased time commitment was also found to be a compounding variable for other factors, such as limited time for family and leisure.

Work hours

Fifteen studies^{2,7,14,20,21,30,34,41,42,44-46,50,52,56} examined work hours and burnout. Of these, 14^{2,7,14,20,21,30,34,42,44-46,50,52,56} found a correlation between increased work hours and burnout, while only 1 study⁴¹ found no correlation between these factors. 

Medical errors

Six studies^{2,14,18,43,49,52} discussed the role of burnout in medical errors. Of these, 5^{2,14,43,49,52} reported a correlation between burnout and medical errors, while 1 study¹⁸ found no link between burnout and medical errors. The medical errors were self-reported.^14,49 They included actions that resulted in patient harm, sample collection error, and errors in medication orders and laboratory test orders.²

Continue to: Institutional and organizational factors

Eighteen studies^{3,13,14,18,20,22,23,29,30,36-38,44,45,47,54,56,57} examined how different organizational factors play a role in burnout. Four studies^3,13,20,37 discussed administrative/bureaucratic work, 4^20,45,54,57 mentioned electronic medical documentation, 2^22,30 covered duty hour regulations, 3^18,45,57 discussed mistreatment of physicians, and 6^{13,18,23,44,47,56} described the importance of workplace support in addressing burnout.

Physical and mental health factors

Eighteen studies^{6,7,14,15,17,20,26,27,29,34,43,44,48,52,54,57-59} discussed aspects of physical and mental health linked to burnout. Among these, 3^34,43,59 discussed the importance of physical health and focused on how improving physical health can reduce stress and burnout. Three studies^6,17,58 noted the prevalence of suicidal ideation in both residents and attendings experiencing prolonged burnout. Five studies^{26,29,43,44,48} described the systematic barriers that inhibit physicians from getting professional help. Two studies^7,27 reported marital status as a factor for burnout; participants who were single reported higher levels of depression and suicidal ideation. Five studies^{6,14,15,54,57} outlined how depression is associated with burnout.

Strategies to mitigate burnout

Fifteen studies^{2,4,5,14,20,22,33,36,47,51,53,55-58} described strategies physicians use to cope with burnout. Table 2^{2,4,5,14,20,22,33,36,47,51,53,55-58} outlines the strategies postulated and reported by these studies as helpful in reducing burnout. Two studies^2,4 mentioned that physicians may turn to maladaptive behaviors, such as substance abuse, to cope with stress and burnout. Four studies^2,4,53,56 mentioned the importance of social support in fighting burnout and building resilience. Ten studies^{2,5,14,20,22,33,36,47,57,58} described the benefits of institutional interventions, such as what administrators can do to reduce the rate of burnout. Three studies^5,36,53 postulated different adaptive behaviors physicians can implement to reduce burnout.

Take-home points 

Research that focused on work/life balance and burnout found excessive time commitment to work is a major factor associated with poor work/life balance. Residents who worked >80 hours a week had a significantly higher burnout rate.⁵⁶ One study found that 70% of residents reported not getting enough sleep, 30% reported not having enough energy for relationships, and 39% reported that they were not eating or exercising due to time constraints.⁴ A high correlation was found between the number of hours worked per week and rates of burnout, emotional exhaustion, and depersonalization. Emotional exhaustion and depersonalization are aspects of burnout measured by the Maslach Burnout Inventory (MBI).²⁴ The excessive time commitment to work not only contributes to burnout but also prevents physicians from getting professional help. In 1 study, both residents (56%) and attendings (24%) reported that 1 of the biggest barriers to getting help for their burnout symptoms was the inability to take time off.³⁴ Research indicates that the hours worked per week and work/home conflicts were independently associated with burnout and career satisfaction.¹⁵ A decrease of weekly work hours may give physicians time to meet their responsibilities at work and home, allowing for a decrease in burnout and an increase in career satisfaction.

Increased work hours have also been found to be correlated with medical errors. One study found that those who worked 60 hours per week were significantly less likely to report any major medical errors in the previous 3 months compared with those who worked 80 hours per week.⁹ The risk for the number of medical errors has been reported as being 2-fold if surgeons are unable to combat the burnout.⁴⁹ On the other hand, a positive and supportive environment with easy access to resources to combat burnout and burnout prevention programs can reduce the frequency of medical errors, which also can reduce the risk of malpractice, thus further reducing stress and burnout.⁴³

Continue to: In response to resident complaints...

In response to resident complaints about long duty hours, a new rule has been implemented that states residents cannot work >16 hours per shift.³⁰ This rule has been found to increase quality of life and prevent burnout.³⁰

The amount of time spent on electronic medical records and documentation has been a major complaint from doctors and was identified as a factor contributing to burnout.⁴⁵ It can act as a time drain that impedes the physician from providing optimal patient care and cause additional stress. This suggests the need for organizations to find solutions to minimize this strain.

A concerning issue reported as an institutional factor and associated with burnout is mistreatment through discrimination, harassment, and physical or verbal abuse. A recent study found 45% of general and vascular surgeons reported being mistreated in some fashion.⁵⁷ The strategies reported as helpful for institutions to combat mistreatment include resilience training, improved mentorship, and implicit bias training.⁵⁷

Burnout has been positively correlated with anxiety and depression.⁶ A recent study reported that 13% of orthopedic surgery residents screened positive for depression.⁴⁴ Higher levels of burnout and depersonalization have been found to be closely associated with increased rates of suicidal ideation.¹⁷ In a study of vascular surgeons, 8% were found to report suicidal ideation, and this increased to 15% among vascular surgeons who had higher levels of depersonalization and emotional exhaustion,⁵⁸ both of which are associated with burnout. In another study, surgery residents and fellows were found to have lower levels of personal achievement and higher levels of depersonalization, depressive symptoms, alcohol abuse, and suicidal ideation compared to attending physicians and the general population.⁵⁴ These findings spell out the association between burnout and depressive symptoms among surgeons and emphasize the need for institutions to create a culture that supports the mental health needs of their physicians. Without access to supportive resources, residents resort to alternative methods that may be detrimental in the long run. In a recent study, 17% of residents admitted to using alcohol, including binge drinking, to cope with their stress.⁴

Burnout and depression are linked to physical health risks such as cardiovascular disease, diabetes, substance abuse, and male infertility.⁶ Exercise has been shown to be beneficial for stress reduction, which can lead to changes in metabolism, inflammation, coagulation, and autonomic function.⁶ One study of surgeons found aerobic exercise and strength training were associated with lower rates of burnout and a higher quality of life.⁵⁹

Continue to: The amount of burnout physicians...

The amount of burnout physicians experience can be determined by how they respond to adversities. Adaptive behaviors such as socializing, mindfulness, volunteering, and exercising have been found to be protective against burnout.^6,37,54 Resilience training and maintaining low stress at work can decrease burnout.³⁷ These findings highlight the need for physicians to be trained in the appropriate ways to combat their burnout symptoms.

Unfortunately, seeking help by health care professionals to improve mental health has been stigmatized, causing physicians to not seek help and instead resort to other ways to cope with their distress.^26,34 While some of these coping methods may be positive, others—such as substance abuse or stress eating—can be maladaptive, leading to a poor quality of life, and in some cases, suicide.⁵⁴ It is vital that effective mental health services become more accessible and for health care professionals to become aware of their maladaptive behaviors.³⁴

Institutions finding ways to ease the path for their physicians to seek professional help to combat burnout may mitigate its negative impact. One strategy is to embed access to mental health services within regular wellness checks. Institutions can use wellness checks to provide resources to physicians who need it. These interventions have been found to be effective because they give physicians a safe space to seek help and become aware of any factors that could lead to burnout.¹⁸ Apart from these direct attempts to combat burnout, program-sponsored social events would also promote social connectedness with colleagues and contribute to a sense of well-being that could help decrease levels of burnout and depression.¹³ Mentorship has been shown to play a crucial role in decreasing burnout among residents. One study that examined the role of mentorship reported that 55% of residents felt supported, and of these, 96% felt mentorship was critical to their success.¹⁸ The role of institutions in helping to improve the well-being of surgeons is highlighted by the finding that increasing workplace support results in psychological resilience that can mitigate burnout at its roots.²⁹

Bottom Line

Surgeons are at risk for burnout, which can impact their mental health and reduce their professional efficacy. Both institutions and surgeons themselves can take action to prevent burnout and treat burnout early when it occurs.

Related Resources

• Pahal P, Lippmann S. Building a better work/life balance. Current Psychiatry. 2021;20(8):e1-e2. doi:10.12788/cp.0158
• Gibson R, Hategan A. Physician burnout vs depression: recognize the signs. Current Psychiatry. 2019;18(10):41-42.

A Risk Evaluation and Mitigation Strategy (REMS) is a drug safety program the FDA can require for certain medications with serious safety concerns to help ensure the benefits of the medication outweigh its risks (Box¹). The FDA may require medication guides, patient package inserts, communication plans for health care professionals, and/or certain packaging and safe disposal technologies for medications that pose a serious risk of abuse or overdose. The FDA may also require elements to assure safe use and/or an implementation system be included in the REMS. Pharmaceutical manufacturers then develop a proposed REMS for FDA review.² If the FDA approves the proposed REMS, the manufacturer is responsible for implementing the REMS requirements.

Box

The REMS program for clozapine³ has been the subject of much discussion in the psychiatric community. The adverse impact of the 2015 update to the clozapine REMS program was emphasized at meetings of both the American Psychiatric Association and the College of Psychiatric and Neurologic Pharmacists. A white paper published by the National Association of State Mental Health Program Directors shortly after the 2015 update concluded, “clozapine is underused due to a variety of barriers related to the drug and its properties, the health care system, regulatory requirements, and reimbursement issues.”⁴ After an update to the clozapine REMS program in 2021, the FDA temporarily suspended enforcement of certain requirements due to concerns from health care professionals about patient access to the medication because of problems with implementing the clozapine REMS program.^5,6 In November 2022, the FDA issued a second announcement of enforcement discretion related to additional requirements of the REMS program.⁵ The FDA had previously announced a decision to not take action regarding adherence to REMS requirements for certain laboratory tests in March 2020, during the COVID-19 pandemic.⁷

REMS programs for other psychiatric medications may also present challenges. The REMS programs for esketamine⁸ and olanzapine for extended-release (ER) injectable suspension⁹ include certain risks that require postadministration monitoring. Some facilities have had to dedicate additional space and clinician time to ensure REMS requirements are met.

To further understand health care professionals’ perspectives regarding the value and burden of these REMS programs, a collaborative effort of the University of Maryland (College Park and Baltimore campuses) Center of Excellence in Regulatory Science and Innovation with the FDA was undertaken. The REMS for clozapine, olanzapine for ER injectable suspension, and esketamine were examined to develop recommendations for improving patient access while ensuring safe medication use and limiting the impact on health care professionals.

Assessing the REMS programs

Focus groups were held with health care professionals nominated by professional organizations to gather their perspectives on the REMS requirements. There was 1 focus group for each of the 3 medications. A facilitator’s guide was developed that contained the details of how to conduct the focus group along with the medication-specific questions. The questions were based on the REMS requirements as of May 2021 and assessed the impact of the REMS on patient safety, patient access, and health care professional workload; effects from the COVID-19 pandemic; and suggestions to improve the REMS programs. The University of Maryland Institutional Review Board reviewed the materials and processes and made the determination of exempt.

Health care professionals were eligible to participate in a focus group if they had ≥1 year of experience working with patients who use the specific medication and ≥6 months of experience within the past year working with the REMS program for that medication. Participants were excluded if they were employed by a pharmaceutical manufacturer or the FDA. The focus groups were conducted virtually using an online conferencing service during summer 2021 and were scheduled for 90 minutes. Prior to the focus group, participants received information from the “Goals” and “Summary” tabs of the FDA REMS website¹⁰ for the specific medication along with patient/caregiver guides, which were available for clozapine and olanzapine for ER injectable suspension. For each focus group, there was a target sample size of 6 to 9 participants. However, there were only 4 participants in the olanzapine for ER injectable suspension focus group, which we believed was due to lower national utilization of this medication. Individuals were only able to participate in 1 focus group, so the unique participant count for all 3 focus groups totaled 17 (Table 1).

Themes extracted from qualitative analysis of the focus group responses were the value of the REMS programs; registration/enrollment processes and REMS websites; monitoring requirements; care transitions; and COVID considerations (Table 2). While the REMS programs were perceived to increase practitioner and patient awareness of potential harms, discussions centered on the relative cost-to-benefit of the required reporting and other REMS requirements. There were challenges with the registration/enrollment processes and REMS websites that also affected patient care during transitions to different health care settings or clinicians. Patient access was affected by disparities in care related to monitoring requirements and clinician availability.

Continue to: COVID impacted all REMS...

COVID impacted all REMS programs. Physical distancing was an issue for medications that required extensive postadministration monitoring (ie, esketamine and olanzapine for ER injectable suspension). Access to laboratory services was an issue for clozapine.

Medication-specific themes are listed in Table 3 and relate to terms and descriptions in the REMS or additional regulatory requirements from the Drug Enforcement Agency (DEA). Suggestions for improvement to the REMS are presented in Table 4.

Recommendations for improving REMS

A group consisting of health care professionals, policy experts, and mental health advocates reviewed the information provided by the focus groups and developed the following recommendations.

Overarching recommendations

Each REMS should include a section providing justification for its existence, including a risk analysis of the data regarding the risk the REMS is designed to mitigate. This analysis should be repeated on a regular basis as scientific evidence regarding the risk and its epidemiology evolves. This additional section should also explain how the program requirements of the REMS as implemented (or planned) will achieve the aims of the REMS and weigh the potential benefits of the REMS requirements as implemented (or planned) by the manufacturer vs the potential risks of the REMS requirements as implemented (or planned) by the manufacturer.

Each REMS should have specific quantifiable outcomes. For example, it should specify a reduction in occurrence of the rate of the concerned risk by a specified amount.

Continue to: Ensure adequate...

Ensure adequate stakeholder input during the REMS development and real-world testing in multiple environments before implementing the REMS to identify unanticipated consequences that might impact patient access, patient safety, and health care professional burden. Implementation testing should explore issues such as purchasing and procurement, billing and reimbursement, and relevant factors such as other federal regulations or requirements (eg, the DEA or Medicare).

Ensure harmonization of the REMS forms and processes (eg, initiation and monitoring) for different medications where possible. A prescriber, pharmacist, or system should not face additional barriers to participate in a REMS based on REMS-specific intricacies (ie, prescription systems, data submission systems, or ordering systems). This streamlining will likely decrease clinical inertia to initiate care with the REMS medication, decrease health care professional burden, and improve compliance with REMS requirements.

REMS should anticipate the need for care transitions and employ provisions to ensure seamless care. Considerations should be given to transitions that occur due to:

• Different care settings (eg, inpatient, outpatient, or long-term care)
• Different geographies (eg, patient moves)
• Changes in clinicians, including leaves or absences
• Changes in facilities (eg, pharmacies).

REMS should mirror normal health care professional workflow, including how monitoring data are collected and how and with which frequency pharmacies fill prescriptions.Enhanced information technology to support REMS programs is needed. For example, REMS should be integrated with major electronic patient health record and pharmacy systems to reduce the effort required for clinicians to supply data and automate REMS processes.

For medications that are subject to other agencies and their regulations (eg, the CDC, Centers for Medicare & Medicaid Services, or the DEA), REMS should be required to meet all standards of all agencies with a single system that accommodates normal health care professional workflow.

Continue to: REMS should have a...

REMS should have a standard disclaimer that allows the health care professional to waive certain provisions of the REMS in cases when the specific provisions of the REMS pose a greater risk to the patient than the risk posed by waiving the requirement.

Assure the actions implemented by the industry to meet the requirements for each REMS program are based on peer-reviewed evidence and provide a reasonable expectation to achieve the anticipated benefit.

Ensure that manufacturers make all accumulated REMS data available in a de­identified manner for use by qualified scientific researchers. Additionally, each REMS should have a plan for data access upon initiation and termination of the REMS.

Each REMS should collect data on the performance of the centers and/or personnel who operate the REMS and submit this data for review by qualified outside reviewers. Parameters to assess could include:

• timeliness of response
• timeliness of problem resolution
• data availability and its helpfulness to patient care
• adequacy of resources.

Recommendations for clozapine REMS

These comments relate to the clozapine REMS program prior to the July 2021 announcement that FDA had approved a modification.

Provide a clear definition for “benign ethnic neutropenia.”

Ensure the REMS includes patient-specific adjustments to allow flexibility for monitoring. During COVID, the FDA allowed clinicians to “use their best medical judgment in weighing the benefits and risks of continuing treatment in the absence of laboratory testing.”⁷ This guidance, which allowed flexibility to absolute neutrophil count (ANC) monitoring, was perceived as positive and safe. Before the changes in the REMS requirements, patients with benign ethnic neutropenia were restricted from accessing their medication or encountered harm from additional pharmacotherapy to mitigate ANC levels.

Continue to: Recommendations for olanzapine for ER injectable suspension REMS

Provide clear explicit instructions on what is required to have “ready access to emergency services.”

Ensure the REMS include patient-specific adjustments to allow flexibility for postadministration monitoring (eg, sedation or blood pressure). Specific patient groups may have differential access to certain types of facilities, transportation, or other resources. For example, consider the administration of olanzapine for ER injectable suspension by a mobile treatment team with an adequate protocol (eg, via videoconferencing or phone calls).

Ensure actions with peer-reviewed evidence demonstrating efficacy/effectiveness are included in the REMS. How was the 3-hour cut-point determined? Has it been reevaluated?

Ensure the REMS requirements allow for seamless care during transitions, particularly when clinicians are on vacation.

Continue to: Recommendations for esketamine REMS

Ensure the REMS includes patient-specific adjustments to allow flexibility for post­administration monitoring. Specific patient groups may have differential access to certain types of facilities, transportation, or other resources. For example, consider the administration of esketamine by a mobile treatment team with an adequate protocol (eg, via videoconferencing or phone calls).

Ensure actions with peer-reviewed evidence demonstrating efficacy/effectiveness of requirements are included in the REMS. How was the 2-hour cut-point determined? Has it been reevaluated?

Ensure that the REMS meet all standards of the DEA, with a single system that accommodates normal health care professional workflow.

A summary of the findings

Overall, the REMS programs for these 3 medications were positively perceived for raising awareness of safe medication use for clinicians and patients. Monitoring patients for safety concerns is important and REMS requirements provide accountability.

Continue to: The use of a single shared...

The use of a single shared REMS system for documenting requirements for clozapine (compared to separate systems for each manufacturer) was a positive move forward in implementation. The focus group welcomed the increased awareness of benign ethnic neutropenia as a result of this condition being incorporated in the revised monitoring requirements of the clozapine REMS.

Focus group participants raised the issue of the real-world efficiency of the REMS programs (reduced access and increased clinician workload) vs the benefits (patient safety). They noted that excessive workload could lead to clinicians becoming unwilling to use a medication that requires a REMS. Clinician workload may be further compromised when REMS logistics disrupt the normal workflow and transitions of care between clinicians or settings. This latter aspect is of particular concern for clozapine.

The complexities of the registration and reporting system for olanzapine for ER injectable suspension and the lack of clarity about monitoring were noted to have discouraged the opening of treatment sites. This scarcity of sites may make clinicians hesitant to use this medication, and instead opt for alternative treatments in patients who may be appropriate candidates.

There has also been limited growth of esketamine treatment sites, especially in comparison to ketamine treatment sites.^11-14 Esketamine is FDA-approved for treatment-resistant depression in adults and for depressive symptoms in adults with major depressive disorder with acute suicidal ideation or behavior. Ketamine is not FDA-approved for treating depression but is being used off-label to treat this disorder.¹⁵ The FDA determined that ketamine does not require a REMS to ensure the benefits outweigh the risks for its approved indications as an anesthetic agent, anesthesia-inducing agent, or supplement to anesthesia. Since ketamine has no REMS requirements, there may be a lower burden for its use. Thus, clinicians are treating patients for depression with this medication without needing to comply with a REMS.¹⁶

Technology plays a role in workload burden, and integrating health care processes within current workflow systems, such as using electronic patient health records and pharmacy systems, is recommended. The FDA has been exploring technologies to facilitate the completion of REMS requirements, including mandatory education within the prescribers’ and pharmacists’ workflow.¹⁷ This is a complex task that requires multiple stakeholders with differing perspectives and incentives to align.

Continue to: The data collected for the REMS...

The data collected for the REMS program belongs to the medication’s manufacturer. Current regulations do not require manufacturers to make this data available to qualified scientific researchers. A regulatory mandate to establish data sharing methods would improve transparency and enhance efforts to better understand the outcomes of the REMS programs.

A few caveats

Both the overarching and medication-specific recommendations were based on a small number of participants’ discussions related to clozapine, olanzapine for ER injectable suspension, and esketamine. These recommendations do not include other medications with REMS that are used to treat psychiatric disorders, such as loxapine, buprenorphine ER, and buprenorphine transmucosal products. Larger-scale qualitative and quantitative research is needed to better understand health care professionals’ perspectives. Lastly, some of the recommendations outlined in this article are beyond the current purview or authority of the FDA and may require legislative or regulatory action to implement.

Bottom Line

Risk Evaluation and Mitigation Strategy (REMS) programs are designed to help reduce the occurrence and/or severity of serious risks or to inform decision-making. However, REMS requirements may adversely impact patient access to certain REMS medications and clinician burden. Health care professionals can provide informed recommendations for improving the REMS programs for clozapine, olanzapine for extended-release injectable suspension, and esketamine.

Related Resources

• FDA. Frequently asked questions (FAQs) about REMS. www.fda.gov/drugs/risk-evaluation-and-mitigation-strategies-rems/frequently-asked-questions-faqs-about-rems

Drug Brand Names

Buprenorphine extended-release • Sublocade
Buprenorphine transmucosal • Subutex, Suboxone
Clozapine • Clozaril
Esketamine • Spravato
Ketamine • Ketalar
Lithium • Eskalith, Lithobid
Loxapine • Adasuve
Olanzapine extended-release injectable suspension • Zyprexa Relprevv

A Risk Evaluation and Mitigation Strategy (REMS) is a drug safety program the FDA can require for certain medications with serious safety concerns to help ensure the benefits of the medication outweigh its risks (Box¹). The FDA may require medication guides, patient package inserts, communication plans for health care professionals, and/or certain packaging and safe disposal technologies for medications that pose a serious risk of abuse or overdose. The FDA may also require elements to assure safe use and/or an implementation system be included in the REMS. Pharmaceutical manufacturers then develop a proposed REMS for FDA review.² If the FDA approves the proposed REMS, the manufacturer is responsible for implementing the REMS requirements.

Box

The REMS program for clozapine³ has been the subject of much discussion in the psychiatric community. The adverse impact of the 2015 update to the clozapine REMS program was emphasized at meetings of both the American Psychiatric Association and the College of Psychiatric and Neurologic Pharmacists. A white paper published by the National Association of State Mental Health Program Directors shortly after the 2015 update concluded, “clozapine is underused due to a variety of barriers related to the drug and its properties, the health care system, regulatory requirements, and reimbursement issues.”⁴ After an update to the clozapine REMS program in 2021, the FDA temporarily suspended enforcement of certain requirements due to concerns from health care professionals about patient access to the medication because of problems with implementing the clozapine REMS program.^5,6 In November 2022, the FDA issued a second announcement of enforcement discretion related to additional requirements of the REMS program.⁵ The FDA had previously announced a decision to not take action regarding adherence to REMS requirements for certain laboratory tests in March 2020, during the COVID-19 pandemic.⁷

REMS programs for other psychiatric medications may also present challenges. The REMS programs for esketamine⁸ and olanzapine for extended-release (ER) injectable suspension⁹ include certain risks that require postadministration monitoring. Some facilities have had to dedicate additional space and clinician time to ensure REMS requirements are met.

To further understand health care professionals’ perspectives regarding the value and burden of these REMS programs, a collaborative effort of the University of Maryland (College Park and Baltimore campuses) Center of Excellence in Regulatory Science and Innovation with the FDA was undertaken. The REMS for clozapine, olanzapine for ER injectable suspension, and esketamine were examined to develop recommendations for improving patient access while ensuring safe medication use and limiting the impact on health care professionals.

Assessing the REMS programs

Focus groups were held with health care professionals nominated by professional organizations to gather their perspectives on the REMS requirements. There was 1 focus group for each of the 3 medications. A facilitator’s guide was developed that contained the details of how to conduct the focus group along with the medication-specific questions. The questions were based on the REMS requirements as of May 2021 and assessed the impact of the REMS on patient safety, patient access, and health care professional workload; effects from the COVID-19 pandemic; and suggestions to improve the REMS programs. The University of Maryland Institutional Review Board reviewed the materials and processes and made the determination of exempt.

Health care professionals were eligible to participate in a focus group if they had ≥1 year of experience working with patients who use the specific medication and ≥6 months of experience within the past year working with the REMS program for that medication. Participants were excluded if they were employed by a pharmaceutical manufacturer or the FDA. The focus groups were conducted virtually using an online conferencing service during summer 2021 and were scheduled for 90 minutes. Prior to the focus group, participants received information from the “Goals” and “Summary” tabs of the FDA REMS website¹⁰ for the specific medication along with patient/caregiver guides, which were available for clozapine and olanzapine for ER injectable suspension. For each focus group, there was a target sample size of 6 to 9 participants. However, there were only 4 participants in the olanzapine for ER injectable suspension focus group, which we believed was due to lower national utilization of this medication. Individuals were only able to participate in 1 focus group, so the unique participant count for all 3 focus groups totaled 17 (Table 1).

Themes extracted from qualitative analysis of the focus group responses were the value of the REMS programs; registration/enrollment processes and REMS websites; monitoring requirements; care transitions; and COVID considerations (Table 2). While the REMS programs were perceived to increase practitioner and patient awareness of potential harms, discussions centered on the relative cost-to-benefit of the required reporting and other REMS requirements. There were challenges with the registration/enrollment processes and REMS websites that also affected patient care during transitions to different health care settings or clinicians. Patient access was affected by disparities in care related to monitoring requirements and clinician availability.

Continue to: COVID impacted all REMS...

COVID impacted all REMS programs. Physical distancing was an issue for medications that required extensive postadministration monitoring (ie, esketamine and olanzapine for ER injectable suspension). Access to laboratory services was an issue for clozapine.

Medication-specific themes are listed in Table 3 and relate to terms and descriptions in the REMS or additional regulatory requirements from the Drug Enforcement Agency (DEA). Suggestions for improvement to the REMS are presented in Table 4.

Recommendations for improving REMS

A group consisting of health care professionals, policy experts, and mental health advocates reviewed the information provided by the focus groups and developed the following recommendations.

Overarching recommendations

Each REMS should include a section providing justification for its existence, including a risk analysis of the data regarding the risk the REMS is designed to mitigate. This analysis should be repeated on a regular basis as scientific evidence regarding the risk and its epidemiology evolves. This additional section should also explain how the program requirements of the REMS as implemented (or planned) will achieve the aims of the REMS and weigh the potential benefits of the REMS requirements as implemented (or planned) by the manufacturer vs the potential risks of the REMS requirements as implemented (or planned) by the manufacturer.

Each REMS should have specific quantifiable outcomes. For example, it should specify a reduction in occurrence of the rate of the concerned risk by a specified amount.

Continue to: Ensure adequate...

Ensure adequate stakeholder input during the REMS development and real-world testing in multiple environments before implementing the REMS to identify unanticipated consequences that might impact patient access, patient safety, and health care professional burden. Implementation testing should explore issues such as purchasing and procurement, billing and reimbursement, and relevant factors such as other federal regulations or requirements (eg, the DEA or Medicare).

Ensure harmonization of the REMS forms and processes (eg, initiation and monitoring) for different medications where possible. A prescriber, pharmacist, or system should not face additional barriers to participate in a REMS based on REMS-specific intricacies (ie, prescription systems, data submission systems, or ordering systems). This streamlining will likely decrease clinical inertia to initiate care with the REMS medication, decrease health care professional burden, and improve compliance with REMS requirements.

REMS should anticipate the need for care transitions and employ provisions to ensure seamless care. Considerations should be given to transitions that occur due to:

• Different care settings (eg, inpatient, outpatient, or long-term care)
• Different geographies (eg, patient moves)
• Changes in clinicians, including leaves or absences
• Changes in facilities (eg, pharmacies).

REMS should mirror normal health care professional workflow, including how monitoring data are collected and how and with which frequency pharmacies fill prescriptions.Enhanced information technology to support REMS programs is needed. For example, REMS should be integrated with major electronic patient health record and pharmacy systems to reduce the effort required for clinicians to supply data and automate REMS processes.

For medications that are subject to other agencies and their regulations (eg, the CDC, Centers for Medicare & Medicaid Services, or the DEA), REMS should be required to meet all standards of all agencies with a single system that accommodates normal health care professional workflow.

Continue to: REMS should have a...

REMS should have a standard disclaimer that allows the health care professional to waive certain provisions of the REMS in cases when the specific provisions of the REMS pose a greater risk to the patient than the risk posed by waiving the requirement.

Assure the actions implemented by the industry to meet the requirements for each REMS program are based on peer-reviewed evidence and provide a reasonable expectation to achieve the anticipated benefit.

Ensure that manufacturers make all accumulated REMS data available in a de­identified manner for use by qualified scientific researchers. Additionally, each REMS should have a plan for data access upon initiation and termination of the REMS.

Each REMS should collect data on the performance of the centers and/or personnel who operate the REMS and submit this data for review by qualified outside reviewers. Parameters to assess could include:

• timeliness of response
• timeliness of problem resolution
• data availability and its helpfulness to patient care
• adequacy of resources.

Recommendations for clozapine REMS

These comments relate to the clozapine REMS program prior to the July 2021 announcement that FDA had approved a modification.

Provide a clear definition for “benign ethnic neutropenia.”

Ensure the REMS includes patient-specific adjustments to allow flexibility for monitoring. During COVID, the FDA allowed clinicians to “use their best medical judgment in weighing the benefits and risks of continuing treatment in the absence of laboratory testing.”⁷ This guidance, which allowed flexibility to absolute neutrophil count (ANC) monitoring, was perceived as positive and safe. Before the changes in the REMS requirements, patients with benign ethnic neutropenia were restricted from accessing their medication or encountered harm from additional pharmacotherapy to mitigate ANC levels.

Continue to: Recommendations for olanzapine for ER injectable suspension REMS

Provide clear explicit instructions on what is required to have “ready access to emergency services.”

Ensure the REMS include patient-specific adjustments to allow flexibility for postadministration monitoring (eg, sedation or blood pressure). Specific patient groups may have differential access to certain types of facilities, transportation, or other resources. For example, consider the administration of olanzapine for ER injectable suspension by a mobile treatment team with an adequate protocol (eg, via videoconferencing or phone calls).

Ensure actions with peer-reviewed evidence demonstrating efficacy/effectiveness are included in the REMS. How was the 3-hour cut-point determined? Has it been reevaluated?

Ensure the REMS requirements allow for seamless care during transitions, particularly when clinicians are on vacation.

Continue to: Recommendations for esketamine REMS

Ensure the REMS includes patient-specific adjustments to allow flexibility for post­administration monitoring. Specific patient groups may have differential access to certain types of facilities, transportation, or other resources. For example, consider the administration of esketamine by a mobile treatment team with an adequate protocol (eg, via videoconferencing or phone calls).

Ensure actions with peer-reviewed evidence demonstrating efficacy/effectiveness of requirements are included in the REMS. How was the 2-hour cut-point determined? Has it been reevaluated?

Ensure that the REMS meet all standards of the DEA, with a single system that accommodates normal health care professional workflow.

A summary of the findings

Overall, the REMS programs for these 3 medications were positively perceived for raising awareness of safe medication use for clinicians and patients. Monitoring patients for safety concerns is important and REMS requirements provide accountability.

Continue to: The use of a single shared...

The use of a single shared REMS system for documenting requirements for clozapine (compared to separate systems for each manufacturer) was a positive move forward in implementation. The focus group welcomed the increased awareness of benign ethnic neutropenia as a result of this condition being incorporated in the revised monitoring requirements of the clozapine REMS.

Focus group participants raised the issue of the real-world efficiency of the REMS programs (reduced access and increased clinician workload) vs the benefits (patient safety). They noted that excessive workload could lead to clinicians becoming unwilling to use a medication that requires a REMS. Clinician workload may be further compromised when REMS logistics disrupt the normal workflow and transitions of care between clinicians or settings. This latter aspect is of particular concern for clozapine.

The complexities of the registration and reporting system for olanzapine for ER injectable suspension and the lack of clarity about monitoring were noted to have discouraged the opening of treatment sites. This scarcity of sites may make clinicians hesitant to use this medication, and instead opt for alternative treatments in patients who may be appropriate candidates.

There has also been limited growth of esketamine treatment sites, especially in comparison to ketamine treatment sites.^11-14 Esketamine is FDA-approved for treatment-resistant depression in adults and for depressive symptoms in adults with major depressive disorder with acute suicidal ideation or behavior. Ketamine is not FDA-approved for treating depression but is being used off-label to treat this disorder.¹⁵ The FDA determined that ketamine does not require a REMS to ensure the benefits outweigh the risks for its approved indications as an anesthetic agent, anesthesia-inducing agent, or supplement to anesthesia. Since ketamine has no REMS requirements, there may be a lower burden for its use. Thus, clinicians are treating patients for depression with this medication without needing to comply with a REMS.¹⁶

Technology plays a role in workload burden, and integrating health care processes within current workflow systems, such as using electronic patient health records and pharmacy systems, is recommended. The FDA has been exploring technologies to facilitate the completion of REMS requirements, including mandatory education within the prescribers’ and pharmacists’ workflow.¹⁷ This is a complex task that requires multiple stakeholders with differing perspectives and incentives to align.

Continue to: The data collected for the REMS...

The data collected for the REMS program belongs to the medication’s manufacturer. Current regulations do not require manufacturers to make this data available to qualified scientific researchers. A regulatory mandate to establish data sharing methods would improve transparency and enhance efforts to better understand the outcomes of the REMS programs.

A few caveats

Both the overarching and medication-specific recommendations were based on a small number of participants’ discussions related to clozapine, olanzapine for ER injectable suspension, and esketamine. These recommendations do not include other medications with REMS that are used to treat psychiatric disorders, such as loxapine, buprenorphine ER, and buprenorphine transmucosal products. Larger-scale qualitative and quantitative research is needed to better understand health care professionals’ perspectives. Lastly, some of the recommendations outlined in this article are beyond the current purview or authority of the FDA and may require legislative or regulatory action to implement.

Bottom Line

Risk Evaluation and Mitigation Strategy (REMS) programs are designed to help reduce the occurrence and/or severity of serious risks or to inform decision-making. However, REMS requirements may adversely impact patient access to certain REMS medications and clinician burden. Health care professionals can provide informed recommendations for improving the REMS programs for clozapine, olanzapine for extended-release injectable suspension, and esketamine.

Related Resources

• FDA. Frequently asked questions (FAQs) about REMS. www.fda.gov/drugs/risk-evaluation-and-mitigation-strategies-rems/frequently-asked-questions-faqs-about-rems

Drug Brand Names

Buprenorphine extended-release • Sublocade
Buprenorphine transmucosal • Subutex, Suboxone
Clozapine • Clozaril
Esketamine • Spravato
Ketamine • Ketalar
Lithium • Eskalith, Lithobid
Loxapine • Adasuve
Olanzapine extended-release injectable suspension • Zyprexa Relprevv

A Risk Evaluation and Mitigation Strategy (REMS) is a drug safety program the FDA can require for certain medications with serious safety concerns to help ensure the benefits of the medication outweigh its risks (Box¹). The FDA may require medication guides, patient package inserts, communication plans for health care professionals, and/or certain packaging and safe disposal technologies for medications that pose a serious risk of abuse or overdose. The FDA may also require elements to assure safe use and/or an implementation system be included in the REMS. Pharmaceutical manufacturers then develop a proposed REMS for FDA review.² If the FDA approves the proposed REMS, the manufacturer is responsible for implementing the REMS requirements.

Box

The REMS program for clozapine³ has been the subject of much discussion in the psychiatric community. The adverse impact of the 2015 update to the clozapine REMS program was emphasized at meetings of both the American Psychiatric Association and the College of Psychiatric and Neurologic Pharmacists. A white paper published by the National Association of State Mental Health Program Directors shortly after the 2015 update concluded, “clozapine is underused due to a variety of barriers related to the drug and its properties, the health care system, regulatory requirements, and reimbursement issues.”⁴ After an update to the clozapine REMS program in 2021, the FDA temporarily suspended enforcement of certain requirements due to concerns from health care professionals about patient access to the medication because of problems with implementing the clozapine REMS program.^5,6 In November 2022, the FDA issued a second announcement of enforcement discretion related to additional requirements of the REMS program.⁵ The FDA had previously announced a decision to not take action regarding adherence to REMS requirements for certain laboratory tests in March 2020, during the COVID-19 pandemic.⁷

REMS programs for other psychiatric medications may also present challenges. The REMS programs for esketamine⁸ and olanzapine for extended-release (ER) injectable suspension⁹ include certain risks that require postadministration monitoring. Some facilities have had to dedicate additional space and clinician time to ensure REMS requirements are met.

To further understand health care professionals’ perspectives regarding the value and burden of these REMS programs, a collaborative effort of the University of Maryland (College Park and Baltimore campuses) Center of Excellence in Regulatory Science and Innovation with the FDA was undertaken. The REMS for clozapine, olanzapine for ER injectable suspension, and esketamine were examined to develop recommendations for improving patient access while ensuring safe medication use and limiting the impact on health care professionals.

Assessing the REMS programs

Focus groups were held with health care professionals nominated by professional organizations to gather their perspectives on the REMS requirements. There was 1 focus group for each of the 3 medications. A facilitator’s guide was developed that contained the details of how to conduct the focus group along with the medication-specific questions. The questions were based on the REMS requirements as of May 2021 and assessed the impact of the REMS on patient safety, patient access, and health care professional workload; effects from the COVID-19 pandemic; and suggestions to improve the REMS programs. The University of Maryland Institutional Review Board reviewed the materials and processes and made the determination of exempt.

Health care professionals were eligible to participate in a focus group if they had ≥1 year of experience working with patients who use the specific medication and ≥6 months of experience within the past year working with the REMS program for that medication. Participants were excluded if they were employed by a pharmaceutical manufacturer or the FDA. The focus groups were conducted virtually using an online conferencing service during summer 2021 and were scheduled for 90 minutes. Prior to the focus group, participants received information from the “Goals” and “Summary” tabs of the FDA REMS website¹⁰ for the specific medication along with patient/caregiver guides, which were available for clozapine and olanzapine for ER injectable suspension. For each focus group, there was a target sample size of 6 to 9 participants. However, there were only 4 participants in the olanzapine for ER injectable suspension focus group, which we believed was due to lower national utilization of this medication. Individuals were only able to participate in 1 focus group, so the unique participant count for all 3 focus groups totaled 17 (Table 1).

Themes extracted from qualitative analysis of the focus group responses were the value of the REMS programs; registration/enrollment processes and REMS websites; monitoring requirements; care transitions; and COVID considerations (Table 2). While the REMS programs were perceived to increase practitioner and patient awareness of potential harms, discussions centered on the relative cost-to-benefit of the required reporting and other REMS requirements. There were challenges with the registration/enrollment processes and REMS websites that also affected patient care during transitions to different health care settings or clinicians. Patient access was affected by disparities in care related to monitoring requirements and clinician availability.

Continue to: COVID impacted all REMS...

COVID impacted all REMS programs. Physical distancing was an issue for medications that required extensive postadministration monitoring (ie, esketamine and olanzapine for ER injectable suspension). Access to laboratory services was an issue for clozapine.

Medication-specific themes are listed in Table 3 and relate to terms and descriptions in the REMS or additional regulatory requirements from the Drug Enforcement Agency (DEA). Suggestions for improvement to the REMS are presented in Table 4.

Recommendations for improving REMS

A group consisting of health care professionals, policy experts, and mental health advocates reviewed the information provided by the focus groups and developed the following recommendations.

Overarching recommendations

Each REMS should include a section providing justification for its existence, including a risk analysis of the data regarding the risk the REMS is designed to mitigate. This analysis should be repeated on a regular basis as scientific evidence regarding the risk and its epidemiology evolves. This additional section should also explain how the program requirements of the REMS as implemented (or planned) will achieve the aims of the REMS and weigh the potential benefits of the REMS requirements as implemented (or planned) by the manufacturer vs the potential risks of the REMS requirements as implemented (or planned) by the manufacturer.

Each REMS should have specific quantifiable outcomes. For example, it should specify a reduction in occurrence of the rate of the concerned risk by a specified amount.

Continue to: Ensure adequate...

Ensure adequate stakeholder input during the REMS development and real-world testing in multiple environments before implementing the REMS to identify unanticipated consequences that might impact patient access, patient safety, and health care professional burden. Implementation testing should explore issues such as purchasing and procurement, billing and reimbursement, and relevant factors such as other federal regulations or requirements (eg, the DEA or Medicare).

Ensure harmonization of the REMS forms and processes (eg, initiation and monitoring) for different medications where possible. A prescriber, pharmacist, or system should not face additional barriers to participate in a REMS based on REMS-specific intricacies (ie, prescription systems, data submission systems, or ordering systems). This streamlining will likely decrease clinical inertia to initiate care with the REMS medication, decrease health care professional burden, and improve compliance with REMS requirements.

REMS should anticipate the need for care transitions and employ provisions to ensure seamless care. Considerations should be given to transitions that occur due to:

• Different care settings (eg, inpatient, outpatient, or long-term care)
• Different geographies (eg, patient moves)
• Changes in clinicians, including leaves or absences
• Changes in facilities (eg, pharmacies).

REMS should mirror normal health care professional workflow, including how monitoring data are collected and how and with which frequency pharmacies fill prescriptions.Enhanced information technology to support REMS programs is needed. For example, REMS should be integrated with major electronic patient health record and pharmacy systems to reduce the effort required for clinicians to supply data and automate REMS processes.

For medications that are subject to other agencies and their regulations (eg, the CDC, Centers for Medicare & Medicaid Services, or the DEA), REMS should be required to meet all standards of all agencies with a single system that accommodates normal health care professional workflow.

Continue to: REMS should have a...

REMS should have a standard disclaimer that allows the health care professional to waive certain provisions of the REMS in cases when the specific provisions of the REMS pose a greater risk to the patient than the risk posed by waiving the requirement.

Assure the actions implemented by the industry to meet the requirements for each REMS program are based on peer-reviewed evidence and provide a reasonable expectation to achieve the anticipated benefit.

Ensure that manufacturers make all accumulated REMS data available in a de­identified manner for use by qualified scientific researchers. Additionally, each REMS should have a plan for data access upon initiation and termination of the REMS.

Each REMS should collect data on the performance of the centers and/or personnel who operate the REMS and submit this data for review by qualified outside reviewers. Parameters to assess could include:

• timeliness of response
• timeliness of problem resolution
• data availability and its helpfulness to patient care
• adequacy of resources.

Recommendations for clozapine REMS

These comments relate to the clozapine REMS program prior to the July 2021 announcement that FDA had approved a modification.

Provide a clear definition for “benign ethnic neutropenia.”

Ensure the REMS includes patient-specific adjustments to allow flexibility for monitoring. During COVID, the FDA allowed clinicians to “use their best medical judgment in weighing the benefits and risks of continuing treatment in the absence of laboratory testing.”⁷ This guidance, which allowed flexibility to absolute neutrophil count (ANC) monitoring, was perceived as positive and safe. Before the changes in the REMS requirements, patients with benign ethnic neutropenia were restricted from accessing their medication or encountered harm from additional pharmacotherapy to mitigate ANC levels.

Continue to: Recommendations for olanzapine for ER injectable suspension REMS

Provide clear explicit instructions on what is required to have “ready access to emergency services.”

Ensure the REMS include patient-specific adjustments to allow flexibility for postadministration monitoring (eg, sedation or blood pressure). Specific patient groups may have differential access to certain types of facilities, transportation, or other resources. For example, consider the administration of olanzapine for ER injectable suspension by a mobile treatment team with an adequate protocol (eg, via videoconferencing or phone calls).

Ensure actions with peer-reviewed evidence demonstrating efficacy/effectiveness are included in the REMS. How was the 3-hour cut-point determined? Has it been reevaluated?

Ensure the REMS requirements allow for seamless care during transitions, particularly when clinicians are on vacation.

Continue to: Recommendations for esketamine REMS

Ensure the REMS includes patient-specific adjustments to allow flexibility for post­administration monitoring. Specific patient groups may have differential access to certain types of facilities, transportation, or other resources. For example, consider the administration of esketamine by a mobile treatment team with an adequate protocol (eg, via videoconferencing or phone calls).

Ensure actions with peer-reviewed evidence demonstrating efficacy/effectiveness of requirements are included in the REMS. How was the 2-hour cut-point determined? Has it been reevaluated?

Ensure that the REMS meet all standards of the DEA, with a single system that accommodates normal health care professional workflow.

A summary of the findings

Overall, the REMS programs for these 3 medications were positively perceived for raising awareness of safe medication use for clinicians and patients. Monitoring patients for safety concerns is important and REMS requirements provide accountability.

Continue to: The use of a single shared...

The use of a single shared REMS system for documenting requirements for clozapine (compared to separate systems for each manufacturer) was a positive move forward in implementation. The focus group welcomed the increased awareness of benign ethnic neutropenia as a result of this condition being incorporated in the revised monitoring requirements of the clozapine REMS.

Focus group participants raised the issue of the real-world efficiency of the REMS programs (reduced access and increased clinician workload) vs the benefits (patient safety). They noted that excessive workload could lead to clinicians becoming unwilling to use a medication that requires a REMS. Clinician workload may be further compromised when REMS logistics disrupt the normal workflow and transitions of care between clinicians or settings. This latter aspect is of particular concern for clozapine.

The complexities of the registration and reporting system for olanzapine for ER injectable suspension and the lack of clarity about monitoring were noted to have discouraged the opening of treatment sites. This scarcity of sites may make clinicians hesitant to use this medication, and instead opt for alternative treatments in patients who may be appropriate candidates.

There has also been limited growth of esketamine treatment sites, especially in comparison to ketamine treatment sites.^11-14 Esketamine is FDA-approved for treatment-resistant depression in adults and for depressive symptoms in adults with major depressive disorder with acute suicidal ideation or behavior. Ketamine is not FDA-approved for treating depression but is being used off-label to treat this disorder.¹⁵ The FDA determined that ketamine does not require a REMS to ensure the benefits outweigh the risks for its approved indications as an anesthetic agent, anesthesia-inducing agent, or supplement to anesthesia. Since ketamine has no REMS requirements, there may be a lower burden for its use. Thus, clinicians are treating patients for depression with this medication without needing to comply with a REMS.¹⁶

Technology plays a role in workload burden, and integrating health care processes within current workflow systems, such as using electronic patient health records and pharmacy systems, is recommended. The FDA has been exploring technologies to facilitate the completion of REMS requirements, including mandatory education within the prescribers’ and pharmacists’ workflow.¹⁷ This is a complex task that requires multiple stakeholders with differing perspectives and incentives to align.

Continue to: The data collected for the REMS...

The data collected for the REMS program belongs to the medication’s manufacturer. Current regulations do not require manufacturers to make this data available to qualified scientific researchers. A regulatory mandate to establish data sharing methods would improve transparency and enhance efforts to better understand the outcomes of the REMS programs.

A few caveats

Both the overarching and medication-specific recommendations were based on a small number of participants’ discussions related to clozapine, olanzapine for ER injectable suspension, and esketamine. These recommendations do not include other medications with REMS that are used to treat psychiatric disorders, such as loxapine, buprenorphine ER, and buprenorphine transmucosal products. Larger-scale qualitative and quantitative research is needed to better understand health care professionals’ perspectives. Lastly, some of the recommendations outlined in this article are beyond the current purview or authority of the FDA and may require legislative or regulatory action to implement.

Bottom Line

Risk Evaluation and Mitigation Strategy (REMS) programs are designed to help reduce the occurrence and/or severity of serious risks or to inform decision-making. However, REMS requirements may adversely impact patient access to certain REMS medications and clinician burden. Health care professionals can provide informed recommendations for improving the REMS programs for clozapine, olanzapine for extended-release injectable suspension, and esketamine.

Related Resources

• FDA. Frequently asked questions (FAQs) about REMS. www.fda.gov/drugs/risk-evaluation-and-mitigation-strategies-rems/frequently-asked-questions-faqs-about-rems

Drug Brand Names

Buprenorphine extended-release • Sublocade
Buprenorphine transmucosal • Subutex, Suboxone
Clozapine • Clozaril
Esketamine • Spravato
Ketamine • Ketalar
Lithium • Eskalith, Lithobid
Loxapine • Adasuve
Olanzapine extended-release injectable suspension • Zyprexa Relprevv

While most psychiatric treatments have traditionally consisted of pharmacotherapy with oral medications, a better understanding of the pathophysiology underlying many mental illnesses has led to the recent increased use of treatments that require specialized administration and the creation of a subspecialty called interventional psychiatry. In Part 1 of this 2-part article (“Interventional psychiatry [Part 1]," Current Psychiatry, May 2023, p. 24-35, doi:10.12788/cp.0356), we highlighted parenteral medications used in psychiatry, as well as stellate ganglion blocks, glabellar botulinum toxin injections, and trigger point injections. In Part 2, we review interventional approaches that involve therapeutic neuromodulation and acupuncture.

Neuromodulation treatments

Neuromodulation—the alteration of nerve activity through targeted delivery of a stimulus, such as electrical stimulation, to specific neurologic sites—is an increasingly common approach to treating a variety of psychiatric conditions. The use of some form of neuromodulation as a medical treatment has a long history (Box^1-6). Modern electric neuromodulation began in the 1930s with electroconvulsive therapy (ECT). The 1960s saw the introduction of deep brain stimulation (DBS), spinal cord stimulation, and later, vagus nerve stimulation (VNS). Target-specific noninvasive brain stimulation became possible with transcranial magnetic stimulation (TMS). These approaches are used for treating major depressive disorder (MDD), obsessive-compulsive disorder (OCD), anxiety disorders, and insomnia. Nearly all these neuromodulatory approaches require clinicians to undergo special training and patients to participate in an invasive procedure. These factors also increase cost. Nonetheless, the high rates of success of some of these approaches have led to relatively rapid and widespread acceptance.

Box

Electroconvulsive therapy

In ECT, electric current is applied to the brain to induce a self-limiting seizure. It is the oldest and best-known interventional psychiatric treatment. ECT can also be considered one of the first treatments specifically developed to address pathophysiologic changes. In 1934, Ladislas J. Meduna, who had observed in neuropathologic studies that microglia were more numerous in patients with epilepsy compared with patients with schizophrenia, injected a patient who had been hospitalized with catatonia for 4 years with camphor, a proconvulsant.⁷ After 5 seizures, the patient began to recover. The therapeutic use of electricity was subsequently developed and optimized in animal models, and first used on human patients in Italy in 1939 and in the United States in 1940.⁸ The link between psychiatric illness and microglia, which was initially observed nearly a century ago, is making a comeback, as excessive micro­glial activation has been demonstrated in animal and human models of depression.⁹

Administering ECT requires specialized equipment, anesthesia, physician training, and nursing observation. ECT also has a negative public image.¹⁰ All of these factors conspire to reduce the availability of ECT. Despite this, approximately 100,000 patients in the United States and >1 million worldwide receive ECT each year.¹⁰ Patients generally require 6 to 12 ECT treatments¹¹ to achieve sufficient response and may require additional maintenance treatments.¹²

Although ECT is used to treat psychiatric illnesses ranging from mood disorders to psychotic disorders and catatonia, it is mainly employed to treat people with severe treatment-resistant depression (TRD).¹³ ECT is associated with significant improvements in depressive symptoms and improvements in quality of life.¹⁴ It is superior to other treatments for TRD, such as ketamine,¹⁵ though a recent study did not show IV ketamine inferiority.¹⁶ ECT is also used to treat other neuropsychiatric disorders, such as Parkinson disease.¹⁷

Clinicians have explored alternate methods of inducing therapeutic seizures. Magnetic seizure therapy (MST) utilizes a modified magnetic stimulation device to deliver a higher energy in such a way to induce a generalized seizure under anesthesia.¹⁸ While patients receiving MST generally experience fewer adverse effects than with ECT, the procedure may be equal to¹⁹ or less effective than ECT.²⁰

Transcranial magnetic stimulation

In neuroimaging research, certain aberrant brain circuits have been implicated in the pathogenesis of depression.²¹ Specifically, anatomical and functional imaging suggests connections in the prefrontal cortex are involved in the depression process. In TMS, a series of magnetic pulses are administered via the scalp to stimulate neurons in areas of the brain associated with MDD. Early case reports on using TMS to stimulate the prefrontal cortex found significant improvement of symptoms in patients with depression.²² These promising results spurred great interest in the procedure. Over time, the dose and duration of stimulation has increased, along with FDA-approved indications. TMS was first FDA-approved for TRD.²³ Although the primary endpoint of the initial clinical trial did not meet criteria for FDA approval, TMS did result in improvement across multiple other measures of depression.²³ After the FDA approved the first TMS device, numerous companies began to produce TMS technology. Most of these companies manufacture devices with the figure-of-eight coil, with 1 company producing the Hesed-coil helmet.²⁴

Continue to: An unintended outcome...

An unintended outcome of the increased interest in TMS has been an increased understanding of brain regions involved in psychiatric illness. TMS was able to bring knowledge of mental health from synapses to circuits.²⁵ Work in this area has further stratified the circuits involved in the manifestation of symptom clusters in depression.²⁶ The exact taxonomy of these brain circuits has not been fully realized, but the default mode, salience, attention, cognitive control, and other circuits have been shown to be involved in specific symptom presentations.^26,27 These circuits can be hyperactive, hypoactive, hyperconnected, or hypoconnected, with the aberrancies compared to normal controls resulting in symptoms of psychiatric illness.²⁸

This enhanced understanding of brain function has led to further research and development of protocols and subsequent FDA approval of TMS for OCD, anxious depression, and smoking cessation.²⁹ In addition, it has allowed for a proliferation of off-label uses for TMS, including (but not limited to) tinnitus, pain, migraines, and various substance use disorders.³⁰ TMS treatment for these conditions involves stimulation of specific anatomical brain regions that are thought to play a role in the pathology of the target disorder. For example, subthreshold stimulation of the motor cortex has shown some utility in managing symptoms of pain disorders and movement disorders,^31,32 the ventromedial prefrontal cortex has been implicated in disorders in the OCD spectrum,³³ stimulation of the frontal poles may help treat substance use disorders,³⁴ and the auditory cortex has been a target for treating tinnitus and auditory hallucinations.³⁵

The location of stimulation for treating depression has evolved. The Talairach-Tournoux coordinate system has been used to determine the location of the dorsolateral prefrontal cortex (DLPFC) in relation to the motor cortex. This was measured to be 5 cm from the motor hotspot and subsequently became “the 5.5 cm rule,” taking skull convexity into account. The treatment paradigm for the Hesed coil also uses a measurement from the motor hotspot. Another commonly used methodology for coil placement involves using the 10 to 20 EEG coordinate system to individualize scalp landmarks. In this method, the F3 location corresponds most accurately to the DLPFC target. More recently, using fMRI-guided navigation for coil placement has been shown to lead to a significant reduction in depressive symptoms.³⁶

For depression, the initial recommended course of treatment is 6 weeks, but most improvement is seen in the first 2 to 3 weeks.¹⁴ Therefore, many clinicians administer an initial course of 3 weeks unless the response is inadequate, in which case a 6-week course is administered. Many patients require ongoing maintenance treatment, which can be weekly or monthly based on response.³⁷

Research to determine the optimal TMS dose for treating neuropsychiatric symptoms is ongoing. Location, intensity of stimulation, and pulse are the components of stimulation. The pulse can be subdivided into frequency, pattern (single pulse, standard, burst), train (numbers of pulse groups), interval between trains, and total number of pulses per session. The Clinical TMS Society has published TMS protocols.³⁸ The standard intensity of stimulation is 120% of the motor threshold (MT), which is defined as the amount of stimulation over the motor cortex required to produce movement in the extensor hallucis longus. Although treatment for depression traditionally utilizes rapid TMS (3,000 pulses delivered per session at a frequency of 10 Hz in 4-second trains), in controlled studies, accelerated protocols such as intermittent theta burst stimulation (iTBS; standard stimulation parameters: triplet 50 Hz bursts at 5 Hz, with an interval of 8 seconds for 600 pulses per session) have shown noninferiority.^36,39 

Recent research has explored fMRI-guided iTBS in an even more accelerated format. The Stanford Neuromodulation Therapy trial involved 1,800 pulses per session for 10 sessions a day for 5 days at 90% MT.³⁶ This treatment paradigm was shown to be more effective than standard protocols and was FDA-approved in 2022. Although this specific iTBS protocol exhibited encouraging results, the need for fMRI for adequate delivery might limit its use.

Continue to: Transcranial direct current stimulation

Therapeutic noninvasive brain stimulation technology is plausible due to the relative lack of adverse effects and ease of administration. In transcranial direct current stimulation (tDCS), a low-intensity, constant electric current is delivered to stimulate the brain via electrodes attached to the scalp. tDCS modulates spontaneous neuronal network activity^40,41 and induces polarization of resting membrane potential at the neuronal level,⁴² though the exact mechanism is yet to be proven. N-methyl-D-aspartate-glutamatergic receptors are involved in inhibitory and facilitatory plasticity induced by tDCS.⁴³

tDCS has been suggested as a treatment for various psychiatric and medical conditions. However, the small sample sizes and experimental design of published studies have limited tDCS from being clinically recommended.³⁰ No recommendation of Level A (definite efficacy) for its use was found for any indication. Level B recommendation (probable efficacy) was proposed for fibromyalgia, MDD episode without drug resistance, and addiction/craving. Level C recommendation (possible efficacy) is proposed for chronic lower limb neuropathic pain secondary to spinal cord lesion. tDCS was found to be probably ineffective as a treatment for tinnitus and drug-resistant MDD.³⁰ Some research has suggested that tDCS targeting the DLPFC is associated with cognitive improvements in healthy individuals as well as those with schizophrenia.⁴⁴ tDCS treatment remains experimental and investigational.

Deep brain stimulation

DBS is a neurosurgical procedure that uses electrical current to directly modulate specific areas of the CNS. In terms of accurate, site-specific anatomical targeting, there can be little doubt of the superiority of DBS. DBS involves the placement of leads into the brain parenchyma. Image guidance techniques are used for accurate placement. DBS is a mainstay for the symptomatic treatment of treatment-resistant movement disorders such as Parkinson disease, essential tremor, and some dystonic disorders. It also has been studied as a potential treatment for chronic pain, cluster headache, Huntington disease, and Tourette syndrome.

For treating depression, researched targets include the subgenual cingulate gyrus (SCG), ventral striatum, nucleus accumbens, inferior thalamic peduncle, medial forebrain bundle, and the red nucleus.⁴⁵ In systematic reviews, improvement of depression is greatest when DBS targets the subgenual cingulate cortex and the medial forebrain bundle.⁴⁶ 

The major limitation of DBS for treating depression is the invasive nature of the procedure. Deep TMS can achieve noninvasive stimulation of the SCG and may be associated with fewer risks, fewer adverse events, and less collateral damage. However, given the evolving concept of abnormal neurologic circuits in depression, as our understanding of circuitry in pathological psychiatric processes increases, DBS may be an attractive option for personalized targeting of symptoms in some patients.

DBS may also be beneficial for severe, treatment-resistant OCD. Electrode implantation in the region of the internal capsule/ventral striatum, including the nucleus accumbens, is used⁴⁷; there is little difference in placement as a treatment for OCD vs for movement disorders.⁴⁸

Continue to: A critical review of 23 trials...

A critical review of 23 trials and case reports of DBS as a treatment for OCD demonstrated a 47.7% mean reduction in score on the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) and a mean response percentage (minimum 35% Y-BOCS reduction) of 58.2%.⁴⁹ Most patients regained a normal quality of life after DBS.⁴⁹ A more rigorous review of 15 meta-analyses of DBS found that conclusions about its efficacy or comparative effectiveness cannot be drawn.⁵⁰ Because of the nature of neurosurgery, DBS has many potential complications, including cognitive changes, headache, infection, seizures, stroke, and hardware failure.

Vagus nerve stimulation

VNS, in which an implanted device stimulates the left vagus nerve with electrical impulses, was FDA-approved for treating chronic TRD in 2005.⁵¹ It had been approved for treatment-resistant epilepsy in 1997. In patients with epilepsy, VNS was shown to improve mood independent of seizure control.⁵² VNS requires a battery-powered pacemaker device to be implanted under the skin over the anterior chest wall, and a wire tunneled to an electrode is wrapped around the left vagus nerve in the neck.⁵³ The pacemaker is then programmed, monitored, and reprogrammed to optimize response.

VNS is believed to stimulate deep brain nuclei that may play a role in depression.⁵⁴ The onset of improvement is slow (it may take many months) but in carefully selected patients VNS can provide significant control of TRD. In addition to rare surgery-related complications such as a trauma to the vagal nerve and surrounding tissues (vocal cord paralysis, implant site infection, left facial nerve paralysis and Horner syndrome), VNS may cause hoarseness, dyspnea, and cough related to the intensity of the current output.⁵¹ Hypomania and mania were also reported; no suicidal behavior has been associated with VNS.⁵¹

Noninvasive vagus nerve stimulationIn noninvasive vagus nerve stimulation (nVNS) or transcutaneous VNS, an external handheld device is applied to the neck overlying the course of the vagus nerve to deliver a sinusoidal alternating current.⁵⁵ nVNS is currently FDA-approved for treating migraine headaches.^55,56 It has demonstrated actions on neurophysiology⁵⁷ and inflammation in patients with MDD.⁵⁸ Exploratory research has found a small beneficial effect in patients with depression.^59,60 A lack of adequate reproducibility prevents this treatment from being more widely recommended, although attempts to standardize the field are evolving.⁶¹

Cranial electrical stimulation

Cranial electrical stimulation (CES) is an older form of electric stimulation developed in the 1970s. In CES, mild electrical pulses are delivered to the ear lobes bilaterally in an episodic fashion (usually 20 to 60 minutes once or twice daily). While CES can be considered a form of neuromodulation, it is not strictly interventional. Patients self-administer CES. The procedure has minimal effects on improving sleep, anxiety, and mood.^62-66 Potential adverse effects include a tingling sensation in the ear lobes, lightheadedness, and fogginess. A review and meta-analysis of CES for treating addiction by Kirsch⁶⁷ showed a wide range of symptoms responding positively to CES treatment, although this study was not peer-reviewed. Because of the low quality of nearly all research that evaluated CES, this form of electric stimulation cannot be viewed as an accepted treatment for any of its listed indications.

Continue to: Other neuromodulation techniques

In addition to the forms of neuromodulation we have already described, there are many other techniques. Several are promising but not yet ready for clinical use. Table 1 and Table 2 summarize the neuromodulation techniques described in this article as well as several that are under development.

Acupuncture

Acupuncture is a Chinese form of medical treatment that began >3,000 years ago; there are written descriptions of it from >2,000 years ago.⁶⁸ It is based on the belief that there are channels within the body through which the Qi (vital energy or life force) flow, and that inserting fine needles into these channels via the skin can rebalance Qi.⁶⁸ Modern mechanistic hypotheses invoke involvement of inflammatory or pain pathways.⁶⁹ Acupuncture frequently uses electric stimulation (electro-acupuncture) to increase the potency of the procedure. Alternatively, in a related procedure (acupressure), pressure can replace the needle. Accreditation in acupuncture generally requires a master’s degree in traditional Chinese medicine but does not require any specific medical training. Acupuncture training courses for physicians are widely available.

All forms of acupuncture are experimental for a wide variety of mental and medical conditions. A meta-analysis found that most research of the utility of acupuncture for depression suffered from various forms of potential bias and was considered low quality.⁷⁰ Nonetheless, active acupuncture was shown to be minimally superior to placebo acupuncture.⁷⁰ A meta-analysis of acupuncture for preoperative anxiety^71,72 and poststroke insomnia⁷³ reported a similar low study quality. A study of 72 patients with primary insomnia revealed that acupuncture was more effective than sham acupuncture for most sleep measures.⁷⁴

Challenges and complications

Psychiatry is increasingly integrating medical tools in addition to psychological tools. Pharmacology remains a cornerstone of biological psychiatry and this will not soon change. However, nonpharmacologic psychiatric treatments such as therapeutic neuromodulation are rapidly emerging. These and novel methods of medication administration may present a challenge to psychiatrists who do not have access to medical personnel or may have forgotten general medical skills.

Our 2-part article has highlighted several interventional psychiatry tools—old and new—that may interest clinicians and benefit patients. As a rule, such treatments are reserved for the most treatment-resistant, challenging psychiatric patients, those with hard-to-treat chronic conditions, and patients who are not helped by more commonly used treatments. An additional complication is that such treatments are frequently not appropriately researched, vetted, or FDA-approved, and therefore are higher risk. Appropriate clinical judgment is always necessary, and potential benefits must be thoroughly weighed against possible adverse effects.

Bottom Line

Several forms of neuromodulation, including electroconvulsive therapy, transcranial magnetic stimulation, transcranial direct current stimulation, deep brain stimulation, and vagus nerve stimulation, may be beneficial for patients with certain treatment-resistant psychiatric disorders, including major depressive disorder and obsessive-compulsive disorder.

Related Resources

• Janicak PG. What’s new in transcranial magnetic stimulation. Current Psychiatry. 2019;18(3):10-16.
• Sharma MS, Ang-Rabanes M, Selek S, et al. Neuromodulatory options for treatment-resistant depression. Current Psychiatry. 2018;17(3):26-28,33-37.

While most psychiatric treatments have traditionally consisted of pharmacotherapy with oral medications, a better understanding of the pathophysiology underlying many mental illnesses has led to the recent increased use of treatments that require specialized administration and the creation of a subspecialty called interventional psychiatry. In Part 1 of this 2-part article (“Interventional psychiatry [Part 1]," Current Psychiatry, May 2023, p. 24-35, doi:10.12788/cp.0356), we highlighted parenteral medications used in psychiatry, as well as stellate ganglion blocks, glabellar botulinum toxin injections, and trigger point injections. In Part 2, we review interventional approaches that involve therapeutic neuromodulation and acupuncture.

Neuromodulation treatments

Neuromodulation—the alteration of nerve activity through targeted delivery of a stimulus, such as electrical stimulation, to specific neurologic sites—is an increasingly common approach to treating a variety of psychiatric conditions. The use of some form of neuromodulation as a medical treatment has a long history (Box^1-6). Modern electric neuromodulation began in the 1930s with electroconvulsive therapy (ECT). The 1960s saw the introduction of deep brain stimulation (DBS), spinal cord stimulation, and later, vagus nerve stimulation (VNS). Target-specific noninvasive brain stimulation became possible with transcranial magnetic stimulation (TMS). These approaches are used for treating major depressive disorder (MDD), obsessive-compulsive disorder (OCD), anxiety disorders, and insomnia. Nearly all these neuromodulatory approaches require clinicians to undergo special training and patients to participate in an invasive procedure. These factors also increase cost. Nonetheless, the high rates of success of some of these approaches have led to relatively rapid and widespread acceptance.

Box

Electroconvulsive therapy

In ECT, electric current is applied to the brain to induce a self-limiting seizure. It is the oldest and best-known interventional psychiatric treatment. ECT can also be considered one of the first treatments specifically developed to address pathophysiologic changes. In 1934, Ladislas J. Meduna, who had observed in neuropathologic studies that microglia were more numerous in patients with epilepsy compared with patients with schizophrenia, injected a patient who had been hospitalized with catatonia for 4 years with camphor, a proconvulsant.⁷ After 5 seizures, the patient began to recover. The therapeutic use of electricity was subsequently developed and optimized in animal models, and first used on human patients in Italy in 1939 and in the United States in 1940.⁸ The link between psychiatric illness and microglia, which was initially observed nearly a century ago, is making a comeback, as excessive micro­glial activation has been demonstrated in animal and human models of depression.⁹

Administering ECT requires specialized equipment, anesthesia, physician training, and nursing observation. ECT also has a negative public image.¹⁰ All of these factors conspire to reduce the availability of ECT. Despite this, approximately 100,000 patients in the United States and >1 million worldwide receive ECT each year.¹⁰ Patients generally require 6 to 12 ECT treatments¹¹ to achieve sufficient response and may require additional maintenance treatments.¹²

Although ECT is used to treat psychiatric illnesses ranging from mood disorders to psychotic disorders and catatonia, it is mainly employed to treat people with severe treatment-resistant depression (TRD).¹³ ECT is associated with significant improvements in depressive symptoms and improvements in quality of life.¹⁴ It is superior to other treatments for TRD, such as ketamine,¹⁵ though a recent study did not show IV ketamine inferiority.¹⁶ ECT is also used to treat other neuropsychiatric disorders, such as Parkinson disease.¹⁷

Clinicians have explored alternate methods of inducing therapeutic seizures. Magnetic seizure therapy (MST) utilizes a modified magnetic stimulation device to deliver a higher energy in such a way to induce a generalized seizure under anesthesia.¹⁸ While patients receiving MST generally experience fewer adverse effects than with ECT, the procedure may be equal to¹⁹ or less effective than ECT.²⁰

Transcranial magnetic stimulation

In neuroimaging research, certain aberrant brain circuits have been implicated in the pathogenesis of depression.²¹ Specifically, anatomical and functional imaging suggests connections in the prefrontal cortex are involved in the depression process. In TMS, a series of magnetic pulses are administered via the scalp to stimulate neurons in areas of the brain associated with MDD. Early case reports on using TMS to stimulate the prefrontal cortex found significant improvement of symptoms in patients with depression.²² These promising results spurred great interest in the procedure. Over time, the dose and duration of stimulation has increased, along with FDA-approved indications. TMS was first FDA-approved for TRD.²³ Although the primary endpoint of the initial clinical trial did not meet criteria for FDA approval, TMS did result in improvement across multiple other measures of depression.²³ After the FDA approved the first TMS device, numerous companies began to produce TMS technology. Most of these companies manufacture devices with the figure-of-eight coil, with 1 company producing the Hesed-coil helmet.²⁴

Continue to: An unintended outcome...

An unintended outcome of the increased interest in TMS has been an increased understanding of brain regions involved in psychiatric illness. TMS was able to bring knowledge of mental health from synapses to circuits.²⁵ Work in this area has further stratified the circuits involved in the manifestation of symptom clusters in depression.²⁶ The exact taxonomy of these brain circuits has not been fully realized, but the default mode, salience, attention, cognitive control, and other circuits have been shown to be involved in specific symptom presentations.^26,27 These circuits can be hyperactive, hypoactive, hyperconnected, or hypoconnected, with the aberrancies compared to normal controls resulting in symptoms of psychiatric illness.²⁸

This enhanced understanding of brain function has led to further research and development of protocols and subsequent FDA approval of TMS for OCD, anxious depression, and smoking cessation.²⁹ In addition, it has allowed for a proliferation of off-label uses for TMS, including (but not limited to) tinnitus, pain, migraines, and various substance use disorders.³⁰ TMS treatment for these conditions involves stimulation of specific anatomical brain regions that are thought to play a role in the pathology of the target disorder. For example, subthreshold stimulation of the motor cortex has shown some utility in managing symptoms of pain disorders and movement disorders,^31,32 the ventromedial prefrontal cortex has been implicated in disorders in the OCD spectrum,³³ stimulation of the frontal poles may help treat substance use disorders,³⁴ and the auditory cortex has been a target for treating tinnitus and auditory hallucinations.³⁵

The location of stimulation for treating depression has evolved. The Talairach-Tournoux coordinate system has been used to determine the location of the dorsolateral prefrontal cortex (DLPFC) in relation to the motor cortex. This was measured to be 5 cm from the motor hotspot and subsequently became “the 5.5 cm rule,” taking skull convexity into account. The treatment paradigm for the Hesed coil also uses a measurement from the motor hotspot. Another commonly used methodology for coil placement involves using the 10 to 20 EEG coordinate system to individualize scalp landmarks. In this method, the F3 location corresponds most accurately to the DLPFC target. More recently, using fMRI-guided navigation for coil placement has been shown to lead to a significant reduction in depressive symptoms.³⁶

For depression, the initial recommended course of treatment is 6 weeks, but most improvement is seen in the first 2 to 3 weeks.¹⁴ Therefore, many clinicians administer an initial course of 3 weeks unless the response is inadequate, in which case a 6-week course is administered. Many patients require ongoing maintenance treatment, which can be weekly or monthly based on response.³⁷

Research to determine the optimal TMS dose for treating neuropsychiatric symptoms is ongoing. Location, intensity of stimulation, and pulse are the components of stimulation. The pulse can be subdivided into frequency, pattern (single pulse, standard, burst), train (numbers of pulse groups), interval between trains, and total number of pulses per session. The Clinical TMS Society has published TMS protocols.³⁸ The standard intensity of stimulation is 120% of the motor threshold (MT), which is defined as the amount of stimulation over the motor cortex required to produce movement in the extensor hallucis longus. Although treatment for depression traditionally utilizes rapid TMS (3,000 pulses delivered per session at a frequency of 10 Hz in 4-second trains), in controlled studies, accelerated protocols such as intermittent theta burst stimulation (iTBS; standard stimulation parameters: triplet 50 Hz bursts at 5 Hz, with an interval of 8 seconds for 600 pulses per session) have shown noninferiority.^36,39 

Recent research has explored fMRI-guided iTBS in an even more accelerated format. The Stanford Neuromodulation Therapy trial involved 1,800 pulses per session for 10 sessions a day for 5 days at 90% MT.³⁶ This treatment paradigm was shown to be more effective than standard protocols and was FDA-approved in 2022. Although this specific iTBS protocol exhibited encouraging results, the need for fMRI for adequate delivery might limit its use.

Continue to: Transcranial direct current stimulation

Therapeutic noninvasive brain stimulation technology is plausible due to the relative lack of adverse effects and ease of administration. In transcranial direct current stimulation (tDCS), a low-intensity, constant electric current is delivered to stimulate the brain via electrodes attached to the scalp. tDCS modulates spontaneous neuronal network activity^40,41 and induces polarization of resting membrane potential at the neuronal level,⁴² though the exact mechanism is yet to be proven. N-methyl-D-aspartate-glutamatergic receptors are involved in inhibitory and facilitatory plasticity induced by tDCS.⁴³

tDCS has been suggested as a treatment for various psychiatric and medical conditions. However, the small sample sizes and experimental design of published studies have limited tDCS from being clinically recommended.³⁰ No recommendation of Level A (definite efficacy) for its use was found for any indication. Level B recommendation (probable efficacy) was proposed for fibromyalgia, MDD episode without drug resistance, and addiction/craving. Level C recommendation (possible efficacy) is proposed for chronic lower limb neuropathic pain secondary to spinal cord lesion. tDCS was found to be probably ineffective as a treatment for tinnitus and drug-resistant MDD.³⁰ Some research has suggested that tDCS targeting the DLPFC is associated with cognitive improvements in healthy individuals as well as those with schizophrenia.⁴⁴ tDCS treatment remains experimental and investigational.

Deep brain stimulation

DBS is a neurosurgical procedure that uses electrical current to directly modulate specific areas of the CNS. In terms of accurate, site-specific anatomical targeting, there can be little doubt of the superiority of DBS. DBS involves the placement of leads into the brain parenchyma. Image guidance techniques are used for accurate placement. DBS is a mainstay for the symptomatic treatment of treatment-resistant movement disorders such as Parkinson disease, essential tremor, and some dystonic disorders. It also has been studied as a potential treatment for chronic pain, cluster headache, Huntington disease, and Tourette syndrome.

For treating depression, researched targets include the subgenual cingulate gyrus (SCG), ventral striatum, nucleus accumbens, inferior thalamic peduncle, medial forebrain bundle, and the red nucleus.⁴⁵ In systematic reviews, improvement of depression is greatest when DBS targets the subgenual cingulate cortex and the medial forebrain bundle.⁴⁶ 

The major limitation of DBS for treating depression is the invasive nature of the procedure. Deep TMS can achieve noninvasive stimulation of the SCG and may be associated with fewer risks, fewer adverse events, and less collateral damage. However, given the evolving concept of abnormal neurologic circuits in depression, as our understanding of circuitry in pathological psychiatric processes increases, DBS may be an attractive option for personalized targeting of symptoms in some patients.

DBS may also be beneficial for severe, treatment-resistant OCD. Electrode implantation in the region of the internal capsule/ventral striatum, including the nucleus accumbens, is used⁴⁷; there is little difference in placement as a treatment for OCD vs for movement disorders.⁴⁸

Continue to: A critical review of 23 trials...

A critical review of 23 trials and case reports of DBS as a treatment for OCD demonstrated a 47.7% mean reduction in score on the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) and a mean response percentage (minimum 35% Y-BOCS reduction) of 58.2%.⁴⁹ Most patients regained a normal quality of life after DBS.⁴⁹ A more rigorous review of 15 meta-analyses of DBS found that conclusions about its efficacy or comparative effectiveness cannot be drawn.⁵⁰ Because of the nature of neurosurgery, DBS has many potential complications, including cognitive changes, headache, infection, seizures, stroke, and hardware failure.

Vagus nerve stimulation

VNS, in which an implanted device stimulates the left vagus nerve with electrical impulses, was FDA-approved for treating chronic TRD in 2005.⁵¹ It had been approved for treatment-resistant epilepsy in 1997. In patients with epilepsy, VNS was shown to improve mood independent of seizure control.⁵² VNS requires a battery-powered pacemaker device to be implanted under the skin over the anterior chest wall, and a wire tunneled to an electrode is wrapped around the left vagus nerve in the neck.⁵³ The pacemaker is then programmed, monitored, and reprogrammed to optimize response.

VNS is believed to stimulate deep brain nuclei that may play a role in depression.⁵⁴ The onset of improvement is slow (it may take many months) but in carefully selected patients VNS can provide significant control of TRD. In addition to rare surgery-related complications such as a trauma to the vagal nerve and surrounding tissues (vocal cord paralysis, implant site infection, left facial nerve paralysis and Horner syndrome), VNS may cause hoarseness, dyspnea, and cough related to the intensity of the current output.⁵¹ Hypomania and mania were also reported; no suicidal behavior has been associated with VNS.⁵¹

Noninvasive vagus nerve stimulationIn noninvasive vagus nerve stimulation (nVNS) or transcutaneous VNS, an external handheld device is applied to the neck overlying the course of the vagus nerve to deliver a sinusoidal alternating current.⁵⁵ nVNS is currently FDA-approved for treating migraine headaches.^55,56 It has demonstrated actions on neurophysiology⁵⁷ and inflammation in patients with MDD.⁵⁸ Exploratory research has found a small beneficial effect in patients with depression.^59,60 A lack of adequate reproducibility prevents this treatment from being more widely recommended, although attempts to standardize the field are evolving.⁶¹

Cranial electrical stimulation

Cranial electrical stimulation (CES) is an older form of electric stimulation developed in the 1970s. In CES, mild electrical pulses are delivered to the ear lobes bilaterally in an episodic fashion (usually 20 to 60 minutes once or twice daily). While CES can be considered a form of neuromodulation, it is not strictly interventional. Patients self-administer CES. The procedure has minimal effects on improving sleep, anxiety, and mood.^62-66 Potential adverse effects include a tingling sensation in the ear lobes, lightheadedness, and fogginess. A review and meta-analysis of CES for treating addiction by Kirsch⁶⁷ showed a wide range of symptoms responding positively to CES treatment, although this study was not peer-reviewed. Because of the low quality of nearly all research that evaluated CES, this form of electric stimulation cannot be viewed as an accepted treatment for any of its listed indications.

Continue to: Other neuromodulation techniques

In addition to the forms of neuromodulation we have already described, there are many other techniques. Several are promising but not yet ready for clinical use. Table 1 and Table 2 summarize the neuromodulation techniques described in this article as well as several that are under development.

Acupuncture

Acupuncture is a Chinese form of medical treatment that began >3,000 years ago; there are written descriptions of it from >2,000 years ago.⁶⁸ It is based on the belief that there are channels within the body through which the Qi (vital energy or life force) flow, and that inserting fine needles into these channels via the skin can rebalance Qi.⁶⁸ Modern mechanistic hypotheses invoke involvement of inflammatory or pain pathways.⁶⁹ Acupuncture frequently uses electric stimulation (electro-acupuncture) to increase the potency of the procedure. Alternatively, in a related procedure (acupressure), pressure can replace the needle. Accreditation in acupuncture generally requires a master’s degree in traditional Chinese medicine but does not require any specific medical training. Acupuncture training courses for physicians are widely available.

All forms of acupuncture are experimental for a wide variety of mental and medical conditions. A meta-analysis found that most research of the utility of acupuncture for depression suffered from various forms of potential bias and was considered low quality.⁷⁰ Nonetheless, active acupuncture was shown to be minimally superior to placebo acupuncture.⁷⁰ A meta-analysis of acupuncture for preoperative anxiety^71,72 and poststroke insomnia⁷³ reported a similar low study quality. A study of 72 patients with primary insomnia revealed that acupuncture was more effective than sham acupuncture for most sleep measures.⁷⁴

Challenges and complications

Psychiatry is increasingly integrating medical tools in addition to psychological tools. Pharmacology remains a cornerstone of biological psychiatry and this will not soon change. However, nonpharmacologic psychiatric treatments such as therapeutic neuromodulation are rapidly emerging. These and novel methods of medication administration may present a challenge to psychiatrists who do not have access to medical personnel or may have forgotten general medical skills.

Our 2-part article has highlighted several interventional psychiatry tools—old and new—that may interest clinicians and benefit patients. As a rule, such treatments are reserved for the most treatment-resistant, challenging psychiatric patients, those with hard-to-treat chronic conditions, and patients who are not helped by more commonly used treatments. An additional complication is that such treatments are frequently not appropriately researched, vetted, or FDA-approved, and therefore are higher risk. Appropriate clinical judgment is always necessary, and potential benefits must be thoroughly weighed against possible adverse effects.

Bottom Line

Several forms of neuromodulation, including electroconvulsive therapy, transcranial magnetic stimulation, transcranial direct current stimulation, deep brain stimulation, and vagus nerve stimulation, may be beneficial for patients with certain treatment-resistant psychiatric disorders, including major depressive disorder and obsessive-compulsive disorder.

Related Resources

• Janicak PG. What’s new in transcranial magnetic stimulation. Current Psychiatry. 2019;18(3):10-16.
• Sharma MS, Ang-Rabanes M, Selek S, et al. Neuromodulatory options for treatment-resistant depression. Current Psychiatry. 2018;17(3):26-28,33-37.

While most psychiatric treatments have traditionally consisted of pharmacotherapy with oral medications, a better understanding of the pathophysiology underlying many mental illnesses has led to the recent increased use of treatments that require specialized administration and the creation of a subspecialty called interventional psychiatry. In Part 1 of this 2-part article (“Interventional psychiatry [Part 1]," Current Psychiatry, May 2023, p. 24-35, doi:10.12788/cp.0356), we highlighted parenteral medications used in psychiatry, as well as stellate ganglion blocks, glabellar botulinum toxin injections, and trigger point injections. In Part 2, we review interventional approaches that involve therapeutic neuromodulation and acupuncture.

Neuromodulation treatments

Neuromodulation—the alteration of nerve activity through targeted delivery of a stimulus, such as electrical stimulation, to specific neurologic sites—is an increasingly common approach to treating a variety of psychiatric conditions. The use of some form of neuromodulation as a medical treatment has a long history (Box^1-6). Modern electric neuromodulation began in the 1930s with electroconvulsive therapy (ECT). The 1960s saw the introduction of deep brain stimulation (DBS), spinal cord stimulation, and later, vagus nerve stimulation (VNS). Target-specific noninvasive brain stimulation became possible with transcranial magnetic stimulation (TMS). These approaches are used for treating major depressive disorder (MDD), obsessive-compulsive disorder (OCD), anxiety disorders, and insomnia. Nearly all these neuromodulatory approaches require clinicians to undergo special training and patients to participate in an invasive procedure. These factors also increase cost. Nonetheless, the high rates of success of some of these approaches have led to relatively rapid and widespread acceptance.

Box

Electroconvulsive therapy

In ECT, electric current is applied to the brain to induce a self-limiting seizure. It is the oldest and best-known interventional psychiatric treatment. ECT can also be considered one of the first treatments specifically developed to address pathophysiologic changes. In 1934, Ladislas J. Meduna, who had observed in neuropathologic studies that microglia were more numerous in patients with epilepsy compared with patients with schizophrenia, injected a patient who had been hospitalized with catatonia for 4 years with camphor, a proconvulsant.⁷ After 5 seizures, the patient began to recover. The therapeutic use of electricity was subsequently developed and optimized in animal models, and first used on human patients in Italy in 1939 and in the United States in 1940.⁸ The link between psychiatric illness and microglia, which was initially observed nearly a century ago, is making a comeback, as excessive micro­glial activation has been demonstrated in animal and human models of depression.⁹

Administering ECT requires specialized equipment, anesthesia, physician training, and nursing observation. ECT also has a negative public image.¹⁰ All of these factors conspire to reduce the availability of ECT. Despite this, approximately 100,000 patients in the United States and >1 million worldwide receive ECT each year.¹⁰ Patients generally require 6 to 12 ECT treatments¹¹ to achieve sufficient response and may require additional maintenance treatments.¹²

Although ECT is used to treat psychiatric illnesses ranging from mood disorders to psychotic disorders and catatonia, it is mainly employed to treat people with severe treatment-resistant depression (TRD).¹³ ECT is associated with significant improvements in depressive symptoms and improvements in quality of life.¹⁴ It is superior to other treatments for TRD, such as ketamine,¹⁵ though a recent study did not show IV ketamine inferiority.¹⁶ ECT is also used to treat other neuropsychiatric disorders, such as Parkinson disease.¹⁷

Clinicians have explored alternate methods of inducing therapeutic seizures. Magnetic seizure therapy (MST) utilizes a modified magnetic stimulation device to deliver a higher energy in such a way to induce a generalized seizure under anesthesia.¹⁸ While patients receiving MST generally experience fewer adverse effects than with ECT, the procedure may be equal to¹⁹ or less effective than ECT.²⁰

Transcranial magnetic stimulation

In neuroimaging research, certain aberrant brain circuits have been implicated in the pathogenesis of depression.²¹ Specifically, anatomical and functional imaging suggests connections in the prefrontal cortex are involved in the depression process. In TMS, a series of magnetic pulses are administered via the scalp to stimulate neurons in areas of the brain associated with MDD. Early case reports on using TMS to stimulate the prefrontal cortex found significant improvement of symptoms in patients with depression.²² These promising results spurred great interest in the procedure. Over time, the dose and duration of stimulation has increased, along with FDA-approved indications. TMS was first FDA-approved for TRD.²³ Although the primary endpoint of the initial clinical trial did not meet criteria for FDA approval, TMS did result in improvement across multiple other measures of depression.²³ After the FDA approved the first TMS device, numerous companies began to produce TMS technology. Most of these companies manufacture devices with the figure-of-eight coil, with 1 company producing the Hesed-coil helmet.²⁴

Continue to: An unintended outcome...

An unintended outcome of the increased interest in TMS has been an increased understanding of brain regions involved in psychiatric illness. TMS was able to bring knowledge of mental health from synapses to circuits.²⁵ Work in this area has further stratified the circuits involved in the manifestation of symptom clusters in depression.²⁶ The exact taxonomy of these brain circuits has not been fully realized, but the default mode, salience, attention, cognitive control, and other circuits have been shown to be involved in specific symptom presentations.^26,27 These circuits can be hyperactive, hypoactive, hyperconnected, or hypoconnected, with the aberrancies compared to normal controls resulting in symptoms of psychiatric illness.²⁸

This enhanced understanding of brain function has led to further research and development of protocols and subsequent FDA approval of TMS for OCD, anxious depression, and smoking cessation.²⁹ In addition, it has allowed for a proliferation of off-label uses for TMS, including (but not limited to) tinnitus, pain, migraines, and various substance use disorders.³⁰ TMS treatment for these conditions involves stimulation of specific anatomical brain regions that are thought to play a role in the pathology of the target disorder. For example, subthreshold stimulation of the motor cortex has shown some utility in managing symptoms of pain disorders and movement disorders,^31,32 the ventromedial prefrontal cortex has been implicated in disorders in the OCD spectrum,³³ stimulation of the frontal poles may help treat substance use disorders,³⁴ and the auditory cortex has been a target for treating tinnitus and auditory hallucinations.³⁵

The location of stimulation for treating depression has evolved. The Talairach-Tournoux coordinate system has been used to determine the location of the dorsolateral prefrontal cortex (DLPFC) in relation to the motor cortex. This was measured to be 5 cm from the motor hotspot and subsequently became “the 5.5 cm rule,” taking skull convexity into account. The treatment paradigm for the Hesed coil also uses a measurement from the motor hotspot. Another commonly used methodology for coil placement involves using the 10 to 20 EEG coordinate system to individualize scalp landmarks. In this method, the F3 location corresponds most accurately to the DLPFC target. More recently, using fMRI-guided navigation for coil placement has been shown to lead to a significant reduction in depressive symptoms.³⁶

For depression, the initial recommended course of treatment is 6 weeks, but most improvement is seen in the first 2 to 3 weeks.¹⁴ Therefore, many clinicians administer an initial course of 3 weeks unless the response is inadequate, in which case a 6-week course is administered. Many patients require ongoing maintenance treatment, which can be weekly or monthly based on response.³⁷

Research to determine the optimal TMS dose for treating neuropsychiatric symptoms is ongoing. Location, intensity of stimulation, and pulse are the components of stimulation. The pulse can be subdivided into frequency, pattern (single pulse, standard, burst), train (numbers of pulse groups), interval between trains, and total number of pulses per session. The Clinical TMS Society has published TMS protocols.³⁸ The standard intensity of stimulation is 120% of the motor threshold (MT), which is defined as the amount of stimulation over the motor cortex required to produce movement in the extensor hallucis longus. Although treatment for depression traditionally utilizes rapid TMS (3,000 pulses delivered per session at a frequency of 10 Hz in 4-second trains), in controlled studies, accelerated protocols such as intermittent theta burst stimulation (iTBS; standard stimulation parameters: triplet 50 Hz bursts at 5 Hz, with an interval of 8 seconds for 600 pulses per session) have shown noninferiority.^36,39 

Recent research has explored fMRI-guided iTBS in an even more accelerated format. The Stanford Neuromodulation Therapy trial involved 1,800 pulses per session for 10 sessions a day for 5 days at 90% MT.³⁶ This treatment paradigm was shown to be more effective than standard protocols and was FDA-approved in 2022. Although this specific iTBS protocol exhibited encouraging results, the need for fMRI for adequate delivery might limit its use.

Continue to: Transcranial direct current stimulation

Therapeutic noninvasive brain stimulation technology is plausible due to the relative lack of adverse effects and ease of administration. In transcranial direct current stimulation (tDCS), a low-intensity, constant electric current is delivered to stimulate the brain via electrodes attached to the scalp. tDCS modulates spontaneous neuronal network activity^40,41 and induces polarization of resting membrane potential at the neuronal level,⁴² though the exact mechanism is yet to be proven. N-methyl-D-aspartate-glutamatergic receptors are involved in inhibitory and facilitatory plasticity induced by tDCS.⁴³

tDCS has been suggested as a treatment for various psychiatric and medical conditions. However, the small sample sizes and experimental design of published studies have limited tDCS from being clinically recommended.³⁰ No recommendation of Level A (definite efficacy) for its use was found for any indication. Level B recommendation (probable efficacy) was proposed for fibromyalgia, MDD episode without drug resistance, and addiction/craving. Level C recommendation (possible efficacy) is proposed for chronic lower limb neuropathic pain secondary to spinal cord lesion. tDCS was found to be probably ineffective as a treatment for tinnitus and drug-resistant MDD.³⁰ Some research has suggested that tDCS targeting the DLPFC is associated with cognitive improvements in healthy individuals as well as those with schizophrenia.⁴⁴ tDCS treatment remains experimental and investigational.

Deep brain stimulation

DBS is a neurosurgical procedure that uses electrical current to directly modulate specific areas of the CNS. In terms of accurate, site-specific anatomical targeting, there can be little doubt of the superiority of DBS. DBS involves the placement of leads into the brain parenchyma. Image guidance techniques are used for accurate placement. DBS is a mainstay for the symptomatic treatment of treatment-resistant movement disorders such as Parkinson disease, essential tremor, and some dystonic disorders. It also has been studied as a potential treatment for chronic pain, cluster headache, Huntington disease, and Tourette syndrome.

For treating depression, researched targets include the subgenual cingulate gyrus (SCG), ventral striatum, nucleus accumbens, inferior thalamic peduncle, medial forebrain bundle, and the red nucleus.⁴⁵ In systematic reviews, improvement of depression is greatest when DBS targets the subgenual cingulate cortex and the medial forebrain bundle.⁴⁶ 

The major limitation of DBS for treating depression is the invasive nature of the procedure. Deep TMS can achieve noninvasive stimulation of the SCG and may be associated with fewer risks, fewer adverse events, and less collateral damage. However, given the evolving concept of abnormal neurologic circuits in depression, as our understanding of circuitry in pathological psychiatric processes increases, DBS may be an attractive option for personalized targeting of symptoms in some patients.

DBS may also be beneficial for severe, treatment-resistant OCD. Electrode implantation in the region of the internal capsule/ventral striatum, including the nucleus accumbens, is used⁴⁷; there is little difference in placement as a treatment for OCD vs for movement disorders.⁴⁸

Continue to: A critical review of 23 trials...

A critical review of 23 trials and case reports of DBS as a treatment for OCD demonstrated a 47.7% mean reduction in score on the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) and a mean response percentage (minimum 35% Y-BOCS reduction) of 58.2%.⁴⁹ Most patients regained a normal quality of life after DBS.⁴⁹ A more rigorous review of 15 meta-analyses of DBS found that conclusions about its efficacy or comparative effectiveness cannot be drawn.⁵⁰ Because of the nature of neurosurgery, DBS has many potential complications, including cognitive changes, headache, infection, seizures, stroke, and hardware failure.

Vagus nerve stimulation

VNS, in which an implanted device stimulates the left vagus nerve with electrical impulses, was FDA-approved for treating chronic TRD in 2005.⁵¹ It had been approved for treatment-resistant epilepsy in 1997. In patients with epilepsy, VNS was shown to improve mood independent of seizure control.⁵² VNS requires a battery-powered pacemaker device to be implanted under the skin over the anterior chest wall, and a wire tunneled to an electrode is wrapped around the left vagus nerve in the neck.⁵³ The pacemaker is then programmed, monitored, and reprogrammed to optimize response.

VNS is believed to stimulate deep brain nuclei that may play a role in depression.⁵⁴ The onset of improvement is slow (it may take many months) but in carefully selected patients VNS can provide significant control of TRD. In addition to rare surgery-related complications such as a trauma to the vagal nerve and surrounding tissues (vocal cord paralysis, implant site infection, left facial nerve paralysis and Horner syndrome), VNS may cause hoarseness, dyspnea, and cough related to the intensity of the current output.⁵¹ Hypomania and mania were also reported; no suicidal behavior has been associated with VNS.⁵¹

Noninvasive vagus nerve stimulationIn noninvasive vagus nerve stimulation (nVNS) or transcutaneous VNS, an external handheld device is applied to the neck overlying the course of the vagus nerve to deliver a sinusoidal alternating current.⁵⁵ nVNS is currently FDA-approved for treating migraine headaches.^55,56 It has demonstrated actions on neurophysiology⁵⁷ and inflammation in patients with MDD.⁵⁸ Exploratory research has found a small beneficial effect in patients with depression.^59,60 A lack of adequate reproducibility prevents this treatment from being more widely recommended, although attempts to standardize the field are evolving.⁶¹

Cranial electrical stimulation

Cranial electrical stimulation (CES) is an older form of electric stimulation developed in the 1970s. In CES, mild electrical pulses are delivered to the ear lobes bilaterally in an episodic fashion (usually 20 to 60 minutes once or twice daily). While CES can be considered a form of neuromodulation, it is not strictly interventional. Patients self-administer CES. The procedure has minimal effects on improving sleep, anxiety, and mood.^62-66 Potential adverse effects include a tingling sensation in the ear lobes, lightheadedness, and fogginess. A review and meta-analysis of CES for treating addiction by Kirsch⁶⁷ showed a wide range of symptoms responding positively to CES treatment, although this study was not peer-reviewed. Because of the low quality of nearly all research that evaluated CES, this form of electric stimulation cannot be viewed as an accepted treatment for any of its listed indications.

Continue to: Other neuromodulation techniques

In addition to the forms of neuromodulation we have already described, there are many other techniques. Several are promising but not yet ready for clinical use. Table 1 and Table 2 summarize the neuromodulation techniques described in this article as well as several that are under development.

Acupuncture

Acupuncture is a Chinese form of medical treatment that began >3,000 years ago; there are written descriptions of it from >2,000 years ago.⁶⁸ It is based on the belief that there are channels within the body through which the Qi (vital energy or life force) flow, and that inserting fine needles into these channels via the skin can rebalance Qi.⁶⁸ Modern mechanistic hypotheses invoke involvement of inflammatory or pain pathways.⁶⁹ Acupuncture frequently uses electric stimulation (electro-acupuncture) to increase the potency of the procedure. Alternatively, in a related procedure (acupressure), pressure can replace the needle. Accreditation in acupuncture generally requires a master’s degree in traditional Chinese medicine but does not require any specific medical training. Acupuncture training courses for physicians are widely available.

All forms of acupuncture are experimental for a wide variety of mental and medical conditions. A meta-analysis found that most research of the utility of acupuncture for depression suffered from various forms of potential bias and was considered low quality.⁷⁰ Nonetheless, active acupuncture was shown to be minimally superior to placebo acupuncture.⁷⁰ A meta-analysis of acupuncture for preoperative anxiety^71,72 and poststroke insomnia⁷³ reported a similar low study quality. A study of 72 patients with primary insomnia revealed that acupuncture was more effective than sham acupuncture for most sleep measures.⁷⁴

Challenges and complications

Psychiatry is increasingly integrating medical tools in addition to psychological tools. Pharmacology remains a cornerstone of biological psychiatry and this will not soon change. However, nonpharmacologic psychiatric treatments such as therapeutic neuromodulation are rapidly emerging. These and novel methods of medication administration may present a challenge to psychiatrists who do not have access to medical personnel or may have forgotten general medical skills.

Our 2-part article has highlighted several interventional psychiatry tools—old and new—that may interest clinicians and benefit patients. As a rule, such treatments are reserved for the most treatment-resistant, challenging psychiatric patients, those with hard-to-treat chronic conditions, and patients who are not helped by more commonly used treatments. An additional complication is that such treatments are frequently not appropriately researched, vetted, or FDA-approved, and therefore are higher risk. Appropriate clinical judgment is always necessary, and potential benefits must be thoroughly weighed against possible adverse effects.

Bottom Line

Several forms of neuromodulation, including electroconvulsive therapy, transcranial magnetic stimulation, transcranial direct current stimulation, deep brain stimulation, and vagus nerve stimulation, may be beneficial for patients with certain treatment-resistant psychiatric disorders, including major depressive disorder and obsessive-compulsive disorder.

Related Resources

• Janicak PG. What’s new in transcranial magnetic stimulation. Current Psychiatry. 2019;18(3):10-16.
• Sharma MS, Ang-Rabanes M, Selek S, et al. Neuromodulatory options for treatment-resistant depression. Current Psychiatry. 2018;17(3):26-28,33-37.

Though once the main treatment for anxiety disorders—often as monotherapy¹—benzodiazepines are now primarily used as adjunctive agents.^2-4 Their ability to produce rapid anxiolysis represents a significant therapeutic advantage, but in recent decades their tolerability, class-specific risks, and lack of antidepressant properties contributed to benzodiazepines being largely replaced by selective serotonin reuptake inhibitors (SSRIs) for the pharmacologic treatment of anxiety. This shift within the pharmacologic armamentarium has decreased many clinicians’ familiarity with benzodiazepines.

While benzodiazepines continue to have an important role in managing anxiety disorders, particularly treatment-resistant anxiety,⁴ clinicians must consider the limitations of these agents. Benzodiazepines can be associated with abuse and dependence, and overdose risk when combined with opiates.^5,6 They may cause memory impairment^7,8 and conflicting data suggest they may contribute to the risk of developing cognitive disorders.^9-11 Benzodiazepines also have been associated with falls and fractures,¹² and worse outcomes in patients with posttraumatic stress disorder.¹³ Some studies of patients with chronic obstructive pulmonary disease (COPD) found benzodiazepines may increase the risk of COPD exacerbations and accidental overdose,¹⁴ though others found that was not always the case.¹⁵ Benzodiazepines may be associated with an increased risk of spontaneous abortion when used early in pregnancy.¹⁶ Prospective research in women who were breastfeeding found benzodiazepines may cause sedation in up to 2% of infants.¹⁷

Despite the potential for adverse effects, benzodiazepine use remains common.¹⁸ These medications have a rapid onset of action, are useful for breakthrough symptoms, may enhance treatment adherence, and alleviate activating symptoms of SSRIs. Like other commonly used medications, benzodiazepines have the potential for both harm and benefit.¹⁹ Similar to other medications with tolerability concerns but established efficacy, particularly in treatment-resistant anxiety disorders, it is important to balance “overprescribing … to patients at risk and underusing these effective medications when indicated.”¹⁹ Though the use of benzodiazepines has been discouraged and perceptions have shifted, knowledge of benzodiazepines and benzodiazepine pharmacology also has been degraded contemporaneously.

This article provides a synthesis of the clinically relevant pharmacology of benzodiazepines, with a focus on orally administered benzodiazepines, which are more common in outpatient clinical practice. Specifically, this review describes the pharmacology of benzodiazepines, benzo­diazepine medication interactions, the relationship between pharmacologic characteristics and treatment response/tolerability, and selection and dosing of oral benzodiazepines (Table²⁰).

Benzodiazepine pharmacodynamics

Benzodiazepines act at the gamma-aminobutyric acid (GABA)-A receptor complex and bind allosterically.^21-23 Comprised of 5 glycoprotein subunits (2 alpha subunits, 2 beta subunits, and 1 gamma subunit), the receptor has 2 distinct sites at which the endogenous inhibitory transmitter GABA binds and 1 benzodiazepine binding site. Benzodiazepines bind within a socket created by the alpha and gamma subunits²² and after binding induce a conformational change in the receptor, which enhances GABA binding. There are 2 types of benzodiazepine receptors: BZ1 and BZ2. The subunits play a critical role in driving the pharmacologic characteristics of the receptor.²⁴ BZ1 and BZ2 receptors bind benzodiazepines, although they are differentially distributed within the brain. Binding at BZ1 receptors—which are distributed in cortical, thalamic, and cerebellar regions—contributes to sedation and deleterious effects of benzodiazepines on memory (eg, anterograde amnesia). BZ2 receptors (which contain gamma-2 subunits) are responsible for anxiolytic and muscle-relaxing effects. They are distributed throughout limbic regions and motor tracts, including motor neurons and neurons in the dorsal horn of the spinal cord.²⁴

Benzodiazepines—positive GABA-A receptor allosteric modulators—produce phasic inhibition, largely through the alpha and gamma subunits discussed above. In contrast, newer positive allosteric modulators (eg, zuranolone) bind at the alpha/beta subunits.²⁵ Mechanistically, endogenous neuroactive steroids and nonbenzodiazepine GABA-A–positive allosteric modulators such as zuranolone and ganaxolone also differ in their regulation of GABA-A (downregulated with benzodiazepines and hypothetically upregulated with zuranolone)²⁶ and their synaptic effects (benzodiazepines synaptically vs endogenous neurosteroids and nonbenzodiazpine positive allosteric modulators extrasynaptically).²⁷

From a developmental perspective, benzodiazepines may have less efficacy for anxiolysis and worse tolerability in some pediatric patients,²⁸ although they generally appear effective for immediate use to treat anxiety in acute settings.²⁹ The differences in efficacy and tolerability may be related to pharmacodynamic differences between pediatric populations and adults. GABA receptor expression and function do not reach adult levels until age 14 to 17½ for subcortical regions and age 18 to 22 for cortical regions, although girls reach adult expression of GABA receptors slightly earlier than boys.³⁰ Data from multiple randomized controlled trials of pediatric patients with anxiety disorders do not suggest efficacy as benzodiazepines are poorly tolerated, especially compared to other psychopharmacologic interventions for pediatric anxiety disorders.³⁰

Continue to: Pharmacology and clinical effects

Benzodiazepine pharmacokinetics are intimately linked with the onset of action and duration of clinical effect and vary based on the route of administration, absorption, and distribution/redistribution.³¹ In this review, we focus on oral administration as opposed to IV, IM, sublingual, or intranasal administration.

Absorption

Benzodiazepines are rapidly absorbed after oral administration and quickly enter the systemic circulation. However, absorption rates vary depending on specific aspects of the gastrointestinal milieu and intrinsic properties of the benzodiazepine. For example, alprazolam is more rapidly absorbed than most other benzodiazepines, with a Tmax of 1.8 hours compared to lorazepam, which has a Tmax of approximately 2 hours. These pharmacokinetic effects instantiate differences in tolerability and efficacy. Thus, following single doses of alprazolam and diazepam, self-rated sedating effects and impairment on a task of working memory suggest that effects have a more rapid onset for alprazolam relative to lorazepam.³² Food and concomitant medications can significantly affect benzodiazepine absorption. A single-dose, 3-way crossover study demonstrated that taking diazepam concomitantly with an antacid (eg, aluminum hydroxide) decreased peak concentrations and prolonged absorption by approximately 30 minutes. However, total absorption of the medication was unaffected.³³ Additionally, administration of diazepam with food significantly slows absorption from 1 hour 15 minutes to approximately 2 hours 30 minutes and increases benzodiazepine absorption by 25% (Figure 1³⁴); the fat content of the meal appears important in moderating this effect.³⁵ The impact of food on alprazolam varies by formulation. For example, when administered in an extended-release (XR) formulation with a high-fat meal, alprazolam absorption increases by one-third, while absorption for administration of the orally disintegrating tablet with a high-fat meal increases from 1 hour 30 minutes to 2 hours. Similarly, for lorazepam, administration with a meal delays absorption by approximately 2 hours; however, this effect does not appear present with the XR formulation. Administering benzodiazepines with food can be clinically leveraged to either accelerate the onset of action or decrease peak-associated adverse effects. Thus, when a highly lipophilic benzodiazepine is needed to treat acute anxiety or prior to an expected anxiogenic stimuli, administering the medication without food may produce a faster onset of action.

CNS penetration

Benzodiazepines enter the CNS by passive diffusion. Because of this, lipophilicity at physiologic pH influences the rate at which a benzodiazepine crosses the blood-brain barrier. The rate at which benzodiazepines enter the CNS influences their clinical effects and the speed at which both efficacy (ie, anxiolysis) and adverse effects (ie, sedation, slowed cognition) are observed. In general, more lipophilic medications initiate their anxiolytic effect more quickly. However, by quickly leaving the CNS (through the same mechanism that allowed them to enter the CNS at such speed), their effects rapidly cease as they redistribute into fat. Thus, highly lipophilic benzodiazepines produce more intense effects compared to less lipophilic benzodiazepines. For these reasons, lipophilicity is more important than half-life for determining the duration of effect in most patients.

Lipophilicity and duration of effect

Benzodiazepines and their metabolites tend to be highly protein-bound and distributed in fat- and lipid-enriched areas such as the CNS. As a result, the more lipophilic agents generally have the highest rates of absorption and the fastest onset of clinical effects. The duration of action for many benzodiazepines is determined by the rate and extent of distribution (a function of lipophilicity) rather than by the rate of elimination. For example, diazepam has a longer half-life than lorazepam, but its duration of action following a single dose is shorter. This is because diazepam is more lipophilic and therefore more extensively distributed (particularly to adipose tissue). This results in it leaving the brain and blood and distributing to other tissues. In turn, its CNS effect (ie, anxiolytic effects) are more quickly terminated.

By contrast, less lipophilic benzodiazepines maintain their CNS concentrations longer; they have a longer duration of action because of their slower redistribution, which culminates in a shorter half-life, and are less extensively distributed to peripheral tissues. In essence, this means that (other things being equal) a less lipophilic benzodiazepine produces a more sustained anxiolytic effect compared to a highly lipophilic benzodiazepine.³⁶ Lipophilicity is also important in predicting some cognitive adverse effects, including amnesia. Benzodiazepines with high lipophilicity have greater absorption and faster onset of action as well as more rapid amnestic effects.^37,38 These effects may relate to overall efficacy differences for oral benzodiazepines. A recent meta-analysis by Stimpfl et al³⁶ found that less lipophilic benzodiazepines produced a greater response compared to more lipophilic benzodiazepines.

Continue to: Metabolism

Regarding cytochrome P450 (CYP) metabolism, polymorphic CYP2C19 and CYP3A4/5 are involved in the metabolism of several benzodiazepines³⁹ and CYP2B6 has been recognized as a contributor to diazepam metabolism. CYP3A5 gene polymorphisms may produce variation in alprazolam metabolism; however, the predominant cytochrome involved in the metabolism of oxidatively metabolized benzodiazepines (ie, benzodiazepines other than lorazepam, oxazepam, and temazepam) is primarily CYP3A4, and most effects on CYP3A4 activity are related to concomitant medications and other non­genetic factors.

Drug-drug interactions

Apart from lorazepam,^40,41 oxazepam,^42,43 and temazepam, most benzodiazepines are metabolized through oxidative mechanisms that involve CYP3A4 (Figure 2²⁰).³⁹ As such, their metabolism is influenced by medications that impact CYP3A4, including antifungals (eg, ketoconazole), calcium channel blockers (eg, verapamil, diltiazem), nefazodone, some protease inhibitors, and macrolide antibiotics. Research has examined the impact of low-dose estrogen oral contraceptives (OCPs) on exposure (eg, plasma concentrations) of several benzodiazepines. The mechanism for this interaction is likely complex and putatively involves multiple pathways, including inhibition of CYP3A4 by OCPs. The effects of OCPs on benzodiazepine pharmacokinetics vary based on the metabolism of the benzodiazepine. In general, medications oxidized and nitroreduced (eg, chlordiazepoxide, alprazolam, diazepam, and nitrazepam) have decreased clearance in patients treated with OCPs. Regarding nonoxidatively metabolized benzodiazepines, data are mixed. Research found no OCP-related effects on the pharmacokinetics of nonoxidatively metabolized benzodiazepines⁴⁴; another study suggested that clearance of these medications—through increased glucuronidation—may be increased.³¹ The effect of smoking on benzodiazepine concentration has been well documented. Smoking increases the clearance of orally administered diazepam,⁴⁵ but not IV diazepam, midazolam, or lorazepam, suggesting that this represents a first-pass effect.⁴⁶ For alprazolam, plasma concentrations are reduced by 15% to 30% in smokers and total body clearance is 24% greater compared to nonsmokers, which results in an approximately 50% increase in half-life in nonsmokers compared to smokers.⁴⁷ The most notable interaction between benzodiazepines and SSRIs is seen with fluvoxamine. Because fluvoxamine moderately inhibits CYP2C19 and CYP3A4 and potently inhibits CYP1A2,⁴⁸ the clearance of oxidatively metabolized benzodiazepines is reduced.⁴⁹ Additionally, the effects of grapefruit juice—a potent inhibitor of CYP3A4—has been evaluated for several benzodiazepines. Yasui et al⁵⁰ found grapefruit juice did not alter alprazolam plasma concentrations. However, in separate research, grapefruit juice tripled diazepam exposure, increased peak concentrations 1.5-fold, and prolonged absorption.⁵¹

Hepatic disease

Exposure to benzodiazepines—other than lorazepam, oxazepam, and temazepam—is influenced by intrinsic hepatic disease and requires dose adjustment in individuals with significant hepatic impairment. The impact of hepatic disease on the clinical pharmacology of benzodiazepines may relate to 2 factors: protein binding and metabolism. In a study of individuals with cirrhosis, lorazepam binding was decreased, although its metabolism and clearance were largely unaffected.⁴⁰

Aging and benzodiazepine metabolism/clearance

Aging is associated with myriad physiologic changes (eg, decrease in renal clearance after age 40, changes in body fat distribution, changes in activity of cytochromes) that are relevant to benzodiazepine pharmacology. They may underlie differences in the tolerability of benzodiazepines and other clinically relevant characteristics (eg, duration of action, accumulation).

Several studies have evaluated the impact of aging on the clearance and disposition of selected benzodiazepines. The respective half-lives of chlordiazepoxide and diazepam increase from 4- to 6-fold from age 20 to 80. Further, with chronic dosing, highly lipophilic benzodiazepines may require additional attention in geriatric patients. In a study that included individuals up to age 78, steady-state plasma concentrations of diazepam and its metabolite, desmethyldiazepam (DMDZ), were 30% to 35% higher in older patients compared to younger individuals.⁵² In this study, the half-lives for the young and older patients were 31 hours and 86 hours, respectively, for diazepam, and 40 hours and 80 hours, respectively, for the active metabolite. The half-life of diazepam is increased by “1 hour for each year of age beginning with a half-life of 20 hours at 20 years of age, as the volume of distribution is increased, and clearance is decreased.”⁵² Clinically, this implies that in older adults, clinicians should expect lower peak concentrations (Cmax), higher trough concentrations (Cmin), and that diazepam will take longer to reach steady-state concentrations. Taken together, these findings raised concern that “slow accumulation and delayed washout of diazepam and DMDZ is probable.”⁵² These findings—which may have more clinical relevance than those of single-dose studies—suggest that the effects related to diazepam would also take longer to resolve in older patients. Finally, lorazepam clearance or distribution does not appear to be affected by aging, at least in patients age 15 to 73.⁴⁰ Alprazolam is more slowly cleared in geriatric patients and its effects may be potentiated by reduced protein binding.

Continue to: Obesity

The distribution of medications, including benzodiazepines, is altered in patients who are obese because of increased adipose tissue.^53,54 This increase in the volume of distribution can attenuate the onset of action, increase medication accumulation in fat, and potentiate the duration of action.^55,56

Obesity may also affect hepatic metabolism by induction of CYP1A2, CYP2C9, and CYP2C19, and inhibition of CYP3A4.⁵⁷ Triazolam, which is metabolized by CYP3A4, is associated with a greater exposure (ie, plasma concentrations) in individuals who are obese.⁵⁸ However, when considering differences in benzodiazepine pharmacokinetics in patients who are obese, clinicians must remember that elimination half-life depends on both volume of distribution and clearance. In patients who are obese (compared to patients who are not obese), the half-lives are increased for alprazolam (22 hours vs 11 hours, P < .001)⁵⁹ and diazepam (82 hours vs 32 hours, P < .005).⁶⁰ In a pharmacokinetic study of diazepam in individuals who were obese and individuals who were not obese, total metabolic clearance did not differ. Rather, the increased half-life was related to a tripling of thevolume of distribution in obese patients (228 liters vs 70 liters, P < .01). This indicates that patients who are obese may experience a much slower onset of maximal effect compared to patients who are not obese because the accumulation of the medication is delayed. Additionally, for benzodiazepines that are conjugated (lorazepam and oxazepam), clearance is significantly enhanced in patients who are obese. For example, lorazepam clearance is 102 mL/min in individuals who are obese compared to 63 mL/min in individuals who are not obese; for oxazepam, clearance is 181 mL/min in patients who are obese compared to 98 mL/min in individuals who are not obese.⁶¹ These differences are attributed to increased uridine diphosphate glucuronyl transferase in obesity and to increases in liver size in obesity.⁵³

How quickly do benzodiazepines work?

Benzodiazepines act quickly. Meta-analyses³⁶ suggest that improvement in anxiety symptoms compared to placebo is greatest initially and then the rate of improvement slows over successive weeks. Research on benzodiazepines reveals statistically significant differences between benzodiazepines and placebo within the first week of treatment, with >80% of the expected improvement by Week 8 of treatment emerging by Week 4 (Figure 3³⁶). The rapid reduction in anxiety symptoms seen with benzodiazepines has important treatment implications, given that traditional psycho­therapeutic and antidepressant treatments are slow to produce improvements. Consistent data suggesting that benzodiazepines work faster than other treatments support that they may have a role during the initiation of other treatments.

What is the ‘best’ dose?

As seen with other classes of psychotropic medications,⁴ the relationship between benzodiazepine dose and response is complex. In a recent meta-analysis of 65 placebo-controlled trials of benzodiazepines in adults with anxiety disorders, there was a superior response over time for low-dose benzodiazepines (<3 mg/d in lorazepam equivalents) compared to a medium dose (3 to 6 mg/d; P = .042); high-dose benzodiazepines (>6 mg/d) yielded less improvement compared to medium doses (P = .001).³⁶ A study of adults with panic disorder similarly found the greatest responses with alprazolam plasma concentrations of 20 to 40 ng/mL, with no additional benefit at <20 ng/mL or >40 ng/mL.⁴⁹ As plasma concentrations increase, adverse effects such as sedation also increase, which may confound the observed loss of a dose-response relationship at higher doses and plasma concentrations.⁶² This may, in part, account for the observation that higher doses of benzodiazepines are associated with greater depressive symptoms and disrupted sleep.⁶³ As such, low doses may represent a delicate equipoise between efficacy and tolerability, yielding the most optimal clinical response.

Which benzodiazepine should I prescribe?

Comparing benzodiazepines is difficult, given the differences in dosing and disorders studied and differences in how each individual clinical trial was conducted. A meta-analysis by Stimpfl et al³⁶ that used Bayesian hierarchical modeling, which allowed some of this heterogeneity to be addressed, found that relative to the reference benzodiazepine (lorazepam), clonazepam had the greatest trajectory/magnitude of response (other specific benzodiazepines did not statistically differ from lorazepam) (Figure 4³⁶).

Continue to: Another aspect of the superiority...

Another aspect of the superiority of clonazepam in some research relates to its pharma­cokinetic properties, particularly when compared with benzodiazepines that have very short half-lives. Short half-life benzodiazepines have been associated with rebound anxiety, which is defined as “the relative worsening of symptoms on discontinuation of treatment as compared to baseline symptoms” and is distinct from withdrawal.⁶⁴ While it is difficult to assess this in clinical trials, Herman et al⁶⁵ provided insight into the contribution of rebound anxiety in a study of patients with panic disorder treated with alprazolam who experienced “interdose anxiety symptoms.” Of the 48 patients in this study, 41 switched to clonazepam, and most who switched (82%) experienced improvement. The improvement was attributed to the decreased frequency of clonazepam (vs alprazolam) administration and lack of interdose anxiety. When selecting an oral benzodiazepine, consider the duration, onset of action, and differences in metabolism that produce varying levels of effectiveness for individual patients. In situations where rapid onset is desired, a short-acting benzodiazepine may be preferable, while a longer-acting benzodiazepine would be preferable in situations where the patient needs sustained effects.

Regarding lipophilicity, differences among benzodiazepines could contribute to differences in psychological dependence and differential utility in some situations. For example, alprazolam rapidly enters the CNS, producing an immediate anxiolytic effect. However, its egress from the CNS is equally rapid, and its anxiolytic effects disappear quickly. This may be desirable for addressing acute, predictable anxiety, but could have unintended consequences in treating chronic anxiety, where it could facilitate psychological dependence.

Practical considerations

When prescribing benzodiazepines, consider a myriad of patient- and medication-specific factors, as these have clinically relevant implications on treatment response. This information, taken together, supports the importance of an individualized approach to benzodiazepine use. Before selecting a benzodiazepine and during treatment, important elements of the patient’s history must be considered, including age, body weight, concomitant medication use (eg, antacids, CYP3A4 inhibitors, OCPs), smoking status, and history of hepatic or renal disease.

Patients age <18 are unlikely to have full expression of GABA receptors in the brain³⁰ and therefore benzodiazepines may not be as efficacious for anxiolysis in this population. Moreover, compared to younger patients, older patients may experience higher steady-state concentrations of benzo­diazepines, especially lipophilic agents, due to an increased volume of distribution and decreased clearance. In patients treated with OCPs, some benzodiazepines may take longer to reach steady-state, and dose adjustments may need to be considered. In patients who smoke, clearance of some oral benzo­diazepines is also accelerated, potentially decreasing half-life by up to 50%.

When dosing and titrating benzodiazepines, consider the patient’s body weight, particularly if they are obese. The effects of obesity on benzodiazepine pharmacokinetics are complex. For glucuronidated benzodiazepines, clearance is increased in patients who are obese; however, the volume of distribution is also increased in such patients, meaning it will take longer for benzodiazepines to achieve steady-state in these individuals compared to patients who are not obese. These effects suggest it may take longer to achieve a response at a given dose in patients who are obese compared to individuals who are not obese.

Continue to: The properties of individual benzodiazepines...

The properties of individual benzodiazepines should also be considered when selecting a benzodiazepine treatment. If circumstances necessitate rapid symptom relief, a lipophilic benzodiazepine, such as diazepam, may be preferred for quick onset and offset of action. Onset of action may also be hastened by taking the benzodiazepine without food; conversely, if peak adverse effects are problematic, concurrent consumption of a high-fat meal may help decrease peak concentration and prolonging absorption. In other circumstances, such as if sustained anxiolysis is desired, a clinician may opt for a less lipophilic benzodiazepine, such as clonazepam. Finally, in terms of general treatment response, benzodiazepines separate from placebo in the first week of treatment, which supports the idea they may be useful during the introduction of other medications (eg, SSRIs) that take a longer time to achieve clinical effect.

Bottom Line

The pharmacokinetics of benzodiazepines are intimately linked with the onset of action and duration of clinical effect and vary based on individual absorption and distribution/redistribution. Benzodiazepines’ clinical profile derives from their pharmacokinetic differences and is influenced by many factors, including age, body weight, concomitant medication use, smoking status, and hepatic or renal disease. Consider these factors to individualize the approach to using benzodiazepines and optimize tolerability and efficacy.

Related Resources

• Weber SR, Duchemin AM. Benzodiazepines: sensible prescribing in light of the risks. Current Psychiatry. 2018;17(2):22-27.
• Balon R. Benzodiazepines for anxious depression. Current Psychiatry. 2018;17(8):9-12.

Drug Brand Names

Alprazolam • Xanax
Chlordiazepoxide • Librium
Clobazam • Onfi
Clonazepam • Klonopin
Clorazepate • Gen-Xene
Diazepam • Valium
Diltiazem • Cardizem
Fluvoxamine • Luvox
Ganaxolone • Ztalmy
Ketoconazole • Nizoral
Lorazepam • Ativan
Midazolam • Versed
Temazepam • Restoril
Triazolam • Halcion
Verapamil • Calan

Though once the main treatment for anxiety disorders—often as monotherapy¹—benzodiazepines are now primarily used as adjunctive agents.^2-4 Their ability to produce rapid anxiolysis represents a significant therapeutic advantage, but in recent decades their tolerability, class-specific risks, and lack of antidepressant properties contributed to benzodiazepines being largely replaced by selective serotonin reuptake inhibitors (SSRIs) for the pharmacologic treatment of anxiety. This shift within the pharmacologic armamentarium has decreased many clinicians’ familiarity with benzodiazepines.

While benzodiazepines continue to have an important role in managing anxiety disorders, particularly treatment-resistant anxiety,⁴ clinicians must consider the limitations of these agents. Benzodiazepines can be associated with abuse and dependence, and overdose risk when combined with opiates.^5,6 They may cause memory impairment^7,8 and conflicting data suggest they may contribute to the risk of developing cognitive disorders.^9-11 Benzodiazepines also have been associated with falls and fractures,¹² and worse outcomes in patients with posttraumatic stress disorder.¹³ Some studies of patients with chronic obstructive pulmonary disease (COPD) found benzodiazepines may increase the risk of COPD exacerbations and accidental overdose,¹⁴ though others found that was not always the case.¹⁵ Benzodiazepines may be associated with an increased risk of spontaneous abortion when used early in pregnancy.¹⁶ Prospective research in women who were breastfeeding found benzodiazepines may cause sedation in up to 2% of infants.¹⁷

Despite the potential for adverse effects, benzodiazepine use remains common.¹⁸ These medications have a rapid onset of action, are useful for breakthrough symptoms, may enhance treatment adherence, and alleviate activating symptoms of SSRIs. Like other commonly used medications, benzodiazepines have the potential for both harm and benefit.¹⁹ Similar to other medications with tolerability concerns but established efficacy, particularly in treatment-resistant anxiety disorders, it is important to balance “overprescribing … to patients at risk and underusing these effective medications when indicated.”¹⁹ Though the use of benzodiazepines has been discouraged and perceptions have shifted, knowledge of benzodiazepines and benzodiazepine pharmacology also has been degraded contemporaneously.

This article provides a synthesis of the clinically relevant pharmacology of benzodiazepines, with a focus on orally administered benzodiazepines, which are more common in outpatient clinical practice. Specifically, this review describes the pharmacology of benzodiazepines, benzo­diazepine medication interactions, the relationship between pharmacologic characteristics and treatment response/tolerability, and selection and dosing of oral benzodiazepines (Table²⁰).

Benzodiazepine pharmacodynamics

Benzodiazepines act at the gamma-aminobutyric acid (GABA)-A receptor complex and bind allosterically.^21-23 Comprised of 5 glycoprotein subunits (2 alpha subunits, 2 beta subunits, and 1 gamma subunit), the receptor has 2 distinct sites at which the endogenous inhibitory transmitter GABA binds and 1 benzodiazepine binding site. Benzodiazepines bind within a socket created by the alpha and gamma subunits²² and after binding induce a conformational change in the receptor, which enhances GABA binding. There are 2 types of benzodiazepine receptors: BZ1 and BZ2. The subunits play a critical role in driving the pharmacologic characteristics of the receptor.²⁴ BZ1 and BZ2 receptors bind benzodiazepines, although they are differentially distributed within the brain. Binding at BZ1 receptors—which are distributed in cortical, thalamic, and cerebellar regions—contributes to sedation and deleterious effects of benzodiazepines on memory (eg, anterograde amnesia). BZ2 receptors (which contain gamma-2 subunits) are responsible for anxiolytic and muscle-relaxing effects. They are distributed throughout limbic regions and motor tracts, including motor neurons and neurons in the dorsal horn of the spinal cord.²⁴

Benzodiazepines—positive GABA-A receptor allosteric modulators—produce phasic inhibition, largely through the alpha and gamma subunits discussed above. In contrast, newer positive allosteric modulators (eg, zuranolone) bind at the alpha/beta subunits.²⁵ Mechanistically, endogenous neuroactive steroids and nonbenzodiazepine GABA-A–positive allosteric modulators such as zuranolone and ganaxolone also differ in their regulation of GABA-A (downregulated with benzodiazepines and hypothetically upregulated with zuranolone)²⁶ and their synaptic effects (benzodiazepines synaptically vs endogenous neurosteroids and nonbenzodiazpine positive allosteric modulators extrasynaptically).²⁷

From a developmental perspective, benzodiazepines may have less efficacy for anxiolysis and worse tolerability in some pediatric patients,²⁸ although they generally appear effective for immediate use to treat anxiety in acute settings.²⁹ The differences in efficacy and tolerability may be related to pharmacodynamic differences between pediatric populations and adults. GABA receptor expression and function do not reach adult levels until age 14 to 17½ for subcortical regions and age 18 to 22 for cortical regions, although girls reach adult expression of GABA receptors slightly earlier than boys.³⁰ Data from multiple randomized controlled trials of pediatric patients with anxiety disorders do not suggest efficacy as benzodiazepines are poorly tolerated, especially compared to other psychopharmacologic interventions for pediatric anxiety disorders.³⁰

Continue to: Pharmacology and clinical effects

Benzodiazepine pharmacokinetics are intimately linked with the onset of action and duration of clinical effect and vary based on the route of administration, absorption, and distribution/redistribution.³¹ In this review, we focus on oral administration as opposed to IV, IM, sublingual, or intranasal administration.

Absorption

Benzodiazepines are rapidly absorbed after oral administration and quickly enter the systemic circulation. However, absorption rates vary depending on specific aspects of the gastrointestinal milieu and intrinsic properties of the benzodiazepine. For example, alprazolam is more rapidly absorbed than most other benzodiazepines, with a Tmax of 1.8 hours compared to lorazepam, which has a Tmax of approximately 2 hours. These pharmacokinetic effects instantiate differences in tolerability and efficacy. Thus, following single doses of alprazolam and diazepam, self-rated sedating effects and impairment on a task of working memory suggest that effects have a more rapid onset for alprazolam relative to lorazepam.³² Food and concomitant medications can significantly affect benzodiazepine absorption. A single-dose, 3-way crossover study demonstrated that taking diazepam concomitantly with an antacid (eg, aluminum hydroxide) decreased peak concentrations and prolonged absorption by approximately 30 minutes. However, total absorption of the medication was unaffected.³³ Additionally, administration of diazepam with food significantly slows absorption from 1 hour 15 minutes to approximately 2 hours 30 minutes and increases benzodiazepine absorption by 25% (Figure 1³⁴); the fat content of the meal appears important in moderating this effect.³⁵ The impact of food on alprazolam varies by formulation. For example, when administered in an extended-release (XR) formulation with a high-fat meal, alprazolam absorption increases by one-third, while absorption for administration of the orally disintegrating tablet with a high-fat meal increases from 1 hour 30 minutes to 2 hours. Similarly, for lorazepam, administration with a meal delays absorption by approximately 2 hours; however, this effect does not appear present with the XR formulation. Administering benzodiazepines with food can be clinically leveraged to either accelerate the onset of action or decrease peak-associated adverse effects. Thus, when a highly lipophilic benzodiazepine is needed to treat acute anxiety or prior to an expected anxiogenic stimuli, administering the medication without food may produce a faster onset of action.

CNS penetration

Benzodiazepines enter the CNS by passive diffusion. Because of this, lipophilicity at physiologic pH influences the rate at which a benzodiazepine crosses the blood-brain barrier. The rate at which benzodiazepines enter the CNS influences their clinical effects and the speed at which both efficacy (ie, anxiolysis) and adverse effects (ie, sedation, slowed cognition) are observed. In general, more lipophilic medications initiate their anxiolytic effect more quickly. However, by quickly leaving the CNS (through the same mechanism that allowed them to enter the CNS at such speed), their effects rapidly cease as they redistribute into fat. Thus, highly lipophilic benzodiazepines produce more intense effects compared to less lipophilic benzodiazepines. For these reasons, lipophilicity is more important than half-life for determining the duration of effect in most patients.

Lipophilicity and duration of effect

Benzodiazepines and their metabolites tend to be highly protein-bound and distributed in fat- and lipid-enriched areas such as the CNS. As a result, the more lipophilic agents generally have the highest rates of absorption and the fastest onset of clinical effects. The duration of action for many benzodiazepines is determined by the rate and extent of distribution (a function of lipophilicity) rather than by the rate of elimination. For example, diazepam has a longer half-life than lorazepam, but its duration of action following a single dose is shorter. This is because diazepam is more lipophilic and therefore more extensively distributed (particularly to adipose tissue). This results in it leaving the brain and blood and distributing to other tissues. In turn, its CNS effect (ie, anxiolytic effects) are more quickly terminated.

By contrast, less lipophilic benzodiazepines maintain their CNS concentrations longer; they have a longer duration of action because of their slower redistribution, which culminates in a shorter half-life, and are less extensively distributed to peripheral tissues. In essence, this means that (other things being equal) a less lipophilic benzodiazepine produces a more sustained anxiolytic effect compared to a highly lipophilic benzodiazepine.³⁶ Lipophilicity is also important in predicting some cognitive adverse effects, including amnesia. Benzodiazepines with high lipophilicity have greater absorption and faster onset of action as well as more rapid amnestic effects.^37,38 These effects may relate to overall efficacy differences for oral benzodiazepines. A recent meta-analysis by Stimpfl et al³⁶ found that less lipophilic benzodiazepines produced a greater response compared to more lipophilic benzodiazepines.

Continue to: Metabolism

Regarding cytochrome P450 (CYP) metabolism, polymorphic CYP2C19 and CYP3A4/5 are involved in the metabolism of several benzodiazepines³⁹ and CYP2B6 has been recognized as a contributor to diazepam metabolism. CYP3A5 gene polymorphisms may produce variation in alprazolam metabolism; however, the predominant cytochrome involved in the metabolism of oxidatively metabolized benzodiazepines (ie, benzodiazepines other than lorazepam, oxazepam, and temazepam) is primarily CYP3A4, and most effects on CYP3A4 activity are related to concomitant medications and other non­genetic factors.

Drug-drug interactions

Apart from lorazepam,^40,41 oxazepam,^42,43 and temazepam, most benzodiazepines are metabolized through oxidative mechanisms that involve CYP3A4 (Figure 2²⁰).³⁹ As such, their metabolism is influenced by medications that impact CYP3A4, including antifungals (eg, ketoconazole), calcium channel blockers (eg, verapamil, diltiazem), nefazodone, some protease inhibitors, and macrolide antibiotics. Research has examined the impact of low-dose estrogen oral contraceptives (OCPs) on exposure (eg, plasma concentrations) of several benzodiazepines. The mechanism for this interaction is likely complex and putatively involves multiple pathways, including inhibition of CYP3A4 by OCPs. The effects of OCPs on benzodiazepine pharmacokinetics vary based on the metabolism of the benzodiazepine. In general, medications oxidized and nitroreduced (eg, chlordiazepoxide, alprazolam, diazepam, and nitrazepam) have decreased clearance in patients treated with OCPs. Regarding nonoxidatively metabolized benzodiazepines, data are mixed. Research found no OCP-related effects on the pharmacokinetics of nonoxidatively metabolized benzodiazepines⁴⁴; another study suggested that clearance of these medications—through increased glucuronidation—may be increased.³¹ The effect of smoking on benzodiazepine concentration has been well documented. Smoking increases the clearance of orally administered diazepam,⁴⁵ but not IV diazepam, midazolam, or lorazepam, suggesting that this represents a first-pass effect.⁴⁶ For alprazolam, plasma concentrations are reduced by 15% to 30% in smokers and total body clearance is 24% greater compared to nonsmokers, which results in an approximately 50% increase in half-life in nonsmokers compared to smokers.⁴⁷ The most notable interaction between benzodiazepines and SSRIs is seen with fluvoxamine. Because fluvoxamine moderately inhibits CYP2C19 and CYP3A4 and potently inhibits CYP1A2,⁴⁸ the clearance of oxidatively metabolized benzodiazepines is reduced.⁴⁹ Additionally, the effects of grapefruit juice—a potent inhibitor of CYP3A4—has been evaluated for several benzodiazepines. Yasui et al⁵⁰ found grapefruit juice did not alter alprazolam plasma concentrations. However, in separate research, grapefruit juice tripled diazepam exposure, increased peak concentrations 1.5-fold, and prolonged absorption.⁵¹

Hepatic disease

Exposure to benzodiazepines—other than lorazepam, oxazepam, and temazepam—is influenced by intrinsic hepatic disease and requires dose adjustment in individuals with significant hepatic impairment. The impact of hepatic disease on the clinical pharmacology of benzodiazepines may relate to 2 factors: protein binding and metabolism. In a study of individuals with cirrhosis, lorazepam binding was decreased, although its metabolism and clearance were largely unaffected.⁴⁰

Aging and benzodiazepine metabolism/clearance

Aging is associated with myriad physiologic changes (eg, decrease in renal clearance after age 40, changes in body fat distribution, changes in activity of cytochromes) that are relevant to benzodiazepine pharmacology. They may underlie differences in the tolerability of benzodiazepines and other clinically relevant characteristics (eg, duration of action, accumulation).

Several studies have evaluated the impact of aging on the clearance and disposition of selected benzodiazepines. The respective half-lives of chlordiazepoxide and diazepam increase from 4- to 6-fold from age 20 to 80. Further, with chronic dosing, highly lipophilic benzodiazepines may require additional attention in geriatric patients. In a study that included individuals up to age 78, steady-state plasma concentrations of diazepam and its metabolite, desmethyldiazepam (DMDZ), were 30% to 35% higher in older patients compared to younger individuals.⁵² In this study, the half-lives for the young and older patients were 31 hours and 86 hours, respectively, for diazepam, and 40 hours and 80 hours, respectively, for the active metabolite. The half-life of diazepam is increased by “1 hour for each year of age beginning with a half-life of 20 hours at 20 years of age, as the volume of distribution is increased, and clearance is decreased.”⁵² Clinically, this implies that in older adults, clinicians should expect lower peak concentrations (Cmax), higher trough concentrations (Cmin), and that diazepam will take longer to reach steady-state concentrations. Taken together, these findings raised concern that “slow accumulation and delayed washout of diazepam and DMDZ is probable.”⁵² These findings—which may have more clinical relevance than those of single-dose studies—suggest that the effects related to diazepam would also take longer to resolve in older patients. Finally, lorazepam clearance or distribution does not appear to be affected by aging, at least in patients age 15 to 73.⁴⁰ Alprazolam is more slowly cleared in geriatric patients and its effects may be potentiated by reduced protein binding.

Continue to: Obesity

The distribution of medications, including benzodiazepines, is altered in patients who are obese because of increased adipose tissue.^53,54 This increase in the volume of distribution can attenuate the onset of action, increase medication accumulation in fat, and potentiate the duration of action.^55,56

Obesity may also affect hepatic metabolism by induction of CYP1A2, CYP2C9, and CYP2C19, and inhibition of CYP3A4.⁵⁷ Triazolam, which is metabolized by CYP3A4, is associated with a greater exposure (ie, plasma concentrations) in individuals who are obese.⁵⁸ However, when considering differences in benzodiazepine pharmacokinetics in patients who are obese, clinicians must remember that elimination half-life depends on both volume of distribution and clearance. In patients who are obese (compared to patients who are not obese), the half-lives are increased for alprazolam (22 hours vs 11 hours, P < .001)⁵⁹ and diazepam (82 hours vs 32 hours, P < .005).⁶⁰ In a pharmacokinetic study of diazepam in individuals who were obese and individuals who were not obese, total metabolic clearance did not differ. Rather, the increased half-life was related to a tripling of thevolume of distribution in obese patients (228 liters vs 70 liters, P < .01). This indicates that patients who are obese may experience a much slower onset of maximal effect compared to patients who are not obese because the accumulation of the medication is delayed. Additionally, for benzodiazepines that are conjugated (lorazepam and oxazepam), clearance is significantly enhanced in patients who are obese. For example, lorazepam clearance is 102 mL/min in individuals who are obese compared to 63 mL/min in individuals who are not obese; for oxazepam, clearance is 181 mL/min in patients who are obese compared to 98 mL/min in individuals who are not obese.⁶¹ These differences are attributed to increased uridine diphosphate glucuronyl transferase in obesity and to increases in liver size in obesity.⁵³

How quickly do benzodiazepines work?

Benzodiazepines act quickly. Meta-analyses³⁶ suggest that improvement in anxiety symptoms compared to placebo is greatest initially and then the rate of improvement slows over successive weeks. Research on benzodiazepines reveals statistically significant differences between benzodiazepines and placebo within the first week of treatment, with >80% of the expected improvement by Week 8 of treatment emerging by Week 4 (Figure 3³⁶). The rapid reduction in anxiety symptoms seen with benzodiazepines has important treatment implications, given that traditional psycho­therapeutic and antidepressant treatments are slow to produce improvements. Consistent data suggesting that benzodiazepines work faster than other treatments support that they may have a role during the initiation of other treatments.

What is the ‘best’ dose?

As seen with other classes of psychotropic medications,⁴ the relationship between benzodiazepine dose and response is complex. In a recent meta-analysis of 65 placebo-controlled trials of benzodiazepines in adults with anxiety disorders, there was a superior response over time for low-dose benzodiazepines (<3 mg/d in lorazepam equivalents) compared to a medium dose (3 to 6 mg/d; P = .042); high-dose benzodiazepines (>6 mg/d) yielded less improvement compared to medium doses (P = .001).³⁶ A study of adults with panic disorder similarly found the greatest responses with alprazolam plasma concentrations of 20 to 40 ng/mL, with no additional benefit at <20 ng/mL or >40 ng/mL.⁴⁹ As plasma concentrations increase, adverse effects such as sedation also increase, which may confound the observed loss of a dose-response relationship at higher doses and plasma concentrations.⁶² This may, in part, account for the observation that higher doses of benzodiazepines are associated with greater depressive symptoms and disrupted sleep.⁶³ As such, low doses may represent a delicate equipoise between efficacy and tolerability, yielding the most optimal clinical response.

Which benzodiazepine should I prescribe?

Comparing benzodiazepines is difficult, given the differences in dosing and disorders studied and differences in how each individual clinical trial was conducted. A meta-analysis by Stimpfl et al³⁶ that used Bayesian hierarchical modeling, which allowed some of this heterogeneity to be addressed, found that relative to the reference benzodiazepine (lorazepam), clonazepam had the greatest trajectory/magnitude of response (other specific benzodiazepines did not statistically differ from lorazepam) (Figure 4³⁶).

Continue to: Another aspect of the superiority...

Another aspect of the superiority of clonazepam in some research relates to its pharma­cokinetic properties, particularly when compared with benzodiazepines that have very short half-lives. Short half-life benzodiazepines have been associated with rebound anxiety, which is defined as “the relative worsening of symptoms on discontinuation of treatment as compared to baseline symptoms” and is distinct from withdrawal.⁶⁴ While it is difficult to assess this in clinical trials, Herman et al⁶⁵ provided insight into the contribution of rebound anxiety in a study of patients with panic disorder treated with alprazolam who experienced “interdose anxiety symptoms.” Of the 48 patients in this study, 41 switched to clonazepam, and most who switched (82%) experienced improvement. The improvement was attributed to the decreased frequency of clonazepam (vs alprazolam) administration and lack of interdose anxiety. When selecting an oral benzodiazepine, consider the duration, onset of action, and differences in metabolism that produce varying levels of effectiveness for individual patients. In situations where rapid onset is desired, a short-acting benzodiazepine may be preferable, while a longer-acting benzodiazepine would be preferable in situations where the patient needs sustained effects.

Regarding lipophilicity, differences among benzodiazepines could contribute to differences in psychological dependence and differential utility in some situations. For example, alprazolam rapidly enters the CNS, producing an immediate anxiolytic effect. However, its egress from the CNS is equally rapid, and its anxiolytic effects disappear quickly. This may be desirable for addressing acute, predictable anxiety, but could have unintended consequences in treating chronic anxiety, where it could facilitate psychological dependence.

Practical considerations

When prescribing benzodiazepines, consider a myriad of patient- and medication-specific factors, as these have clinically relevant implications on treatment response. This information, taken together, supports the importance of an individualized approach to benzodiazepine use. Before selecting a benzodiazepine and during treatment, important elements of the patient’s history must be considered, including age, body weight, concomitant medication use (eg, antacids, CYP3A4 inhibitors, OCPs), smoking status, and history of hepatic or renal disease.

Patients age <18 are unlikely to have full expression of GABA receptors in the brain³⁰ and therefore benzodiazepines may not be as efficacious for anxiolysis in this population. Moreover, compared to younger patients, older patients may experience higher steady-state concentrations of benzo­diazepines, especially lipophilic agents, due to an increased volume of distribution and decreased clearance. In patients treated with OCPs, some benzodiazepines may take longer to reach steady-state, and dose adjustments may need to be considered. In patients who smoke, clearance of some oral benzo­diazepines is also accelerated, potentially decreasing half-life by up to 50%.

When dosing and titrating benzodiazepines, consider the patient’s body weight, particularly if they are obese. The effects of obesity on benzodiazepine pharmacokinetics are complex. For glucuronidated benzodiazepines, clearance is increased in patients who are obese; however, the volume of distribution is also increased in such patients, meaning it will take longer for benzodiazepines to achieve steady-state in these individuals compared to patients who are not obese. These effects suggest it may take longer to achieve a response at a given dose in patients who are obese compared to individuals who are not obese.

Continue to: The properties of individual benzodiazepines...

The properties of individual benzodiazepines should also be considered when selecting a benzodiazepine treatment. If circumstances necessitate rapid symptom relief, a lipophilic benzodiazepine, such as diazepam, may be preferred for quick onset and offset of action. Onset of action may also be hastened by taking the benzodiazepine without food; conversely, if peak adverse effects are problematic, concurrent consumption of a high-fat meal may help decrease peak concentration and prolonging absorption. In other circumstances, such as if sustained anxiolysis is desired, a clinician may opt for a less lipophilic benzodiazepine, such as clonazepam. Finally, in terms of general treatment response, benzodiazepines separate from placebo in the first week of treatment, which supports the idea they may be useful during the introduction of other medications (eg, SSRIs) that take a longer time to achieve clinical effect.

Bottom Line

The pharmacokinetics of benzodiazepines are intimately linked with the onset of action and duration of clinical effect and vary based on individual absorption and distribution/redistribution. Benzodiazepines’ clinical profile derives from their pharmacokinetic differences and is influenced by many factors, including age, body weight, concomitant medication use, smoking status, and hepatic or renal disease. Consider these factors to individualize the approach to using benzodiazepines and optimize tolerability and efficacy.

Related Resources

• Weber SR, Duchemin AM. Benzodiazepines: sensible prescribing in light of the risks. Current Psychiatry. 2018;17(2):22-27.
• Balon R. Benzodiazepines for anxious depression. Current Psychiatry. 2018;17(8):9-12.

Drug Brand Names

Alprazolam • Xanax
Chlordiazepoxide • Librium
Clobazam • Onfi
Clonazepam • Klonopin
Clorazepate • Gen-Xene
Diazepam • Valium
Diltiazem • Cardizem
Fluvoxamine • Luvox
Ganaxolone • Ztalmy
Ketoconazole • Nizoral
Lorazepam • Ativan
Midazolam • Versed
Temazepam • Restoril
Triazolam • Halcion
Verapamil • Calan

Though once the main treatment for anxiety disorders—often as monotherapy¹—benzodiazepines are now primarily used as adjunctive agents.^2-4 Their ability to produce rapid anxiolysis represents a significant therapeutic advantage, but in recent decades their tolerability, class-specific risks, and lack of antidepressant properties contributed to benzodiazepines being largely replaced by selective serotonin reuptake inhibitors (SSRIs) for the pharmacologic treatment of anxiety. This shift within the pharmacologic armamentarium has decreased many clinicians’ familiarity with benzodiazepines.

While benzodiazepines continue to have an important role in managing anxiety disorders, particularly treatment-resistant anxiety,⁴ clinicians must consider the limitations of these agents. Benzodiazepines can be associated with abuse and dependence, and overdose risk when combined with opiates.^5,6 They may cause memory impairment^7,8 and conflicting data suggest they may contribute to the risk of developing cognitive disorders.^9-11 Benzodiazepines also have been associated with falls and fractures,¹² and worse outcomes in patients with posttraumatic stress disorder.¹³ Some studies of patients with chronic obstructive pulmonary disease (COPD) found benzodiazepines may increase the risk of COPD exacerbations and accidental overdose,¹⁴ though others found that was not always the case.¹⁵ Benzodiazepines may be associated with an increased risk of spontaneous abortion when used early in pregnancy.¹⁶ Prospective research in women who were breastfeeding found benzodiazepines may cause sedation in up to 2% of infants.¹⁷

Despite the potential for adverse effects, benzodiazepine use remains common.¹⁸ These medications have a rapid onset of action, are useful for breakthrough symptoms, may enhance treatment adherence, and alleviate activating symptoms of SSRIs. Like other commonly used medications, benzodiazepines have the potential for both harm and benefit.¹⁹ Similar to other medications with tolerability concerns but established efficacy, particularly in treatment-resistant anxiety disorders, it is important to balance “overprescribing … to patients at risk and underusing these effective medications when indicated.”¹⁹ Though the use of benzodiazepines has been discouraged and perceptions have shifted, knowledge of benzodiazepines and benzodiazepine pharmacology also has been degraded contemporaneously.

This article provides a synthesis of the clinically relevant pharmacology of benzodiazepines, with a focus on orally administered benzodiazepines, which are more common in outpatient clinical practice. Specifically, this review describes the pharmacology of benzodiazepines, benzo­diazepine medication interactions, the relationship between pharmacologic characteristics and treatment response/tolerability, and selection and dosing of oral benzodiazepines (Table²⁰).

Benzodiazepine pharmacodynamics

Benzodiazepines act at the gamma-aminobutyric acid (GABA)-A receptor complex and bind allosterically.^21-23 Comprised of 5 glycoprotein subunits (2 alpha subunits, 2 beta subunits, and 1 gamma subunit), the receptor has 2 distinct sites at which the endogenous inhibitory transmitter GABA binds and 1 benzodiazepine binding site. Benzodiazepines bind within a socket created by the alpha and gamma subunits²² and after binding induce a conformational change in the receptor, which enhances GABA binding. There are 2 types of benzodiazepine receptors: BZ1 and BZ2. The subunits play a critical role in driving the pharmacologic characteristics of the receptor.²⁴ BZ1 and BZ2 receptors bind benzodiazepines, although they are differentially distributed within the brain. Binding at BZ1 receptors—which are distributed in cortical, thalamic, and cerebellar regions—contributes to sedation and deleterious effects of benzodiazepines on memory (eg, anterograde amnesia). BZ2 receptors (which contain gamma-2 subunits) are responsible for anxiolytic and muscle-relaxing effects. They are distributed throughout limbic regions and motor tracts, including motor neurons and neurons in the dorsal horn of the spinal cord.²⁴

Benzodiazepines—positive GABA-A receptor allosteric modulators—produce phasic inhibition, largely through the alpha and gamma subunits discussed above. In contrast, newer positive allosteric modulators (eg, zuranolone) bind at the alpha/beta subunits.²⁵ Mechanistically, endogenous neuroactive steroids and nonbenzodiazepine GABA-A–positive allosteric modulators such as zuranolone and ganaxolone also differ in their regulation of GABA-A (downregulated with benzodiazepines and hypothetically upregulated with zuranolone)²⁶ and their synaptic effects (benzodiazepines synaptically vs endogenous neurosteroids and nonbenzodiazpine positive allosteric modulators extrasynaptically).²⁷

From a developmental perspective, benzodiazepines may have less efficacy for anxiolysis and worse tolerability in some pediatric patients,²⁸ although they generally appear effective for immediate use to treat anxiety in acute settings.²⁹ The differences in efficacy and tolerability may be related to pharmacodynamic differences between pediatric populations and adults. GABA receptor expression and function do not reach adult levels until age 14 to 17½ for subcortical regions and age 18 to 22 for cortical regions, although girls reach adult expression of GABA receptors slightly earlier than boys.³⁰ Data from multiple randomized controlled trials of pediatric patients with anxiety disorders do not suggest efficacy as benzodiazepines are poorly tolerated, especially compared to other psychopharmacologic interventions for pediatric anxiety disorders.³⁰

Continue to: Pharmacology and clinical effects

Benzodiazepine pharmacokinetics are intimately linked with the onset of action and duration of clinical effect and vary based on the route of administration, absorption, and distribution/redistribution.³¹ In this review, we focus on oral administration as opposed to IV, IM, sublingual, or intranasal administration.

Absorption

Benzodiazepines are rapidly absorbed after oral administration and quickly enter the systemic circulation. However, absorption rates vary depending on specific aspects of the gastrointestinal milieu and intrinsic properties of the benzodiazepine. For example, alprazolam is more rapidly absorbed than most other benzodiazepines, with a Tmax of 1.8 hours compared to lorazepam, which has a Tmax of approximately 2 hours. These pharmacokinetic effects instantiate differences in tolerability and efficacy. Thus, following single doses of alprazolam and diazepam, self-rated sedating effects and impairment on a task of working memory suggest that effects have a more rapid onset for alprazolam relative to lorazepam.³² Food and concomitant medications can significantly affect benzodiazepine absorption. A single-dose, 3-way crossover study demonstrated that taking diazepam concomitantly with an antacid (eg, aluminum hydroxide) decreased peak concentrations and prolonged absorption by approximately 30 minutes. However, total absorption of the medication was unaffected.³³ Additionally, administration of diazepam with food significantly slows absorption from 1 hour 15 minutes to approximately 2 hours 30 minutes and increases benzodiazepine absorption by 25% (Figure 1³⁴); the fat content of the meal appears important in moderating this effect.³⁵ The impact of food on alprazolam varies by formulation. For example, when administered in an extended-release (XR) formulation with a high-fat meal, alprazolam absorption increases by one-third, while absorption for administration of the orally disintegrating tablet with a high-fat meal increases from 1 hour 30 minutes to 2 hours. Similarly, for lorazepam, administration with a meal delays absorption by approximately 2 hours; however, this effect does not appear present with the XR formulation. Administering benzodiazepines with food can be clinically leveraged to either accelerate the onset of action or decrease peak-associated adverse effects. Thus, when a highly lipophilic benzodiazepine is needed to treat acute anxiety or prior to an expected anxiogenic stimuli, administering the medication without food may produce a faster onset of action.

CNS penetration

Benzodiazepines enter the CNS by passive diffusion. Because of this, lipophilicity at physiologic pH influences the rate at which a benzodiazepine crosses the blood-brain barrier. The rate at which benzodiazepines enter the CNS influences their clinical effects and the speed at which both efficacy (ie, anxiolysis) and adverse effects (ie, sedation, slowed cognition) are observed. In general, more lipophilic medications initiate their anxiolytic effect more quickly. However, by quickly leaving the CNS (through the same mechanism that allowed them to enter the CNS at such speed), their effects rapidly cease as they redistribute into fat. Thus, highly lipophilic benzodiazepines produce more intense effects compared to less lipophilic benzodiazepines. For these reasons, lipophilicity is more important than half-life for determining the duration of effect in most patients.

Lipophilicity and duration of effect

Benzodiazepines and their metabolites tend to be highly protein-bound and distributed in fat- and lipid-enriched areas such as the CNS. As a result, the more lipophilic agents generally have the highest rates of absorption and the fastest onset of clinical effects. The duration of action for many benzodiazepines is determined by the rate and extent of distribution (a function of lipophilicity) rather than by the rate of elimination. For example, diazepam has a longer half-life than lorazepam, but its duration of action following a single dose is shorter. This is because diazepam is more lipophilic and therefore more extensively distributed (particularly to adipose tissue). This results in it leaving the brain and blood and distributing to other tissues. In turn, its CNS effect (ie, anxiolytic effects) are more quickly terminated.

By contrast, less lipophilic benzodiazepines maintain their CNS concentrations longer; they have a longer duration of action because of their slower redistribution, which culminates in a shorter half-life, and are less extensively distributed to peripheral tissues. In essence, this means that (other things being equal) a less lipophilic benzodiazepine produces a more sustained anxiolytic effect compared to a highly lipophilic benzodiazepine.³⁶ Lipophilicity is also important in predicting some cognitive adverse effects, including amnesia. Benzodiazepines with high lipophilicity have greater absorption and faster onset of action as well as more rapid amnestic effects.^37,38 These effects may relate to overall efficacy differences for oral benzodiazepines. A recent meta-analysis by Stimpfl et al³⁶ found that less lipophilic benzodiazepines produced a greater response compared to more lipophilic benzodiazepines.

Continue to: Metabolism

Regarding cytochrome P450 (CYP) metabolism, polymorphic CYP2C19 and CYP3A4/5 are involved in the metabolism of several benzodiazepines³⁹ and CYP2B6 has been recognized as a contributor to diazepam metabolism. CYP3A5 gene polymorphisms may produce variation in alprazolam metabolism; however, the predominant cytochrome involved in the metabolism of oxidatively metabolized benzodiazepines (ie, benzodiazepines other than lorazepam, oxazepam, and temazepam) is primarily CYP3A4, and most effects on CYP3A4 activity are related to concomitant medications and other non­genetic factors.

Drug-drug interactions

Apart from lorazepam,^40,41 oxazepam,^42,43 and temazepam, most benzodiazepines are metabolized through oxidative mechanisms that involve CYP3A4 (Figure 2²⁰).³⁹ As such, their metabolism is influenced by medications that impact CYP3A4, including antifungals (eg, ketoconazole), calcium channel blockers (eg, verapamil, diltiazem), nefazodone, some protease inhibitors, and macrolide antibiotics. Research has examined the impact of low-dose estrogen oral contraceptives (OCPs) on exposure (eg, plasma concentrations) of several benzodiazepines. The mechanism for this interaction is likely complex and putatively involves multiple pathways, including inhibition of CYP3A4 by OCPs. The effects of OCPs on benzodiazepine pharmacokinetics vary based on the metabolism of the benzodiazepine. In general, medications oxidized and nitroreduced (eg, chlordiazepoxide, alprazolam, diazepam, and nitrazepam) have decreased clearance in patients treated with OCPs. Regarding nonoxidatively metabolized benzodiazepines, data are mixed. Research found no OCP-related effects on the pharmacokinetics of nonoxidatively metabolized benzodiazepines⁴⁴; another study suggested that clearance of these medications—through increased glucuronidation—may be increased.³¹ The effect of smoking on benzodiazepine concentration has been well documented. Smoking increases the clearance of orally administered diazepam,⁴⁵ but not IV diazepam, midazolam, or lorazepam, suggesting that this represents a first-pass effect.⁴⁶ For alprazolam, plasma concentrations are reduced by 15% to 30% in smokers and total body clearance is 24% greater compared to nonsmokers, which results in an approximately 50% increase in half-life in nonsmokers compared to smokers.⁴⁷ The most notable interaction between benzodiazepines and SSRIs is seen with fluvoxamine. Because fluvoxamine moderately inhibits CYP2C19 and CYP3A4 and potently inhibits CYP1A2,⁴⁸ the clearance of oxidatively metabolized benzodiazepines is reduced.⁴⁹ Additionally, the effects of grapefruit juice—a potent inhibitor of CYP3A4—has been evaluated for several benzodiazepines. Yasui et al⁵⁰ found grapefruit juice did not alter alprazolam plasma concentrations. However, in separate research, grapefruit juice tripled diazepam exposure, increased peak concentrations 1.5-fold, and prolonged absorption.⁵¹

Hepatic disease

Exposure to benzodiazepines—other than lorazepam, oxazepam, and temazepam—is influenced by intrinsic hepatic disease and requires dose adjustment in individuals with significant hepatic impairment. The impact of hepatic disease on the clinical pharmacology of benzodiazepines may relate to 2 factors: protein binding and metabolism. In a study of individuals with cirrhosis, lorazepam binding was decreased, although its metabolism and clearance were largely unaffected.⁴⁰

Aging and benzodiazepine metabolism/clearance

Aging is associated with myriad physiologic changes (eg, decrease in renal clearance after age 40, changes in body fat distribution, changes in activity of cytochromes) that are relevant to benzodiazepine pharmacology. They may underlie differences in the tolerability of benzodiazepines and other clinically relevant characteristics (eg, duration of action, accumulation).

Several studies have evaluated the impact of aging on the clearance and disposition of selected benzodiazepines. The respective half-lives of chlordiazepoxide and diazepam increase from 4- to 6-fold from age 20 to 80. Further, with chronic dosing, highly lipophilic benzodiazepines may require additional attention in geriatric patients. In a study that included individuals up to age 78, steady-state plasma concentrations of diazepam and its metabolite, desmethyldiazepam (DMDZ), were 30% to 35% higher in older patients compared to younger individuals.⁵² In this study, the half-lives for the young and older patients were 31 hours and 86 hours, respectively, for diazepam, and 40 hours and 80 hours, respectively, for the active metabolite. The half-life of diazepam is increased by “1 hour for each year of age beginning with a half-life of 20 hours at 20 years of age, as the volume of distribution is increased, and clearance is decreased.”⁵² Clinically, this implies that in older adults, clinicians should expect lower peak concentrations (Cmax), higher trough concentrations (Cmin), and that diazepam will take longer to reach steady-state concentrations. Taken together, these findings raised concern that “slow accumulation and delayed washout of diazepam and DMDZ is probable.”⁵² These findings—which may have more clinical relevance than those of single-dose studies—suggest that the effects related to diazepam would also take longer to resolve in older patients. Finally, lorazepam clearance or distribution does not appear to be affected by aging, at least in patients age 15 to 73.⁴⁰ Alprazolam is more slowly cleared in geriatric patients and its effects may be potentiated by reduced protein binding.

Continue to: Obesity

The distribution of medications, including benzodiazepines, is altered in patients who are obese because of increased adipose tissue.^53,54 This increase in the volume of distribution can attenuate the onset of action, increase medication accumulation in fat, and potentiate the duration of action.^55,56

Obesity may also affect hepatic metabolism by induction of CYP1A2, CYP2C9, and CYP2C19, and inhibition of CYP3A4.⁵⁷ Triazolam, which is metabolized by CYP3A4, is associated with a greater exposure (ie, plasma concentrations) in individuals who are obese.⁵⁸ However, when considering differences in benzodiazepine pharmacokinetics in patients who are obese, clinicians must remember that elimination half-life depends on both volume of distribution and clearance. In patients who are obese (compared to patients who are not obese), the half-lives are increased for alprazolam (22 hours vs 11 hours, P < .001)⁵⁹ and diazepam (82 hours vs 32 hours, P < .005).⁶⁰ In a pharmacokinetic study of diazepam in individuals who were obese and individuals who were not obese, total metabolic clearance did not differ. Rather, the increased half-life was related to a tripling of thevolume of distribution in obese patients (228 liters vs 70 liters, P < .01). This indicates that patients who are obese may experience a much slower onset of maximal effect compared to patients who are not obese because the accumulation of the medication is delayed. Additionally, for benzodiazepines that are conjugated (lorazepam and oxazepam), clearance is significantly enhanced in patients who are obese. For example, lorazepam clearance is 102 mL/min in individuals who are obese compared to 63 mL/min in individuals who are not obese; for oxazepam, clearance is 181 mL/min in patients who are obese compared to 98 mL/min in individuals who are not obese.⁶¹ These differences are attributed to increased uridine diphosphate glucuronyl transferase in obesity and to increases in liver size in obesity.⁵³

How quickly do benzodiazepines work?

Benzodiazepines act quickly. Meta-analyses³⁶ suggest that improvement in anxiety symptoms compared to placebo is greatest initially and then the rate of improvement slows over successive weeks. Research on benzodiazepines reveals statistically significant differences between benzodiazepines and placebo within the first week of treatment, with >80% of the expected improvement by Week 8 of treatment emerging by Week 4 (Figure 3³⁶). The rapid reduction in anxiety symptoms seen with benzodiazepines has important treatment implications, given that traditional psycho­therapeutic and antidepressant treatments are slow to produce improvements. Consistent data suggesting that benzodiazepines work faster than other treatments support that they may have a role during the initiation of other treatments.

What is the ‘best’ dose?

As seen with other classes of psychotropic medications,⁴ the relationship between benzodiazepine dose and response is complex. In a recent meta-analysis of 65 placebo-controlled trials of benzodiazepines in adults with anxiety disorders, there was a superior response over time for low-dose benzodiazepines (<3 mg/d in lorazepam equivalents) compared to a medium dose (3 to 6 mg/d; P = .042); high-dose benzodiazepines (>6 mg/d) yielded less improvement compared to medium doses (P = .001).³⁶ A study of adults with panic disorder similarly found the greatest responses with alprazolam plasma concentrations of 20 to 40 ng/mL, with no additional benefit at <20 ng/mL or >40 ng/mL.⁴⁹ As plasma concentrations increase, adverse effects such as sedation also increase, which may confound the observed loss of a dose-response relationship at higher doses and plasma concentrations.⁶² This may, in part, account for the observation that higher doses of benzodiazepines are associated with greater depressive symptoms and disrupted sleep.⁶³ As such, low doses may represent a delicate equipoise between efficacy and tolerability, yielding the most optimal clinical response.

Which benzodiazepine should I prescribe?

Comparing benzodiazepines is difficult, given the differences in dosing and disorders studied and differences in how each individual clinical trial was conducted. A meta-analysis by Stimpfl et al³⁶ that used Bayesian hierarchical modeling, which allowed some of this heterogeneity to be addressed, found that relative to the reference benzodiazepine (lorazepam), clonazepam had the greatest trajectory/magnitude of response (other specific benzodiazepines did not statistically differ from lorazepam) (Figure 4³⁶).

Continue to: Another aspect of the superiority...

Another aspect of the superiority of clonazepam in some research relates to its pharma­cokinetic properties, particularly when compared with benzodiazepines that have very short half-lives. Short half-life benzodiazepines have been associated with rebound anxiety, which is defined as “the relative worsening of symptoms on discontinuation of treatment as compared to baseline symptoms” and is distinct from withdrawal.⁶⁴ While it is difficult to assess this in clinical trials, Herman et al⁶⁵ provided insight into the contribution of rebound anxiety in a study of patients with panic disorder treated with alprazolam who experienced “interdose anxiety symptoms.” Of the 48 patients in this study, 41 switched to clonazepam, and most who switched (82%) experienced improvement. The improvement was attributed to the decreased frequency of clonazepam (vs alprazolam) administration and lack of interdose anxiety. When selecting an oral benzodiazepine, consider the duration, onset of action, and differences in metabolism that produce varying levels of effectiveness for individual patients. In situations where rapid onset is desired, a short-acting benzodiazepine may be preferable, while a longer-acting benzodiazepine would be preferable in situations where the patient needs sustained effects.

Regarding lipophilicity, differences among benzodiazepines could contribute to differences in psychological dependence and differential utility in some situations. For example, alprazolam rapidly enters the CNS, producing an immediate anxiolytic effect. However, its egress from the CNS is equally rapid, and its anxiolytic effects disappear quickly. This may be desirable for addressing acute, predictable anxiety, but could have unintended consequences in treating chronic anxiety, where it could facilitate psychological dependence.

Practical considerations

When prescribing benzodiazepines, consider a myriad of patient- and medication-specific factors, as these have clinically relevant implications on treatment response. This information, taken together, supports the importance of an individualized approach to benzodiazepine use. Before selecting a benzodiazepine and during treatment, important elements of the patient’s history must be considered, including age, body weight, concomitant medication use (eg, antacids, CYP3A4 inhibitors, OCPs), smoking status, and history of hepatic or renal disease.

Patients age <18 are unlikely to have full expression of GABA receptors in the brain³⁰ and therefore benzodiazepines may not be as efficacious for anxiolysis in this population. Moreover, compared to younger patients, older patients may experience higher steady-state concentrations of benzo­diazepines, especially lipophilic agents, due to an increased volume of distribution and decreased clearance. In patients treated with OCPs, some benzodiazepines may take longer to reach steady-state, and dose adjustments may need to be considered. In patients who smoke, clearance of some oral benzo­diazepines is also accelerated, potentially decreasing half-life by up to 50%.

When dosing and titrating benzodiazepines, consider the patient’s body weight, particularly if they are obese. The effects of obesity on benzodiazepine pharmacokinetics are complex. For glucuronidated benzodiazepines, clearance is increased in patients who are obese; however, the volume of distribution is also increased in such patients, meaning it will take longer for benzodiazepines to achieve steady-state in these individuals compared to patients who are not obese. These effects suggest it may take longer to achieve a response at a given dose in patients who are obese compared to individuals who are not obese.

Continue to: The properties of individual benzodiazepines...

The properties of individual benzodiazepines should also be considered when selecting a benzodiazepine treatment. If circumstances necessitate rapid symptom relief, a lipophilic benzodiazepine, such as diazepam, may be preferred for quick onset and offset of action. Onset of action may also be hastened by taking the benzodiazepine without food; conversely, if peak adverse effects are problematic, concurrent consumption of a high-fat meal may help decrease peak concentration and prolonging absorption. In other circumstances, such as if sustained anxiolysis is desired, a clinician may opt for a less lipophilic benzodiazepine, such as clonazepam. Finally, in terms of general treatment response, benzodiazepines separate from placebo in the first week of treatment, which supports the idea they may be useful during the introduction of other medications (eg, SSRIs) that take a longer time to achieve clinical effect.

Bottom Line

The pharmacokinetics of benzodiazepines are intimately linked with the onset of action and duration of clinical effect and vary based on individual absorption and distribution/redistribution. Benzodiazepines’ clinical profile derives from their pharmacokinetic differences and is influenced by many factors, including age, body weight, concomitant medication use, smoking status, and hepatic or renal disease. Consider these factors to individualize the approach to using benzodiazepines and optimize tolerability and efficacy.

Related Resources

• Weber SR, Duchemin AM. Benzodiazepines: sensible prescribing in light of the risks. Current Psychiatry. 2018;17(2):22-27.
• Balon R. Benzodiazepines for anxious depression. Current Psychiatry. 2018;17(8):9-12.

Drug Brand Names

Alprazolam • Xanax
Chlordiazepoxide • Librium
Clobazam • Onfi
Clonazepam • Klonopin
Clorazepate • Gen-Xene
Diazepam • Valium
Diltiazem • Cardizem
Fluvoxamine • Luvox
Ganaxolone • Ztalmy
Ketoconazole • Nizoral
Lorazepam • Ativan
Midazolam • Versed
Temazepam • Restoril
Triazolam • Halcion
Verapamil • Calan

Deaths of children who are killed by their parents often make the news. Cases of maternal infanticide may be particularly shocking, since women are expected to be selfless nurturers. Yet when a child is murdered, the most common perpetrator is their parent, and mothers and fathers kill at similar rates.¹

As psychiatrists, we may see these cases in the news and worry about the risks of our own patients killing their children. In approximately 500 cases annually, an American parent is arrested for the homicide of their child.² This is not even the entire story, since a large percentage of such cases end in suicide—and no arrest. This article reviews the reasons parents kill their children, and considers common characteristics of these parents, dispelling some myths, before discussing the importance of prevention efforts.

Types of child murder by parents

Child murder by parents is termed filicide. Infanticide has various meanings but often refers to the murder of a child younger than age 1. Approximately 2 dozen nations (but not the United States) have Infanticide Acts that decrease the penalty for mothers who kill their young child.³ Neonaticide refers to murder of the infant at birth or in the first day of life.⁴

Epidemiology and common characteristics

Approximately 15%—or 1 in 7 murders with an arrest—is a filicide.² The younger the child, the greater the risk, but older children are killed as well.² Internationally, fathers and mothers are found to kill at similar rates. For other types of homicide, offenders are overwhelmingly male. This makes child murder by parents the singular type of murder in which women and men perpetrate in equal numbers. Fathers are more likely than mothers to also commit suicide after they kill their children.⁵ The “Cinderella effect” refers to the elevated risk of a stepchild being killed compared to the risk for a biological child.⁶

In the general international population, mothers who commit filicide tend to have multiple stressors and limited resources. They may be socially isolated and may be victims themselves as well as potentially experiencing substance abuse.¹ Some mothers view the child they killed as abnormal.

Less research has been conducted about fathers who kill. Fathers are more likely to also commit partner homicide.^5,7 They are more likely to complete filicide-suicide and use firearms or other violent means.^5,7-9 Fathers may have a history of violence, substance abuse, and/or mental illness.⁷

Neonaticide

Mothers are the most common perpetrator of neonaticide.⁴ It is unusual for a father to be involved in a neonaticide, or for the father and mother to perpetrate the act together. Rates of neonaticide are considered underestimates because of the number of hidden pregnancies, hidden corpses, and the difficulty that forensic pathologists may have in determining whether a baby was born alive or dead.

Continue to: Perpetrators of neonaticide...

Perpetrators of neonaticide tend to be single, relatively young women acting alone. They often live with their parents and are fearful of the repercussions of being pregnant. Pregnancies are often hidden, with no prenatal care. This includes both denial and concealment of pregnancy.⁴ Perpetrators of neonaticide commonly lack a premorbid serious mental illness, though after the homicide they may develop anxiety, depression, posttraumatic stress disorder (PTSD), or adjustment disorder.⁴ (Individuals who unwittingly find a murdered baby’s corpse may also be at risk of PTSD.)

Hidden pregnancies may be due to concealment or denial of pregnancy.^10,11 Concealment of pregnancy involves a woman knowing she is pregnant, but purposely hiding from others. Concealment may occur after a period of denial of pregnancy. Denial of pregnancy has several subtypes: pervasive denial, affective denial, and psychotic denial. In cases of pervasive denial, the existence of the pregnancy and the pregnancy’s emotional significance is outside the woman’s awareness. Alternatively, in affective denial, she is intellectually aware that she is pregnant but makes little emotional or physical preparation. In the rarest form, psychotic denial, a woman with a psychotic disorder such as schizophrenia may intermittently deny her pregnancy. This may be correlated with a history of custody loss.^10,11 Unlike denial of other medical conditions, in cases of denial of pregnancy, there will exist a very specific point in time (delivery) when the reality of the baby confronts the woman. Risks in cases of hidden pregnancies include those from lack of prenatal care and an assisted delivery as well as neonaticide. An FBI study¹² of law enforcement files found most neonaticide offenders were single young women with no criminal or psychological history. A caveat is that in the rare cases in which a woman with psychotic illness commits neonaticide, she may have different characteristics from those generally reported.¹³

Motives

Fathers and mothers have a similar set of motives for killing their child (Table 1^13-15). Motives are critical to understand not only within forensics, but also for prevention. In performing assessments after a filicide, forensic psychiatrists must be mindful of gender bias.^7,16 Resnick¹⁵ initially described 5 motives based on his 1969 review of the world literature. Our work^5,17 has subsequently further explored these motives.

In child homicides from “fatal maltreatment,” the child has often been a chronic victim of abuse or neglect. National American data indicate that approximately 2 per 100,000 children are killed from child maltreatment annually. Of note in conceptualizing prevention, out of the same population of 100,000, there will be 471 referrals to Child Protective Services and 91 substantiated cases.¹⁸ However, only a minority of children who die from maltreatment had previous Child Protective Services involvement. While a child may be killed by fatal maltreatment at any age, one-half are younger than age 1, and three-quarters are younger than age 3.¹⁸ In rare cases, a parent who engages in medical child abuse (including factitious disorder imposed upon another) kills the child. Depending on the location and whether or not the death appeared to be intended, parents who kill because of fatal maltreatment might face charges of various levels of murder or manslaughter.

“Unwanted child” homicides occur when the parent has determined that they do not want to have the child, especially in comparison to another need or want. Unwanted child motive is the most common in neonaticide cases, occurring after a hidden pregnancy.⁴

Continue to: In "partner revenge" cases...

In “partner revenge” cases, parenting disputes, a custody battle, infidelity, or a difficult relationship breakup is often present. The parent wants to make the other parent suffer, and does so by killing their child. A parent may make statements such as “If I can’t have [the child], no one can,” and the child is used as a pawn.

In the final 2 motives—“altruistic” and “acutely psychotic”—mental illness is common. These are the populations we tend to find in samples of filicide-suicide cases where the parent has killed themselves and their child, and those found not guilty by reason of insanity.^5,17 Altruistic filicide has been described as “murder out of love.” How can a parent kill their child out of love? Our research has shown several ways. First, the parent may be severely depressed and suicidal. They may be planning their own suicide, and as a parent who loves their child, they plan to take their child with them in death and not leave them alone in the “cruel world” that they themselves are departing. Or the parent may believe they are killing the child out of love to prevent or relieve the child’s suffering. The psychotic parent may believe that a terrible fate will befall their child, and they are killing them “gently.” For example, the parent may believe the child will be tortured or sex trafficked. Some parents may believe that their child has a devastating disease and think they would be better off dead. (Similar thinking of misguided altruism is seen in some cases of intimate partner homicide among older adults.¹⁹)

Alternatively, in rare cases of acutely psychotic filicide, parents with psychosis kill their child with no comprehensible motive. For example, they may be in a postictal state or may hear a command hallucination from God in the context of their psychosis.¹⁵

Myths vs realities of filicide

Common myths vs the realities of filicide are noted in Table 2. There are issues with believing these myths. For example, if we believe that most parents who kill their child have mental illness, this conflates mental illness and child homicide in our minds as well as the mind of the public. This can lead to further stigmatization of mental illness, and a lack of help-seeking behaviors because parents experiencing psychiatric symptoms may be afraid that if they report their symptoms, their child will be removed by Child Protective Services. However, treated mental illness decreases the risks of child abuse, similar to how treating mental illness decreases risks of other types of violence.^20,21

Focusing on prevention

On a local level, we need to understand these tragedies to better understand prevention. To this end, across the United States, counties have Child Fatality Review teams.²² These teams are a partnership across sectors and disciplines, including professionals from health services, law enforcement, and social services—among others—working together to understand cases and consider preventive strategies and additional services needed within our communities.

Continue to: When conceptualizing prevention...

When conceptualizing prevention of child murder by parents, we can think of primary, secondary, and tertiary prevention. This means we want to encourage healthy families and healthy relationships within the family, as well as screening for risk and targeting interventions for families that have experienced difficulties, as well as for parents who have mental illness or substance use disorders.

Understanding the motive behind an individual committing filicide is also critical so that we do not conflate filicide and mental illness. Conflating these concepts leads to increased stigmatization and less help-seeking behavior.

Table 3^{3,4,7,18,22,23} describes the importance of understanding the motives for child murder by a parent in order to conceptualize appropriate prevention. Prevention efforts for 1 type of child murder will not necessarily help prevent murders that occur due to the other motives. Regarding prevention for fatal maltreatment cases, poor parenting skills, including inappropriate expressions of discipline, anger, and frustration, are common. In some cases, substance abuse is involved or the parent was acutely mentally unwell. Reporting to Child Protective Services can be helpful, but as previously noted, it is difficult to ascertain which cases will lead to a homicide. Recommendations from Child Fatality Review teams also are valuable.

Though many parents have frustrations with their children or thoughts of child harm, the act of filicide is rare, and individual cases may be difficult to predict. Regarding prediction, some mothers who committed filicide saw their psychiatrist within days to weeks before the murders.¹⁷ A small New Zealand study found that psychotic mothers reported no plans for killing their children in advance, whereas depressed mothers had contemplated the killing for days to weeks.²⁴

Several studies have asked mothers about thoughts of harming their child. Among mothers with colicky infants, 70% reported “explicit aggressive thoughts and fantasies” while 26% had “infanticidal thoughts” during a colic episode.²⁵ Another study²⁶ found that among depressed mothers of infants and toddlers, 41% revealed thoughts of harming their child. Women with postpartum depression preferred not to share infanticidal thoughts with their doctor but were more likely to disclose that they were having suicidal thoughts in order to get needed help.²⁷ Psychiatrists need to feel comfortable asking mothers about their coping skills, their suicidal thoughts, and their filicidal thoughts.^14,23,28 Screening and treatment of mental illness is critical. Postpartum psychosis is well-known to pose an elevated risk of filicide and suicide.²³ Obsessive-compulsive disorder may cause a parent to ruminate over ego-dystonic child harm but should be treated and the risk conceptualized very differently than in postpartum psychosis.^23,29 Screening for postpartum depression and appropriate treatment of depression during pregnancy and the postpartum period decrease risk.³⁰

Continue to: Regarding prevention of neonaticide...

Regarding prevention of neonaticide, Safe Haven laws, baby boxes, anonymous birth options, and increased contraceptive information and availability can help decrease the risk of this well-defined type of homicide.⁴ Safe Haven laws originated from Child Fatality Review teams.²⁴ Though each state has its own variation, in general, parents can drop off an unharmed unwanted infant into Safe Havens in their state, which may include hospitals, police stations, or fire stations. In general, the mother remains anonymous and has immunity from prosecution for (safe) abandonment. There are drawbacks, such as lack of information regarding adoption and paternal rights. Safe Haven laws do not prevent all deaths and all unsafe abandonments. Baby boxes and baby hatches are used in various nations, including in Europe, and in some places have been used for centuries. In anonymous birth options, such as in France, a mother is not identified but is able to give birth at a hospital. This can decrease the risk from unattended delivery, but many women with denial of pregnancy report that they did not realize when they were about to give birth.⁴

Bottom Line

Knowledge about the intersection of mental illness and filicide can help in prevention. Parents who experience mental health concerns should be encouraged to obtain needed treatment, which aids prevention. However, many other factors elevate the risk of child murder by parents.

Related Resources

• National Center for Fatality Review and Prevention. https://ncfrp.org/
• Child Welfare Information Gateway. https://www.childwelfare.gov/topics/preventing/overview/federal-agencies/

Deaths of children who are killed by their parents often make the news. Cases of maternal infanticide may be particularly shocking, since women are expected to be selfless nurturers. Yet when a child is murdered, the most common perpetrator is their parent, and mothers and fathers kill at similar rates.¹

As psychiatrists, we may see these cases in the news and worry about the risks of our own patients killing their children. In approximately 500 cases annually, an American parent is arrested for the homicide of their child.² This is not even the entire story, since a large percentage of such cases end in suicide—and no arrest. This article reviews the reasons parents kill their children, and considers common characteristics of these parents, dispelling some myths, before discussing the importance of prevention efforts.

Types of child murder by parents

Child murder by parents is termed filicide. Infanticide has various meanings but often refers to the murder of a child younger than age 1. Approximately 2 dozen nations (but not the United States) have Infanticide Acts that decrease the penalty for mothers who kill their young child.³ Neonaticide refers to murder of the infant at birth or in the first day of life.⁴

Epidemiology and common characteristics

Approximately 15%—or 1 in 7 murders with an arrest—is a filicide.² The younger the child, the greater the risk, but older children are killed as well.² Internationally, fathers and mothers are found to kill at similar rates. For other types of homicide, offenders are overwhelmingly male. This makes child murder by parents the singular type of murder in which women and men perpetrate in equal numbers. Fathers are more likely than mothers to also commit suicide after they kill their children.⁵ The “Cinderella effect” refers to the elevated risk of a stepchild being killed compared to the risk for a biological child.⁶

In the general international population, mothers who commit filicide tend to have multiple stressors and limited resources. They may be socially isolated and may be victims themselves as well as potentially experiencing substance abuse.¹ Some mothers view the child they killed as abnormal.

Less research has been conducted about fathers who kill. Fathers are more likely to also commit partner homicide.^5,7 They are more likely to complete filicide-suicide and use firearms or other violent means.^5,7-9 Fathers may have a history of violence, substance abuse, and/or mental illness.⁷

Neonaticide

Mothers are the most common perpetrator of neonaticide.⁴ It is unusual for a father to be involved in a neonaticide, or for the father and mother to perpetrate the act together. Rates of neonaticide are considered underestimates because of the number of hidden pregnancies, hidden corpses, and the difficulty that forensic pathologists may have in determining whether a baby was born alive or dead.

Continue to: Perpetrators of neonaticide...

Perpetrators of neonaticide tend to be single, relatively young women acting alone. They often live with their parents and are fearful of the repercussions of being pregnant. Pregnancies are often hidden, with no prenatal care. This includes both denial and concealment of pregnancy.⁴ Perpetrators of neonaticide commonly lack a premorbid serious mental illness, though after the homicide they may develop anxiety, depression, posttraumatic stress disorder (PTSD), or adjustment disorder.⁴ (Individuals who unwittingly find a murdered baby’s corpse may also be at risk of PTSD.)

Hidden pregnancies may be due to concealment or denial of pregnancy.^10,11 Concealment of pregnancy involves a woman knowing she is pregnant, but purposely hiding from others. Concealment may occur after a period of denial of pregnancy. Denial of pregnancy has several subtypes: pervasive denial, affective denial, and psychotic denial. In cases of pervasive denial, the existence of the pregnancy and the pregnancy’s emotional significance is outside the woman’s awareness. Alternatively, in affective denial, she is intellectually aware that she is pregnant but makes little emotional or physical preparation. In the rarest form, psychotic denial, a woman with a psychotic disorder such as schizophrenia may intermittently deny her pregnancy. This may be correlated with a history of custody loss.^10,11 Unlike denial of other medical conditions, in cases of denial of pregnancy, there will exist a very specific point in time (delivery) when the reality of the baby confronts the woman. Risks in cases of hidden pregnancies include those from lack of prenatal care and an assisted delivery as well as neonaticide. An FBI study¹² of law enforcement files found most neonaticide offenders were single young women with no criminal or psychological history. A caveat is that in the rare cases in which a woman with psychotic illness commits neonaticide, she may have different characteristics from those generally reported.¹³

Motives

Fathers and mothers have a similar set of motives for killing their child (Table 1^13-15). Motives are critical to understand not only within forensics, but also for prevention. In performing assessments after a filicide, forensic psychiatrists must be mindful of gender bias.^7,16 Resnick¹⁵ initially described 5 motives based on his 1969 review of the world literature. Our work^5,17 has subsequently further explored these motives.

In child homicides from “fatal maltreatment,” the child has often been a chronic victim of abuse or neglect. National American data indicate that approximately 2 per 100,000 children are killed from child maltreatment annually. Of note in conceptualizing prevention, out of the same population of 100,000, there will be 471 referrals to Child Protective Services and 91 substantiated cases.¹⁸ However, only a minority of children who die from maltreatment had previous Child Protective Services involvement. While a child may be killed by fatal maltreatment at any age, one-half are younger than age 1, and three-quarters are younger than age 3.¹⁸ In rare cases, a parent who engages in medical child abuse (including factitious disorder imposed upon another) kills the child. Depending on the location and whether or not the death appeared to be intended, parents who kill because of fatal maltreatment might face charges of various levels of murder or manslaughter.

“Unwanted child” homicides occur when the parent has determined that they do not want to have the child, especially in comparison to another need or want. Unwanted child motive is the most common in neonaticide cases, occurring after a hidden pregnancy.⁴

Continue to: In "partner revenge" cases...

In “partner revenge” cases, parenting disputes, a custody battle, infidelity, or a difficult relationship breakup is often present. The parent wants to make the other parent suffer, and does so by killing their child. A parent may make statements such as “If I can’t have [the child], no one can,” and the child is used as a pawn.

In the final 2 motives—“altruistic” and “acutely psychotic”—mental illness is common. These are the populations we tend to find in samples of filicide-suicide cases where the parent has killed themselves and their child, and those found not guilty by reason of insanity.^5,17 Altruistic filicide has been described as “murder out of love.” How can a parent kill their child out of love? Our research has shown several ways. First, the parent may be severely depressed and suicidal. They may be planning their own suicide, and as a parent who loves their child, they plan to take their child with them in death and not leave them alone in the “cruel world” that they themselves are departing. Or the parent may believe they are killing the child out of love to prevent or relieve the child’s suffering. The psychotic parent may believe that a terrible fate will befall their child, and they are killing them “gently.” For example, the parent may believe the child will be tortured or sex trafficked. Some parents may believe that their child has a devastating disease and think they would be better off dead. (Similar thinking of misguided altruism is seen in some cases of intimate partner homicide among older adults.¹⁹)

Alternatively, in rare cases of acutely psychotic filicide, parents with psychosis kill their child with no comprehensible motive. For example, they may be in a postictal state or may hear a command hallucination from God in the context of their psychosis.¹⁵

Myths vs realities of filicide

Common myths vs the realities of filicide are noted in Table 2. There are issues with believing these myths. For example, if we believe that most parents who kill their child have mental illness, this conflates mental illness and child homicide in our minds as well as the mind of the public. This can lead to further stigmatization of mental illness, and a lack of help-seeking behaviors because parents experiencing psychiatric symptoms may be afraid that if they report their symptoms, their child will be removed by Child Protective Services. However, treated mental illness decreases the risks of child abuse, similar to how treating mental illness decreases risks of other types of violence.^20,21

Focusing on prevention

On a local level, we need to understand these tragedies to better understand prevention. To this end, across the United States, counties have Child Fatality Review teams.²² These teams are a partnership across sectors and disciplines, including professionals from health services, law enforcement, and social services—among others—working together to understand cases and consider preventive strategies and additional services needed within our communities.

Continue to: When conceptualizing prevention...

When conceptualizing prevention of child murder by parents, we can think of primary, secondary, and tertiary prevention. This means we want to encourage healthy families and healthy relationships within the family, as well as screening for risk and targeting interventions for families that have experienced difficulties, as well as for parents who have mental illness or substance use disorders.

Understanding the motive behind an individual committing filicide is also critical so that we do not conflate filicide and mental illness. Conflating these concepts leads to increased stigmatization and less help-seeking behavior.

Table 3^{3,4,7,18,22,23} describes the importance of understanding the motives for child murder by a parent in order to conceptualize appropriate prevention. Prevention efforts for 1 type of child murder will not necessarily help prevent murders that occur due to the other motives. Regarding prevention for fatal maltreatment cases, poor parenting skills, including inappropriate expressions of discipline, anger, and frustration, are common. In some cases, substance abuse is involved or the parent was acutely mentally unwell. Reporting to Child Protective Services can be helpful, but as previously noted, it is difficult to ascertain which cases will lead to a homicide. Recommendations from Child Fatality Review teams also are valuable.

Though many parents have frustrations with their children or thoughts of child harm, the act of filicide is rare, and individual cases may be difficult to predict. Regarding prediction, some mothers who committed filicide saw their psychiatrist within days to weeks before the murders.¹⁷ A small New Zealand study found that psychotic mothers reported no plans for killing their children in advance, whereas depressed mothers had contemplated the killing for days to weeks.²⁴

Several studies have asked mothers about thoughts of harming their child. Among mothers with colicky infants, 70% reported “explicit aggressive thoughts and fantasies” while 26% had “infanticidal thoughts” during a colic episode.²⁵ Another study²⁶ found that among depressed mothers of infants and toddlers, 41% revealed thoughts of harming their child. Women with postpartum depression preferred not to share infanticidal thoughts with their doctor but were more likely to disclose that they were having suicidal thoughts in order to get needed help.²⁷ Psychiatrists need to feel comfortable asking mothers about their coping skills, their suicidal thoughts, and their filicidal thoughts.^14,23,28 Screening and treatment of mental illness is critical. Postpartum psychosis is well-known to pose an elevated risk of filicide and suicide.²³ Obsessive-compulsive disorder may cause a parent to ruminate over ego-dystonic child harm but should be treated and the risk conceptualized very differently than in postpartum psychosis.^23,29 Screening for postpartum depression and appropriate treatment of depression during pregnancy and the postpartum period decrease risk.³⁰

Continue to: Regarding prevention of neonaticide...

Regarding prevention of neonaticide, Safe Haven laws, baby boxes, anonymous birth options, and increased contraceptive information and availability can help decrease the risk of this well-defined type of homicide.⁴ Safe Haven laws originated from Child Fatality Review teams.²⁴ Though each state has its own variation, in general, parents can drop off an unharmed unwanted infant into Safe Havens in their state, which may include hospitals, police stations, or fire stations. In general, the mother remains anonymous and has immunity from prosecution for (safe) abandonment. There are drawbacks, such as lack of information regarding adoption and paternal rights. Safe Haven laws do not prevent all deaths and all unsafe abandonments. Baby boxes and baby hatches are used in various nations, including in Europe, and in some places have been used for centuries. In anonymous birth options, such as in France, a mother is not identified but is able to give birth at a hospital. This can decrease the risk from unattended delivery, but many women with denial of pregnancy report that they did not realize when they were about to give birth.⁴

Bottom Line

Knowledge about the intersection of mental illness and filicide can help in prevention. Parents who experience mental health concerns should be encouraged to obtain needed treatment, which aids prevention. However, many other factors elevate the risk of child murder by parents.

Related Resources

• National Center for Fatality Review and Prevention. https://ncfrp.org/
• Child Welfare Information Gateway. https://www.childwelfare.gov/topics/preventing/overview/federal-agencies/

Deaths of children who are killed by their parents often make the news. Cases of maternal infanticide may be particularly shocking, since women are expected to be selfless nurturers. Yet when a child is murdered, the most common perpetrator is their parent, and mothers and fathers kill at similar rates.¹

As psychiatrists, we may see these cases in the news and worry about the risks of our own patients killing their children. In approximately 500 cases annually, an American parent is arrested for the homicide of their child.² This is not even the entire story, since a large percentage of such cases end in suicide—and no arrest. This article reviews the reasons parents kill their children, and considers common characteristics of these parents, dispelling some myths, before discussing the importance of prevention efforts.

Types of child murder by parents

Child murder by parents is termed filicide. Infanticide has various meanings but often refers to the murder of a child younger than age 1. Approximately 2 dozen nations (but not the United States) have Infanticide Acts that decrease the penalty for mothers who kill their young child.³ Neonaticide refers to murder of the infant at birth or in the first day of life.⁴

Epidemiology and common characteristics

Approximately 15%—or 1 in 7 murders with an arrest—is a filicide.² The younger the child, the greater the risk, but older children are killed as well.² Internationally, fathers and mothers are found to kill at similar rates. For other types of homicide, offenders are overwhelmingly male. This makes child murder by parents the singular type of murder in which women and men perpetrate in equal numbers. Fathers are more likely than mothers to also commit suicide after they kill their children.⁵ The “Cinderella effect” refers to the elevated risk of a stepchild being killed compared to the risk for a biological child.⁶

In the general international population, mothers who commit filicide tend to have multiple stressors and limited resources. They may be socially isolated and may be victims themselves as well as potentially experiencing substance abuse.¹ Some mothers view the child they killed as abnormal.

Less research has been conducted about fathers who kill. Fathers are more likely to also commit partner homicide.^5,7 They are more likely to complete filicide-suicide and use firearms or other violent means.^5,7-9 Fathers may have a history of violence, substance abuse, and/or mental illness.⁷

Neonaticide

Mothers are the most common perpetrator of neonaticide.⁴ It is unusual for a father to be involved in a neonaticide, or for the father and mother to perpetrate the act together. Rates of neonaticide are considered underestimates because of the number of hidden pregnancies, hidden corpses, and the difficulty that forensic pathologists may have in determining whether a baby was born alive or dead.

Continue to: Perpetrators of neonaticide...

Perpetrators of neonaticide tend to be single, relatively young women acting alone. They often live with their parents and are fearful of the repercussions of being pregnant. Pregnancies are often hidden, with no prenatal care. This includes both denial and concealment of pregnancy.⁴ Perpetrators of neonaticide commonly lack a premorbid serious mental illness, though after the homicide they may develop anxiety, depression, posttraumatic stress disorder (PTSD), or adjustment disorder.⁴ (Individuals who unwittingly find a murdered baby’s corpse may also be at risk of PTSD.)

Hidden pregnancies may be due to concealment or denial of pregnancy.^10,11 Concealment of pregnancy involves a woman knowing she is pregnant, but purposely hiding from others. Concealment may occur after a period of denial of pregnancy. Denial of pregnancy has several subtypes: pervasive denial, affective denial, and psychotic denial. In cases of pervasive denial, the existence of the pregnancy and the pregnancy’s emotional significance is outside the woman’s awareness. Alternatively, in affective denial, she is intellectually aware that she is pregnant but makes little emotional or physical preparation. In the rarest form, psychotic denial, a woman with a psychotic disorder such as schizophrenia may intermittently deny her pregnancy. This may be correlated with a history of custody loss.^10,11 Unlike denial of other medical conditions, in cases of denial of pregnancy, there will exist a very specific point in time (delivery) when the reality of the baby confronts the woman. Risks in cases of hidden pregnancies include those from lack of prenatal care and an assisted delivery as well as neonaticide. An FBI study¹² of law enforcement files found most neonaticide offenders were single young women with no criminal or psychological history. A caveat is that in the rare cases in which a woman with psychotic illness commits neonaticide, she may have different characteristics from those generally reported.¹³

Motives

Fathers and mothers have a similar set of motives for killing their child (Table 1^13-15). Motives are critical to understand not only within forensics, but also for prevention. In performing assessments after a filicide, forensic psychiatrists must be mindful of gender bias.^7,16 Resnick¹⁵ initially described 5 motives based on his 1969 review of the world literature. Our work^5,17 has subsequently further explored these motives.

In child homicides from “fatal maltreatment,” the child has often been a chronic victim of abuse or neglect. National American data indicate that approximately 2 per 100,000 children are killed from child maltreatment annually. Of note in conceptualizing prevention, out of the same population of 100,000, there will be 471 referrals to Child Protective Services and 91 substantiated cases.¹⁸ However, only a minority of children who die from maltreatment had previous Child Protective Services involvement. While a child may be killed by fatal maltreatment at any age, one-half are younger than age 1, and three-quarters are younger than age 3.¹⁸ In rare cases, a parent who engages in medical child abuse (including factitious disorder imposed upon another) kills the child. Depending on the location and whether or not the death appeared to be intended, parents who kill because of fatal maltreatment might face charges of various levels of murder or manslaughter.

“Unwanted child” homicides occur when the parent has determined that they do not want to have the child, especially in comparison to another need or want. Unwanted child motive is the most common in neonaticide cases, occurring after a hidden pregnancy.⁴

Continue to: In "partner revenge" cases...

In “partner revenge” cases, parenting disputes, a custody battle, infidelity, or a difficult relationship breakup is often present. The parent wants to make the other parent suffer, and does so by killing their child. A parent may make statements such as “If I can’t have [the child], no one can,” and the child is used as a pawn.

In the final 2 motives—“altruistic” and “acutely psychotic”—mental illness is common. These are the populations we tend to find in samples of filicide-suicide cases where the parent has killed themselves and their child, and those found not guilty by reason of insanity.^5,17 Altruistic filicide has been described as “murder out of love.” How can a parent kill their child out of love? Our research has shown several ways. First, the parent may be severely depressed and suicidal. They may be planning their own suicide, and as a parent who loves their child, they plan to take their child with them in death and not leave them alone in the “cruel world” that they themselves are departing. Or the parent may believe they are killing the child out of love to prevent or relieve the child’s suffering. The psychotic parent may believe that a terrible fate will befall their child, and they are killing them “gently.” For example, the parent may believe the child will be tortured or sex trafficked. Some parents may believe that their child has a devastating disease and think they would be better off dead. (Similar thinking of misguided altruism is seen in some cases of intimate partner homicide among older adults.¹⁹)

Alternatively, in rare cases of acutely psychotic filicide, parents with psychosis kill their child with no comprehensible motive. For example, they may be in a postictal state or may hear a command hallucination from God in the context of their psychosis.¹⁵

Myths vs realities of filicide

Common myths vs the realities of filicide are noted in Table 2. There are issues with believing these myths. For example, if we believe that most parents who kill their child have mental illness, this conflates mental illness and child homicide in our minds as well as the mind of the public. This can lead to further stigmatization of mental illness, and a lack of help-seeking behaviors because parents experiencing psychiatric symptoms may be afraid that if they report their symptoms, their child will be removed by Child Protective Services. However, treated mental illness decreases the risks of child abuse, similar to how treating mental illness decreases risks of other types of violence.^20,21

Focusing on prevention

On a local level, we need to understand these tragedies to better understand prevention. To this end, across the United States, counties have Child Fatality Review teams.²² These teams are a partnership across sectors and disciplines, including professionals from health services, law enforcement, and social services—among others—working together to understand cases and consider preventive strategies and additional services needed within our communities.

Continue to: When conceptualizing prevention...

When conceptualizing prevention of child murder by parents, we can think of primary, secondary, and tertiary prevention. This means we want to encourage healthy families and healthy relationships within the family, as well as screening for risk and targeting interventions for families that have experienced difficulties, as well as for parents who have mental illness or substance use disorders.

Understanding the motive behind an individual committing filicide is also critical so that we do not conflate filicide and mental illness. Conflating these concepts leads to increased stigmatization and less help-seeking behavior.

Table 3^{3,4,7,18,22,23} describes the importance of understanding the motives for child murder by a parent in order to conceptualize appropriate prevention. Prevention efforts for 1 type of child murder will not necessarily help prevent murders that occur due to the other motives. Regarding prevention for fatal maltreatment cases, poor parenting skills, including inappropriate expressions of discipline, anger, and frustration, are common. In some cases, substance abuse is involved or the parent was acutely mentally unwell. Reporting to Child Protective Services can be helpful, but as previously noted, it is difficult to ascertain which cases will lead to a homicide. Recommendations from Child Fatality Review teams also are valuable.

Though many parents have frustrations with their children or thoughts of child harm, the act of filicide is rare, and individual cases may be difficult to predict. Regarding prediction, some mothers who committed filicide saw their psychiatrist within days to weeks before the murders.¹⁷ A small New Zealand study found that psychotic mothers reported no plans for killing their children in advance, whereas depressed mothers had contemplated the killing for days to weeks.²⁴

Several studies have asked mothers about thoughts of harming their child. Among mothers with colicky infants, 70% reported “explicit aggressive thoughts and fantasies” while 26% had “infanticidal thoughts” during a colic episode.²⁵ Another study²⁶ found that among depressed mothers of infants and toddlers, 41% revealed thoughts of harming their child. Women with postpartum depression preferred not to share infanticidal thoughts with their doctor but were more likely to disclose that they were having suicidal thoughts in order to get needed help.²⁷ Psychiatrists need to feel comfortable asking mothers about their coping skills, their suicidal thoughts, and their filicidal thoughts.^14,23,28 Screening and treatment of mental illness is critical. Postpartum psychosis is well-known to pose an elevated risk of filicide and suicide.²³ Obsessive-compulsive disorder may cause a parent to ruminate over ego-dystonic child harm but should be treated and the risk conceptualized very differently than in postpartum psychosis.^23,29 Screening for postpartum depression and appropriate treatment of depression during pregnancy and the postpartum period decrease risk.³⁰

Continue to: Regarding prevention of neonaticide...

Regarding prevention of neonaticide, Safe Haven laws, baby boxes, anonymous birth options, and increased contraceptive information and availability can help decrease the risk of this well-defined type of homicide.⁴ Safe Haven laws originated from Child Fatality Review teams.²⁴ Though each state has its own variation, in general, parents can drop off an unharmed unwanted infant into Safe Havens in their state, which may include hospitals, police stations, or fire stations. In general, the mother remains anonymous and has immunity from prosecution for (safe) abandonment. There are drawbacks, such as lack of information regarding adoption and paternal rights. Safe Haven laws do not prevent all deaths and all unsafe abandonments. Baby boxes and baby hatches are used in various nations, including in Europe, and in some places have been used for centuries. In anonymous birth options, such as in France, a mother is not identified but is able to give birth at a hospital. This can decrease the risk from unattended delivery, but many women with denial of pregnancy report that they did not realize when they were about to give birth.⁴

Bottom Line

Knowledge about the intersection of mental illness and filicide can help in prevention. Parents who experience mental health concerns should be encouraged to obtain needed treatment, which aids prevention. However, many other factors elevate the risk of child murder by parents.

Related Resources

• National Center for Fatality Review and Prevention. https://ncfrp.org/
• Child Welfare Information Gateway. https://www.childwelfare.gov/topics/preventing/overview/federal-agencies/

Advances in the understanding of neurobiological and neuro­psychiatric pathophysiology have opened new avenues of treatment for psychiatric patients. Historically, with a few exceptions, most psychiatric medications have been administered orally. However, many of the newer treatments require some form of specialized administration because they cannot be taken orally due to their chemical property (such as aducanumab); because there is the need to produce stable blood levels of the medication (such as brexanolone); because oral administration greatly diminished efficacy (such as oral vs IV magnesium or scopolamine), or because the treatment is focused on specific brain structures. This need for specialized administration has created a subspecialty called interventional psychiatry.

Part 1 of this 2-part article provides an overview of 1 type of interventional psychiatry: parenterally administered medications, including those administered via IV. We also describe 3 other interventional approaches to treatment: stellate ganglion blocks, glabellar botulinum toxin (BT) injections, and trigger point injections. In Part 2 we will review interventional approaches that involve neuromodulation.

Parenteral medications in psychiatry

In general, IV and IM medications can be more potent that oral medications due to their overall faster onset of action and higher blood concentrations. These more invasive forms of administration can have significant limitations, such as a risk of infection at the injection site, the need to be administered in a medical setting, additional time, and patient discomfort.

Table 1 lists short-acting injectable medications used in psychiatry, and Table 2 lists long-acting injectable medications. Parenteral administration of antipsychotics is performed to alleviate acute agitation or for chronic symptom control. These medications generally are not considered interventional treatments, but could be classified as such due to their invasive nature.¹ Furthermore, inhalable loxapine—which is indicated for managing acute agitation—requires a Risk Evaluation and Mitigation Strategy program consisting of 2 hours observation and monitoring of respiratory status.^2,3 Other indications for parenteral treatments include IM naltrexone extended release⁴ and subcutaneous injections of buprenorphine extended release⁵ and risperidone.⁶

IV administration

Most IV treatments described in this article are not FDA-approved for psychiatric treatment. Despite this, many interventional psychiatric treatments are part of clinical practice. IV infusion of ketamine is the most widely known and most researched of these. Table 3 lists other IV treatments that could be used as psychiatric treatment.

Ketamine

Since the early 1960s, ketamine has been used as a surgical anesthetic for animals. In the United States, it was approved for human surgical anesthesia in 1970. It was widely used during the Vietnam War due to its lack of inhibition of respiratory drive; medical staff first noticed an improvement in depressive symptoms and the resolution of suicidal ideation in patients who received ketamine. This led to further research on ketamine, particularly to determine its application in treatment-resistant depression (TRD) and other conditions.⁷ IV ketamine administration is most widely researched, but IM injections, intranasal sprays, and lozenges are also available. The dissociative properties of ketamine have led to its recreational use.⁸

Hypotheses for the mechanism of action of ketamine as an antidepressant include direct synaptic or extrasynaptic (GluN2B-selective), N-methyl-D-aspartate receptor (NMDAR) inhibition, selectively greater inhibition of NMDARs localized on GABAergic (gamma-aminobutyric acid) interneurons, and the role of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor activation. There are links between ketamine’s antidepressant actions and downstream mechanisms regulating synaptic plasticity, including brain-derived neurotrophic factor, eukaryotic elongation factor 2, mammalian target of rapamycin, and glycogen synthase kinase-3. Multiple other ketamine-associated mechanisms also have been described.^9,10 Action on the mu-opioid receptor is also known, possibly contributing to both antidepressant and anesthetic properties of ketamine.¹¹ Rapid onset of ketamine antidepressant action is especially valuable.¹²

Continue to: Ketamine is a schedule...

Ketamine is a schedule III medication with addictive properties. Delirium, panic attacks, hallucinations, nightmares, dysphoria, and paranoia may occur during and after use.¹³ Premedication with benzodiazepines, most notably lorazepam, is occasionally used to minimize ketamine’s adverse effects, but this generally is not recommended because doing so reduces ketamine’s antidepressant effects.¹⁴ Driving and operating heavy machinery is contraindicated after IV infusion. The usual protocol involves an IV infusion of ketamine 0.4 mg/kg to 1 mg/kg dosing over 1 hour. Doses between 0.4 mg/kg and 0.6 mg/kg are most common. Ketamine has a therapeutic window; doses >0.5 mg/kg are progressively less effective.¹⁵ Unlike the recommendation after esketamine administration, after receiving ketamine, patients remain in the care of their treatment team for <2 hours.

Esketamine, the S enantiomer of ketamine, was FDA-approved for TRD as an intranasal formulation. Esketamine is more commonly used than IV ketamine because it is FDA-approved and typically covered by insurance, but it may not be as effective.¹⁶ An economic analysis by Brendle et al¹⁷ suggested insurance companies would lower costs if they covered ketamine infusions vs intranasal esketamine.

Aducanumab and lecanemab

The most recent FDA-approved interventional agents are aducanumab and lecanemab, which are indicated for treating Alzheimer disease.^18,19 Both are human monoclonal antibodies that bind selectively and with high affinity to amyloid beta plaque aggregates and promote their removal by Fc receptor–mediated phagocytosis.²⁰

FDA approval of aducanumab and lecanemab was controversial. Initially, aducanumab’s safety monitoring board performed a futility analysis that suggested aducanumab was unlikely to separate from placebo, and the research was stopped.²¹ The manufacturer petitioned the FDA to consider the medication for accelerated approval on the basis of biomarker data showing that amyloid beta plaque aggregates become smaller. Current FDA approval is temporary to allow patients access to this potentially beneficial agent, but the manufacturer must supply clinical evidence that the reduction of amyloid beta plaques is associated with desirable changes in the course of Alzheimer disease, or risk losing the approval.

Lecanemab is also a human monoclonal antibody intended to remove amyloid beta plaques that was FDA-approved under the accelerated approval pathway.²² Unlike aducanumab, lecanemab demonstrated a statistically significant (although clinically imperceptible) reduction in the rate of cognitive decline; it did not show cognitive improvement.²³ Lecanemab also significantly reduced amyloid beta plaques.²³

Continue to: Aducanumab and lecanemab are generally...

Aducanumab and lecanemab are generally not covered by insurance and typically cost >$26,000 annually. Both are administered by IV infusion once a month. More monoclonal antibody medications for treating early Alzheimer disease are in the late stages of development, most notably donanebab.²⁴ Observations during clinical trials found that in the later stages of Alzheimer disease, forceful removal of plaques by the autoimmune process damages neurons, while in less dense deposits of early dementia such removal is not harmful to the cells and prevents amyloid buildup.

Brexanolone

Brexanolone is an aqueous formulation of allopregnanolone, a major metabolite of progesterone and a positive allosteric modulator of GABA-A receptors.²⁵ Its levels are maximal at the end of the third trimester of pregnancy and fall rapidly following delivery. Research showed a 3-day infusion was rapidly and significantly effective for treating postpartum depression²⁶ and brexanolone received FDA approval for this indication in March 2019.²⁷ However, various administrative, economic, insurance, and other hurdles make it difficult for patients to access this treatment. Despite its rapid onset of action (usually 48 hours), brexanolone takes an average of 15 days to go through the prior authorization process.²⁸ In addition to the need for prior authorization, the main impediment to the use of brexanolone is the 3-day infusion schedule, which greatly magnifies the cost but is partially circumvented by the availability of dedicated outpatient centers.

Magnesium

Magnesium is on the World Health Organization’s Model List of Essential Medicines.²⁹ There has been extensive research on the use of magnesium sulfate for psychiatric indications, especially for depression.³⁰ Magnesium functions similarly to calcium channel blockers by competitively blocking intracellular calcium channels, decreasing calcium availability, and inhibiting smooth muscle contractility.³¹ It also competes with calcium at the motor end plate, reducing excitation by inhibiting the release of acetylcholine.³² This property is used for high-dose IV magnesium treatment of impending preterm labor in obstetrics. Magnesium sulfate is the drug of choice in treating eclamptic seizures and preventing seizures in severe preeclampsia or gestational hypertension with severe features.³³ It is also used to treat torsade de pointes, severe asthma exacerbations, constipation, and barium poisoning.³⁴ Beneficial use in asthma treatment³⁵ and the treatment of migraine³⁶ have also been reported.

IV magnesium in myocardial infarction may be harmful,³⁷ though outside of acute cardiac events, magnesium is found to be safe.³⁸

Oral magnesium sulfate is a common over-the-counter anxiety remedy. As a general cell stabilizer (mediated by the reduction of intracellular calcium), magnesium is potentially beneficial outside of its muscle-relaxing properties, although muscle relaxing can benefit anxious patients. It is used to treat anxiety,³⁹ alcohol withdrawal,⁴⁰ and fear.⁴¹ Low magnesium blood levels are found in patients with depression, schizophrenia,⁴² and attention-deficit/hyperactivity disorder.⁴³ However, it is important to note that the therapeutic effect of magnesium when treating anxiety and headache is independent of preinfusion magnesium blood levels.⁴³

Continue to: The efficacy of oral magnesium...

The efficacy of oral magnesium is not robust. However, IV administration has a pronounced beneficial effect as an abortive and preventative treatment in many patients with anxiety.⁴⁴

IV administration of magnesium can produce adverse effects, including flushing, sweating, hypotension, depressed reflexes, flaccid paralysis, hypothermia, circulatory collapse, and cardiac and CNS depression. These complications are very rare and dose-dependent.⁴⁵ Magnesium is excreted by the kidneys, and dosing must be decreased in patients with kidney failure. The most common adverse effect is local burning along the vein upon infusion; small doses of IV lidocaine can remedy this. Hot flashes are also common.⁴⁵

Various dosing strategies are available. In patients with anxiety, application dosing is based on the recommended preeclampsia IV dose of 4 g diluted in 250 mL of 5% dextrose. Much higher doses may be used in obstetrics. Unlike in obstetrics, for psychiatric indications, magnesium is administered over 60 to 90 minutes. Heart monitoring is recommended.

Scopolamine

Scopolamine is primarily used to relieve nausea, vomiting, and dizziness associated with motion sickness and recovery from anesthesia. It is also used in ophthalmology and in patients with excessive sweating. In off-label and experimental applications, scopolamine has been used in patients with TRD.⁴⁶

Scopolamine is an anticholinergic medication. It is a nonselective antagonist at muscarinic receptors.⁴⁷ Tricyclic antidepressants (TCAs) possess strong anticholinergic function. Newer generations of antidepressants were designed specifically not to have this function because it was believed to be an unwanted and potentially dangerous adverse effect. However, data suggest that anticholinergic action is important in decreasing depressive symptoms. Several hypotheses of anticholinergic effects on depression have been published since the 1970s. They include the cholinergic-adrenergic hypothesis,⁴⁸ acetylcholine predominance relative to adrenergic action hypothesis,⁴⁹ and insecticide poisoning observations.⁵⁰ Centrally acting physostigmine (but not peripherally acting neostigmine) was reported to control mania.^48,51 A genetic connection between the M2acetylcholine receptor in patients with major depressive disorder (MDD) and alcohol use disorder is also suggestive.⁵²

Continue to: Multiple animal studies show...

Multiple animal studies show direct improvement in mobility and a decrease in despair upon introducing anticholinergic substances.^53-55 The cholinergic theory of depression has been studied in several controlled clinical human studies.^56,57 Use of a short-acting anticholinergic glycopyrrolate during electroconvulsive therapy (ECT) may contribute to the procedure’s efficacy.

Human research shows scopolamine has a higher efficacy as an antidepressant and anti-anxiety medication in women than in men,⁵⁸ possibly because estrogen increases the activity of choline acetyltransferase and release of acetylcholine.^59,60 M2receptors mediate estrogen influence on the NMDAR, which may explain the anticholinergic effects of depression treatments in women.⁶¹

Another proposed mechanism of action of scopolamine is a potent inhibition of the NMDAR.⁶² Rapid treatments of depression may be based on this mechanism. Examples of such treatments include IV ketamine and sleep deprivation.⁶³ IV scopolamine shows potency in treating MDD and bipolar depression. This treatment should be reserved for patients who do not respond to or are not candidates for other usual treatment modalities of MDD and for the most severe cases. Scopolamine is 30 times more potent than amitriptyline in anticholinergic effect and reportedly produces sustained improvement in MDD.⁶⁴

Scopolamine has no black-box warnings. It has not been studied in pregnant women and is not recommended for use during pregnancy. Due to possible negative cardiovascular effects, a normal electrocardiogram is required before the start of treatment. Exercise caution in patients with glaucoma, benign prostatic enlargement, gastroparesis, unstable cardiovascular status, or severe renal impairment.

Treatment with scopolamine is not indicated for patients with myasthenia gravis, psychosis, or seizures. Patients must be off potassium for 3 days before beginning scopolamine treatment. Patients should consult with their cardiologist before having a scopolamine infusion. Adverse reactions may include psychosis, tachycardia, seizures, paralytic ileus, and glaucoma exacerbation. The most common adverse effects of scopolamine infusion treatment include drowsiness, dry mouth, blurred vision, lightheadedness, and dizziness. Due to possible drowsiness, operating motor vehicles or heavy machinery must be avoided on the day of treatment.⁶⁵ Overall, the adverse effects of scopolamine are preventable and manageable, and its antidepressant efficacy is noteworthy.⁶⁶

Continue to: Treatment typically consists of 3 consecutive infusions...

Treatment typically consists of 3 consecutive infusions of 4 mcg/kg separated by 3 to 5 days.⁵⁶ It is possible to have a longer treatment course if the patient experiences only partial improvement. Repeated courses or maintenance treatment (similar to ECT maintenance) are utilized in some patients if indicated. Cardiac monitoring is mandatory.

Clomipramine

Clomipramine, a TCA, acts as a preferential inhibitor of 5-hydroxytryptamine uptake and has proven effective in managing depression, TRD, and obsessive-compulsive disorder (OCD).⁶⁷ Although this medication has reported treatment benefits for patients with phobia, panic disorder,¹⁵ chronic pain,⁶⁸ Tourette syndrome,⁶⁹ premature ejaculation, anorexia nervosa,⁷⁰ cataplexy,⁴⁹ and enuresis,⁷¹ it is FDA-approved only for the treatment of OCD.⁷² Clomipramine may also be beneficial for pain and headache, possibly because of its anti-inflammatory action.⁷³ The anticholinergic effects of clomipramine may add to its efficacy in depression.

The pathophysiology of MDD is connected to hyperactivity of the HPA axis and elevated cortisol levels. Higher clomipramine plasma levels show a linear correlation with lower cortisol secretion and levels, possibly aiding in the treatment of MDD and anxiety.⁷⁴ The higher the blood level, the more pronounced clomipramine’s therapeutic effect across multiple domains.⁷⁵

IV infusion of clomipramine produces the highest concentration in the shortest time, but overall, research does not necessarily support increased efficacy of IV over oral administration. There is evidence suggesting that subgroups of patients with severe, treatment-refractory OCD may benefit from IV agents and research suggests a faster onset of action.⁷⁶ Faster onset of symptom relief is the basis for IV clomipramine use. In patients with OCD, it can take several months for oral medications to produce therapeutic benefits; not all patients can tolerate this. In such scenarios, IV administration may be considered, though it is not appropriate for routine use until more research is available. Patients with treatment-resistant OCD who have exhausted other means of symptom relief may also be candidates for IV treatment.

The adverse effects of IV clomipramine are no different from oral use, though they may be more pronounced. A pretreatment cardiac exam is desirable because clomipramine, like other TCAs, may be cardiotoxic. The anticholinergic adverse effects of TCAs are well known to clinicians⁷⁷ and partially explained in the scopolamine section of this article. It is not advisable to combine clomipramine with other TCAs or serotonin reuptake inhibitors. Clomipramine also should not be combined with monoamine oxidase inhibitors, though such a combination was reported in medical literature.⁷⁸ Combination with antiarrhythmics such as lidocaine or opioids such as fentanyl or and tramadol is highly discouraged (fentanyl and tramadol also have serotonergic effects).⁷⁹

Continue to: Clomipramine for IV use is not commercially available...

Clomipramine for IV use is not commercially available and must be sterilely compounded. The usual course of treatment is a series of 3 infusions: 150 mg on Day 1, 200 mg on Day 2 or Day 3, and 250 mg on Day 3, Day 4, or Day 5, depending on tolerability. A protocol with a 50 mg/d starting dose and titration up to a maximum dose of 225 mg/d over 5 to 7 days has been suggested for inpatient settings.⁶⁷ Titration to 250 mg is more common.⁸⁰

A longer series may be performed, but this increases the likelihood of adverse effects. Booster and maintenance treatments are also completed when required. Cardiac monitoring is mandatory.

Vortioxetine and citalopram

IV treatment of depression with vortioxetine and citalopram has been explored but has not yet taken hold in clinical psychiatry.^81,82

Injections and blocks

Three interventional approaches to treatment that possess psychotherapeutic potential include stellate ganglion blocks (SGBs), glabellar BT injections, and trigger point injections (TPIs). None of these are FDA-approved for psychiatric treatment.

Stellate ganglion blocks

The sympathetic nervous system is involved in autonomic hyperarousal and is at the core of posttraumatic symptomatology.⁸³ Insomnia, anxiety, irritability, hypervigilance, and other excitatory CNS events are connected to the sympathetic nervous system and amygdala activation is commonly observed in those exposed to extreme stress or traumatic events.⁸⁴

Continue to: SGBs were first performed 100 years ago...

SGBs were first performed 100 years ago and reported to have beneficial psychiatric effects at the end of the 1940s. In 1998 in Finland, improvement of posttraumatic stress disorder (PTSD) symptoms was observed accidentally via thoracic level spine blocks.⁸⁵ In 2006, cervical level sympathetic blocks were shown to be effective for PTSD symptom control.⁸⁶ By the end of 2010, Veterans Administration hospitals adopted SGBs to treat veterans with PTSD.^87,88 The first multisite, randomized clinical trial of SGB for PTSD confirmed multiple previous reports of treatment efficacy. Specifically, 2 SGB treatments 2 weeks apart effectively reduced total symptom severity scores over 8 weeks.⁸⁷

Since the stellate ganglion is connected to the amygdala, SGB has also been assessed for treating anxiety and depression.^89,90 Outside of PTSD, SGBs are used to treat complex regional pain syndrome,⁹¹ phantom limb pain, trigeminal neuralgia,⁹² intractable angina,⁹³ and postherpetic neuralgia in the head, neck, upper chest, or arms.⁹⁴ The procedure consists of an injection of a local anesthetic through a 25-gauge needle into the stellate sympathetic ganglion at the C6 or C7 vertebral levels. An injection into C6 is considered safer because of specific cervical spine anatomy. Ideally, fluoroscopic guidance or ultrasound is used to guide needle insertion.⁹⁵

A severe drop in blood pressure may be associated with SGBs and is mitigated by IV hydration. Other adverse effects include red eyes, drooping of the eyelids, nasal congestion, hoarseness, difficulty swallowing, a sensation of a “lump” in the throat, and a sensation of warmth or tingling in the arm or hand. Bilateral SGB is contraindicated due to the danger of respiratory arrest.⁹⁶

Glabellar BT injections

OnabotulinumtoxinA (BT) injection was first approved for therapeutic use in 1989 for eye muscle disorders such as strabismus⁹⁷ and blepharospasm.⁹⁸ It was later approved for several other indications, including cosmetic use, hyperhidrosis, migraine prevention, neurogenic bladder disorder, overactive bladder, urinary incontinence, and spasticity.^99-104 BT is used off-label for achalasia and sialorrhea.^105,106 Its mechanism of action is primarily attributed to muscle paralysis by blocking presynaptic acetylcholine release into neuromuscular junctions.¹⁰⁷

Facial BT injections are usually administered for cosmetic purposes, but smoothing forehead wrinkles and frown lines (the glabellar region of the face) both have antidepressant effects.¹⁰⁸ BT injections into the glabellar region also demonstrate antidepressant effects, particularly in patients with comorbid migraines and MDD.¹⁰⁹ Early case observations supported the independent benefit of the toxin on MDD when the toxin was injected into the glabellar region.^110,111 The most frequent protocol involves injections in the procerus and corrugator muscles.

Continue to: The facial feedback/emotional proprioception hypothesis...

The facial feedback/emotional proprioception hypothesis has dominated thinking about the mood-improving effects of BT. The theory is that blocking muscular expression of sadness (especially in the face) interrupts the experience of sadness; therefore, depression subsides.^112,113 However, BT injections in the muscles involved in the smile and an expression of positive emotions (lateral part of the musculus orbicularis oculi) have been associated with increased MDD scores.¹¹⁴ Thus, the mechanism clearly involves more than the cosmetic effect, since facial muscle injections in rats also have antidepressant effects.¹¹⁵

The use of progressive muscle relaxation is well-established in psychiatric treatment. The investigated conditions of increased muscle tone, especially torticollis and blepharospasm, are associated with MDD, and it may be speculated that proprioceptive feedback from the affected muscles may be causally involved in this association.^116-118 Activity of the corrugator muscle has been positively associated with increased amygdala activity.¹¹⁹ This suggests a potential similar mechanism to that hypothesized for SGB.

Alternatively, BT is commonly used to treat chronic conditions that may contribute to depression; its success in relieving the underlying problem may indirectly relieve MDD. Thus, in a postmarketing safety evaluation of BT, MDD was demonstrated 40% to 88% less often by patients treated with BT for 6 of the 8 conditions and injection sites, such as in spasms and spasticity of arms and legs, torticollis and neck pain, and axilla and palm injections for hyperhidrosis. In a parotid and submandibular glands BT injection subcohort, no patients experienced depressive symptoms.¹²⁰

Medicinal BT is generally considered safe. The most common adverse effects are hypersensitivity, injection site reactions, and other adverse effects specific to the injection site.¹²¹ Additionally, the cosmetic effects are transient, given the nature of the medication.

Trigger point injections

TPIs in the neck and shoulders are frequently used to treat tension headaches and various referred pain locations in the face and arms. Tension and depression frequently overlap in clinical practice.¹²² Relieving muscle tension (with resulting trigger points) improves muscle function and mood.

Continue to: The higher the number of active...

The higher the number of active trigger points (TPs), the greater the physical burden of headache and the higher the anxiety level. Gender differences in TP prevalence and TPI efficacy have been described in the literature. For example, the number of active TPs seems directly associated with anxiety levels in women but not in men.¹²³ Although TPs appear to be more closely associated with anxiety than depression,¹²⁴ depression associated with muscle tension does improve with TPIs. European studies have demonstrated a decrease in scores on the Hamilton Depression Rating Scale and Hamilton Anxiety Rating Scale following TPI treatment.¹²⁵ The effect may be indirect, as when a patient’s pain is relieved, sleep and other psychiatric symptoms improve.¹²⁶

A randomized controlled trial by Castro Sánchez et al¹²⁷ demonstrated that dry needling therapy in patients with fibromyalgia syndrome (FMS) showed improvements in pain pressure thresholds, body pain, vitality, and social function, as well as total FMS symptoms, quality of sleep, anxiety, hospital anxiety and depression, general pain intensity, and fatigue.

Myofascial pain syndrome, catastrophizing, and muscle tension are common in patients with depression, anxiety, and somatization. Local TPI therapy aimed at inactivating pain generators is supported by moderate quality evidence. All manner of therapies have been described, including injection of saline, corticosteroids, local anesthetic agents, and dry needling. BT injections in chronic TPs are also practiced, though no specific injection therapy has been reliably shown to be more advantageous than another. The benefits of TPIs may be derived from the needle itself rather than from any specific substance injected. Stimulation of a local twitch response with direct needling of the TP appears of importance. There is no established consensus regarding the number of injection points, frequency of administration, and volume or type of injectate.¹²⁸

Adverse effects of TPIs relate to the nature of the invasive therapy, with the risk of tissue damage and bleeding. Pneumothorax risk is present with needle insertion at the neck and thorax.¹²⁹ Patients with diabetes may experience variations in blood sugar control if steroids are used.

Bottom Line

Interventional treatment modalities that may have a role in psychiatric treatment include IV administration of ketamine, aducanumab, lecanemab, brexanolone, magnesium, scopolamine, and clomipramine. Other interventional approaches include stellate ganglion blocks, glabellar botulinum toxin injections, and trigger point injections.

Related Resources

• Dokucu ME, Janicak PG. Nontraditional therapies for treatment-resistant depression. Current Psychiatry. 2021; 20(9):38-43,49. doi:10.12788/cp.0166
• Kim J, Khoury R, Grossberg GT. Botulinum toxin: emerging psychiatric indications. Current Psychiatry. 2018;17(12):8-18.

Drug Brand Names

Aducanumab • Aduhelm
Aripiprazole • Abilify
Aripiprazole lauroxil • Aristada
Brexanolone • Zulresso
Buprenorphine • Sublocade
Citalopram • Celexa
Clomipramine • Anafranil
Diazepam • Valium
Droperidol • Inapsine
Esketamine • Spravato
Fentanyl • Actiq
Fluphenazine decanoate • Modecate
Fluphenazine hydrochloride • Prolixin
Haloperidol decanoate • Haldol decanoate
Haloperidol lactate • Haldol
Ketamine • Ketalar
Lecanemab • Leqembi
Lidocaine • Xylocaine
Lorazepam • Ativan
Loxapine inhaled • Adasuve
Naltrexone • Vivitrol
Magnesium sulfate • Sulfamag
Midazolam • Versed
Olanzapine • Zyprexa
OnabotulinumtoxinA injection • Botox
Paliperidone • Invega Hafyera, Invega Sustenna, Invega Trinza
Rapamycin • Rapamune, Sirolimus
Risperidone • Perseris
Risperidone microspheres • Risperdal Consta, Rykindo
Scopolamine • Hyoscine
Tramadol • Conzip
Vortioxetine • Trintellix
Ziprasidone • Geodon

Advances in the understanding of neurobiological and neuro­psychiatric pathophysiology have opened new avenues of treatment for psychiatric patients. Historically, with a few exceptions, most psychiatric medications have been administered orally. However, many of the newer treatments require some form of specialized administration because they cannot be taken orally due to their chemical property (such as aducanumab); because there is the need to produce stable blood levels of the medication (such as brexanolone); because oral administration greatly diminished efficacy (such as oral vs IV magnesium or scopolamine), or because the treatment is focused on specific brain structures. This need for specialized administration has created a subspecialty called interventional psychiatry.

Part 1 of this 2-part article provides an overview of 1 type of interventional psychiatry: parenterally administered medications, including those administered via IV. We also describe 3 other interventional approaches to treatment: stellate ganglion blocks, glabellar botulinum toxin (BT) injections, and trigger point injections. In Part 2 we will review interventional approaches that involve neuromodulation.

Parenteral medications in psychiatry

In general, IV and IM medications can be more potent that oral medications due to their overall faster onset of action and higher blood concentrations. These more invasive forms of administration can have significant limitations, such as a risk of infection at the injection site, the need to be administered in a medical setting, additional time, and patient discomfort.

Table 1 lists short-acting injectable medications used in psychiatry, and Table 2 lists long-acting injectable medications. Parenteral administration of antipsychotics is performed to alleviate acute agitation or for chronic symptom control. These medications generally are not considered interventional treatments, but could be classified as such due to their invasive nature.¹ Furthermore, inhalable loxapine—which is indicated for managing acute agitation—requires a Risk Evaluation and Mitigation Strategy program consisting of 2 hours observation and monitoring of respiratory status.^2,3 Other indications for parenteral treatments include IM naltrexone extended release⁴ and subcutaneous injections of buprenorphine extended release⁵ and risperidone.⁶

IV administration

Most IV treatments described in this article are not FDA-approved for psychiatric treatment. Despite this, many interventional psychiatric treatments are part of clinical practice. IV infusion of ketamine is the most widely known and most researched of these. Table 3 lists other IV treatments that could be used as psychiatric treatment.

Ketamine

Since the early 1960s, ketamine has been used as a surgical anesthetic for animals. In the United States, it was approved for human surgical anesthesia in 1970. It was widely used during the Vietnam War due to its lack of inhibition of respiratory drive; medical staff first noticed an improvement in depressive symptoms and the resolution of suicidal ideation in patients who received ketamine. This led to further research on ketamine, particularly to determine its application in treatment-resistant depression (TRD) and other conditions.⁷ IV ketamine administration is most widely researched, but IM injections, intranasal sprays, and lozenges are also available. The dissociative properties of ketamine have led to its recreational use.⁸

Hypotheses for the mechanism of action of ketamine as an antidepressant include direct synaptic or extrasynaptic (GluN2B-selective), N-methyl-D-aspartate receptor (NMDAR) inhibition, selectively greater inhibition of NMDARs localized on GABAergic (gamma-aminobutyric acid) interneurons, and the role of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor activation. There are links between ketamine’s antidepressant actions and downstream mechanisms regulating synaptic plasticity, including brain-derived neurotrophic factor, eukaryotic elongation factor 2, mammalian target of rapamycin, and glycogen synthase kinase-3. Multiple other ketamine-associated mechanisms also have been described.^9,10 Action on the mu-opioid receptor is also known, possibly contributing to both antidepressant and anesthetic properties of ketamine.¹¹ Rapid onset of ketamine antidepressant action is especially valuable.¹²

Continue to: Ketamine is a schedule...

Ketamine is a schedule III medication with addictive properties. Delirium, panic attacks, hallucinations, nightmares, dysphoria, and paranoia may occur during and after use.¹³ Premedication with benzodiazepines, most notably lorazepam, is occasionally used to minimize ketamine’s adverse effects, but this generally is not recommended because doing so reduces ketamine’s antidepressant effects.¹⁴ Driving and operating heavy machinery is contraindicated after IV infusion. The usual protocol involves an IV infusion of ketamine 0.4 mg/kg to 1 mg/kg dosing over 1 hour. Doses between 0.4 mg/kg and 0.6 mg/kg are most common. Ketamine has a therapeutic window; doses >0.5 mg/kg are progressively less effective.¹⁵ Unlike the recommendation after esketamine administration, after receiving ketamine, patients remain in the care of their treatment team for <2 hours.

Esketamine, the S enantiomer of ketamine, was FDA-approved for TRD as an intranasal formulation. Esketamine is more commonly used than IV ketamine because it is FDA-approved and typically covered by insurance, but it may not be as effective.¹⁶ An economic analysis by Brendle et al¹⁷ suggested insurance companies would lower costs if they covered ketamine infusions vs intranasal esketamine.

Aducanumab and lecanemab

The most recent FDA-approved interventional agents are aducanumab and lecanemab, which are indicated for treating Alzheimer disease.^18,19 Both are human monoclonal antibodies that bind selectively and with high affinity to amyloid beta plaque aggregates and promote their removal by Fc receptor–mediated phagocytosis.²⁰

FDA approval of aducanumab and lecanemab was controversial. Initially, aducanumab’s safety monitoring board performed a futility analysis that suggested aducanumab was unlikely to separate from placebo, and the research was stopped.²¹ The manufacturer petitioned the FDA to consider the medication for accelerated approval on the basis of biomarker data showing that amyloid beta plaque aggregates become smaller. Current FDA approval is temporary to allow patients access to this potentially beneficial agent, but the manufacturer must supply clinical evidence that the reduction of amyloid beta plaques is associated with desirable changes in the course of Alzheimer disease, or risk losing the approval.

Lecanemab is also a human monoclonal antibody intended to remove amyloid beta plaques that was FDA-approved under the accelerated approval pathway.²² Unlike aducanumab, lecanemab demonstrated a statistically significant (although clinically imperceptible) reduction in the rate of cognitive decline; it did not show cognitive improvement.²³ Lecanemab also significantly reduced amyloid beta plaques.²³

Continue to: Aducanumab and lecanemab are generally...

Aducanumab and lecanemab are generally not covered by insurance and typically cost >$26,000 annually. Both are administered by IV infusion once a month. More monoclonal antibody medications for treating early Alzheimer disease are in the late stages of development, most notably donanebab.²⁴ Observations during clinical trials found that in the later stages of Alzheimer disease, forceful removal of plaques by the autoimmune process damages neurons, while in less dense deposits of early dementia such removal is not harmful to the cells and prevents amyloid buildup.

Brexanolone

Brexanolone is an aqueous formulation of allopregnanolone, a major metabolite of progesterone and a positive allosteric modulator of GABA-A receptors.²⁵ Its levels are maximal at the end of the third trimester of pregnancy and fall rapidly following delivery. Research showed a 3-day infusion was rapidly and significantly effective for treating postpartum depression²⁶ and brexanolone received FDA approval for this indication in March 2019.²⁷ However, various administrative, economic, insurance, and other hurdles make it difficult for patients to access this treatment. Despite its rapid onset of action (usually 48 hours), brexanolone takes an average of 15 days to go through the prior authorization process.²⁸ In addition to the need for prior authorization, the main impediment to the use of brexanolone is the 3-day infusion schedule, which greatly magnifies the cost but is partially circumvented by the availability of dedicated outpatient centers.

Magnesium

Magnesium is on the World Health Organization’s Model List of Essential Medicines.²⁹ There has been extensive research on the use of magnesium sulfate for psychiatric indications, especially for depression.³⁰ Magnesium functions similarly to calcium channel blockers by competitively blocking intracellular calcium channels, decreasing calcium availability, and inhibiting smooth muscle contractility.³¹ It also competes with calcium at the motor end plate, reducing excitation by inhibiting the release of acetylcholine.³² This property is used for high-dose IV magnesium treatment of impending preterm labor in obstetrics. Magnesium sulfate is the drug of choice in treating eclamptic seizures and preventing seizures in severe preeclampsia or gestational hypertension with severe features.³³ It is also used to treat torsade de pointes, severe asthma exacerbations, constipation, and barium poisoning.³⁴ Beneficial use in asthma treatment³⁵ and the treatment of migraine³⁶ have also been reported.

IV magnesium in myocardial infarction may be harmful,³⁷ though outside of acute cardiac events, magnesium is found to be safe.³⁸

Oral magnesium sulfate is a common over-the-counter anxiety remedy. As a general cell stabilizer (mediated by the reduction of intracellular calcium), magnesium is potentially beneficial outside of its muscle-relaxing properties, although muscle relaxing can benefit anxious patients. It is used to treat anxiety,³⁹ alcohol withdrawal,⁴⁰ and fear.⁴¹ Low magnesium blood levels are found in patients with depression, schizophrenia,⁴² and attention-deficit/hyperactivity disorder.⁴³ However, it is important to note that the therapeutic effect of magnesium when treating anxiety and headache is independent of preinfusion magnesium blood levels.⁴³

Continue to: The efficacy of oral magnesium...

The efficacy of oral magnesium is not robust. However, IV administration has a pronounced beneficial effect as an abortive and preventative treatment in many patients with anxiety.⁴⁴

IV administration of magnesium can produce adverse effects, including flushing, sweating, hypotension, depressed reflexes, flaccid paralysis, hypothermia, circulatory collapse, and cardiac and CNS depression. These complications are very rare and dose-dependent.⁴⁵ Magnesium is excreted by the kidneys, and dosing must be decreased in patients with kidney failure. The most common adverse effect is local burning along the vein upon infusion; small doses of IV lidocaine can remedy this. Hot flashes are also common.⁴⁵

Various dosing strategies are available. In patients with anxiety, application dosing is based on the recommended preeclampsia IV dose of 4 g diluted in 250 mL of 5% dextrose. Much higher doses may be used in obstetrics. Unlike in obstetrics, for psychiatric indications, magnesium is administered over 60 to 90 minutes. Heart monitoring is recommended.

Scopolamine

Scopolamine is primarily used to relieve nausea, vomiting, and dizziness associated with motion sickness and recovery from anesthesia. It is also used in ophthalmology and in patients with excessive sweating. In off-label and experimental applications, scopolamine has been used in patients with TRD.⁴⁶

Scopolamine is an anticholinergic medication. It is a nonselective antagonist at muscarinic receptors.⁴⁷ Tricyclic antidepressants (TCAs) possess strong anticholinergic function. Newer generations of antidepressants were designed specifically not to have this function because it was believed to be an unwanted and potentially dangerous adverse effect. However, data suggest that anticholinergic action is important in decreasing depressive symptoms. Several hypotheses of anticholinergic effects on depression have been published since the 1970s. They include the cholinergic-adrenergic hypothesis,⁴⁸ acetylcholine predominance relative to adrenergic action hypothesis,⁴⁹ and insecticide poisoning observations.⁵⁰ Centrally acting physostigmine (but not peripherally acting neostigmine) was reported to control mania.^48,51 A genetic connection between the M2acetylcholine receptor in patients with major depressive disorder (MDD) and alcohol use disorder is also suggestive.⁵²

Continue to: Multiple animal studies show...

Multiple animal studies show direct improvement in mobility and a decrease in despair upon introducing anticholinergic substances.^53-55 The cholinergic theory of depression has been studied in several controlled clinical human studies.^56,57 Use of a short-acting anticholinergic glycopyrrolate during electroconvulsive therapy (ECT) may contribute to the procedure’s efficacy.

Human research shows scopolamine has a higher efficacy as an antidepressant and anti-anxiety medication in women than in men,⁵⁸ possibly because estrogen increases the activity of choline acetyltransferase and release of acetylcholine.^59,60 M2receptors mediate estrogen influence on the NMDAR, which may explain the anticholinergic effects of depression treatments in women.⁶¹

Another proposed mechanism of action of scopolamine is a potent inhibition of the NMDAR.⁶² Rapid treatments of depression may be based on this mechanism. Examples of such treatments include IV ketamine and sleep deprivation.⁶³ IV scopolamine shows potency in treating MDD and bipolar depression. This treatment should be reserved for patients who do not respond to or are not candidates for other usual treatment modalities of MDD and for the most severe cases. Scopolamine is 30 times more potent than amitriptyline in anticholinergic effect and reportedly produces sustained improvement in MDD.⁶⁴

Scopolamine has no black-box warnings. It has not been studied in pregnant women and is not recommended for use during pregnancy. Due to possible negative cardiovascular effects, a normal electrocardiogram is required before the start of treatment. Exercise caution in patients with glaucoma, benign prostatic enlargement, gastroparesis, unstable cardiovascular status, or severe renal impairment.

Treatment with scopolamine is not indicated for patients with myasthenia gravis, psychosis, or seizures. Patients must be off potassium for 3 days before beginning scopolamine treatment. Patients should consult with their cardiologist before having a scopolamine infusion. Adverse reactions may include psychosis, tachycardia, seizures, paralytic ileus, and glaucoma exacerbation. The most common adverse effects of scopolamine infusion treatment include drowsiness, dry mouth, blurred vision, lightheadedness, and dizziness. Due to possible drowsiness, operating motor vehicles or heavy machinery must be avoided on the day of treatment.⁶⁵ Overall, the adverse effects of scopolamine are preventable and manageable, and its antidepressant efficacy is noteworthy.⁶⁶

Continue to: Treatment typically consists of 3 consecutive infusions...

Treatment typically consists of 3 consecutive infusions of 4 mcg/kg separated by 3 to 5 days.⁵⁶ It is possible to have a longer treatment course if the patient experiences only partial improvement. Repeated courses or maintenance treatment (similar to ECT maintenance) are utilized in some patients if indicated. Cardiac monitoring is mandatory.

Clomipramine

Clomipramine, a TCA, acts as a preferential inhibitor of 5-hydroxytryptamine uptake and has proven effective in managing depression, TRD, and obsessive-compulsive disorder (OCD).⁶⁷ Although this medication has reported treatment benefits for patients with phobia, panic disorder,¹⁵ chronic pain,⁶⁸ Tourette syndrome,⁶⁹ premature ejaculation, anorexia nervosa,⁷⁰ cataplexy,⁴⁹ and enuresis,⁷¹ it is FDA-approved only for the treatment of OCD.⁷² Clomipramine may also be beneficial for pain and headache, possibly because of its anti-inflammatory action.⁷³ The anticholinergic effects of clomipramine may add to its efficacy in depression.

The pathophysiology of MDD is connected to hyperactivity of the HPA axis and elevated cortisol levels. Higher clomipramine plasma levels show a linear correlation with lower cortisol secretion and levels, possibly aiding in the treatment of MDD and anxiety.⁷⁴ The higher the blood level, the more pronounced clomipramine’s therapeutic effect across multiple domains.⁷⁵

IV infusion of clomipramine produces the highest concentration in the shortest time, but overall, research does not necessarily support increased efficacy of IV over oral administration. There is evidence suggesting that subgroups of patients with severe, treatment-refractory OCD may benefit from IV agents and research suggests a faster onset of action.⁷⁶ Faster onset of symptom relief is the basis for IV clomipramine use. In patients with OCD, it can take several months for oral medications to produce therapeutic benefits; not all patients can tolerate this. In such scenarios, IV administration may be considered, though it is not appropriate for routine use until more research is available. Patients with treatment-resistant OCD who have exhausted other means of symptom relief may also be candidates for IV treatment.

The adverse effects of IV clomipramine are no different from oral use, though they may be more pronounced. A pretreatment cardiac exam is desirable because clomipramine, like other TCAs, may be cardiotoxic. The anticholinergic adverse effects of TCAs are well known to clinicians⁷⁷ and partially explained in the scopolamine section of this article. It is not advisable to combine clomipramine with other TCAs or serotonin reuptake inhibitors. Clomipramine also should not be combined with monoamine oxidase inhibitors, though such a combination was reported in medical literature.⁷⁸ Combination with antiarrhythmics such as lidocaine or opioids such as fentanyl or and tramadol is highly discouraged (fentanyl and tramadol also have serotonergic effects).⁷⁹

Continue to: Clomipramine for IV use is not commercially available...

Clomipramine for IV use is not commercially available and must be sterilely compounded. The usual course of treatment is a series of 3 infusions: 150 mg on Day 1, 200 mg on Day 2 or Day 3, and 250 mg on Day 3, Day 4, or Day 5, depending on tolerability. A protocol with a 50 mg/d starting dose and titration up to a maximum dose of 225 mg/d over 5 to 7 days has been suggested for inpatient settings.⁶⁷ Titration to 250 mg is more common.⁸⁰

A longer series may be performed, but this increases the likelihood of adverse effects. Booster and maintenance treatments are also completed when required. Cardiac monitoring is mandatory.

Vortioxetine and citalopram

IV treatment of depression with vortioxetine and citalopram has been explored but has not yet taken hold in clinical psychiatry.^81,82

Injections and blocks

Three interventional approaches to treatment that possess psychotherapeutic potential include stellate ganglion blocks (SGBs), glabellar BT injections, and trigger point injections (TPIs). None of these are FDA-approved for psychiatric treatment.

Stellate ganglion blocks

The sympathetic nervous system is involved in autonomic hyperarousal and is at the core of posttraumatic symptomatology.⁸³ Insomnia, anxiety, irritability, hypervigilance, and other excitatory CNS events are connected to the sympathetic nervous system and amygdala activation is commonly observed in those exposed to extreme stress or traumatic events.⁸⁴

Continue to: SGBs were first performed 100 years ago...

SGBs were first performed 100 years ago and reported to have beneficial psychiatric effects at the end of the 1940s. In 1998 in Finland, improvement of posttraumatic stress disorder (PTSD) symptoms was observed accidentally via thoracic level spine blocks.⁸⁵ In 2006, cervical level sympathetic blocks were shown to be effective for PTSD symptom control.⁸⁶ By the end of 2010, Veterans Administration hospitals adopted SGBs to treat veterans with PTSD.^87,88 The first multisite, randomized clinical trial of SGB for PTSD confirmed multiple previous reports of treatment efficacy. Specifically, 2 SGB treatments 2 weeks apart effectively reduced total symptom severity scores over 8 weeks.⁸⁷

Since the stellate ganglion is connected to the amygdala, SGB has also been assessed for treating anxiety and depression.^89,90 Outside of PTSD, SGBs are used to treat complex regional pain syndrome,⁹¹ phantom limb pain, trigeminal neuralgia,⁹² intractable angina,⁹³ and postherpetic neuralgia in the head, neck, upper chest, or arms.⁹⁴ The procedure consists of an injection of a local anesthetic through a 25-gauge needle into the stellate sympathetic ganglion at the C6 or C7 vertebral levels. An injection into C6 is considered safer because of specific cervical spine anatomy. Ideally, fluoroscopic guidance or ultrasound is used to guide needle insertion.⁹⁵

A severe drop in blood pressure may be associated with SGBs and is mitigated by IV hydration. Other adverse effects include red eyes, drooping of the eyelids, nasal congestion, hoarseness, difficulty swallowing, a sensation of a “lump” in the throat, and a sensation of warmth or tingling in the arm or hand. Bilateral SGB is contraindicated due to the danger of respiratory arrest.⁹⁶

Glabellar BT injections

OnabotulinumtoxinA (BT) injection was first approved for therapeutic use in 1989 for eye muscle disorders such as strabismus⁹⁷ and blepharospasm.⁹⁸ It was later approved for several other indications, including cosmetic use, hyperhidrosis, migraine prevention, neurogenic bladder disorder, overactive bladder, urinary incontinence, and spasticity.^99-104 BT is used off-label for achalasia and sialorrhea.^105,106 Its mechanism of action is primarily attributed to muscle paralysis by blocking presynaptic acetylcholine release into neuromuscular junctions.¹⁰⁷

Facial BT injections are usually administered for cosmetic purposes, but smoothing forehead wrinkles and frown lines (the glabellar region of the face) both have antidepressant effects.¹⁰⁸ BT injections into the glabellar region also demonstrate antidepressant effects, particularly in patients with comorbid migraines and MDD.¹⁰⁹ Early case observations supported the independent benefit of the toxin on MDD when the toxin was injected into the glabellar region.^110,111 The most frequent protocol involves injections in the procerus and corrugator muscles.

Continue to: The facial feedback/emotional proprioception hypothesis...

The facial feedback/emotional proprioception hypothesis has dominated thinking about the mood-improving effects of BT. The theory is that blocking muscular expression of sadness (especially in the face) interrupts the experience of sadness; therefore, depression subsides.^112,113 However, BT injections in the muscles involved in the smile and an expression of positive emotions (lateral part of the musculus orbicularis oculi) have been associated with increased MDD scores.¹¹⁴ Thus, the mechanism clearly involves more than the cosmetic effect, since facial muscle injections in rats also have antidepressant effects.¹¹⁵

The use of progressive muscle relaxation is well-established in psychiatric treatment. The investigated conditions of increased muscle tone, especially torticollis and blepharospasm, are associated with MDD, and it may be speculated that proprioceptive feedback from the affected muscles may be causally involved in this association.^116-118 Activity of the corrugator muscle has been positively associated with increased amygdala activity.¹¹⁹ This suggests a potential similar mechanism to that hypothesized for SGB.

Alternatively, BT is commonly used to treat chronic conditions that may contribute to depression; its success in relieving the underlying problem may indirectly relieve MDD. Thus, in a postmarketing safety evaluation of BT, MDD was demonstrated 40% to 88% less often by patients treated with BT for 6 of the 8 conditions and injection sites, such as in spasms and spasticity of arms and legs, torticollis and neck pain, and axilla and palm injections for hyperhidrosis. In a parotid and submandibular glands BT injection subcohort, no patients experienced depressive symptoms.¹²⁰

Medicinal BT is generally considered safe. The most common adverse effects are hypersensitivity, injection site reactions, and other adverse effects specific to the injection site.¹²¹ Additionally, the cosmetic effects are transient, given the nature of the medication.

Trigger point injections

TPIs in the neck and shoulders are frequently used to treat tension headaches and various referred pain locations in the face and arms. Tension and depression frequently overlap in clinical practice.¹²² Relieving muscle tension (with resulting trigger points) improves muscle function and mood.

Continue to: The higher the number of active...

The higher the number of active trigger points (TPs), the greater the physical burden of headache and the higher the anxiety level. Gender differences in TP prevalence and TPI efficacy have been described in the literature. For example, the number of active TPs seems directly associated with anxiety levels in women but not in men.¹²³ Although TPs appear to be more closely associated with anxiety than depression,¹²⁴ depression associated with muscle tension does improve with TPIs. European studies have demonstrated a decrease in scores on the Hamilton Depression Rating Scale and Hamilton Anxiety Rating Scale following TPI treatment.¹²⁵ The effect may be indirect, as when a patient’s pain is relieved, sleep and other psychiatric symptoms improve.¹²⁶

A randomized controlled trial by Castro Sánchez et al¹²⁷ demonstrated that dry needling therapy in patients with fibromyalgia syndrome (FMS) showed improvements in pain pressure thresholds, body pain, vitality, and social function, as well as total FMS symptoms, quality of sleep, anxiety, hospital anxiety and depression, general pain intensity, and fatigue.

Myofascial pain syndrome, catastrophizing, and muscle tension are common in patients with depression, anxiety, and somatization. Local TPI therapy aimed at inactivating pain generators is supported by moderate quality evidence. All manner of therapies have been described, including injection of saline, corticosteroids, local anesthetic agents, and dry needling. BT injections in chronic TPs are also practiced, though no specific injection therapy has been reliably shown to be more advantageous than another. The benefits of TPIs may be derived from the needle itself rather than from any specific substance injected. Stimulation of a local twitch response with direct needling of the TP appears of importance. There is no established consensus regarding the number of injection points, frequency of administration, and volume or type of injectate.¹²⁸

Adverse effects of TPIs relate to the nature of the invasive therapy, with the risk of tissue damage and bleeding. Pneumothorax risk is present with needle insertion at the neck and thorax.¹²⁹ Patients with diabetes may experience variations in blood sugar control if steroids are used.

Bottom Line

Interventional treatment modalities that may have a role in psychiatric treatment include IV administration of ketamine, aducanumab, lecanemab, brexanolone, magnesium, scopolamine, and clomipramine. Other interventional approaches include stellate ganglion blocks, glabellar botulinum toxin injections, and trigger point injections.

Related Resources

• Dokucu ME, Janicak PG. Nontraditional therapies for treatment-resistant depression. Current Psychiatry. 2021; 20(9):38-43,49. doi:10.12788/cp.0166
• Kim J, Khoury R, Grossberg GT. Botulinum toxin: emerging psychiatric indications. Current Psychiatry. 2018;17(12):8-18.

Drug Brand Names

Aducanumab • Aduhelm
Aripiprazole • Abilify
Aripiprazole lauroxil • Aristada
Brexanolone • Zulresso
Buprenorphine • Sublocade
Citalopram • Celexa
Clomipramine • Anafranil
Diazepam • Valium
Droperidol • Inapsine
Esketamine • Spravato
Fentanyl • Actiq
Fluphenazine decanoate • Modecate
Fluphenazine hydrochloride • Prolixin
Haloperidol decanoate • Haldol decanoate
Haloperidol lactate • Haldol
Ketamine • Ketalar
Lecanemab • Leqembi
Lidocaine • Xylocaine
Lorazepam • Ativan
Loxapine inhaled • Adasuve
Naltrexone • Vivitrol
Magnesium sulfate • Sulfamag
Midazolam • Versed
Olanzapine • Zyprexa
OnabotulinumtoxinA injection • Botox
Paliperidone • Invega Hafyera, Invega Sustenna, Invega Trinza
Rapamycin • Rapamune, Sirolimus
Risperidone • Perseris
Risperidone microspheres • Risperdal Consta, Rykindo
Scopolamine • Hyoscine
Tramadol • Conzip
Vortioxetine • Trintellix
Ziprasidone • Geodon

Advances in the understanding of neurobiological and neuro­psychiatric pathophysiology have opened new avenues of treatment for psychiatric patients. Historically, with a few exceptions, most psychiatric medications have been administered orally. However, many of the newer treatments require some form of specialized administration because they cannot be taken orally due to their chemical property (such as aducanumab); because there is the need to produce stable blood levels of the medication (such as brexanolone); because oral administration greatly diminished efficacy (such as oral vs IV magnesium or scopolamine), or because the treatment is focused on specific brain structures. This need for specialized administration has created a subspecialty called interventional psychiatry.

Part 1 of this 2-part article provides an overview of 1 type of interventional psychiatry: parenterally administered medications, including those administered via IV. We also describe 3 other interventional approaches to treatment: stellate ganglion blocks, glabellar botulinum toxin (BT) injections, and trigger point injections. In Part 2 we will review interventional approaches that involve neuromodulation.

Parenteral medications in psychiatry

In general, IV and IM medications can be more potent that oral medications due to their overall faster onset of action and higher blood concentrations. These more invasive forms of administration can have significant limitations, such as a risk of infection at the injection site, the need to be administered in a medical setting, additional time, and patient discomfort.

Table 1 lists short-acting injectable medications used in psychiatry, and Table 2 lists long-acting injectable medications. Parenteral administration of antipsychotics is performed to alleviate acute agitation or for chronic symptom control. These medications generally are not considered interventional treatments, but could be classified as such due to their invasive nature.¹ Furthermore, inhalable loxapine—which is indicated for managing acute agitation—requires a Risk Evaluation and Mitigation Strategy program consisting of 2 hours observation and monitoring of respiratory status.^2,3 Other indications for parenteral treatments include IM naltrexone extended release⁴ and subcutaneous injections of buprenorphine extended release⁵ and risperidone.⁶

IV administration

Most IV treatments described in this article are not FDA-approved for psychiatric treatment. Despite this, many interventional psychiatric treatments are part of clinical practice. IV infusion of ketamine is the most widely known and most researched of these. Table 3 lists other IV treatments that could be used as psychiatric treatment.

Ketamine

Since the early 1960s, ketamine has been used as a surgical anesthetic for animals. In the United States, it was approved for human surgical anesthesia in 1970. It was widely used during the Vietnam War due to its lack of inhibition of respiratory drive; medical staff first noticed an improvement in depressive symptoms and the resolution of suicidal ideation in patients who received ketamine. This led to further research on ketamine, particularly to determine its application in treatment-resistant depression (TRD) and other conditions.⁷ IV ketamine administration is most widely researched, but IM injections, intranasal sprays, and lozenges are also available. The dissociative properties of ketamine have led to its recreational use.⁸

Hypotheses for the mechanism of action of ketamine as an antidepressant include direct synaptic or extrasynaptic (GluN2B-selective), N-methyl-D-aspartate receptor (NMDAR) inhibition, selectively greater inhibition of NMDARs localized on GABAergic (gamma-aminobutyric acid) interneurons, and the role of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor activation. There are links between ketamine’s antidepressant actions and downstream mechanisms regulating synaptic plasticity, including brain-derived neurotrophic factor, eukaryotic elongation factor 2, mammalian target of rapamycin, and glycogen synthase kinase-3. Multiple other ketamine-associated mechanisms also have been described.^9,10 Action on the mu-opioid receptor is also known, possibly contributing to both antidepressant and anesthetic properties of ketamine.¹¹ Rapid onset of ketamine antidepressant action is especially valuable.¹²

Continue to: Ketamine is a schedule...

Ketamine is a schedule III medication with addictive properties. Delirium, panic attacks, hallucinations, nightmares, dysphoria, and paranoia may occur during and after use.¹³ Premedication with benzodiazepines, most notably lorazepam, is occasionally used to minimize ketamine’s adverse effects, but this generally is not recommended because doing so reduces ketamine’s antidepressant effects.¹⁴ Driving and operating heavy machinery is contraindicated after IV infusion. The usual protocol involves an IV infusion of ketamine 0.4 mg/kg to 1 mg/kg dosing over 1 hour. Doses between 0.4 mg/kg and 0.6 mg/kg are most common. Ketamine has a therapeutic window; doses >0.5 mg/kg are progressively less effective.¹⁵ Unlike the recommendation after esketamine administration, after receiving ketamine, patients remain in the care of their treatment team for <2 hours.

Esketamine, the S enantiomer of ketamine, was FDA-approved for TRD as an intranasal formulation. Esketamine is more commonly used than IV ketamine because it is FDA-approved and typically covered by insurance, but it may not be as effective.¹⁶ An economic analysis by Brendle et al¹⁷ suggested insurance companies would lower costs if they covered ketamine infusions vs intranasal esketamine.

Aducanumab and lecanemab

The most recent FDA-approved interventional agents are aducanumab and lecanemab, which are indicated for treating Alzheimer disease.^18,19 Both are human monoclonal antibodies that bind selectively and with high affinity to amyloid beta plaque aggregates and promote their removal by Fc receptor–mediated phagocytosis.²⁰

FDA approval of aducanumab and lecanemab was controversial. Initially, aducanumab’s safety monitoring board performed a futility analysis that suggested aducanumab was unlikely to separate from placebo, and the research was stopped.²¹ The manufacturer petitioned the FDA to consider the medication for accelerated approval on the basis of biomarker data showing that amyloid beta plaque aggregates become smaller. Current FDA approval is temporary to allow patients access to this potentially beneficial agent, but the manufacturer must supply clinical evidence that the reduction of amyloid beta plaques is associated with desirable changes in the course of Alzheimer disease, or risk losing the approval.

Lecanemab is also a human monoclonal antibody intended to remove amyloid beta plaques that was FDA-approved under the accelerated approval pathway.²² Unlike aducanumab, lecanemab demonstrated a statistically significant (although clinically imperceptible) reduction in the rate of cognitive decline; it did not show cognitive improvement.²³ Lecanemab also significantly reduced amyloid beta plaques.²³

Continue to: Aducanumab and lecanemab are generally...

Aducanumab and lecanemab are generally not covered by insurance and typically cost >$26,000 annually. Both are administered by IV infusion once a month. More monoclonal antibody medications for treating early Alzheimer disease are in the late stages of development, most notably donanebab.²⁴ Observations during clinical trials found that in the later stages of Alzheimer disease, forceful removal of plaques by the autoimmune process damages neurons, while in less dense deposits of early dementia such removal is not harmful to the cells and prevents amyloid buildup.

Brexanolone

Brexanolone is an aqueous formulation of allopregnanolone, a major metabolite of progesterone and a positive allosteric modulator of GABA-A receptors.²⁵ Its levels are maximal at the end of the third trimester of pregnancy and fall rapidly following delivery. Research showed a 3-day infusion was rapidly and significantly effective for treating postpartum depression²⁶ and brexanolone received FDA approval for this indication in March 2019.²⁷ However, various administrative, economic, insurance, and other hurdles make it difficult for patients to access this treatment. Despite its rapid onset of action (usually 48 hours), brexanolone takes an average of 15 days to go through the prior authorization process.²⁸ In addition to the need for prior authorization, the main impediment to the use of brexanolone is the 3-day infusion schedule, which greatly magnifies the cost but is partially circumvented by the availability of dedicated outpatient centers.

Magnesium

Magnesium is on the World Health Organization’s Model List of Essential Medicines.²⁹ There has been extensive research on the use of magnesium sulfate for psychiatric indications, especially for depression.³⁰ Magnesium functions similarly to calcium channel blockers by competitively blocking intracellular calcium channels, decreasing calcium availability, and inhibiting smooth muscle contractility.³¹ It also competes with calcium at the motor end plate, reducing excitation by inhibiting the release of acetylcholine.³² This property is used for high-dose IV magnesium treatment of impending preterm labor in obstetrics. Magnesium sulfate is the drug of choice in treating eclamptic seizures and preventing seizures in severe preeclampsia or gestational hypertension with severe features.³³ It is also used to treat torsade de pointes, severe asthma exacerbations, constipation, and barium poisoning.³⁴ Beneficial use in asthma treatment³⁵ and the treatment of migraine³⁶ have also been reported.

IV magnesium in myocardial infarction may be harmful,³⁷ though outside of acute cardiac events, magnesium is found to be safe.³⁸

Oral magnesium sulfate is a common over-the-counter anxiety remedy. As a general cell stabilizer (mediated by the reduction of intracellular calcium), magnesium is potentially beneficial outside of its muscle-relaxing properties, although muscle relaxing can benefit anxious patients. It is used to treat anxiety,³⁹ alcohol withdrawal,⁴⁰ and fear.⁴¹ Low magnesium blood levels are found in patients with depression, schizophrenia,⁴² and attention-deficit/hyperactivity disorder.⁴³ However, it is important to note that the therapeutic effect of magnesium when treating anxiety and headache is independent of preinfusion magnesium blood levels.⁴³

Continue to: The efficacy of oral magnesium...

The efficacy of oral magnesium is not robust. However, IV administration has a pronounced beneficial effect as an abortive and preventative treatment in many patients with anxiety.⁴⁴

IV administration of magnesium can produce adverse effects, including flushing, sweating, hypotension, depressed reflexes, flaccid paralysis, hypothermia, circulatory collapse, and cardiac and CNS depression. These complications are very rare and dose-dependent.⁴⁵ Magnesium is excreted by the kidneys, and dosing must be decreased in patients with kidney failure. The most common adverse effect is local burning along the vein upon infusion; small doses of IV lidocaine can remedy this. Hot flashes are also common.⁴⁵

Various dosing strategies are available. In patients with anxiety, application dosing is based on the recommended preeclampsia IV dose of 4 g diluted in 250 mL of 5% dextrose. Much higher doses may be used in obstetrics. Unlike in obstetrics, for psychiatric indications, magnesium is administered over 60 to 90 minutes. Heart monitoring is recommended.

Scopolamine

Scopolamine is primarily used to relieve nausea, vomiting, and dizziness associated with motion sickness and recovery from anesthesia. It is also used in ophthalmology and in patients with excessive sweating. In off-label and experimental applications, scopolamine has been used in patients with TRD.⁴⁶

Scopolamine is an anticholinergic medication. It is a nonselective antagonist at muscarinic receptors.⁴⁷ Tricyclic antidepressants (TCAs) possess strong anticholinergic function. Newer generations of antidepressants were designed specifically not to have this function because it was believed to be an unwanted and potentially dangerous adverse effect. However, data suggest that anticholinergic action is important in decreasing depressive symptoms. Several hypotheses of anticholinergic effects on depression have been published since the 1970s. They include the cholinergic-adrenergic hypothesis,⁴⁸ acetylcholine predominance relative to adrenergic action hypothesis,⁴⁹ and insecticide poisoning observations.⁵⁰ Centrally acting physostigmine (but not peripherally acting neostigmine) was reported to control mania.^48,51 A genetic connection between the M2acetylcholine receptor in patients with major depressive disorder (MDD) and alcohol use disorder is also suggestive.⁵²

Continue to: Multiple animal studies show...

Multiple animal studies show direct improvement in mobility and a decrease in despair upon introducing anticholinergic substances.^53-55 The cholinergic theory of depression has been studied in several controlled clinical human studies.^56,57 Use of a short-acting anticholinergic glycopyrrolate during electroconvulsive therapy (ECT) may contribute to the procedure’s efficacy.

Human research shows scopolamine has a higher efficacy as an antidepressant and anti-anxiety medication in women than in men,⁵⁸ possibly because estrogen increases the activity of choline acetyltransferase and release of acetylcholine.^59,60 M2receptors mediate estrogen influence on the NMDAR, which may explain the anticholinergic effects of depression treatments in women.⁶¹

Another proposed mechanism of action of scopolamine is a potent inhibition of the NMDAR.⁶² Rapid treatments of depression may be based on this mechanism. Examples of such treatments include IV ketamine and sleep deprivation.⁶³ IV scopolamine shows potency in treating MDD and bipolar depression. This treatment should be reserved for patients who do not respond to or are not candidates for other usual treatment modalities of MDD and for the most severe cases. Scopolamine is 30 times more potent than amitriptyline in anticholinergic effect and reportedly produces sustained improvement in MDD.⁶⁴

Scopolamine has no black-box warnings. It has not been studied in pregnant women and is not recommended for use during pregnancy. Due to possible negative cardiovascular effects, a normal electrocardiogram is required before the start of treatment. Exercise caution in patients with glaucoma, benign prostatic enlargement, gastroparesis, unstable cardiovascular status, or severe renal impairment.

Treatment with scopolamine is not indicated for patients with myasthenia gravis, psychosis, or seizures. Patients must be off potassium for 3 days before beginning scopolamine treatment. Patients should consult with their cardiologist before having a scopolamine infusion. Adverse reactions may include psychosis, tachycardia, seizures, paralytic ileus, and glaucoma exacerbation. The most common adverse effects of scopolamine infusion treatment include drowsiness, dry mouth, blurred vision, lightheadedness, and dizziness. Due to possible drowsiness, operating motor vehicles or heavy machinery must be avoided on the day of treatment.⁶⁵ Overall, the adverse effects of scopolamine are preventable and manageable, and its antidepressant efficacy is noteworthy.⁶⁶

Continue to: Treatment typically consists of 3 consecutive infusions...

Treatment typically consists of 3 consecutive infusions of 4 mcg/kg separated by 3 to 5 days.⁵⁶ It is possible to have a longer treatment course if the patient experiences only partial improvement. Repeated courses or maintenance treatment (similar to ECT maintenance) are utilized in some patients if indicated. Cardiac monitoring is mandatory.

Clomipramine

Clomipramine, a TCA, acts as a preferential inhibitor of 5-hydroxytryptamine uptake and has proven effective in managing depression, TRD, and obsessive-compulsive disorder (OCD).⁶⁷ Although this medication has reported treatment benefits for patients with phobia, panic disorder,¹⁵ chronic pain,⁶⁸ Tourette syndrome,⁶⁹ premature ejaculation, anorexia nervosa,⁷⁰ cataplexy,⁴⁹ and enuresis,⁷¹ it is FDA-approved only for the treatment of OCD.⁷² Clomipramine may also be beneficial for pain and headache, possibly because of its anti-inflammatory action.⁷³ The anticholinergic effects of clomipramine may add to its efficacy in depression.

The pathophysiology of MDD is connected to hyperactivity of the HPA axis and elevated cortisol levels. Higher clomipramine plasma levels show a linear correlation with lower cortisol secretion and levels, possibly aiding in the treatment of MDD and anxiety.⁷⁴ The higher the blood level, the more pronounced clomipramine’s therapeutic effect across multiple domains.⁷⁵

IV infusion of clomipramine produces the highest concentration in the shortest time, but overall, research does not necessarily support increased efficacy of IV over oral administration. There is evidence suggesting that subgroups of patients with severe, treatment-refractory OCD may benefit from IV agents and research suggests a faster onset of action.⁷⁶ Faster onset of symptom relief is the basis for IV clomipramine use. In patients with OCD, it can take several months for oral medications to produce therapeutic benefits; not all patients can tolerate this. In such scenarios, IV administration may be considered, though it is not appropriate for routine use until more research is available. Patients with treatment-resistant OCD who have exhausted other means of symptom relief may also be candidates for IV treatment.

The adverse effects of IV clomipramine are no different from oral use, though they may be more pronounced. A pretreatment cardiac exam is desirable because clomipramine, like other TCAs, may be cardiotoxic. The anticholinergic adverse effects of TCAs are well known to clinicians⁷⁷ and partially explained in the scopolamine section of this article. It is not advisable to combine clomipramine with other TCAs or serotonin reuptake inhibitors. Clomipramine also should not be combined with monoamine oxidase inhibitors, though such a combination was reported in medical literature.⁷⁸ Combination with antiarrhythmics such as lidocaine or opioids such as fentanyl or and tramadol is highly discouraged (fentanyl and tramadol also have serotonergic effects).⁷⁹

Continue to: Clomipramine for IV use is not commercially available...

Clomipramine for IV use is not commercially available and must be sterilely compounded. The usual course of treatment is a series of 3 infusions: 150 mg on Day 1, 200 mg on Day 2 or Day 3, and 250 mg on Day 3, Day 4, or Day 5, depending on tolerability. A protocol with a 50 mg/d starting dose and titration up to a maximum dose of 225 mg/d over 5 to 7 days has been suggested for inpatient settings.⁶⁷ Titration to 250 mg is more common.⁸⁰

A longer series may be performed, but this increases the likelihood of adverse effects. Booster and maintenance treatments are also completed when required. Cardiac monitoring is mandatory.

Vortioxetine and citalopram

IV treatment of depression with vortioxetine and citalopram has been explored but has not yet taken hold in clinical psychiatry.^81,82

Injections and blocks

Three interventional approaches to treatment that possess psychotherapeutic potential include stellate ganglion blocks (SGBs), glabellar BT injections, and trigger point injections (TPIs). None of these are FDA-approved for psychiatric treatment.

Stellate ganglion blocks

The sympathetic nervous system is involved in autonomic hyperarousal and is at the core of posttraumatic symptomatology.⁸³ Insomnia, anxiety, irritability, hypervigilance, and other excitatory CNS events are connected to the sympathetic nervous system and amygdala activation is commonly observed in those exposed to extreme stress or traumatic events.⁸⁴

Continue to: SGBs were first performed 100 years ago...

SGBs were first performed 100 years ago and reported to have beneficial psychiatric effects at the end of the 1940s. In 1998 in Finland, improvement of posttraumatic stress disorder (PTSD) symptoms was observed accidentally via thoracic level spine blocks.⁸⁵ In 2006, cervical level sympathetic blocks were shown to be effective for PTSD symptom control.⁸⁶ By the end of 2010, Veterans Administration hospitals adopted SGBs to treat veterans with PTSD.^87,88 The first multisite, randomized clinical trial of SGB for PTSD confirmed multiple previous reports of treatment efficacy. Specifically, 2 SGB treatments 2 weeks apart effectively reduced total symptom severity scores over 8 weeks.⁸⁷

Since the stellate ganglion is connected to the amygdala, SGB has also been assessed for treating anxiety and depression.^89,90 Outside of PTSD, SGBs are used to treat complex regional pain syndrome,⁹¹ phantom limb pain, trigeminal neuralgia,⁹² intractable angina,⁹³ and postherpetic neuralgia in the head, neck, upper chest, or arms.⁹⁴ The procedure consists of an injection of a local anesthetic through a 25-gauge needle into the stellate sympathetic ganglion at the C6 or C7 vertebral levels. An injection into C6 is considered safer because of specific cervical spine anatomy. Ideally, fluoroscopic guidance or ultrasound is used to guide needle insertion.⁹⁵

A severe drop in blood pressure may be associated with SGBs and is mitigated by IV hydration. Other adverse effects include red eyes, drooping of the eyelids, nasal congestion, hoarseness, difficulty swallowing, a sensation of a “lump” in the throat, and a sensation of warmth or tingling in the arm or hand. Bilateral SGB is contraindicated due to the danger of respiratory arrest.⁹⁶

Glabellar BT injections

OnabotulinumtoxinA (BT) injection was first approved for therapeutic use in 1989 for eye muscle disorders such as strabismus⁹⁷ and blepharospasm.⁹⁸ It was later approved for several other indications, including cosmetic use, hyperhidrosis, migraine prevention, neurogenic bladder disorder, overactive bladder, urinary incontinence, and spasticity.^99-104 BT is used off-label for achalasia and sialorrhea.^105,106 Its mechanism of action is primarily attributed to muscle paralysis by blocking presynaptic acetylcholine release into neuromuscular junctions.¹⁰⁷

Facial BT injections are usually administered for cosmetic purposes, but smoothing forehead wrinkles and frown lines (the glabellar region of the face) both have antidepressant effects.¹⁰⁸ BT injections into the glabellar region also demonstrate antidepressant effects, particularly in patients with comorbid migraines and MDD.¹⁰⁹ Early case observations supported the independent benefit of the toxin on MDD when the toxin was injected into the glabellar region.^110,111 The most frequent protocol involves injections in the procerus and corrugator muscles.

Continue to: The facial feedback/emotional proprioception hypothesis...

The facial feedback/emotional proprioception hypothesis has dominated thinking about the mood-improving effects of BT. The theory is that blocking muscular expression of sadness (especially in the face) interrupts the experience of sadness; therefore, depression subsides.^112,113 However, BT injections in the muscles involved in the smile and an expression of positive emotions (lateral part of the musculus orbicularis oculi) have been associated with increased MDD scores.¹¹⁴ Thus, the mechanism clearly involves more than the cosmetic effect, since facial muscle injections in rats also have antidepressant effects.¹¹⁵

The use of progressive muscle relaxation is well-established in psychiatric treatment. The investigated conditions of increased muscle tone, especially torticollis and blepharospasm, are associated with MDD, and it may be speculated that proprioceptive feedback from the affected muscles may be causally involved in this association.^116-118 Activity of the corrugator muscle has been positively associated with increased amygdala activity.¹¹⁹ This suggests a potential similar mechanism to that hypothesized for SGB.

Alternatively, BT is commonly used to treat chronic conditions that may contribute to depression; its success in relieving the underlying problem may indirectly relieve MDD. Thus, in a postmarketing safety evaluation of BT, MDD was demonstrated 40% to 88% less often by patients treated with BT for 6 of the 8 conditions and injection sites, such as in spasms and spasticity of arms and legs, torticollis and neck pain, and axilla and palm injections for hyperhidrosis. In a parotid and submandibular glands BT injection subcohort, no patients experienced depressive symptoms.¹²⁰

Medicinal BT is generally considered safe. The most common adverse effects are hypersensitivity, injection site reactions, and other adverse effects specific to the injection site.¹²¹ Additionally, the cosmetic effects are transient, given the nature of the medication.

Trigger point injections

TPIs in the neck and shoulders are frequently used to treat tension headaches and various referred pain locations in the face and arms. Tension and depression frequently overlap in clinical practice.¹²² Relieving muscle tension (with resulting trigger points) improves muscle function and mood.

Continue to: The higher the number of active...

The higher the number of active trigger points (TPs), the greater the physical burden of headache and the higher the anxiety level. Gender differences in TP prevalence and TPI efficacy have been described in the literature. For example, the number of active TPs seems directly associated with anxiety levels in women but not in men.¹²³ Although TPs appear to be more closely associated with anxiety than depression,¹²⁴ depression associated with muscle tension does improve with TPIs. European studies have demonstrated a decrease in scores on the Hamilton Depression Rating Scale and Hamilton Anxiety Rating Scale following TPI treatment.¹²⁵ The effect may be indirect, as when a patient’s pain is relieved, sleep and other psychiatric symptoms improve.¹²⁶

A randomized controlled trial by Castro Sánchez et al¹²⁷ demonstrated that dry needling therapy in patients with fibromyalgia syndrome (FMS) showed improvements in pain pressure thresholds, body pain, vitality, and social function, as well as total FMS symptoms, quality of sleep, anxiety, hospital anxiety and depression, general pain intensity, and fatigue.

Myofascial pain syndrome, catastrophizing, and muscle tension are common in patients with depression, anxiety, and somatization. Local TPI therapy aimed at inactivating pain generators is supported by moderate quality evidence. All manner of therapies have been described, including injection of saline, corticosteroids, local anesthetic agents, and dry needling. BT injections in chronic TPs are also practiced, though no specific injection therapy has been reliably shown to be more advantageous than another. The benefits of TPIs may be derived from the needle itself rather than from any specific substance injected. Stimulation of a local twitch response with direct needling of the TP appears of importance. There is no established consensus regarding the number of injection points, frequency of administration, and volume or type of injectate.¹²⁸

Adverse effects of TPIs relate to the nature of the invasive therapy, with the risk of tissue damage and bleeding. Pneumothorax risk is present with needle insertion at the neck and thorax.¹²⁹ Patients with diabetes may experience variations in blood sugar control if steroids are used.

Bottom Line

Interventional treatment modalities that may have a role in psychiatric treatment include IV administration of ketamine, aducanumab, lecanemab, brexanolone, magnesium, scopolamine, and clomipramine. Other interventional approaches include stellate ganglion blocks, glabellar botulinum toxin injections, and trigger point injections.

Related Resources

• Dokucu ME, Janicak PG. Nontraditional therapies for treatment-resistant depression. Current Psychiatry. 2021; 20(9):38-43,49. doi:10.12788/cp.0166
• Kim J, Khoury R, Grossberg GT. Botulinum toxin: emerging psychiatric indications. Current Psychiatry. 2018;17(12):8-18.

Drug Brand Names

Aducanumab • Aduhelm
Aripiprazole • Abilify
Aripiprazole lauroxil • Aristada
Brexanolone • Zulresso
Buprenorphine • Sublocade
Citalopram • Celexa
Clomipramine • Anafranil
Diazepam • Valium
Droperidol • Inapsine
Esketamine • Spravato
Fentanyl • Actiq
Fluphenazine decanoate • Modecate
Fluphenazine hydrochloride • Prolixin
Haloperidol decanoate • Haldol decanoate
Haloperidol lactate • Haldol
Ketamine • Ketalar
Lecanemab • Leqembi
Lidocaine • Xylocaine
Lorazepam • Ativan
Loxapine inhaled • Adasuve
Naltrexone • Vivitrol
Magnesium sulfate • Sulfamag
Midazolam • Versed
Olanzapine • Zyprexa
OnabotulinumtoxinA injection • Botox
Paliperidone • Invega Hafyera, Invega Sustenna, Invega Trinza
Rapamycin • Rapamune, Sirolimus
Risperidone • Perseris
Risperidone microspheres • Risperdal Consta, Rykindo
Scopolamine • Hyoscine
Tramadol • Conzip
Vortioxetine • Trintellix
Ziprasidone • Geodon