When patients with major depressive disorder (MDD) do not achieve optimal outcomes after FDA-approved first-line treatments and standard adjunctive strategies, clinicians look for additional approaches to alleviate their patients’ symptoms. Recent research suggests that several “nontraditional” treatments used primarily as adjuncts to standard antidepressants have promise for treatment-resistant depression.

In Part 1 of this article (Current Psychiatry, September 2021), we examined off-label medications. In Part 2, we will review other nontraditional approaches to treatment-resistant depression, including herbal/nutraceutical agents, anti-inflammatory/immune system therapies, device-based treatments, and other alternative approaches. Importantly, some treatments also demonstrate adverse effects (Table^1-32). With a careful consideration of the risk/benefit balance, this article reviews some of the better-studied nontraditional treatment options for patients with treatment-resistant depression.

Herbal/nutraceutical agents

This category encompasses a variety of commonly available “natural” options patients often ask about and at times self-prescribe. Examples evaluated in clinical trials include:

• vitamin D
• essential fatty acids (omega-3, omega-6)
• S-adenosyl-L-methionine (SAMe)
• hypericum perforatum (St. John’s Wort)
• probiotics.

Vitamin D deficiency has been linked to depression, possibly by lowering serotonin, norepinephrine, and dopamine concentrations.^1-3

A meta-analysis of 3 prospective, observational studies (N = 8,815) found an elevated risk of affective disorders in patients with low vitamin D levels.⁴ In addition, a systematic review and meta-analysis supported a potential role for vitamin D supplementation for patients with treatment-resistant depresssion.⁵

Toxicity can occur at levels >100 ng/mL, and resulting adverse effects may include weakness, fatigue, sleepiness, headache, loss of appetite, dry mouth, metallic taste, nausea, and vomiting. This vitamin can be considered as an adjunct to standard antidepressants, particularly in patients with treatment-resistant depression who have low vitamin D levels, but regular monitoring is necessary to avoid toxicity.

Essential fatty acids. Protein receptors embedded in lipid membranes and their binding affinities are influenced by omega-3 and omega-6 polyunsaturated fatty acids. Thus, essential fatty acids may benefit depression by maintaining membrane integrity and fluidity, as well as via their anti-inflammatory activity.

Continue to: Although results from...

Although results from controlled trials are mixed, a systematic review and meta-analysis of adjunctive nutraceuticals supported a potential role for essential fatty acids, primarily eicosapentaenoic acid (EPA), by itself or in combination with docosahexaenoic acid (DHA), with total EPA >60%.⁵ A second meta-analysis of 26 studies (N = 2,160) that considered only essential fatty acids concluded that EPA ≥60% at ≤1 g/d could benefit depression.⁶ Furthermore, omega-3 fatty acids may be helpful as an add-on agent for postpartum depression.⁷

Be aware that a diet rich in omega-6 greatly increases oxidized low-density lipoprotein levels in adipose tissue, potentially posing a cardiac risk factor. Clinicians need to be aware that self-prescribed use of essential fatty acids is common, and to ask about and monitor their patients’ use of these agents.

S-adenosyl-L-methionine (SAMe) is an intracellular amino acid and methyl donor. Among other actions, it is involved in the biosynthesis of hormones and neurotransmitters. There is promising but limited preliminary evidence of its efficacy and safety as a monotherapy or for antidepressant augmentation.⁸ For example, when compared with placebo for depressive symptoms in 19 randomized controlled trials (RCTs) (N = 878) ⁸:

• Five out of 6 earlier controlled studies reported SAMe IV (200 to 400 mg/d) or IM (45 to 50 mg/d) was more effective than placebo
• When the above studies were added to 14 subsequent studies for a meta-analysis, 12 of 19 RCTs reported that parenteral or oral SAMe was significantly more effective than placebo for depression (P < .05).

Overall, the safety and tolerability of SAMe are good. Common adverse effects include nausea, mild insomnia, dizziness, irritability, and anxiety. This is another compound widely available without a prescription and at times self-prescribed. It carries an acceptable risk/benefit balance, with decades of experience.

Hypericum perforatum (St. John’s Wort) is widely prescribed for depression in China and Europe, typically in doses ranging from 500 to 900 mg/d. Its mechanism of action in depression may relate to inhibition of serotonin, dopamine, and norepinephrine uptake from the synaptic cleft of these interconnecting neurotransmitter systems.

Continue to: A meta-analysis of 7 clinical trials...

A meta-analysis of 7 clinical trials (N = 3,808) comparing St. John’s Wort with various selective serotonin reuptake inhibitors (SSRIs) reported comparable rates of response (pooled relative risk .983, 95% CI .924 to 1.042; P < .001) and remission (pooled relative risk 1.013, 95% CI .892 to 1.134; P < .001).⁹ Further, there were significantly lower discontinuation/dropout rates (pooled odds ratio .587, 95% CI .478 to 0.697; P < .001) for St. John’s Wort compared with the SSRIs.

Existing evidence on the long-term efficacy and safety is limited (studies ranged from 4 to 12 weeks), as is evidence for patients with more severe depression or high suicidality.

Serious drug interactions include the potential for serotonin syndrome when St. John’s Wort is combined with certain antidepressants, compromised efficacy of benzodiazepines and standard antidepressants, and severe skin reactions to sun exposure. In addition, St. John’s Wort may not be safe to use during pregnancy or while breastfeeding. Because potential drug interactions can be serious and individuals often self-prescribe this agent, it is important to ask patients about their use of St. John’s Wort, and to be vigilant for such potential adverse interactions.

Probiotics. These agents produce neuroactive substances that act on the brain/gut axis. Preliminary evidence suggests that these “psychobiotics” confer mental health benefits.^10-12 Relative to other approaches, their low-risk profile make them an attractive option for some patients.

Anti-inflammatory/immune system therapies

Inflammation is linked to various medical and brain disorders. For example, patients with depression often demonstrate increased levels of peripheral blood inflammatory biomarkers (such as C-reactive protein and interleukin-6 and -17) that are known to alter norepinephrine, neuroendocrine (eg, the hypothalamic-pituitary-adrenal axis), and microglia function in addition to neuro­plasticity. Thus, targeting inflammation may facilitate the development of novel antidepressants. In addition, these agents may benefit depression associated with comorbid autoimmune disorders, such as psoriasis or rheumatoid arthritis. A systematic review and meta-analysis of 36 RCTs (N = 10,000) found 5 out of 6 anti-inflammatory agents improved depression.^13,14 In general, reported disadvantages of anti-inflammatories/immunosuppressants include the potential to block the antidepressant effect of some agents, the risk of opportunistic infections, and an increased risk of suicide.

Continue to: Statins

 

 

Statins

In a meta-analysis of 3 randomized, double-blind trials, 3 statins (lovastatin, atorvastatin, and simvastatin) significantly improved depression scores when used as an adjunctive therapy to fluoxetine and citalopram, compared with adjunctive placebo (N = 165, P < .001).¹⁵

Specific adverse effects of statins include headaches, muscle pain (rarely rhabdomyolysis), dizziness, rash, and liver damage. Statins also have the potential for adverse interactions with other medications. Given the limited efficacy literature on statins for depression and the potential for serious adverse effects, these agents probably should be limited to patients with treatment-resistant depression for whom a statin is indicated for a comorbid medical disorder, such as hypercholesteremia.

Neurosteroids

Brexanolone is FDA-approved for the treatment of postpartum depression. It is an IV formulation of the neuroactive steroid hormone allopregnanolone (a metabolite of progesterone), which acts as a positive allosteric modulator of the GABA-A receptor. Unfortunately, the infusion needs to occur over a 60-hour period.

Ganaxolone is an oral analog formulation of allopregnanolone. In an uncontrolled, open-label pilot study, this medication was administered for 8 weeks as an adjunct to an adequately dosed antidepressant to 10 postmenopausal women with persistent MDD.¹⁶ Of the 9 women who completed the study, 4 (44%) improved significantly (P < .019) and the benefit was sustained for 2 additional weeks.¹⁶ Adverse effects of ganaxolone included dizziness in 60% of participants, and sleepiness and fatigue in all of them with twice-daily dosing. If the FDA approves ganaxolone, it would become an easier-to-administer option to brexanolone.

Zuranolone is an investigational agent being studied as a treatment for postpartum depression. In a double-blind RCT that evaluated 151 women with postpartum depression, those who took oral zuranolone, 30 mg daily at bedtime for 2 weeks, experienced significant reductions in Hamilton Depression Rating Scale-17 (HDRS-17) scores compared with placebo (P < .003).¹⁷ Improvement in core depression symptom ratings was seen as early as Day 3 and persisted through Day 45.

Continue to: The most common...

The most common (≥5%) treatment-emergent adverse effects were somnolence (15%), headache (9%), dizziness (8%), upper respiratory tract infection (8%), diarrhea (6%), and sedation (5%). Two patients experienced a serious adverse event: one who received zuranolone (confusional state) and one who received placebo (pancreatitis). One patient discontinued zuranolone due to adverse effects vs no discontinuations among those who received placebo. The risk of taking zuranolone while breastfeeding is not known.

Device-based strategies

In addition to FDA-cleared approaches (eg, electroconvulsive therapy [ECT], vagus nerve stimulation [VNS], transcranial magnetic stimulation [TMS]), other devices have also demonstrated promising results.

Transcranial direct current stimulation (tDCS) involves delivering weak electrical current to the cerebral cortex through small scalp electrodes to produce the following effects:

• anodal tDCS enhances cortical excitability
• cathodal tDCS reduces cortical excitability.

A typical protocol consists of delivering 1 to 2 mA over 20 minutes with scalp electrodes placed in different configurations based on the targeted symptom(s).

While tDCS has been evaluated as a treatment for various neuropsychiatric disorders, including bipolar depression, Parkinson’s disease, and schizophrenia, most trials have looked at its use for treating depression. Results have been promising but mixed. For example, 1 meta-analysis of 6 RCTs (comprising 96 active and 80 sham tDCS courses) reported that active tDCS was superior to a sham procedure (Hedges’ g = 0.743) for symptoms of depression.¹⁸ By contrast, another meta-analysis of 6 RCTs (N = 200) did not find a significant difference between active and sham tDCS for response and remission rates.¹⁹ More recently, a group of experts created an evidence-based guideline using a systematic review of the controlled trial literature. These authors concluded there is “probable efficacy for anodal tDCS of the left dorsolateral prefrontal cortex (DLPFC) (with right orbitofrontal cathode) in major depressive episodes without drug resistance but probable inefficacy for drug-resistant major depressive episodes.”²⁰

Continue to: Adverse effects of tDCS...

Adverse effects of tDCS are typically mild but may include persistent skin lesions similar to burns; mania or hypomania; and one reported seizure in a pediatric patient.

Because various over-the-counter direct current stimulation devices are available for purchase at modest cost, clinicians should ask patients if they have been self-administering this treatment.

Chronotherapy strategies

Agomelatine combines serotonergic (5-HT2B and 5-HT2C antagonist) and melatonergic (MT1-MT2 agonist in the suprachiasmatic nucleus) actions that contribute to stabilization of circadian rhythms and subsequent improvement in sleep patterns. Agomelatine (n = 1,274) significantly lowered depression symptoms compared with placebo (n = 689) (standardized mean difference −0.26; P < 3.48×10^-11), but the clinical relevance was questionable.²¹ A recent review of the literature and expert opinion suggest this agent may also have efficacy for anhedonia; however, in placebo-controlled, relapse prevention studies, its long-term efficacy was not consistent.²²

Common adverse effects include anxiety; nausea, vomiting, and stomach pain; abnormal dreams and insomnia; dizziness; drowsiness and fatigue; and weight gain. Some reviewers have expressed concerns about agomelatine’s potential for hepatotoxicity and the need for repeated clinical laboratory tests. Although agomelatine is approved outside of the United States, limited efficacy data and the potential for serious adverse effects have precluded FDA approval of this agent.

Sleep deprivation as a treatment technique for depression has been developed over the past 50 years. With total sleep deprivation (TSD) over 1 cycle, patients stay awake for approximately 36 hours, from daytime until the next day’s evening. While 1 to 6 cycles can produce acute antidepressant effects, prompt relapse after sleep recovery is common.

Continue to: In a systematic review...

In a systematic review and meta-analysis of 7 studies that included a total of 311 patients with bipolar depression²³:

• TSD plus medications resulted in a significant decrease in depressive symptoms at 1 week compared with medications alone
• higher response rates were maintained after 3 months with lithium.

Adverse effects commonly include general fatigue and headaches; possible switch into mania with bipolar depression; and rarely, seizures or other unexpected medical conditions (eg, acute coronary syndrome). Presently, this approach is limited to research laboratories with the appropriate sophistication to safely conduct such trials.

Other nontraditional strategies

Cardiovascular exercise, resistance training, mindfulness, and yoga have been shown to decrease severe depressive symptoms when used as adjuncts for patients with treatment-resistant depression, or as monotherapy to treat patients with milder depression.

Exercise. The significant benefits of exercise in various forms as treatment for mild to moderate depression are well described in the literature, but it is less clear if it is effective for treatment-resistant depression. A 2013 Cochrane report²⁴ (39 studies with 2,326 participants total) and 2 meta-analyses undertaken in 2015 (Kvam et al²⁵ included 23 studies with 977 participants, and Schuh et al²⁶ included 25 trials with 1,487 participants) reported that various types of exercise ameliorate depression of differing subtypes and severity, with effect sizes ranging from small to large. Schuh et al²⁶ found that publication bias underestimated effect size. Also, not surprisingly, separate analysis of only higher-quality trials decreased effect size.^24-26 A meta-analysis that included tai chi and yoga in addition to aerobic exercise and strength training (25 trials with 2,083 participants) found low to moderate benefit for exercise and yoga.²⁷ Finally, a meta-analysis by Cramer et al²⁸ that included 12 RCTs (N = 619) supported the use of yoga plus controlled breathing techniques as an ancillary treatment for depression.

Two small exercise trials specifically evaluated patients with treatment-resistant depression.^29,30 Mota-Pereira et al²⁹ compared 22 participants who walked for 30 to 45 minutes, 5 days a week for 12 weeks in addition to pharmacotherapy with 11 patients who received pharmacotherapy only. Exercise improved all outcomes, including HDRS score (both compared to baseline and to the control group). Moreover, 26% of the exercise group went into remission. Pilu et al³⁰ evaluated strength training as an adjunctive treatment. Participants received 1 hour of strength training twice weekly for 8 months (n = 10), or pharmacotherapy only (n = 20). The adjunct strength training group had a statistically significant (P < .0001) improvement in HDRS scores at the end of the 8 months, whereas the control group did not (P < .28).

Continue to: Adverse effects...

Adverse effects of exercise are typically limited to sprains or strains; rarely, participants experience serious injuries.

Mindfulness-based interventions involve purposely paying attention in the present moment to enhance self-understanding and decrease anxiety about the future and regrets about the past, both of which complicate depression. A meta-analysis of 12 RCTs (N = 578) found this approach significantly reduced depression severity when used as an adjunctive therapy.³¹ There may be risks if mindfulness-based interventions are practiced incorrectly. For example, some reports have linked mindfulness-based interventions to psychotic episodes, meditation addiction, and antisocial or asocial behavior.³²

Bottom Line

Nonpharmacologic options for patients with treatment-resistant depression include herbal/nutraceuticals, anti-inflammatory/immune system therapies, and devices. While research suggests some of these approaches are promising, clinicians need to carefully consider potential adverse effects, some of which may be serious.

Related Resources

• Kaur M, Sanches M. Experimental therapeutics in treatmentresistant major depressive disorder. J Exp Pharmacol. 2021;13:181-196.
• Janicak PG. What’s new in transcranial magnetic stimulation. Current Psychiatry. 2019;18(3):10-16.

Drug Brand Names

Atorvastatin • Lipitor
Brexanolone • Zulresso
Citalopram • Celexa
Fluoxetine • Prozac
Lithium • Eskalith, Lithobid
Lovastatin • Altoprev, Mevacor
Minocycline • Dynacin, Minocin
Simvastatin • Flolipid, Zocor

When patients with major depressive disorder (MDD) do not achieve optimal outcomes after FDA-approved first-line treatments and standard adjunctive strategies, clinicians look for additional approaches to alleviate their patients’ symptoms. Recent research suggests that several “nontraditional” treatments used primarily as adjuncts to standard antidepressants have promise for treatment-resistant depression.

In Part 1 of this article (Current Psychiatry, September 2021), we examined off-label medications. In Part 2, we will review other nontraditional approaches to treatment-resistant depression, including herbal/nutraceutical agents, anti-inflammatory/immune system therapies, device-based treatments, and other alternative approaches. Importantly, some treatments also demonstrate adverse effects (Table^1-32). With a careful consideration of the risk/benefit balance, this article reviews some of the better-studied nontraditional treatment options for patients with treatment-resistant depression.

Herbal/nutraceutical agents

This category encompasses a variety of commonly available “natural” options patients often ask about and at times self-prescribe. Examples evaluated in clinical trials include:

• vitamin D
• essential fatty acids (omega-3, omega-6)
• S-adenosyl-L-methionine (SAMe)
• hypericum perforatum (St. John’s Wort)
• probiotics.

Vitamin D deficiency has been linked to depression, possibly by lowering serotonin, norepinephrine, and dopamine concentrations.^1-3

A meta-analysis of 3 prospective, observational studies (N = 8,815) found an elevated risk of affective disorders in patients with low vitamin D levels.⁴ In addition, a systematic review and meta-analysis supported a potential role for vitamin D supplementation for patients with treatment-resistant depresssion.⁵

Toxicity can occur at levels >100 ng/mL, and resulting adverse effects may include weakness, fatigue, sleepiness, headache, loss of appetite, dry mouth, metallic taste, nausea, and vomiting. This vitamin can be considered as an adjunct to standard antidepressants, particularly in patients with treatment-resistant depression who have low vitamin D levels, but regular monitoring is necessary to avoid toxicity.

Essential fatty acids. Protein receptors embedded in lipid membranes and their binding affinities are influenced by omega-3 and omega-6 polyunsaturated fatty acids. Thus, essential fatty acids may benefit depression by maintaining membrane integrity and fluidity, as well as via their anti-inflammatory activity.

Continue to: Although results from...

Although results from controlled trials are mixed, a systematic review and meta-analysis of adjunctive nutraceuticals supported a potential role for essential fatty acids, primarily eicosapentaenoic acid (EPA), by itself or in combination with docosahexaenoic acid (DHA), with total EPA >60%.⁵ A second meta-analysis of 26 studies (N = 2,160) that considered only essential fatty acids concluded that EPA ≥60% at ≤1 g/d could benefit depression.⁶ Furthermore, omega-3 fatty acids may be helpful as an add-on agent for postpartum depression.⁷

Be aware that a diet rich in omega-6 greatly increases oxidized low-density lipoprotein levels in adipose tissue, potentially posing a cardiac risk factor. Clinicians need to be aware that self-prescribed use of essential fatty acids is common, and to ask about and monitor their patients’ use of these agents.

S-adenosyl-L-methionine (SAMe) is an intracellular amino acid and methyl donor. Among other actions, it is involved in the biosynthesis of hormones and neurotransmitters. There is promising but limited preliminary evidence of its efficacy and safety as a monotherapy or for antidepressant augmentation.⁸ For example, when compared with placebo for depressive symptoms in 19 randomized controlled trials (RCTs) (N = 878) ⁸:

• Five out of 6 earlier controlled studies reported SAMe IV (200 to 400 mg/d) or IM (45 to 50 mg/d) was more effective than placebo
• When the above studies were added to 14 subsequent studies for a meta-analysis, 12 of 19 RCTs reported that parenteral or oral SAMe was significantly more effective than placebo for depression (P < .05).

Overall, the safety and tolerability of SAMe are good. Common adverse effects include nausea, mild insomnia, dizziness, irritability, and anxiety. This is another compound widely available without a prescription and at times self-prescribed. It carries an acceptable risk/benefit balance, with decades of experience.

Hypericum perforatum (St. John’s Wort) is widely prescribed for depression in China and Europe, typically in doses ranging from 500 to 900 mg/d. Its mechanism of action in depression may relate to inhibition of serotonin, dopamine, and norepinephrine uptake from the synaptic cleft of these interconnecting neurotransmitter systems.

Continue to: A meta-analysis of 7 clinical trials...

A meta-analysis of 7 clinical trials (N = 3,808) comparing St. John’s Wort with various selective serotonin reuptake inhibitors (SSRIs) reported comparable rates of response (pooled relative risk .983, 95% CI .924 to 1.042; P < .001) and remission (pooled relative risk 1.013, 95% CI .892 to 1.134; P < .001).⁹ Further, there were significantly lower discontinuation/dropout rates (pooled odds ratio .587, 95% CI .478 to 0.697; P < .001) for St. John’s Wort compared with the SSRIs.

Existing evidence on the long-term efficacy and safety is limited (studies ranged from 4 to 12 weeks), as is evidence for patients with more severe depression or high suicidality.

Serious drug interactions include the potential for serotonin syndrome when St. John’s Wort is combined with certain antidepressants, compromised efficacy of benzodiazepines and standard antidepressants, and severe skin reactions to sun exposure. In addition, St. John’s Wort may not be safe to use during pregnancy or while breastfeeding. Because potential drug interactions can be serious and individuals often self-prescribe this agent, it is important to ask patients about their use of St. John’s Wort, and to be vigilant for such potential adverse interactions.

Probiotics. These agents produce neuroactive substances that act on the brain/gut axis. Preliminary evidence suggests that these “psychobiotics” confer mental health benefits.^10-12 Relative to other approaches, their low-risk profile make them an attractive option for some patients.

Anti-inflammatory/immune system therapies

Inflammation is linked to various medical and brain disorders. For example, patients with depression often demonstrate increased levels of peripheral blood inflammatory biomarkers (such as C-reactive protein and interleukin-6 and -17) that are known to alter norepinephrine, neuroendocrine (eg, the hypothalamic-pituitary-adrenal axis), and microglia function in addition to neuro­plasticity. Thus, targeting inflammation may facilitate the development of novel antidepressants. In addition, these agents may benefit depression associated with comorbid autoimmune disorders, such as psoriasis or rheumatoid arthritis. A systematic review and meta-analysis of 36 RCTs (N = 10,000) found 5 out of 6 anti-inflammatory agents improved depression.^13,14 In general, reported disadvantages of anti-inflammatories/immunosuppressants include the potential to block the antidepressant effect of some agents, the risk of opportunistic infections, and an increased risk of suicide.

Continue to: Statins

 

 

Statins

In a meta-analysis of 3 randomized, double-blind trials, 3 statins (lovastatin, atorvastatin, and simvastatin) significantly improved depression scores when used as an adjunctive therapy to fluoxetine and citalopram, compared with adjunctive placebo (N = 165, P < .001).¹⁵

Specific adverse effects of statins include headaches, muscle pain (rarely rhabdomyolysis), dizziness, rash, and liver damage. Statins also have the potential for adverse interactions with other medications. Given the limited efficacy literature on statins for depression and the potential for serious adverse effects, these agents probably should be limited to patients with treatment-resistant depression for whom a statin is indicated for a comorbid medical disorder, such as hypercholesteremia.

Neurosteroids

Brexanolone is FDA-approved for the treatment of postpartum depression. It is an IV formulation of the neuroactive steroid hormone allopregnanolone (a metabolite of progesterone), which acts as a positive allosteric modulator of the GABA-A receptor. Unfortunately, the infusion needs to occur over a 60-hour period.

Ganaxolone is an oral analog formulation of allopregnanolone. In an uncontrolled, open-label pilot study, this medication was administered for 8 weeks as an adjunct to an adequately dosed antidepressant to 10 postmenopausal women with persistent MDD.¹⁶ Of the 9 women who completed the study, 4 (44%) improved significantly (P < .019) and the benefit was sustained for 2 additional weeks.¹⁶ Adverse effects of ganaxolone included dizziness in 60% of participants, and sleepiness and fatigue in all of them with twice-daily dosing. If the FDA approves ganaxolone, it would become an easier-to-administer option to brexanolone.

Zuranolone is an investigational agent being studied as a treatment for postpartum depression. In a double-blind RCT that evaluated 151 women with postpartum depression, those who took oral zuranolone, 30 mg daily at bedtime for 2 weeks, experienced significant reductions in Hamilton Depression Rating Scale-17 (HDRS-17) scores compared with placebo (P < .003).¹⁷ Improvement in core depression symptom ratings was seen as early as Day 3 and persisted through Day 45.

Continue to: The most common...

The most common (≥5%) treatment-emergent adverse effects were somnolence (15%), headache (9%), dizziness (8%), upper respiratory tract infection (8%), diarrhea (6%), and sedation (5%). Two patients experienced a serious adverse event: one who received zuranolone (confusional state) and one who received placebo (pancreatitis). One patient discontinued zuranolone due to adverse effects vs no discontinuations among those who received placebo. The risk of taking zuranolone while breastfeeding is not known.

Device-based strategies

In addition to FDA-cleared approaches (eg, electroconvulsive therapy [ECT], vagus nerve stimulation [VNS], transcranial magnetic stimulation [TMS]), other devices have also demonstrated promising results.

Transcranial direct current stimulation (tDCS) involves delivering weak electrical current to the cerebral cortex through small scalp electrodes to produce the following effects:

• anodal tDCS enhances cortical excitability
• cathodal tDCS reduces cortical excitability.

A typical protocol consists of delivering 1 to 2 mA over 20 minutes with scalp electrodes placed in different configurations based on the targeted symptom(s).

While tDCS has been evaluated as a treatment for various neuropsychiatric disorders, including bipolar depression, Parkinson’s disease, and schizophrenia, most trials have looked at its use for treating depression. Results have been promising but mixed. For example, 1 meta-analysis of 6 RCTs (comprising 96 active and 80 sham tDCS courses) reported that active tDCS was superior to a sham procedure (Hedges’ g = 0.743) for symptoms of depression.¹⁸ By contrast, another meta-analysis of 6 RCTs (N = 200) did not find a significant difference between active and sham tDCS for response and remission rates.¹⁹ More recently, a group of experts created an evidence-based guideline using a systematic review of the controlled trial literature. These authors concluded there is “probable efficacy for anodal tDCS of the left dorsolateral prefrontal cortex (DLPFC) (with right orbitofrontal cathode) in major depressive episodes without drug resistance but probable inefficacy for drug-resistant major depressive episodes.”²⁰

Continue to: Adverse effects of tDCS...

Adverse effects of tDCS are typically mild but may include persistent skin lesions similar to burns; mania or hypomania; and one reported seizure in a pediatric patient.

Because various over-the-counter direct current stimulation devices are available for purchase at modest cost, clinicians should ask patients if they have been self-administering this treatment.

Chronotherapy strategies

Agomelatine combines serotonergic (5-HT2B and 5-HT2C antagonist) and melatonergic (MT1-MT2 agonist in the suprachiasmatic nucleus) actions that contribute to stabilization of circadian rhythms and subsequent improvement in sleep patterns. Agomelatine (n = 1,274) significantly lowered depression symptoms compared with placebo (n = 689) (standardized mean difference −0.26; P < 3.48×10^-11), but the clinical relevance was questionable.²¹ A recent review of the literature and expert opinion suggest this agent may also have efficacy for anhedonia; however, in placebo-controlled, relapse prevention studies, its long-term efficacy was not consistent.²²

Common adverse effects include anxiety; nausea, vomiting, and stomach pain; abnormal dreams and insomnia; dizziness; drowsiness and fatigue; and weight gain. Some reviewers have expressed concerns about agomelatine’s potential for hepatotoxicity and the need for repeated clinical laboratory tests. Although agomelatine is approved outside of the United States, limited efficacy data and the potential for serious adverse effects have precluded FDA approval of this agent.

Sleep deprivation as a treatment technique for depression has been developed over the past 50 years. With total sleep deprivation (TSD) over 1 cycle, patients stay awake for approximately 36 hours, from daytime until the next day’s evening. While 1 to 6 cycles can produce acute antidepressant effects, prompt relapse after sleep recovery is common.

Continue to: In a systematic review...

In a systematic review and meta-analysis of 7 studies that included a total of 311 patients with bipolar depression²³:

• TSD plus medications resulted in a significant decrease in depressive symptoms at 1 week compared with medications alone
• higher response rates were maintained after 3 months with lithium.

Adverse effects commonly include general fatigue and headaches; possible switch into mania with bipolar depression; and rarely, seizures or other unexpected medical conditions (eg, acute coronary syndrome). Presently, this approach is limited to research laboratories with the appropriate sophistication to safely conduct such trials.

Other nontraditional strategies

Cardiovascular exercise, resistance training, mindfulness, and yoga have been shown to decrease severe depressive symptoms when used as adjuncts for patients with treatment-resistant depression, or as monotherapy to treat patients with milder depression.

Exercise. The significant benefits of exercise in various forms as treatment for mild to moderate depression are well described in the literature, but it is less clear if it is effective for treatment-resistant depression. A 2013 Cochrane report²⁴ (39 studies with 2,326 participants total) and 2 meta-analyses undertaken in 2015 (Kvam et al²⁵ included 23 studies with 977 participants, and Schuh et al²⁶ included 25 trials with 1,487 participants) reported that various types of exercise ameliorate depression of differing subtypes and severity, with effect sizes ranging from small to large. Schuh et al²⁶ found that publication bias underestimated effect size. Also, not surprisingly, separate analysis of only higher-quality trials decreased effect size.^24-26 A meta-analysis that included tai chi and yoga in addition to aerobic exercise and strength training (25 trials with 2,083 participants) found low to moderate benefit for exercise and yoga.²⁷ Finally, a meta-analysis by Cramer et al²⁸ that included 12 RCTs (N = 619) supported the use of yoga plus controlled breathing techniques as an ancillary treatment for depression.

Two small exercise trials specifically evaluated patients with treatment-resistant depression.^29,30 Mota-Pereira et al²⁹ compared 22 participants who walked for 30 to 45 minutes, 5 days a week for 12 weeks in addition to pharmacotherapy with 11 patients who received pharmacotherapy only. Exercise improved all outcomes, including HDRS score (both compared to baseline and to the control group). Moreover, 26% of the exercise group went into remission. Pilu et al³⁰ evaluated strength training as an adjunctive treatment. Participants received 1 hour of strength training twice weekly for 8 months (n = 10), or pharmacotherapy only (n = 20). The adjunct strength training group had a statistically significant (P < .0001) improvement in HDRS scores at the end of the 8 months, whereas the control group did not (P < .28).

Continue to: Adverse effects...

Adverse effects of exercise are typically limited to sprains or strains; rarely, participants experience serious injuries.

Mindfulness-based interventions involve purposely paying attention in the present moment to enhance self-understanding and decrease anxiety about the future and regrets about the past, both of which complicate depression. A meta-analysis of 12 RCTs (N = 578) found this approach significantly reduced depression severity when used as an adjunctive therapy.³¹ There may be risks if mindfulness-based interventions are practiced incorrectly. For example, some reports have linked mindfulness-based interventions to psychotic episodes, meditation addiction, and antisocial or asocial behavior.³²

Bottom Line

Nonpharmacologic options for patients with treatment-resistant depression include herbal/nutraceuticals, anti-inflammatory/immune system therapies, and devices. While research suggests some of these approaches are promising, clinicians need to carefully consider potential adverse effects, some of which may be serious.

Related Resources

• Kaur M, Sanches M. Experimental therapeutics in treatmentresistant major depressive disorder. J Exp Pharmacol. 2021;13:181-196.
• Janicak PG. What’s new in transcranial magnetic stimulation. Current Psychiatry. 2019;18(3):10-16.

Drug Brand Names

Atorvastatin • Lipitor
Brexanolone • Zulresso
Citalopram • Celexa
Fluoxetine • Prozac
Lithium • Eskalith, Lithobid
Lovastatin • Altoprev, Mevacor
Minocycline • Dynacin, Minocin
Simvastatin • Flolipid, Zocor

When patients with major depressive disorder (MDD) do not achieve optimal outcomes after FDA-approved first-line treatments and standard adjunctive strategies, clinicians look for additional approaches to alleviate their patients’ symptoms. Recent research suggests that several “nontraditional” treatments used primarily as adjuncts to standard antidepressants have promise for treatment-resistant depression.

In Part 1 of this article (Current Psychiatry, September 2021), we examined off-label medications. In Part 2, we will review other nontraditional approaches to treatment-resistant depression, including herbal/nutraceutical agents, anti-inflammatory/immune system therapies, device-based treatments, and other alternative approaches. Importantly, some treatments also demonstrate adverse effects (Table^1-32). With a careful consideration of the risk/benefit balance, this article reviews some of the better-studied nontraditional treatment options for patients with treatment-resistant depression.

Herbal/nutraceutical agents

This category encompasses a variety of commonly available “natural” options patients often ask about and at times self-prescribe. Examples evaluated in clinical trials include:

• vitamin D
• essential fatty acids (omega-3, omega-6)
• S-adenosyl-L-methionine (SAMe)
• hypericum perforatum (St. John’s Wort)
• probiotics.

Vitamin D deficiency has been linked to depression, possibly by lowering serotonin, norepinephrine, and dopamine concentrations.^1-3

A meta-analysis of 3 prospective, observational studies (N = 8,815) found an elevated risk of affective disorders in patients with low vitamin D levels.⁴ In addition, a systematic review and meta-analysis supported a potential role for vitamin D supplementation for patients with treatment-resistant depresssion.⁵

Toxicity can occur at levels >100 ng/mL, and resulting adverse effects may include weakness, fatigue, sleepiness, headache, loss of appetite, dry mouth, metallic taste, nausea, and vomiting. This vitamin can be considered as an adjunct to standard antidepressants, particularly in patients with treatment-resistant depression who have low vitamin D levels, but regular monitoring is necessary to avoid toxicity.

Essential fatty acids. Protein receptors embedded in lipid membranes and their binding affinities are influenced by omega-3 and omega-6 polyunsaturated fatty acids. Thus, essential fatty acids may benefit depression by maintaining membrane integrity and fluidity, as well as via their anti-inflammatory activity.

Continue to: Although results from...

Although results from controlled trials are mixed, a systematic review and meta-analysis of adjunctive nutraceuticals supported a potential role for essential fatty acids, primarily eicosapentaenoic acid (EPA), by itself or in combination with docosahexaenoic acid (DHA), with total EPA >60%.⁵ A second meta-analysis of 26 studies (N = 2,160) that considered only essential fatty acids concluded that EPA ≥60% at ≤1 g/d could benefit depression.⁶ Furthermore, omega-3 fatty acids may be helpful as an add-on agent for postpartum depression.⁷

Be aware that a diet rich in omega-6 greatly increases oxidized low-density lipoprotein levels in adipose tissue, potentially posing a cardiac risk factor. Clinicians need to be aware that self-prescribed use of essential fatty acids is common, and to ask about and monitor their patients’ use of these agents.

S-adenosyl-L-methionine (SAMe) is an intracellular amino acid and methyl donor. Among other actions, it is involved in the biosynthesis of hormones and neurotransmitters. There is promising but limited preliminary evidence of its efficacy and safety as a monotherapy or for antidepressant augmentation.⁸ For example, when compared with placebo for depressive symptoms in 19 randomized controlled trials (RCTs) (N = 878) ⁸:

• Five out of 6 earlier controlled studies reported SAMe IV (200 to 400 mg/d) or IM (45 to 50 mg/d) was more effective than placebo
• When the above studies were added to 14 subsequent studies for a meta-analysis, 12 of 19 RCTs reported that parenteral or oral SAMe was significantly more effective than placebo for depression (P < .05).

Overall, the safety and tolerability of SAMe are good. Common adverse effects include nausea, mild insomnia, dizziness, irritability, and anxiety. This is another compound widely available without a prescription and at times self-prescribed. It carries an acceptable risk/benefit balance, with decades of experience.

Hypericum perforatum (St. John’s Wort) is widely prescribed for depression in China and Europe, typically in doses ranging from 500 to 900 mg/d. Its mechanism of action in depression may relate to inhibition of serotonin, dopamine, and norepinephrine uptake from the synaptic cleft of these interconnecting neurotransmitter systems.

Continue to: A meta-analysis of 7 clinical trials...

A meta-analysis of 7 clinical trials (N = 3,808) comparing St. John’s Wort with various selective serotonin reuptake inhibitors (SSRIs) reported comparable rates of response (pooled relative risk .983, 95% CI .924 to 1.042; P < .001) and remission (pooled relative risk 1.013, 95% CI .892 to 1.134; P < .001).⁹ Further, there were significantly lower discontinuation/dropout rates (pooled odds ratio .587, 95% CI .478 to 0.697; P < .001) for St. John’s Wort compared with the SSRIs.

Existing evidence on the long-term efficacy and safety is limited (studies ranged from 4 to 12 weeks), as is evidence for patients with more severe depression or high suicidality.

Serious drug interactions include the potential for serotonin syndrome when St. John’s Wort is combined with certain antidepressants, compromised efficacy of benzodiazepines and standard antidepressants, and severe skin reactions to sun exposure. In addition, St. John’s Wort may not be safe to use during pregnancy or while breastfeeding. Because potential drug interactions can be serious and individuals often self-prescribe this agent, it is important to ask patients about their use of St. John’s Wort, and to be vigilant for such potential adverse interactions.

Probiotics. These agents produce neuroactive substances that act on the brain/gut axis. Preliminary evidence suggests that these “psychobiotics” confer mental health benefits.^10-12 Relative to other approaches, their low-risk profile make them an attractive option for some patients.

Anti-inflammatory/immune system therapies

Inflammation is linked to various medical and brain disorders. For example, patients with depression often demonstrate increased levels of peripheral blood inflammatory biomarkers (such as C-reactive protein and interleukin-6 and -17) that are known to alter norepinephrine, neuroendocrine (eg, the hypothalamic-pituitary-adrenal axis), and microglia function in addition to neuro­plasticity. Thus, targeting inflammation may facilitate the development of novel antidepressants. In addition, these agents may benefit depression associated with comorbid autoimmune disorders, such as psoriasis or rheumatoid arthritis. A systematic review and meta-analysis of 36 RCTs (N = 10,000) found 5 out of 6 anti-inflammatory agents improved depression.^13,14 In general, reported disadvantages of anti-inflammatories/immunosuppressants include the potential to block the antidepressant effect of some agents, the risk of opportunistic infections, and an increased risk of suicide.

Continue to: Statins

 

 

Statins

In a meta-analysis of 3 randomized, double-blind trials, 3 statins (lovastatin, atorvastatin, and simvastatin) significantly improved depression scores when used as an adjunctive therapy to fluoxetine and citalopram, compared with adjunctive placebo (N = 165, P < .001).¹⁵

Specific adverse effects of statins include headaches, muscle pain (rarely rhabdomyolysis), dizziness, rash, and liver damage. Statins also have the potential for adverse interactions with other medications. Given the limited efficacy literature on statins for depression and the potential for serious adverse effects, these agents probably should be limited to patients with treatment-resistant depression for whom a statin is indicated for a comorbid medical disorder, such as hypercholesteremia.

Neurosteroids

Brexanolone is FDA-approved for the treatment of postpartum depression. It is an IV formulation of the neuroactive steroid hormone allopregnanolone (a metabolite of progesterone), which acts as a positive allosteric modulator of the GABA-A receptor. Unfortunately, the infusion needs to occur over a 60-hour period.

Ganaxolone is an oral analog formulation of allopregnanolone. In an uncontrolled, open-label pilot study, this medication was administered for 8 weeks as an adjunct to an adequately dosed antidepressant to 10 postmenopausal women with persistent MDD.¹⁶ Of the 9 women who completed the study, 4 (44%) improved significantly (P < .019) and the benefit was sustained for 2 additional weeks.¹⁶ Adverse effects of ganaxolone included dizziness in 60% of participants, and sleepiness and fatigue in all of them with twice-daily dosing. If the FDA approves ganaxolone, it would become an easier-to-administer option to brexanolone.

Zuranolone is an investigational agent being studied as a treatment for postpartum depression. In a double-blind RCT that evaluated 151 women with postpartum depression, those who took oral zuranolone, 30 mg daily at bedtime for 2 weeks, experienced significant reductions in Hamilton Depression Rating Scale-17 (HDRS-17) scores compared with placebo (P < .003).¹⁷ Improvement in core depression symptom ratings was seen as early as Day 3 and persisted through Day 45.

Continue to: The most common...

The most common (≥5%) treatment-emergent adverse effects were somnolence (15%), headache (9%), dizziness (8%), upper respiratory tract infection (8%), diarrhea (6%), and sedation (5%). Two patients experienced a serious adverse event: one who received zuranolone (confusional state) and one who received placebo (pancreatitis). One patient discontinued zuranolone due to adverse effects vs no discontinuations among those who received placebo. The risk of taking zuranolone while breastfeeding is not known.

Device-based strategies

In addition to FDA-cleared approaches (eg, electroconvulsive therapy [ECT], vagus nerve stimulation [VNS], transcranial magnetic stimulation [TMS]), other devices have also demonstrated promising results.

Transcranial direct current stimulation (tDCS) involves delivering weak electrical current to the cerebral cortex through small scalp electrodes to produce the following effects:

• anodal tDCS enhances cortical excitability
• cathodal tDCS reduces cortical excitability.

A typical protocol consists of delivering 1 to 2 mA over 20 minutes with scalp electrodes placed in different configurations based on the targeted symptom(s).

While tDCS has been evaluated as a treatment for various neuropsychiatric disorders, including bipolar depression, Parkinson’s disease, and schizophrenia, most trials have looked at its use for treating depression. Results have been promising but mixed. For example, 1 meta-analysis of 6 RCTs (comprising 96 active and 80 sham tDCS courses) reported that active tDCS was superior to a sham procedure (Hedges’ g = 0.743) for symptoms of depression.¹⁸ By contrast, another meta-analysis of 6 RCTs (N = 200) did not find a significant difference between active and sham tDCS for response and remission rates.¹⁹ More recently, a group of experts created an evidence-based guideline using a systematic review of the controlled trial literature. These authors concluded there is “probable efficacy for anodal tDCS of the left dorsolateral prefrontal cortex (DLPFC) (with right orbitofrontal cathode) in major depressive episodes without drug resistance but probable inefficacy for drug-resistant major depressive episodes.”²⁰

Continue to: Adverse effects of tDCS...

Adverse effects of tDCS are typically mild but may include persistent skin lesions similar to burns; mania or hypomania; and one reported seizure in a pediatric patient.

Because various over-the-counter direct current stimulation devices are available for purchase at modest cost, clinicians should ask patients if they have been self-administering this treatment.

Chronotherapy strategies

Agomelatine combines serotonergic (5-HT2B and 5-HT2C antagonist) and melatonergic (MT1-MT2 agonist in the suprachiasmatic nucleus) actions that contribute to stabilization of circadian rhythms and subsequent improvement in sleep patterns. Agomelatine (n = 1,274) significantly lowered depression symptoms compared with placebo (n = 689) (standardized mean difference −0.26; P < 3.48×10^-11), but the clinical relevance was questionable.²¹ A recent review of the literature and expert opinion suggest this agent may also have efficacy for anhedonia; however, in placebo-controlled, relapse prevention studies, its long-term efficacy was not consistent.²²

Common adverse effects include anxiety; nausea, vomiting, and stomach pain; abnormal dreams and insomnia; dizziness; drowsiness and fatigue; and weight gain. Some reviewers have expressed concerns about agomelatine’s potential for hepatotoxicity and the need for repeated clinical laboratory tests. Although agomelatine is approved outside of the United States, limited efficacy data and the potential for serious adverse effects have precluded FDA approval of this agent.

Sleep deprivation as a treatment technique for depression has been developed over the past 50 years. With total sleep deprivation (TSD) over 1 cycle, patients stay awake for approximately 36 hours, from daytime until the next day’s evening. While 1 to 6 cycles can produce acute antidepressant effects, prompt relapse after sleep recovery is common.

Continue to: In a systematic review...

In a systematic review and meta-analysis of 7 studies that included a total of 311 patients with bipolar depression²³:

• TSD plus medications resulted in a significant decrease in depressive symptoms at 1 week compared with medications alone
• higher response rates were maintained after 3 months with lithium.

Adverse effects commonly include general fatigue and headaches; possible switch into mania with bipolar depression; and rarely, seizures or other unexpected medical conditions (eg, acute coronary syndrome). Presently, this approach is limited to research laboratories with the appropriate sophistication to safely conduct such trials.

Other nontraditional strategies

Cardiovascular exercise, resistance training, mindfulness, and yoga have been shown to decrease severe depressive symptoms when used as adjuncts for patients with treatment-resistant depression, or as monotherapy to treat patients with milder depression.

Exercise. The significant benefits of exercise in various forms as treatment for mild to moderate depression are well described in the literature, but it is less clear if it is effective for treatment-resistant depression. A 2013 Cochrane report²⁴ (39 studies with 2,326 participants total) and 2 meta-analyses undertaken in 2015 (Kvam et al²⁵ included 23 studies with 977 participants, and Schuh et al²⁶ included 25 trials with 1,487 participants) reported that various types of exercise ameliorate depression of differing subtypes and severity, with effect sizes ranging from small to large. Schuh et al²⁶ found that publication bias underestimated effect size. Also, not surprisingly, separate analysis of only higher-quality trials decreased effect size.^24-26 A meta-analysis that included tai chi and yoga in addition to aerobic exercise and strength training (25 trials with 2,083 participants) found low to moderate benefit for exercise and yoga.²⁷ Finally, a meta-analysis by Cramer et al²⁸ that included 12 RCTs (N = 619) supported the use of yoga plus controlled breathing techniques as an ancillary treatment for depression.

Two small exercise trials specifically evaluated patients with treatment-resistant depression.^29,30 Mota-Pereira et al²⁹ compared 22 participants who walked for 30 to 45 minutes, 5 days a week for 12 weeks in addition to pharmacotherapy with 11 patients who received pharmacotherapy only. Exercise improved all outcomes, including HDRS score (both compared to baseline and to the control group). Moreover, 26% of the exercise group went into remission. Pilu et al³⁰ evaluated strength training as an adjunctive treatment. Participants received 1 hour of strength training twice weekly for 8 months (n = 10), or pharmacotherapy only (n = 20). The adjunct strength training group had a statistically significant (P < .0001) improvement in HDRS scores at the end of the 8 months, whereas the control group did not (P < .28).

Continue to: Adverse effects...

Adverse effects of exercise are typically limited to sprains or strains; rarely, participants experience serious injuries.

Mindfulness-based interventions involve purposely paying attention in the present moment to enhance self-understanding and decrease anxiety about the future and regrets about the past, both of which complicate depression. A meta-analysis of 12 RCTs (N = 578) found this approach significantly reduced depression severity when used as an adjunctive therapy.³¹ There may be risks if mindfulness-based interventions are practiced incorrectly. For example, some reports have linked mindfulness-based interventions to psychotic episodes, meditation addiction, and antisocial or asocial behavior.³²

Bottom Line

Nonpharmacologic options for patients with treatment-resistant depression include herbal/nutraceuticals, anti-inflammatory/immune system therapies, and devices. While research suggests some of these approaches are promising, clinicians need to carefully consider potential adverse effects, some of which may be serious.

Related Resources

• Kaur M, Sanches M. Experimental therapeutics in treatmentresistant major depressive disorder. J Exp Pharmacol. 2021;13:181-196.
• Janicak PG. What’s new in transcranial magnetic stimulation. Current Psychiatry. 2019;18(3):10-16.

Drug Brand Names

Atorvastatin • Lipitor
Brexanolone • Zulresso
Citalopram • Celexa
Fluoxetine • Prozac
Lithium • Eskalith, Lithobid
Lovastatin • Altoprev, Mevacor
Minocycline • Dynacin, Minocin
Simvastatin • Flolipid, Zocor

It’s an all-too-common news item: The crash and burn of yet another politician, celebrity, or prominent individual. It’s painful to watch someone who spent years to achieve the status of a household name suddenly, and often ignominiously, lose it all. This is the equivalent of a human train wreck.

Some adversaries (who doesn’t have a few?) will rejoice or express schadenfreude, but many people will experience some empathy or sorrow as they witness the implosion of a celebrity. Fans, followers, or voters may grieve as the object of their respect and adulation falls off the high pedestal of fame. What starts as a drip-drip of rumors and innuendos soon eventuates in a denouement. And with time, as additional public figures fall from grace, the previous casualties will become mere footnotes in the annals of human self-destruction. Their loss of face, shame, and wrenching emotional and financial toll will be forgotten from the public’s collective memory, but the embers of bitterness and regret will continue to smolder in the hearts and souls of those who inadvertently contributed to their own social or professional demise due to a mistake, error of judgement, or plain old-fashioned stupidity. For the fallen, forgiveness and redemption are hard to come by.

Oh, how the mighty have fallen over centuries, and they include historical figures such as kings, military leaders, religious leaders, and politicians. The fall from grace in the past often led to executions, excommunication, or persecution. In the contemporary era, the oppressive “cancel culture” will mercilessly discard anyone, regardless of stature, after only 1 “wrong” tweet. In the digital age of mass communication, being “cancelled” is a frequent fall from grace and is the equivalent of being ostracized from millions of denizens on social media, which can spell doom for one’s career and social interactions.

The list of those whose careers ended calamitously include many familiar names, but I will only cite their prominent roles (you can easily guess their names!):

• emperors, kings, presidents, prime ministers, and political demagogues
• congressmen, senators, governors, and mayors
• Nobel Laureates (a Medicine and Physiology winner went to prison for pedophilia, and a Peace Prize winner fell from grace for supporting a military dictatorship)
• Cardinals and bishops in various countries (for sexual or financial crimes)
• billionaires, often for erratic personal lives
• sport legends, including decorated athletes and coaches of college and professional teams
• world chess masters
• Wall Street moguls
• Hollywood celebrities, including actors and directors, some with Oscars and related recognitions
• television news anchors and commentators
• comedians of various stripes
• CEOs of major media companies
• talk show hosts watched by millions
• celebrated musicians (classical, pop, rap, or blues)
• university presidents
• others in esteemed positions (including some psychiatrists).

Why is this so common?

From a psychiatric perspective, the most compelling question is why is the fall from grace so common? What are the transgressions, flaws, and shortcomings of successful individuals whose reputations end up smeared or who lose everything they worked for? Why do high achievers, talented and successful, at the apogee of fame and fortune, lose it all with nary a chance for recovery

The answer is all too obvious: human frailties. Successful persons are by no means immune from poor judgment. They can be as error-prone as the rest of us mortals. Having robust cognitive intelligence can be undermined by stunted emotional intelligence or poor interpersonal or social judgment. In Freudian terms, famous people who crash and burn may have a “Swiss cheese superego” that allows their id to viciously weaken their ego. From a neuroscience perspective, their limbic system conquers their cortical circuitry with relentless innate forces, including:

• fervent sexual appetite, compounded by the cockiness that comes with fame
• felonious paraphilias, such as pedophilia or public indecency
• intense greed that clouds one’s judgment (a trait exhibited by some ultra-rich persons)
• narcissism, either inborn or acquired with unexpected success and power
• impulsivity and recklessness, with injurious words or actions.
• substance use.

Consideration should be given to psychopathology. Some may have a personality disorder. Others may be both blessed and cursed with hypomania that leads to high achievement but also to foolish and impulsive behavior.¹ Some may have maladaptive social skills seen in autism spectrum disorder (recently, a very prominent and innovative billionaire casually announced that he has autistic traits). And others my have limited coping skills to deal with fame and fortune and unwittingly end up shooting themselves in both feet.

Continue to: But perhaps the most common thread...

But perhaps the most common thread across all the tragic cases of self-destruction is hubris. As humans become rich, famous, or powerful, they gradually develop the fallacious belief that they can get away with anything because they have masses of fans and followers who “love them no matter what.” This dangerous “acquired narcissism” is an unfortunate byproduct of success. Humility is rare among celebrities and powerful leaders. Modest celebrities almost never fall from grace and are endowed with an innate antidote to self-aggrandizement. A few years ago, I wrote an editorial in Current Psychiatry titled “Should psychiatry list hubris in DSM-V?”² While hubris is not regarded as a psychiatric disorder, it is certainly an affliction that often ends badly. The mental repercussions can include depression, anxiety, posttraumatic stress disorder, despair, and even falling on one’s sword. Hubris can be a fatal flaw with devastating consequences to one’s career. Perhaps those who aspire to become a celebrity should receive mentorship about hubris as a hazard of fame and fortune, when they are still in the “rising star” stage of their lives.

In contemporary society, with the era of social media and toxic political zeitgeist, there are many inadvertent “opportunities” to stumble and ruin one’s career by uttering an “unacceptable” word or dispatching an “offensive tweet” or posting a politically incorrect photo. And even if one is currently careful, there are now social media detectives and fact-finding “archeologists” who can excavate and disseminate the faux pas, peccadillos, or misdeeds from a prominent person’s immature youth, which will destroy a famous person overnight. That can be a nightmare for anyone who becomes a bona fide celebrity after years of working hard to get there.

High achievers: Beware!

It’s an all-too-common news item: The crash and burn of yet another politician, celebrity, or prominent individual. It’s painful to watch someone who spent years to achieve the status of a household name suddenly, and often ignominiously, lose it all. This is the equivalent of a human train wreck.

Some adversaries (who doesn’t have a few?) will rejoice or express schadenfreude, but many people will experience some empathy or sorrow as they witness the implosion of a celebrity. Fans, followers, or voters may grieve as the object of their respect and adulation falls off the high pedestal of fame. What starts as a drip-drip of rumors and innuendos soon eventuates in a denouement. And with time, as additional public figures fall from grace, the previous casualties will become mere footnotes in the annals of human self-destruction. Their loss of face, shame, and wrenching emotional and financial toll will be forgotten from the public’s collective memory, but the embers of bitterness and regret will continue to smolder in the hearts and souls of those who inadvertently contributed to their own social or professional demise due to a mistake, error of judgement, or plain old-fashioned stupidity. For the fallen, forgiveness and redemption are hard to come by.

Oh, how the mighty have fallen over centuries, and they include historical figures such as kings, military leaders, religious leaders, and politicians. The fall from grace in the past often led to executions, excommunication, or persecution. In the contemporary era, the oppressive “cancel culture” will mercilessly discard anyone, regardless of stature, after only 1 “wrong” tweet. In the digital age of mass communication, being “cancelled” is a frequent fall from grace and is the equivalent of being ostracized from millions of denizens on social media, which can spell doom for one’s career and social interactions.

The list of those whose careers ended calamitously include many familiar names, but I will only cite their prominent roles (you can easily guess their names!):

• emperors, kings, presidents, prime ministers, and political demagogues
• congressmen, senators, governors, and mayors
• Nobel Laureates (a Medicine and Physiology winner went to prison for pedophilia, and a Peace Prize winner fell from grace for supporting a military dictatorship)
• Cardinals and bishops in various countries (for sexual or financial crimes)
• billionaires, often for erratic personal lives
• sport legends, including decorated athletes and coaches of college and professional teams
• world chess masters
• Wall Street moguls
• Hollywood celebrities, including actors and directors, some with Oscars and related recognitions
• television news anchors and commentators
• comedians of various stripes
• CEOs of major media companies
• talk show hosts watched by millions
• celebrated musicians (classical, pop, rap, or blues)
• university presidents
• others in esteemed positions (including some psychiatrists).

Why is this so common?

From a psychiatric perspective, the most compelling question is why is the fall from grace so common? What are the transgressions, flaws, and shortcomings of successful individuals whose reputations end up smeared or who lose everything they worked for? Why do high achievers, talented and successful, at the apogee of fame and fortune, lose it all with nary a chance for recovery

The answer is all too obvious: human frailties. Successful persons are by no means immune from poor judgment. They can be as error-prone as the rest of us mortals. Having robust cognitive intelligence can be undermined by stunted emotional intelligence or poor interpersonal or social judgment. In Freudian terms, famous people who crash and burn may have a “Swiss cheese superego” that allows their id to viciously weaken their ego. From a neuroscience perspective, their limbic system conquers their cortical circuitry with relentless innate forces, including:

• fervent sexual appetite, compounded by the cockiness that comes with fame
• felonious paraphilias, such as pedophilia or public indecency
• intense greed that clouds one’s judgment (a trait exhibited by some ultra-rich persons)
• narcissism, either inborn or acquired with unexpected success and power
• impulsivity and recklessness, with injurious words or actions.
• substance use.

Consideration should be given to psychopathology. Some may have a personality disorder. Others may be both blessed and cursed with hypomania that leads to high achievement but also to foolish and impulsive behavior.¹ Some may have maladaptive social skills seen in autism spectrum disorder (recently, a very prominent and innovative billionaire casually announced that he has autistic traits). And others my have limited coping skills to deal with fame and fortune and unwittingly end up shooting themselves in both feet.

Continue to: But perhaps the most common thread...

But perhaps the most common thread across all the tragic cases of self-destruction is hubris. As humans become rich, famous, or powerful, they gradually develop the fallacious belief that they can get away with anything because they have masses of fans and followers who “love them no matter what.” This dangerous “acquired narcissism” is an unfortunate byproduct of success. Humility is rare among celebrities and powerful leaders. Modest celebrities almost never fall from grace and are endowed with an innate antidote to self-aggrandizement. A few years ago, I wrote an editorial in Current Psychiatry titled “Should psychiatry list hubris in DSM-V?”² While hubris is not regarded as a psychiatric disorder, it is certainly an affliction that often ends badly. The mental repercussions can include depression, anxiety, posttraumatic stress disorder, despair, and even falling on one’s sword. Hubris can be a fatal flaw with devastating consequences to one’s career. Perhaps those who aspire to become a celebrity should receive mentorship about hubris as a hazard of fame and fortune, when they are still in the “rising star” stage of their lives.

In contemporary society, with the era of social media and toxic political zeitgeist, there are many inadvertent “opportunities” to stumble and ruin one’s career by uttering an “unacceptable” word or dispatching an “offensive tweet” or posting a politically incorrect photo. And even if one is currently careful, there are now social media detectives and fact-finding “archeologists” who can excavate and disseminate the faux pas, peccadillos, or misdeeds from a prominent person’s immature youth, which will destroy a famous person overnight. That can be a nightmare for anyone who becomes a bona fide celebrity after years of working hard to get there.

High achievers: Beware!

It’s an all-too-common news item: The crash and burn of yet another politician, celebrity, or prominent individual. It’s painful to watch someone who spent years to achieve the status of a household name suddenly, and often ignominiously, lose it all. This is the equivalent of a human train wreck.

Some adversaries (who doesn’t have a few?) will rejoice or express schadenfreude, but many people will experience some empathy or sorrow as they witness the implosion of a celebrity. Fans, followers, or voters may grieve as the object of their respect and adulation falls off the high pedestal of fame. What starts as a drip-drip of rumors and innuendos soon eventuates in a denouement. And with time, as additional public figures fall from grace, the previous casualties will become mere footnotes in the annals of human self-destruction. Their loss of face, shame, and wrenching emotional and financial toll will be forgotten from the public’s collective memory, but the embers of bitterness and regret will continue to smolder in the hearts and souls of those who inadvertently contributed to their own social or professional demise due to a mistake, error of judgement, or plain old-fashioned stupidity. For the fallen, forgiveness and redemption are hard to come by.

Oh, how the mighty have fallen over centuries, and they include historical figures such as kings, military leaders, religious leaders, and politicians. The fall from grace in the past often led to executions, excommunication, or persecution. In the contemporary era, the oppressive “cancel culture” will mercilessly discard anyone, regardless of stature, after only 1 “wrong” tweet. In the digital age of mass communication, being “cancelled” is a frequent fall from grace and is the equivalent of being ostracized from millions of denizens on social media, which can spell doom for one’s career and social interactions.

The list of those whose careers ended calamitously include many familiar names, but I will only cite their prominent roles (you can easily guess their names!):

• emperors, kings, presidents, prime ministers, and political demagogues
• congressmen, senators, governors, and mayors
• Nobel Laureates (a Medicine and Physiology winner went to prison for pedophilia, and a Peace Prize winner fell from grace for supporting a military dictatorship)
• Cardinals and bishops in various countries (for sexual or financial crimes)
• billionaires, often for erratic personal lives
• sport legends, including decorated athletes and coaches of college and professional teams
• world chess masters
• Wall Street moguls
• Hollywood celebrities, including actors and directors, some with Oscars and related recognitions
• television news anchors and commentators
• comedians of various stripes
• CEOs of major media companies
• talk show hosts watched by millions
• celebrated musicians (classical, pop, rap, or blues)
• university presidents
• others in esteemed positions (including some psychiatrists).

Why is this so common?

From a psychiatric perspective, the most compelling question is why is the fall from grace so common? What are the transgressions, flaws, and shortcomings of successful individuals whose reputations end up smeared or who lose everything they worked for? Why do high achievers, talented and successful, at the apogee of fame and fortune, lose it all with nary a chance for recovery

The answer is all too obvious: human frailties. Successful persons are by no means immune from poor judgment. They can be as error-prone as the rest of us mortals. Having robust cognitive intelligence can be undermined by stunted emotional intelligence or poor interpersonal or social judgment. In Freudian terms, famous people who crash and burn may have a “Swiss cheese superego” that allows their id to viciously weaken their ego. From a neuroscience perspective, their limbic system conquers their cortical circuitry with relentless innate forces, including:

• fervent sexual appetite, compounded by the cockiness that comes with fame
• felonious paraphilias, such as pedophilia or public indecency
• intense greed that clouds one’s judgment (a trait exhibited by some ultra-rich persons)
• narcissism, either inborn or acquired with unexpected success and power
• impulsivity and recklessness, with injurious words or actions.
• substance use.

Consideration should be given to psychopathology. Some may have a personality disorder. Others may be both blessed and cursed with hypomania that leads to high achievement but also to foolish and impulsive behavior.¹ Some may have maladaptive social skills seen in autism spectrum disorder (recently, a very prominent and innovative billionaire casually announced that he has autistic traits). And others my have limited coping skills to deal with fame and fortune and unwittingly end up shooting themselves in both feet.

Continue to: But perhaps the most common thread...

But perhaps the most common thread across all the tragic cases of self-destruction is hubris. As humans become rich, famous, or powerful, they gradually develop the fallacious belief that they can get away with anything because they have masses of fans and followers who “love them no matter what.” This dangerous “acquired narcissism” is an unfortunate byproduct of success. Humility is rare among celebrities and powerful leaders. Modest celebrities almost never fall from grace and are endowed with an innate antidote to self-aggrandizement. A few years ago, I wrote an editorial in Current Psychiatry titled “Should psychiatry list hubris in DSM-V?”² While hubris is not regarded as a psychiatric disorder, it is certainly an affliction that often ends badly. The mental repercussions can include depression, anxiety, posttraumatic stress disorder, despair, and even falling on one’s sword. Hubris can be a fatal flaw with devastating consequences to one’s career. Perhaps those who aspire to become a celebrity should receive mentorship about hubris as a hazard of fame and fortune, when they are still in the “rising star” stage of their lives.

In contemporary society, with the era of social media and toxic political zeitgeist, there are many inadvertent “opportunities” to stumble and ruin one’s career by uttering an “unacceptable” word or dispatching an “offensive tweet” or posting a politically incorrect photo. And even if one is currently careful, there are now social media detectives and fact-finding “archeologists” who can excavate and disseminate the faux pas, peccadillos, or misdeeds from a prominent person’s immature youth, which will destroy a famous person overnight. That can be a nightmare for anyone who becomes a bona fide celebrity after years of working hard to get there.

High achievers: Beware!

CASE Sluggish, weak, and incoherent

Mr. O, age 24, who has a history of schizophrenia and obesity, presents to the emergency department (ED) for altered mental status (AMS). His mother reports that he has been sluggish, weak, incoherent, had no appetite, and that on the day before admission, he was drinking excessive amounts of water and urinating every 10 minutes.

HISTORY Multiple ineffective antipsychotics

Mr. O was diagnosed with schizophrenia at age 21 and struggled with medication adherence, which resulted in multiple hospitalizations for stabilization. Trials of haloperidol, risperidone, paliperidone palmitate, and valproic acid had been ineffective. At the time of admission, his psychotropic medication regimen is fluphenazine decanoate, 25 mg injection every 2 weeks; clozapine, 50 mg/d; lithium carbonate, 300 mg twice a day; benztropine, 2 mg every night; and trazodone, 50 mg every night.

EVALUATION Fever, tachycardia, and diabetic ketoacidosis

Upon arrival to the ED, Mr. O is obtunded, unable to follow commands, and does not respond to painful stimuli. On physical exam, he has a fever of 38.4°C (reference range 35.1°C to 37.9°C); tachycardia with a heart rate of 142 beats per minute (bpm) (reference range 60 to 100); tachypnea with a respiratory rate of 35 breaths per minute (reference range 12 to 20); a blood pressure of 116/76 mmHg (reference range 90/60 to 130/80); and hypoxemia with an oxygen saturation of 90% on room air (reference range 94% to 100%).

Mr. O is admitted to the hospital and his laboratory workup indicates diabetic ketoacidosis (DKA), with a glucose of 1,700 mg/dL; anion gap of 30 (reference range 4 to 12 mmol/L); pH 7.04 (reference range 7.32 to 7.42); serum bicarbonate 6 (reference range 20 to 24 mEq/L); beta-hydroxybutyrate 11.04 (reference range 0 to 0.27 mmol/L); urine ketones, serum osmolality 407 (reference range 280 to 300 mOsm/kg); and an elevated white blood cell count of 18.4 (reference range 4.5 to 11.0 × 10⁹/L). A CT scan of the head is negative for acute pathology.

Initially, all psychotropic medications are held. On Day 3 of hospitalization, psychiatry is consulted and clozapine, 50 mg/d; lithium, 300 mg/d; and benztropine, 1 mg at night, are restarted; however, fluphenazine decanoate and trazodone are held. The team recommends IV haloperidol, 2 mg as needed for agitation; however, it is never administered.

Imaging rules out deep vein thrombosis, cardiac dysfunction, and stroke, but a CT chest scan is notable for bilateral lung infiltrates, which suggests aspiration pneumonia.

Mr. O is diagnosed with diabetes, complicated by DKA, and is treated in the intensive care unit (ICU). Despite resolution of the DKA, he remains altered with fever and tachycardia.

Continue to: On Day 6 of hospitalization...

On Day 6 of hospitalization, Mr. O continues to be tachycardic and obtunded with nuchal rigidity. The team decides to transfer Mr. O to another hospital for a higher level of care and continued workup of his persistent AMS.

Immediately upon arrival at the second hospital, infectious disease and neurology teams are consulted for further evaluation. Mr. O’s AMS continues despite no clear signs of infection or other neurologic insults.

[polldaddy:10930631]

The authors’ observations

Based on Mr. O’s psychiatric history and laboratory results, the first medical team concluded his initial AMS was likely secondary to DKA; however, the AMS continued after the DKA resolved. At the second hospital, Mr. O’s treatment team continued to dig for answers.

EVALUATION Exploring the differential diagnosis

At the second hospital, Mr. O is admitted to the ICU with fever (37.8°C), tachycardia (120 bpm), tachypnea, withdrawal from painful stimuli, decreased reflexes, and muscle rigidity, including clenched jaw. The differential diagnoses include meningitis, sepsis from aspiration pneumonia, severe metabolic encephalopathy with prolonged recovery, central pontine myelinolysis, anoxic brain injury, and subclinical seizures.

Empiric vancomycin, 1.75 g every 12 hours; ceftriaxone, 2 g/d; and acyclovir, 900 mg every 8 hours are started for meningoencephalitis, and all psychotropic medications are discontinued. Case reports have documented a relationship between hyperglycemic hyperosmolar syndrome (HHS) and malignant hyperthermia in rare cases¹; however, HHS is ruled out based on Mr. O’s laboratory results.A lumbar puncture and imaging rules out CNS infection. Antibiotic treatment is narrowed to ampicillin-sulbactam due to Mr. O’s prior CT chest showing concern for aspiration pneumonia. An MRI of the brain rules out central pontine myelinolysis, acute stroke, and anoxic brain injury, and an EEG shows nonspecific encephalopathy. On Day 10 of hospitalization, a neurologic exam shows flaccid paralysis and bilateral clonus, and Mr. O is mute. On Day 14 of hospitalization, his fever resolves, and his blood cultures are negative. On Day 15 of hospitalization, Mr. O’s creatine kinase (CK) level is elevated at 1,308 U/L (reference range 26 to 192 U/L), suggesting rhabdomyolysis.

Continue to: Given the neurologic exam findings...

Given the neurologic exam findings, and the limited evidence of infection, the differential diagnosis for Mr. O’s AMS is broadened to include catatonia, neuroleptic malignant syndrome (NMS), serotonin syndrome, and autoimmune encephalitis. The psychiatry team evaluates Mr. O for catatonia. He scores 14 on the Bush-Francis Catatonia Rating Scale, with findings of immobility/stupor, mutism, staring, autonomic instability, and withdrawal indicating the presence of catatonia.²

The authors’ observations

When Mr. O was transferred to the second hospital, the primary concern was to rule out meningitis due to his unstable vitals, obtunded mental state, and nuchal rigidity. A comprehensive infectious workup, including lumbar puncture, was imperative because infection can not only lead to AMS, but also precipitate episodes of DKA. Mr. O’s persistently abnormal vital signs indicated an underlying process may have been missed by focusing on treating DKA.

TREATMENT Finally, the diagnosis is established

A lorazepam challenge is performed, and Mr. O receives 4 mg of lorazepam over 24 hours with little change in his catatonia symptoms. Given his persistent fever, tachycardia, and an elevated CK levels in the context of recent exposure to antipsychotic medications, Mr. O is diagnosed with NMS (Table 1^3,4 ) and is started on bromocriptine, 5 mg 3 times daily.

[polldaddy:10930632]

The authors’ observations

Mr. O’s complicated medical state—starting with DKA, halting the use of antipsychotic medications, and the suspicion of catatonia due to his history of schizophrenia—all distracted from the ultimate diagnosis of NMS as the cause of his enduring AMS and autonomic instability. Catatonia and NMS have overlapping symptomatology, including rigidity, autonomic instability, and stupor, which make the diagnosis of either condition complicated. A positive lorazepam test to diagnose catatonia is defined as a marked reduction in catatonia symptoms (typically a 50% reduction) as measured on a standardized rating scale.⁵ However, a negative lorazepam challenge does not definitely rule out catatonia because some cases are resistant to benzodiazepines.⁶

NMS risk factors relevant in this case include male sex, young age, acute medical illness, dehydration, and exposure to multiple psychotropic medications, including 2 antipsychotics, clozapine and fluphenazine.⁷ DKA is especially pertinent due to its acute onset and cause of significant dehydration. NMS can occur at any point of antipsychotic exposure, although the risk is highest during the initial weeks of treatment and during dosage changes. Unfortunately, Mr. O’s treatment team was unable to determine whether his medication had been recently changed, so it is not known what role this may have played in the development of NMS. Although first-generation antipsychotics are considered more likely to cause NMS, second-generation antipsychotics (SGAs) dominate the treatment of schizophrenia and bipolar disorder, and these medications also can cause NMS.⁸ As occurred in this case, long-acting injectable antipsychotics can be easily forgotten when not administered in the hospital, and their presence in the body persists for weeks. For example, the half-life of fluphenazine decanoate is approximately 10 days, and the half-life of haloperidol decanoate is 21 days.⁹

Continue to: OUTCOME Improvement with bromocriptine

 

 

OUTCOME Improvement with bromocriptine

After 4 days of bromocriptine, 5 mg 3 times daily, Mr. O is more alert, able to say “hello,” and can follow 1-step commands. By Day 26 of hospitalization, his CK levels decrease to 296 U/L, his CSF autoimmune panel is negative, and he is able to participate in physical therapy. After failing multiple swallow tests, Mr. O requires a percutaneous endoscopic gastrostomy (PEG) tube. He is discharged from the hospital to a long-term acute care facility with the plan to taper bromocriptine and restart a psychotropic regimen with his outpatient psychiatrist. At the time of discharge, he is able to sit at the edge of the bed independently, state his name, and respond to questions with multiple-word answers.

[polldaddy:10930633]

The authors’ observations

The most common pharmacologic treatments for NMS are dantrolene, bromocriptine, benzodiazepines (lorazepam or diazepam), and amantadine.³ Mild cases of NMS should be treated with discontinuation of all antipsychotics, supportive care, and benzodiazepines.³ Bromocriptine or amantadine are more appropriate for moderate cases and dantrolene for severe cases of NMS.³ All antipsychotics should be discontinued while a patient is experiencing an episode of NMS; however, once the NMS has resolved, clinicians must thoroughly evaluate the risks and benefits of restarting antipsychotic medication. After a patient has experienced an episode of NMS, clinicians generally should avoid prescribing the agent(s) that caused NMS and long-acting injections, and slowly titrate a low-potency SGA such as quetiapine.¹⁰Table 2^3,11,12 outlines the pharmacologic treatment of NMS.

Bottom Line

Neuroleptic malignant syndrome (NMS) should always be part of the differential diagnosis in patients with mental illness and altered mental status. The risk of NMS is especially high in patients with acute medical illness and exposure to antipsychotic medications.

Related Resource

• Turner AH, Kim JJ, McCarron RM. Differentiating serotonin syndrome and neuroleptic malignant syndrome. Current Psychiatry. 2019;18(2):30-36.

Drug Brand Names

Acyclovir • Zovirax
Amantadine • Gocovri
Ampicillin-sulbactam • Unasyn
Aripiprazole • Abilify Maintena
Benztropine • Cogentin
Bromocriptine • Cycloset, Parlodel
Ceftriaxone • Rocephin
Clozapine • Clozaril
Dantrolene • Dantrium
Diazepam • Valium
Haloperidol • Haldol
Lithium • Eskalith, Lithobid
Lorazepam • Ativan
Paliperidone palmitate • Invega Sustenna
Quetiapine • Seroquel
Risperidone • Risperdal
Valproate sodium • Depakote
Trazodone • Oleptro
Vancomycin • Vancocin

CASE Sluggish, weak, and incoherent

Mr. O, age 24, who has a history of schizophrenia and obesity, presents to the emergency department (ED) for altered mental status (AMS). His mother reports that he has been sluggish, weak, incoherent, had no appetite, and that on the day before admission, he was drinking excessive amounts of water and urinating every 10 minutes.

HISTORY Multiple ineffective antipsychotics

Mr. O was diagnosed with schizophrenia at age 21 and struggled with medication adherence, which resulted in multiple hospitalizations for stabilization. Trials of haloperidol, risperidone, paliperidone palmitate, and valproic acid had been ineffective. At the time of admission, his psychotropic medication regimen is fluphenazine decanoate, 25 mg injection every 2 weeks; clozapine, 50 mg/d; lithium carbonate, 300 mg twice a day; benztropine, 2 mg every night; and trazodone, 50 mg every night.

EVALUATION Fever, tachycardia, and diabetic ketoacidosis

Upon arrival to the ED, Mr. O is obtunded, unable to follow commands, and does not respond to painful stimuli. On physical exam, he has a fever of 38.4°C (reference range 35.1°C to 37.9°C); tachycardia with a heart rate of 142 beats per minute (bpm) (reference range 60 to 100); tachypnea with a respiratory rate of 35 breaths per minute (reference range 12 to 20); a blood pressure of 116/76 mmHg (reference range 90/60 to 130/80); and hypoxemia with an oxygen saturation of 90% on room air (reference range 94% to 100%).

Mr. O is admitted to the hospital and his laboratory workup indicates diabetic ketoacidosis (DKA), with a glucose of 1,700 mg/dL; anion gap of 30 (reference range 4 to 12 mmol/L); pH 7.04 (reference range 7.32 to 7.42); serum bicarbonate 6 (reference range 20 to 24 mEq/L); beta-hydroxybutyrate 11.04 (reference range 0 to 0.27 mmol/L); urine ketones, serum osmolality 407 (reference range 280 to 300 mOsm/kg); and an elevated white blood cell count of 18.4 (reference range 4.5 to 11.0 × 10⁹/L). A CT scan of the head is negative for acute pathology.

Initially, all psychotropic medications are held. On Day 3 of hospitalization, psychiatry is consulted and clozapine, 50 mg/d; lithium, 300 mg/d; and benztropine, 1 mg at night, are restarted; however, fluphenazine decanoate and trazodone are held. The team recommends IV haloperidol, 2 mg as needed for agitation; however, it is never administered.

Imaging rules out deep vein thrombosis, cardiac dysfunction, and stroke, but a CT chest scan is notable for bilateral lung infiltrates, which suggests aspiration pneumonia.

Mr. O is diagnosed with diabetes, complicated by DKA, and is treated in the intensive care unit (ICU). Despite resolution of the DKA, he remains altered with fever and tachycardia.

Continue to: On Day 6 of hospitalization...

On Day 6 of hospitalization, Mr. O continues to be tachycardic and obtunded with nuchal rigidity. The team decides to transfer Mr. O to another hospital for a higher level of care and continued workup of his persistent AMS.

Immediately upon arrival at the second hospital, infectious disease and neurology teams are consulted for further evaluation. Mr. O’s AMS continues despite no clear signs of infection or other neurologic insults.

[polldaddy:10930631]

The authors’ observations

Based on Mr. O’s psychiatric history and laboratory results, the first medical team concluded his initial AMS was likely secondary to DKA; however, the AMS continued after the DKA resolved. At the second hospital, Mr. O’s treatment team continued to dig for answers.

EVALUATION Exploring the differential diagnosis

At the second hospital, Mr. O is admitted to the ICU with fever (37.8°C), tachycardia (120 bpm), tachypnea, withdrawal from painful stimuli, decreased reflexes, and muscle rigidity, including clenched jaw. The differential diagnoses include meningitis, sepsis from aspiration pneumonia, severe metabolic encephalopathy with prolonged recovery, central pontine myelinolysis, anoxic brain injury, and subclinical seizures.

Empiric vancomycin, 1.75 g every 12 hours; ceftriaxone, 2 g/d; and acyclovir, 900 mg every 8 hours are started for meningoencephalitis, and all psychotropic medications are discontinued. Case reports have documented a relationship between hyperglycemic hyperosmolar syndrome (HHS) and malignant hyperthermia in rare cases¹; however, HHS is ruled out based on Mr. O’s laboratory results.A lumbar puncture and imaging rules out CNS infection. Antibiotic treatment is narrowed to ampicillin-sulbactam due to Mr. O’s prior CT chest showing concern for aspiration pneumonia. An MRI of the brain rules out central pontine myelinolysis, acute stroke, and anoxic brain injury, and an EEG shows nonspecific encephalopathy. On Day 10 of hospitalization, a neurologic exam shows flaccid paralysis and bilateral clonus, and Mr. O is mute. On Day 14 of hospitalization, his fever resolves, and his blood cultures are negative. On Day 15 of hospitalization, Mr. O’s creatine kinase (CK) level is elevated at 1,308 U/L (reference range 26 to 192 U/L), suggesting rhabdomyolysis.

Continue to: Given the neurologic exam findings...

Given the neurologic exam findings, and the limited evidence of infection, the differential diagnosis for Mr. O’s AMS is broadened to include catatonia, neuroleptic malignant syndrome (NMS), serotonin syndrome, and autoimmune encephalitis. The psychiatry team evaluates Mr. O for catatonia. He scores 14 on the Bush-Francis Catatonia Rating Scale, with findings of immobility/stupor, mutism, staring, autonomic instability, and withdrawal indicating the presence of catatonia.²

The authors’ observations

When Mr. O was transferred to the second hospital, the primary concern was to rule out meningitis due to his unstable vitals, obtunded mental state, and nuchal rigidity. A comprehensive infectious workup, including lumbar puncture, was imperative because infection can not only lead to AMS, but also precipitate episodes of DKA. Mr. O’s persistently abnormal vital signs indicated an underlying process may have been missed by focusing on treating DKA.

TREATMENT Finally, the diagnosis is established

A lorazepam challenge is performed, and Mr. O receives 4 mg of lorazepam over 24 hours with little change in his catatonia symptoms. Given his persistent fever, tachycardia, and an elevated CK levels in the context of recent exposure to antipsychotic medications, Mr. O is diagnosed with NMS (Table 1^3,4 ) and is started on bromocriptine, 5 mg 3 times daily.

[polldaddy:10930632]

The authors’ observations

Mr. O’s complicated medical state—starting with DKA, halting the use of antipsychotic medications, and the suspicion of catatonia due to his history of schizophrenia—all distracted from the ultimate diagnosis of NMS as the cause of his enduring AMS and autonomic instability. Catatonia and NMS have overlapping symptomatology, including rigidity, autonomic instability, and stupor, which make the diagnosis of either condition complicated. A positive lorazepam test to diagnose catatonia is defined as a marked reduction in catatonia symptoms (typically a 50% reduction) as measured on a standardized rating scale.⁵ However, a negative lorazepam challenge does not definitely rule out catatonia because some cases are resistant to benzodiazepines.⁶

NMS risk factors relevant in this case include male sex, young age, acute medical illness, dehydration, and exposure to multiple psychotropic medications, including 2 antipsychotics, clozapine and fluphenazine.⁷ DKA is especially pertinent due to its acute onset and cause of significant dehydration. NMS can occur at any point of antipsychotic exposure, although the risk is highest during the initial weeks of treatment and during dosage changes. Unfortunately, Mr. O’s treatment team was unable to determine whether his medication had been recently changed, so it is not known what role this may have played in the development of NMS. Although first-generation antipsychotics are considered more likely to cause NMS, second-generation antipsychotics (SGAs) dominate the treatment of schizophrenia and bipolar disorder, and these medications also can cause NMS.⁸ As occurred in this case, long-acting injectable antipsychotics can be easily forgotten when not administered in the hospital, and their presence in the body persists for weeks. For example, the half-life of fluphenazine decanoate is approximately 10 days, and the half-life of haloperidol decanoate is 21 days.⁹

Continue to: OUTCOME Improvement with bromocriptine

 

 

OUTCOME Improvement with bromocriptine

After 4 days of bromocriptine, 5 mg 3 times daily, Mr. O is more alert, able to say “hello,” and can follow 1-step commands. By Day 26 of hospitalization, his CK levels decrease to 296 U/L, his CSF autoimmune panel is negative, and he is able to participate in physical therapy. After failing multiple swallow tests, Mr. O requires a percutaneous endoscopic gastrostomy (PEG) tube. He is discharged from the hospital to a long-term acute care facility with the plan to taper bromocriptine and restart a psychotropic regimen with his outpatient psychiatrist. At the time of discharge, he is able to sit at the edge of the bed independently, state his name, and respond to questions with multiple-word answers.

[polldaddy:10930633]

The authors’ observations

The most common pharmacologic treatments for NMS are dantrolene, bromocriptine, benzodiazepines (lorazepam or diazepam), and amantadine.³ Mild cases of NMS should be treated with discontinuation of all antipsychotics, supportive care, and benzodiazepines.³ Bromocriptine or amantadine are more appropriate for moderate cases and dantrolene for severe cases of NMS.³ All antipsychotics should be discontinued while a patient is experiencing an episode of NMS; however, once the NMS has resolved, clinicians must thoroughly evaluate the risks and benefits of restarting antipsychotic medication. After a patient has experienced an episode of NMS, clinicians generally should avoid prescribing the agent(s) that caused NMS and long-acting injections, and slowly titrate a low-potency SGA such as quetiapine.¹⁰Table 2^3,11,12 outlines the pharmacologic treatment of NMS.

Bottom Line

Neuroleptic malignant syndrome (NMS) should always be part of the differential diagnosis in patients with mental illness and altered mental status. The risk of NMS is especially high in patients with acute medical illness and exposure to antipsychotic medications.

Related Resource

• Turner AH, Kim JJ, McCarron RM. Differentiating serotonin syndrome and neuroleptic malignant syndrome. Current Psychiatry. 2019;18(2):30-36.

Drug Brand Names

Acyclovir • Zovirax
Amantadine • Gocovri
Ampicillin-sulbactam • Unasyn
Aripiprazole • Abilify Maintena
Benztropine • Cogentin
Bromocriptine • Cycloset, Parlodel
Ceftriaxone • Rocephin
Clozapine • Clozaril
Dantrolene • Dantrium
Diazepam • Valium
Haloperidol • Haldol
Lithium • Eskalith, Lithobid
Lorazepam • Ativan
Paliperidone palmitate • Invega Sustenna
Quetiapine • Seroquel
Risperidone • Risperdal
Valproate sodium • Depakote
Trazodone • Oleptro
Vancomycin • Vancocin

CASE Sluggish, weak, and incoherent

Mr. O, age 24, who has a history of schizophrenia and obesity, presents to the emergency department (ED) for altered mental status (AMS). His mother reports that he has been sluggish, weak, incoherent, had no appetite, and that on the day before admission, he was drinking excessive amounts of water and urinating every 10 minutes.

HISTORY Multiple ineffective antipsychotics

Mr. O was diagnosed with schizophrenia at age 21 and struggled with medication adherence, which resulted in multiple hospitalizations for stabilization. Trials of haloperidol, risperidone, paliperidone palmitate, and valproic acid had been ineffective. At the time of admission, his psychotropic medication regimen is fluphenazine decanoate, 25 mg injection every 2 weeks; clozapine, 50 mg/d; lithium carbonate, 300 mg twice a day; benztropine, 2 mg every night; and trazodone, 50 mg every night.

EVALUATION Fever, tachycardia, and diabetic ketoacidosis

Upon arrival to the ED, Mr. O is obtunded, unable to follow commands, and does not respond to painful stimuli. On physical exam, he has a fever of 38.4°C (reference range 35.1°C to 37.9°C); tachycardia with a heart rate of 142 beats per minute (bpm) (reference range 60 to 100); tachypnea with a respiratory rate of 35 breaths per minute (reference range 12 to 20); a blood pressure of 116/76 mmHg (reference range 90/60 to 130/80); and hypoxemia with an oxygen saturation of 90% on room air (reference range 94% to 100%).

Mr. O is admitted to the hospital and his laboratory workup indicates diabetic ketoacidosis (DKA), with a glucose of 1,700 mg/dL; anion gap of 30 (reference range 4 to 12 mmol/L); pH 7.04 (reference range 7.32 to 7.42); serum bicarbonate 6 (reference range 20 to 24 mEq/L); beta-hydroxybutyrate 11.04 (reference range 0 to 0.27 mmol/L); urine ketones, serum osmolality 407 (reference range 280 to 300 mOsm/kg); and an elevated white blood cell count of 18.4 (reference range 4.5 to 11.0 × 10⁹/L). A CT scan of the head is negative for acute pathology.

Initially, all psychotropic medications are held. On Day 3 of hospitalization, psychiatry is consulted and clozapine, 50 mg/d; lithium, 300 mg/d; and benztropine, 1 mg at night, are restarted; however, fluphenazine decanoate and trazodone are held. The team recommends IV haloperidol, 2 mg as needed for agitation; however, it is never administered.

Imaging rules out deep vein thrombosis, cardiac dysfunction, and stroke, but a CT chest scan is notable for bilateral lung infiltrates, which suggests aspiration pneumonia.

Mr. O is diagnosed with diabetes, complicated by DKA, and is treated in the intensive care unit (ICU). Despite resolution of the DKA, he remains altered with fever and tachycardia.

Continue to: On Day 6 of hospitalization...

On Day 6 of hospitalization, Mr. O continues to be tachycardic and obtunded with nuchal rigidity. The team decides to transfer Mr. O to another hospital for a higher level of care and continued workup of his persistent AMS.

Immediately upon arrival at the second hospital, infectious disease and neurology teams are consulted for further evaluation. Mr. O’s AMS continues despite no clear signs of infection or other neurologic insults.

[polldaddy:10930631]

The authors’ observations

Based on Mr. O’s psychiatric history and laboratory results, the first medical team concluded his initial AMS was likely secondary to DKA; however, the AMS continued after the DKA resolved. At the second hospital, Mr. O’s treatment team continued to dig for answers.

EVALUATION Exploring the differential diagnosis

At the second hospital, Mr. O is admitted to the ICU with fever (37.8°C), tachycardia (120 bpm), tachypnea, withdrawal from painful stimuli, decreased reflexes, and muscle rigidity, including clenched jaw. The differential diagnoses include meningitis, sepsis from aspiration pneumonia, severe metabolic encephalopathy with prolonged recovery, central pontine myelinolysis, anoxic brain injury, and subclinical seizures.

Empiric vancomycin, 1.75 g every 12 hours; ceftriaxone, 2 g/d; and acyclovir, 900 mg every 8 hours are started for meningoencephalitis, and all psychotropic medications are discontinued. Case reports have documented a relationship between hyperglycemic hyperosmolar syndrome (HHS) and malignant hyperthermia in rare cases¹; however, HHS is ruled out based on Mr. O’s laboratory results.A lumbar puncture and imaging rules out CNS infection. Antibiotic treatment is narrowed to ampicillin-sulbactam due to Mr. O’s prior CT chest showing concern for aspiration pneumonia. An MRI of the brain rules out central pontine myelinolysis, acute stroke, and anoxic brain injury, and an EEG shows nonspecific encephalopathy. On Day 10 of hospitalization, a neurologic exam shows flaccid paralysis and bilateral clonus, and Mr. O is mute. On Day 14 of hospitalization, his fever resolves, and his blood cultures are negative. On Day 15 of hospitalization, Mr. O’s creatine kinase (CK) level is elevated at 1,308 U/L (reference range 26 to 192 U/L), suggesting rhabdomyolysis.

Continue to: Given the neurologic exam findings...

Given the neurologic exam findings, and the limited evidence of infection, the differential diagnosis for Mr. O’s AMS is broadened to include catatonia, neuroleptic malignant syndrome (NMS), serotonin syndrome, and autoimmune encephalitis. The psychiatry team evaluates Mr. O for catatonia. He scores 14 on the Bush-Francis Catatonia Rating Scale, with findings of immobility/stupor, mutism, staring, autonomic instability, and withdrawal indicating the presence of catatonia.²

The authors’ observations

When Mr. O was transferred to the second hospital, the primary concern was to rule out meningitis due to his unstable vitals, obtunded mental state, and nuchal rigidity. A comprehensive infectious workup, including lumbar puncture, was imperative because infection can not only lead to AMS, but also precipitate episodes of DKA. Mr. O’s persistently abnormal vital signs indicated an underlying process may have been missed by focusing on treating DKA.

TREATMENT Finally, the diagnosis is established

A lorazepam challenge is performed, and Mr. O receives 4 mg of lorazepam over 24 hours with little change in his catatonia symptoms. Given his persistent fever, tachycardia, and an elevated CK levels in the context of recent exposure to antipsychotic medications, Mr. O is diagnosed with NMS (Table 1^3,4 ) and is started on bromocriptine, 5 mg 3 times daily.

[polldaddy:10930632]

The authors’ observations

Mr. O’s complicated medical state—starting with DKA, halting the use of antipsychotic medications, and the suspicion of catatonia due to his history of schizophrenia—all distracted from the ultimate diagnosis of NMS as the cause of his enduring AMS and autonomic instability. Catatonia and NMS have overlapping symptomatology, including rigidity, autonomic instability, and stupor, which make the diagnosis of either condition complicated. A positive lorazepam test to diagnose catatonia is defined as a marked reduction in catatonia symptoms (typically a 50% reduction) as measured on a standardized rating scale.⁵ However, a negative lorazepam challenge does not definitely rule out catatonia because some cases are resistant to benzodiazepines.⁶

NMS risk factors relevant in this case include male sex, young age, acute medical illness, dehydration, and exposure to multiple psychotropic medications, including 2 antipsychotics, clozapine and fluphenazine.⁷ DKA is especially pertinent due to its acute onset and cause of significant dehydration. NMS can occur at any point of antipsychotic exposure, although the risk is highest during the initial weeks of treatment and during dosage changes. Unfortunately, Mr. O’s treatment team was unable to determine whether his medication had been recently changed, so it is not known what role this may have played in the development of NMS. Although first-generation antipsychotics are considered more likely to cause NMS, second-generation antipsychotics (SGAs) dominate the treatment of schizophrenia and bipolar disorder, and these medications also can cause NMS.⁸ As occurred in this case, long-acting injectable antipsychotics can be easily forgotten when not administered in the hospital, and their presence in the body persists for weeks. For example, the half-life of fluphenazine decanoate is approximately 10 days, and the half-life of haloperidol decanoate is 21 days.⁹

Continue to: OUTCOME Improvement with bromocriptine

 

 

OUTCOME Improvement with bromocriptine

After 4 days of bromocriptine, 5 mg 3 times daily, Mr. O is more alert, able to say “hello,” and can follow 1-step commands. By Day 26 of hospitalization, his CK levels decrease to 296 U/L, his CSF autoimmune panel is negative, and he is able to participate in physical therapy. After failing multiple swallow tests, Mr. O requires a percutaneous endoscopic gastrostomy (PEG) tube. He is discharged from the hospital to a long-term acute care facility with the plan to taper bromocriptine and restart a psychotropic regimen with his outpatient psychiatrist. At the time of discharge, he is able to sit at the edge of the bed independently, state his name, and respond to questions with multiple-word answers.

[polldaddy:10930633]

The authors’ observations

The most common pharmacologic treatments for NMS are dantrolene, bromocriptine, benzodiazepines (lorazepam or diazepam), and amantadine.³ Mild cases of NMS should be treated with discontinuation of all antipsychotics, supportive care, and benzodiazepines.³ Bromocriptine or amantadine are more appropriate for moderate cases and dantrolene for severe cases of NMS.³ All antipsychotics should be discontinued while a patient is experiencing an episode of NMS; however, once the NMS has resolved, clinicians must thoroughly evaluate the risks and benefits of restarting antipsychotic medication. After a patient has experienced an episode of NMS, clinicians generally should avoid prescribing the agent(s) that caused NMS and long-acting injections, and slowly titrate a low-potency SGA such as quetiapine.¹⁰Table 2^3,11,12 outlines the pharmacologic treatment of NMS.

Bottom Line

Neuroleptic malignant syndrome (NMS) should always be part of the differential diagnosis in patients with mental illness and altered mental status. The risk of NMS is especially high in patients with acute medical illness and exposure to antipsychotic medications.

Related Resource

• Turner AH, Kim JJ, McCarron RM. Differentiating serotonin syndrome and neuroleptic malignant syndrome. Current Psychiatry. 2019;18(2):30-36.

Drug Brand Names

Acyclovir • Zovirax
Amantadine • Gocovri
Ampicillin-sulbactam • Unasyn
Aripiprazole • Abilify Maintena
Benztropine • Cogentin
Bromocriptine • Cycloset, Parlodel
Ceftriaxone • Rocephin
Clozapine • Clozaril
Dantrolene • Dantrium
Diazepam • Valium
Haloperidol • Haldol
Lithium • Eskalith, Lithobid
Lorazepam • Ativan
Paliperidone palmitate • Invega Sustenna
Quetiapine • Seroquel
Risperidone • Risperdal
Valproate sodium • Depakote
Trazodone • Oleptro
Vancomycin • Vancocin

Intimate partner violence (IPV) includes “physical violence, sexual violence, stalking, and psychological aggression (including coercive tactics) by a current or former intimate partner.”¹Intimate partner violence was a widespread problem even before COVID-19, with lifetime rates of nearly 35% among White women, 28% among White men, and highest amongst those who identify as people of color, lesbian, or bisexual.¹ The COVID-19 pandemic has magnified risk factors for IPV such as unemployment and social isolation—particularly in marginalized communities—while decreasing access to resources such as childcare and shelters.² Because most individuals do not voluntarily disclose or seek treatment for IPV, it is critical we use the following recommendations to complete safe, trauma-informed, recovery-oriented assessment in patients presenting for care, whether in person or via telehealth.

Ensure a safe environment

At the onset of a telehealth appointment, ask the patient “Who is in the room with you?” If an adult or child age >2 years is present, do not assess for IPV because it may be unsafe for the patient to answer such questions. Encourage the patient to use privacy-enhancing strategies (eg, wearing headphones, going outside, calling from a vehicle). Be flexible; someone may not be able to discuss IPV during an appointment but might be able to at a different time, such as when their partner goes to work. For patients who disclose IPV, identify a word, phrase, or gesture to quickly communicate their partner’s presence or need for immediate help.² While the “Signal for Help” (ie, thumb first tucked into the palm, then covered with fingers to form a fist) has been developed,³ it is not universally familiar; until then, establish specific communications and preferences with each patient. Include a plan for the patient to abruptly disconnect (eg, “You have the wrong number”) with a pre-determined method of follow-up.

Obtain informed consent

Before asking a patient about IPV, provide psychoeducation about the purpose, including its relationship to one’s health. Acknowledge reasons it may not be safe to provide and/or document answers, and describe limits of confidentiality and local mandated reporting requirements.

Standardize the assessment

Intimate partner violence assessment should be normalized (eg, “Because violence is common, I ask everyone about their relationships”), direct, and well-integrated. Know whether your site uses a specific IPV screening tool, such as the Relationship Health and Safety Screen (RHSS), which is used at the VA; if so, learn and practice asking the specific questions aloud until it feels routine and you can maintain eye contact throughout. Examples of other IPV assessment instruments include the Abuse Assessment Screen (AAS); Hurt, Insult, Threaten, and Scream (HITS), Partner Violence Screen (PVS), and Women Abuse Screening Tool (WAST).⁴ Pay attention to the populations in which a tool has been studied, any associated copyright fees, and gender-neutral and non-heteronormative language. Avoid asking leading questions (eg, “You’re not being hurt, are you?”) or using charged/interpretable terms (eg, “Is someone abusing you?”).

Document with intention

Use person-centered, recovery-oriented language (eg, someone who experiences or uses IPV) rather than stigmatizing language (eg, victim, batterer, abuser). Describe what happened using the individual’s own words and clearly identify the source of information, witnesses, and any weapons used. Choose nonpejorative language (ie, “states” instead of “claims”). Do not document details of the safety plan in the chart because doing so can compromise safety.

Provide resources and referrals

Regardless of whether a patient consents to screening/documentation or discloses IPV, you should offer universal education, resources, and referrals. Review national contacts (National Domestic Violence Hotline: 1-800-799-7233), community agencies (available through www.domesticshelters.org), and suggested safety apps such as myPlan (www.myplanapp.org), but do not send a patient electronic or physical materials without first confirming it is safe to do so. Assess the patient’s interest in legal steps (eg, obtaining a protection order, pressing charges) while recognizing and respecting valid concerns about law enforcement involvement, particularly among the Black community and Black transgender women. Provide options instead of instructions, which will empower patients to choose what is best for their situation, and support their decisions.

Intimate partner violence (IPV) includes “physical violence, sexual violence, stalking, and psychological aggression (including coercive tactics) by a current or former intimate partner.”¹Intimate partner violence was a widespread problem even before COVID-19, with lifetime rates of nearly 35% among White women, 28% among White men, and highest amongst those who identify as people of color, lesbian, or bisexual.¹ The COVID-19 pandemic has magnified risk factors for IPV such as unemployment and social isolation—particularly in marginalized communities—while decreasing access to resources such as childcare and shelters.² Because most individuals do not voluntarily disclose or seek treatment for IPV, it is critical we use the following recommendations to complete safe, trauma-informed, recovery-oriented assessment in patients presenting for care, whether in person or via telehealth.

Ensure a safe environment

At the onset of a telehealth appointment, ask the patient “Who is in the room with you?” If an adult or child age >2 years is present, do not assess for IPV because it may be unsafe for the patient to answer such questions. Encourage the patient to use privacy-enhancing strategies (eg, wearing headphones, going outside, calling from a vehicle). Be flexible; someone may not be able to discuss IPV during an appointment but might be able to at a different time, such as when their partner goes to work. For patients who disclose IPV, identify a word, phrase, or gesture to quickly communicate their partner’s presence or need for immediate help.² While the “Signal for Help” (ie, thumb first tucked into the palm, then covered with fingers to form a fist) has been developed,³ it is not universally familiar; until then, establish specific communications and preferences with each patient. Include a plan for the patient to abruptly disconnect (eg, “You have the wrong number”) with a pre-determined method of follow-up.

Obtain informed consent

Before asking a patient about IPV, provide psychoeducation about the purpose, including its relationship to one’s health. Acknowledge reasons it may not be safe to provide and/or document answers, and describe limits of confidentiality and local mandated reporting requirements.

Standardize the assessment

Intimate partner violence assessment should be normalized (eg, “Because violence is common, I ask everyone about their relationships”), direct, and well-integrated. Know whether your site uses a specific IPV screening tool, such as the Relationship Health and Safety Screen (RHSS), which is used at the VA; if so, learn and practice asking the specific questions aloud until it feels routine and you can maintain eye contact throughout. Examples of other IPV assessment instruments include the Abuse Assessment Screen (AAS); Hurt, Insult, Threaten, and Scream (HITS), Partner Violence Screen (PVS), and Women Abuse Screening Tool (WAST).⁴ Pay attention to the populations in which a tool has been studied, any associated copyright fees, and gender-neutral and non-heteronormative language. Avoid asking leading questions (eg, “You’re not being hurt, are you?”) or using charged/interpretable terms (eg, “Is someone abusing you?”).

Document with intention

Use person-centered, recovery-oriented language (eg, someone who experiences or uses IPV) rather than stigmatizing language (eg, victim, batterer, abuser). Describe what happened using the individual’s own words and clearly identify the source of information, witnesses, and any weapons used. Choose nonpejorative language (ie, “states” instead of “claims”). Do not document details of the safety plan in the chart because doing so can compromise safety.

Provide resources and referrals

Regardless of whether a patient consents to screening/documentation or discloses IPV, you should offer universal education, resources, and referrals. Review national contacts (National Domestic Violence Hotline: 1-800-799-7233), community agencies (available through www.domesticshelters.org), and suggested safety apps such as myPlan (www.myplanapp.org), but do not send a patient electronic or physical materials without first confirming it is safe to do so. Assess the patient’s interest in legal steps (eg, obtaining a protection order, pressing charges) while recognizing and respecting valid concerns about law enforcement involvement, particularly among the Black community and Black transgender women. Provide options instead of instructions, which will empower patients to choose what is best for their situation, and support their decisions.

Intimate partner violence (IPV) includes “physical violence, sexual violence, stalking, and psychological aggression (including coercive tactics) by a current or former intimate partner.”¹Intimate partner violence was a widespread problem even before COVID-19, with lifetime rates of nearly 35% among White women, 28% among White men, and highest amongst those who identify as people of color, lesbian, or bisexual.¹ The COVID-19 pandemic has magnified risk factors for IPV such as unemployment and social isolation—particularly in marginalized communities—while decreasing access to resources such as childcare and shelters.² Because most individuals do not voluntarily disclose or seek treatment for IPV, it is critical we use the following recommendations to complete safe, trauma-informed, recovery-oriented assessment in patients presenting for care, whether in person or via telehealth.

Ensure a safe environment

At the onset of a telehealth appointment, ask the patient “Who is in the room with you?” If an adult or child age >2 years is present, do not assess for IPV because it may be unsafe for the patient to answer such questions. Encourage the patient to use privacy-enhancing strategies (eg, wearing headphones, going outside, calling from a vehicle). Be flexible; someone may not be able to discuss IPV during an appointment but might be able to at a different time, such as when their partner goes to work. For patients who disclose IPV, identify a word, phrase, or gesture to quickly communicate their partner’s presence or need for immediate help.² While the “Signal for Help” (ie, thumb first tucked into the palm, then covered with fingers to form a fist) has been developed,³ it is not universally familiar; until then, establish specific communications and preferences with each patient. Include a plan for the patient to abruptly disconnect (eg, “You have the wrong number”) with a pre-determined method of follow-up.

Obtain informed consent

Before asking a patient about IPV, provide psychoeducation about the purpose, including its relationship to one’s health. Acknowledge reasons it may not be safe to provide and/or document answers, and describe limits of confidentiality and local mandated reporting requirements.

Standardize the assessment

Intimate partner violence assessment should be normalized (eg, “Because violence is common, I ask everyone about their relationships”), direct, and well-integrated. Know whether your site uses a specific IPV screening tool, such as the Relationship Health and Safety Screen (RHSS), which is used at the VA; if so, learn and practice asking the specific questions aloud until it feels routine and you can maintain eye contact throughout. Examples of other IPV assessment instruments include the Abuse Assessment Screen (AAS); Hurt, Insult, Threaten, and Scream (HITS), Partner Violence Screen (PVS), and Women Abuse Screening Tool (WAST).⁴ Pay attention to the populations in which a tool has been studied, any associated copyright fees, and gender-neutral and non-heteronormative language. Avoid asking leading questions (eg, “You’re not being hurt, are you?”) or using charged/interpretable terms (eg, “Is someone abusing you?”).

Document with intention

Use person-centered, recovery-oriented language (eg, someone who experiences or uses IPV) rather than stigmatizing language (eg, victim, batterer, abuser). Describe what happened using the individual’s own words and clearly identify the source of information, witnesses, and any weapons used. Choose nonpejorative language (ie, “states” instead of “claims”). Do not document details of the safety plan in the chart because doing so can compromise safety.

Provide resources and referrals

Regardless of whether a patient consents to screening/documentation or discloses IPV, you should offer universal education, resources, and referrals. Review national contacts (National Domestic Violence Hotline: 1-800-799-7233), community agencies (available through www.domesticshelters.org), and suggested safety apps such as myPlan (www.myplanapp.org), but do not send a patient electronic or physical materials without first confirming it is safe to do so. Assess the patient’s interest in legal steps (eg, obtaining a protection order, pressing charges) while recognizing and respecting valid concerns about law enforcement involvement, particularly among the Black community and Black transgender women. Provide options instead of instructions, which will empower patients to choose what is best for their situation, and support their decisions.

Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are commonly used first-line agents for treating major depressive disorder. Less than one-half of patients with major depressive disorder experience remission after 1 acute trial of an antidepressant.¹ After optimization of an initial agent’s dose and duration, potential next steps include switching agents or augmentation. Augmentation strategies may lead to clinical improvement but carry the risks of polypharmacy, including increased risk of adverse effects and drug interactions. Clinicians can consider the following evidence-based options for a patient with a limited response to an initial SSRI or SNRI.

Second-generation antipsychotics, when used as augmentation agents to treat a patient with major depressive disorder, can lead to an approximately 10% improvement in remission rate compared with placebo.² Aripiprazole, brexpiprazole, olanzapine (in combination with fluoxetine only), and quetiapine are FDA-approved as adjunctive therapies with an antidepressant (Table 1). Second-generation antipsychotics should be started at lower doses than those used for schizophrenia, and these agents have an increased risk of metabolic adverse effects as well as extrapyramidal symptoms.

Atypical antidepressants are those that are not classified as an SSRI, SNRI, tricyclic antidepressant (TCA), or monoamine oxidase inhibitor (MAOI). These include bupropion, mirtazapine, trazodone, vilazodone, and vortioxetine (Table 2). Bupropion is a dopamine and norepinephrine reuptake inhibitor. When used for augmentation in clinical studies, it led to a 30% remission rate.³ Mirtazapine is an alpha-2 antagonist that can be used as monotherapy or in combination with another antidepressant.⁴ Trazodone is an antidepressant with activity at histamine and alpha-1-adrenergic receptors that is often used off-label for insomnia. Trazodone can be used safely and effectively in combination with other agents for treatment-resistant depression.⁵ Vilazodone is a 5-HT1A partial agonist, and vortioxetine is a 5-HT1A agonist and 5-HT3 antagonist; both are FDA-approved as alternative agents for monotherapy for major depressive disorder. Choosing among these agents for switching or augmenting can be guided by patient preference, adverse effect profile, and targeting specific symptoms, such as using mirtazapine to address poor sleep and appetite.

Lithium augmentation has been frequently investigated in placebo-controlled, double-blind studies. A meta-analysis showed that patients receiving lithium augmentation with a serum level of ≥0.5 mEq/L were >3 times more likely to respond than those receiving placebo.⁶ When lithium is used to treat bipolar disorder, the therapeutic serum range for lithium is 0.8 to 1.2 mEq/L, with an increased risk of adverse effects (including toxicity) at higher levels.⁷

Triiodothyronine (T3) augmentation of antidepressants led to remission in approximately 1 in 4 patients who had not achieved remission or who were intolerant to an initial treatment with citalopram and a second switch or augmentation trial.⁸ In this study, the mean dose of T3 was 45.2 µg/d, with an average length of treatment of 9 weeks.

Tricyclic antidepressants are another option when considering switching agents (Table 3). TCAs are additionally effective for comorbid pain conditions.⁹ When TCAs are used in combination with SSRIs, drug interactions may occur that increase TCA plasma levels. There is also an increased risk of serotonin syndrome when used with serotonergic agents, though an SSRI/ TCA combination may be appropriate for a patient with treatment-resistant depression.¹⁰ Additionally, TCAs carry unique risks of cardiovascular effects, including cardiac arrhythmias. A meta-analysis comparing fluoxetine, paroxetine, and sertraline to TCAs (amitriptyline, clomipramine, desipramine, doxepin, imipramine, and nortriptyline) concluded that both classes had similar efficacy in treating depression, though the drop-out rate was significantly higher among patients receiving TCAs.¹¹

Buspirone is approved for generalized anxiety disorder. In studies where buspirone was used as an augmentation agent for major depressive disorder at a mean daily dose of 40.9 mg divided into 2 doses, it led to a remission rate >30%.³

Continue to: Monoamine oxidase inhibitors

Monoamine oxidase inhibitors should typically be avoided in initial or early treatment of depression due to tolerability issues, drug interactions, and dietary restrictions to avoid hypertensive crisis. MAOIs are generally not recommended to be used with SSRIs, SNRIs, or TCAs, and typically require a “washout” period from other antidepressants (Table 4). One review found that MAOI treatment had advantage over TCA treatment for patients with early-stage treatment-resistant depression, though this advantage decreased as the number of failed antidepressant trials increased.¹² One MAOI, selegiline, is available in a transdermal patch, and the 6-mg patch does not require dietary restriction.

Esketamine (intranasal) is FDA-approved for treatment-resistant depression (failure of response after at least 2 antidepressant trials with adequate dose and duration) in conjunction with an oral antidepressant. In clinical studies, a significant response was noted after 1 week of treatment.¹³ Esketamine requires an induction period of twice-weekly doses of 56 or 84 mg, with maintenance doses every 1 to 2 weeks. Each dosage administration requires monitoring for at least 2 hours by a health care professional at a certified treatment center. Esketamine’s indication was recently expanded to include treatment of patients with major depressive disorder with suicidal ideation or behavior.

Stimulants such as amphetamines, methylphenidate, or modafinil have been effective in open studies for augmentation in depression.¹⁴ However, no stimulant is FDA-approved for the treatment of depression. In addition to other adverse effects, these medications are controlled substances and carry risk of misuse, and their use may not be appropriate for all patients.

Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are commonly used first-line agents for treating major depressive disorder. Less than one-half of patients with major depressive disorder experience remission after 1 acute trial of an antidepressant.¹ After optimization of an initial agent’s dose and duration, potential next steps include switching agents or augmentation. Augmentation strategies may lead to clinical improvement but carry the risks of polypharmacy, including increased risk of adverse effects and drug interactions. Clinicians can consider the following evidence-based options for a patient with a limited response to an initial SSRI or SNRI.

Second-generation antipsychotics, when used as augmentation agents to treat a patient with major depressive disorder, can lead to an approximately 10% improvement in remission rate compared with placebo.² Aripiprazole, brexpiprazole, olanzapine (in combination with fluoxetine only), and quetiapine are FDA-approved as adjunctive therapies with an antidepressant (Table 1). Second-generation antipsychotics should be started at lower doses than those used for schizophrenia, and these agents have an increased risk of metabolic adverse effects as well as extrapyramidal symptoms.

Atypical antidepressants are those that are not classified as an SSRI, SNRI, tricyclic antidepressant (TCA), or monoamine oxidase inhibitor (MAOI). These include bupropion, mirtazapine, trazodone, vilazodone, and vortioxetine (Table 2). Bupropion is a dopamine and norepinephrine reuptake inhibitor. When used for augmentation in clinical studies, it led to a 30% remission rate.³ Mirtazapine is an alpha-2 antagonist that can be used as monotherapy or in combination with another antidepressant.⁴ Trazodone is an antidepressant with activity at histamine and alpha-1-adrenergic receptors that is often used off-label for insomnia. Trazodone can be used safely and effectively in combination with other agents for treatment-resistant depression.⁵ Vilazodone is a 5-HT1A partial agonist, and vortioxetine is a 5-HT1A agonist and 5-HT3 antagonist; both are FDA-approved as alternative agents for monotherapy for major depressive disorder. Choosing among these agents for switching or augmenting can be guided by patient preference, adverse effect profile, and targeting specific symptoms, such as using mirtazapine to address poor sleep and appetite.

Lithium augmentation has been frequently investigated in placebo-controlled, double-blind studies. A meta-analysis showed that patients receiving lithium augmentation with a serum level of ≥0.5 mEq/L were >3 times more likely to respond than those receiving placebo.⁶ When lithium is used to treat bipolar disorder, the therapeutic serum range for lithium is 0.8 to 1.2 mEq/L, with an increased risk of adverse effects (including toxicity) at higher levels.⁷

Triiodothyronine (T3) augmentation of antidepressants led to remission in approximately 1 in 4 patients who had not achieved remission or who were intolerant to an initial treatment with citalopram and a second switch or augmentation trial.⁸ In this study, the mean dose of T3 was 45.2 µg/d, with an average length of treatment of 9 weeks.

Tricyclic antidepressants are another option when considering switching agents (Table 3). TCAs are additionally effective for comorbid pain conditions.⁹ When TCAs are used in combination with SSRIs, drug interactions may occur that increase TCA plasma levels. There is also an increased risk of serotonin syndrome when used with serotonergic agents, though an SSRI/ TCA combination may be appropriate for a patient with treatment-resistant depression.¹⁰ Additionally, TCAs carry unique risks of cardiovascular effects, including cardiac arrhythmias. A meta-analysis comparing fluoxetine, paroxetine, and sertraline to TCAs (amitriptyline, clomipramine, desipramine, doxepin, imipramine, and nortriptyline) concluded that both classes had similar efficacy in treating depression, though the drop-out rate was significantly higher among patients receiving TCAs.¹¹

Buspirone is approved for generalized anxiety disorder. In studies where buspirone was used as an augmentation agent for major depressive disorder at a mean daily dose of 40.9 mg divided into 2 doses, it led to a remission rate >30%.³

Continue to: Monoamine oxidase inhibitors

Monoamine oxidase inhibitors should typically be avoided in initial or early treatment of depression due to tolerability issues, drug interactions, and dietary restrictions to avoid hypertensive crisis. MAOIs are generally not recommended to be used with SSRIs, SNRIs, or TCAs, and typically require a “washout” period from other antidepressants (Table 4). One review found that MAOI treatment had advantage over TCA treatment for patients with early-stage treatment-resistant depression, though this advantage decreased as the number of failed antidepressant trials increased.¹² One MAOI, selegiline, is available in a transdermal patch, and the 6-mg patch does not require dietary restriction.

Esketamine (intranasal) is FDA-approved for treatment-resistant depression (failure of response after at least 2 antidepressant trials with adequate dose and duration) in conjunction with an oral antidepressant. In clinical studies, a significant response was noted after 1 week of treatment.¹³ Esketamine requires an induction period of twice-weekly doses of 56 or 84 mg, with maintenance doses every 1 to 2 weeks. Each dosage administration requires monitoring for at least 2 hours by a health care professional at a certified treatment center. Esketamine’s indication was recently expanded to include treatment of patients with major depressive disorder with suicidal ideation or behavior.

Stimulants such as amphetamines, methylphenidate, or modafinil have been effective in open studies for augmentation in depression.¹⁴ However, no stimulant is FDA-approved for the treatment of depression. In addition to other adverse effects, these medications are controlled substances and carry risk of misuse, and their use may not be appropriate for all patients.

Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are commonly used first-line agents for treating major depressive disorder. Less than one-half of patients with major depressive disorder experience remission after 1 acute trial of an antidepressant.¹ After optimization of an initial agent’s dose and duration, potential next steps include switching agents or augmentation. Augmentation strategies may lead to clinical improvement but carry the risks of polypharmacy, including increased risk of adverse effects and drug interactions. Clinicians can consider the following evidence-based options for a patient with a limited response to an initial SSRI or SNRI.

Second-generation antipsychotics, when used as augmentation agents to treat a patient with major depressive disorder, can lead to an approximately 10% improvement in remission rate compared with placebo.² Aripiprazole, brexpiprazole, olanzapine (in combination with fluoxetine only), and quetiapine are FDA-approved as adjunctive therapies with an antidepressant (Table 1). Second-generation antipsychotics should be started at lower doses than those used for schizophrenia, and these agents have an increased risk of metabolic adverse effects as well as extrapyramidal symptoms.

Atypical antidepressants are those that are not classified as an SSRI, SNRI, tricyclic antidepressant (TCA), or monoamine oxidase inhibitor (MAOI). These include bupropion, mirtazapine, trazodone, vilazodone, and vortioxetine (Table 2). Bupropion is a dopamine and norepinephrine reuptake inhibitor. When used for augmentation in clinical studies, it led to a 30% remission rate.³ Mirtazapine is an alpha-2 antagonist that can be used as monotherapy or in combination with another antidepressant.⁴ Trazodone is an antidepressant with activity at histamine and alpha-1-adrenergic receptors that is often used off-label for insomnia. Trazodone can be used safely and effectively in combination with other agents for treatment-resistant depression.⁵ Vilazodone is a 5-HT1A partial agonist, and vortioxetine is a 5-HT1A agonist and 5-HT3 antagonist; both are FDA-approved as alternative agents for monotherapy for major depressive disorder. Choosing among these agents for switching or augmenting can be guided by patient preference, adverse effect profile, and targeting specific symptoms, such as using mirtazapine to address poor sleep and appetite.

Lithium augmentation has been frequently investigated in placebo-controlled, double-blind studies. A meta-analysis showed that patients receiving lithium augmentation with a serum level of ≥0.5 mEq/L were >3 times more likely to respond than those receiving placebo.⁶ When lithium is used to treat bipolar disorder, the therapeutic serum range for lithium is 0.8 to 1.2 mEq/L, with an increased risk of adverse effects (including toxicity) at higher levels.⁷

Triiodothyronine (T3) augmentation of antidepressants led to remission in approximately 1 in 4 patients who had not achieved remission or who were intolerant to an initial treatment with citalopram and a second switch or augmentation trial.⁸ In this study, the mean dose of T3 was 45.2 µg/d, with an average length of treatment of 9 weeks.

Tricyclic antidepressants are another option when considering switching agents (Table 3). TCAs are additionally effective for comorbid pain conditions.⁹ When TCAs are used in combination with SSRIs, drug interactions may occur that increase TCA plasma levels. There is also an increased risk of serotonin syndrome when used with serotonergic agents, though an SSRI/ TCA combination may be appropriate for a patient with treatment-resistant depression.¹⁰ Additionally, TCAs carry unique risks of cardiovascular effects, including cardiac arrhythmias. A meta-analysis comparing fluoxetine, paroxetine, and sertraline to TCAs (amitriptyline, clomipramine, desipramine, doxepin, imipramine, and nortriptyline) concluded that both classes had similar efficacy in treating depression, though the drop-out rate was significantly higher among patients receiving TCAs.¹¹

Buspirone is approved for generalized anxiety disorder. In studies where buspirone was used as an augmentation agent for major depressive disorder at a mean daily dose of 40.9 mg divided into 2 doses, it led to a remission rate >30%.³

Continue to: Monoamine oxidase inhibitors

Monoamine oxidase inhibitors should typically be avoided in initial or early treatment of depression due to tolerability issues, drug interactions, and dietary restrictions to avoid hypertensive crisis. MAOIs are generally not recommended to be used with SSRIs, SNRIs, or TCAs, and typically require a “washout” period from other antidepressants (Table 4). One review found that MAOI treatment had advantage over TCA treatment for patients with early-stage treatment-resistant depression, though this advantage decreased as the number of failed antidepressant trials increased.¹² One MAOI, selegiline, is available in a transdermal patch, and the 6-mg patch does not require dietary restriction.

Esketamine (intranasal) is FDA-approved for treatment-resistant depression (failure of response after at least 2 antidepressant trials with adequate dose and duration) in conjunction with an oral antidepressant. In clinical studies, a significant response was noted after 1 week of treatment.¹³ Esketamine requires an induction period of twice-weekly doses of 56 or 84 mg, with maintenance doses every 1 to 2 weeks. Each dosage administration requires monitoring for at least 2 hours by a health care professional at a certified treatment center. Esketamine’s indication was recently expanded to include treatment of patients with major depressive disorder with suicidal ideation or behavior.

Stimulants such as amphetamines, methylphenidate, or modafinil have been effective in open studies for augmentation in depression.¹⁴ However, no stimulant is FDA-approved for the treatment of depression. In addition to other adverse effects, these medications are controlled substances and carry risk of misuse, and their use may not be appropriate for all patients.

Editor’s note: Readers’ Forum is a department for correspondence from readers that is not in response to articles published in Current Psychiatry . All submissions to Readers’ Forum undergo peer review and are subject to editing for length and style. For more information, contact letters@currentpsychiatry.com.

Childhood and adolescence are periods with marked psychobehavioral development of the brain. The sense of self, identity, and role are established. This process is not without risk because brain regions governing reward, impulsivity, and sensation-seeking are relatively more developed and influential than higher-order cognitive regions regulating behavioral inhibition, decision-making, and planning, which continue to mature into one’s early to mid-20s. Consequently, while the developing brain is “under construction” by forging new pathways and taking advantage of its immense neuroplasticity, it is also prone to psychological insults under exposure to stressful events, attitudes, and behaviors, including those that can arise in the family.¹

Most people would agree that there is no stronger emotion than parental love. The origins of this powerful biobehavioral bonding with a child have been attributed to maternal release of oxytocin, known colloquially as the “love hormone,” during the birthing process, and to both biological parents experiencing psychosocial attachment with their infant. Therefore, common sense dictates that parents would do anything to protect their offspring, and that no parent would deliberately behave in a manner that harms their child.

Common sense notwithstanding, reports of both child neglect and abuse are common. States have established agencies to protect children from their own parents. The answers to the question “Whose kids are they?” and under what circumstances the state has the authority to warn or reprimand parents, or even temporarily or permanently separate minors from their parents, are complex and vary by state.

In this commentary, we describe harmful actions committed by parents with the intention of protecting the impressionable minds of their children from malevolent forces or intrusive and unhealthy ideas. Second, we examine how to protect a minor from parental actions that are well-meaning but potentially harmful.

Parent-child communication

Delusional family interactions. Originally described in 1877 as “folie à deux,”² shared madness is an extreme and uncommon parental psychiatric condition harmful to a child’s mental health. It is primarily characterized by parental-initiated delusions shared with the child that are typically persecutory and attributed to danger from vengeful folks or grandiose in nature. The question of whether the “folie” or “madness” is contagious arises due to the propensity of the child to adopt these delusions under an imposed insular or restrictive environment. Separating the child from the environment dominated by the delusional adult usually is sufficient to reverse the symptoms due to reality testing.

Normative familial communication. In contrary to a delusional familial interaction, normative family traditions and values are a unifying psychosocial force and a source of bonding and loyalty from an early age. A ubiquitous example is the support of a local sports team, and the emotional turmoil associated with the team’s wins and losses, accompanied by “hating” a rival. These family rituals are commonly devoid of emotional negative consequences for an impressionable young mind unless the child is exposed to unsportsmanlike emotional, verbal, or aggressive behavior by an adult at home in front of the television or in the stands at a game.

Continue to: Unfortunately...

Unfortunately, the “love-hate” dichotomy rooted in family-generated traditions of loyalty is becoming more evident in today’s turbulent sociopolitical environment. Children and young adolescents are not prepared to cope with the stressful effects of repeated exposure to intense conflictual events at home when parents adopt opposing sociopolitical ideologies. Furthermore, a parent might intentionally expose their child to emotionally conflictual circumstances in the name of a perceived value that might create and exacerbate stress, fear, and self-loathing. Ironically, by doing what a parent believes is right for their child, they might be transforming the child without their consent into a variant of a “toy soldier by proxy.” Such a child is a tool expected to follow the parental pathway and belief system without questioning, or even having the cognitive ability to do so, given their ongoing bio-behavioral and moral developmental phase.³

This new normative exposure to conflictual situations at the will of the parent is not only limited to watching them remotely but also may include participating in what is meant to be a peaceful protest or march. As we all witnessed in 2020, such events can easily deteriorate into unsafe environments rife with lawlessness and uncontrolled violence. This has included clashes between opposing groups who are matched in zeal and conviction, as well as opposition to or endangerment by law enforcement personnel trying to restore order by force. This is not where a responsible parent should take their child. Furthermore, there is the danger of loss of privacy of children exposed by media following their participation in public activity. This may lead to hate mail as that would further confuse and jeopardize a peaceful lifestyle, which is highly desirable for a developing child.

Cognitive dissonance. Have these parents temporarily allowed the limbic system to trump the restraints of the prefrontal cortex, as exhibited by an impulsive and risky behavior driven by poor insight? Have these parents thoughtfully weighed the balance between the merit of a child’s exposure to such conflictual circumstances and the peril of negative emotional consequences? This is illustrated by a mother who has been taking her preadolescent son to demonstrations regularly because “I want him to see how democracy works.”

Might this be a case of cognitive dissonance (CD) that amounts to unwitting mental child abuse if it happens repeatedly? According to the CD theory, there is a tendency to seek consistency between cognitions (eg, beliefs, opinions) and attitudes or behaviors. Inconsistency between these variables is termed “dissonance.”^4,5 The importance attached to the dissonant belief affects the severity of the dissonance. The dissonance occurs when a parent must choose between 2 incompatible beliefs or actions. A classic demonstration of CD is when an adult requests that an adolescent follows his instructions (eg, “do not smoke or drink alcohol”), yet the adult does not act accordingly (eg, they smoke or drink). Role modeling demonstrated by such a discrepancy is a cause of confusion in the child. In terms of this article, the CD is between what the parent believes is an important learning experience by exercising the perceived right to pass to the child the parental value system vs compromising the protection of the child by exposing them to the potential negative consequences of a risky situation.

What can parents and therapists do?

Usually, parents mean well. It is important to communicate to parents the importance of refraining from forcing their children to join their battles. Calculating risks based on an intuitive approach is flawed because doing so is based on beliefs and emotions that originated in the limbic system (“I feel that”…) and are neither precise nor accurate.⁶ Teaching our youth in the school system how to think (eg, the science of logic and history of science) vs what to think (ie, indoctrination) is a key to healthy cognitive development. Furthermore, children need to have the time, space, and opportunities (learning moments) to develop this capacity. It is not until approximately age 16 that abstract thinking capabilities are developed. Cognitive dissonance can be eliminated by reducing the valence of the conflicting beliefs or by removing the conflicting attitude or behavior.

As parents and as mental health professionals, we should carry the necessary burden of responsibility to prevent the risk of “lost childhood” due to parental emotional zeal and righteousness that lead to early exposure to damaging adversity. We cannot afford to turn our children into exploitable tools (ie, toy soldiers) in conflicts they do not fully grasp.

Editor’s note: Readers’ Forum is a department for correspondence from readers that is not in response to articles published in Current Psychiatry . All submissions to Readers’ Forum undergo peer review and are subject to editing for length and style. For more information, contact letters@currentpsychiatry.com.

Childhood and adolescence are periods with marked psychobehavioral development of the brain. The sense of self, identity, and role are established. This process is not without risk because brain regions governing reward, impulsivity, and sensation-seeking are relatively more developed and influential than higher-order cognitive regions regulating behavioral inhibition, decision-making, and planning, which continue to mature into one’s early to mid-20s. Consequently, while the developing brain is “under construction” by forging new pathways and taking advantage of its immense neuroplasticity, it is also prone to psychological insults under exposure to stressful events, attitudes, and behaviors, including those that can arise in the family.¹

Most people would agree that there is no stronger emotion than parental love. The origins of this powerful biobehavioral bonding with a child have been attributed to maternal release of oxytocin, known colloquially as the “love hormone,” during the birthing process, and to both biological parents experiencing psychosocial attachment with their infant. Therefore, common sense dictates that parents would do anything to protect their offspring, and that no parent would deliberately behave in a manner that harms their child.

Common sense notwithstanding, reports of both child neglect and abuse are common. States have established agencies to protect children from their own parents. The answers to the question “Whose kids are they?” and under what circumstances the state has the authority to warn or reprimand parents, or even temporarily or permanently separate minors from their parents, are complex and vary by state.

In this commentary, we describe harmful actions committed by parents with the intention of protecting the impressionable minds of their children from malevolent forces or intrusive and unhealthy ideas. Second, we examine how to protect a minor from parental actions that are well-meaning but potentially harmful.

Parent-child communication

Delusional family interactions. Originally described in 1877 as “folie à deux,”² shared madness is an extreme and uncommon parental psychiatric condition harmful to a child’s mental health. It is primarily characterized by parental-initiated delusions shared with the child that are typically persecutory and attributed to danger from vengeful folks or grandiose in nature. The question of whether the “folie” or “madness” is contagious arises due to the propensity of the child to adopt these delusions under an imposed insular or restrictive environment. Separating the child from the environment dominated by the delusional adult usually is sufficient to reverse the symptoms due to reality testing.

Normative familial communication. In contrary to a delusional familial interaction, normative family traditions and values are a unifying psychosocial force and a source of bonding and loyalty from an early age. A ubiquitous example is the support of a local sports team, and the emotional turmoil associated with the team’s wins and losses, accompanied by “hating” a rival. These family rituals are commonly devoid of emotional negative consequences for an impressionable young mind unless the child is exposed to unsportsmanlike emotional, verbal, or aggressive behavior by an adult at home in front of the television or in the stands at a game.

Continue to: Unfortunately...

Unfortunately, the “love-hate” dichotomy rooted in family-generated traditions of loyalty is becoming more evident in today’s turbulent sociopolitical environment. Children and young adolescents are not prepared to cope with the stressful effects of repeated exposure to intense conflictual events at home when parents adopt opposing sociopolitical ideologies. Furthermore, a parent might intentionally expose their child to emotionally conflictual circumstances in the name of a perceived value that might create and exacerbate stress, fear, and self-loathing. Ironically, by doing what a parent believes is right for their child, they might be transforming the child without their consent into a variant of a “toy soldier by proxy.” Such a child is a tool expected to follow the parental pathway and belief system without questioning, or even having the cognitive ability to do so, given their ongoing bio-behavioral and moral developmental phase.³

This new normative exposure to conflictual situations at the will of the parent is not only limited to watching them remotely but also may include participating in what is meant to be a peaceful protest or march. As we all witnessed in 2020, such events can easily deteriorate into unsafe environments rife with lawlessness and uncontrolled violence. This has included clashes between opposing groups who are matched in zeal and conviction, as well as opposition to or endangerment by law enforcement personnel trying to restore order by force. This is not where a responsible parent should take their child. Furthermore, there is the danger of loss of privacy of children exposed by media following their participation in public activity. This may lead to hate mail as that would further confuse and jeopardize a peaceful lifestyle, which is highly desirable for a developing child.

Cognitive dissonance. Have these parents temporarily allowed the limbic system to trump the restraints of the prefrontal cortex, as exhibited by an impulsive and risky behavior driven by poor insight? Have these parents thoughtfully weighed the balance between the merit of a child’s exposure to such conflictual circumstances and the peril of negative emotional consequences? This is illustrated by a mother who has been taking her preadolescent son to demonstrations regularly because “I want him to see how democracy works.”

Might this be a case of cognitive dissonance (CD) that amounts to unwitting mental child abuse if it happens repeatedly? According to the CD theory, there is a tendency to seek consistency between cognitions (eg, beliefs, opinions) and attitudes or behaviors. Inconsistency between these variables is termed “dissonance.”^4,5 The importance attached to the dissonant belief affects the severity of the dissonance. The dissonance occurs when a parent must choose between 2 incompatible beliefs or actions. A classic demonstration of CD is when an adult requests that an adolescent follows his instructions (eg, “do not smoke or drink alcohol”), yet the adult does not act accordingly (eg, they smoke or drink). Role modeling demonstrated by such a discrepancy is a cause of confusion in the child. In terms of this article, the CD is between what the parent believes is an important learning experience by exercising the perceived right to pass to the child the parental value system vs compromising the protection of the child by exposing them to the potential negative consequences of a risky situation.

What can parents and therapists do?

Usually, parents mean well. It is important to communicate to parents the importance of refraining from forcing their children to join their battles. Calculating risks based on an intuitive approach is flawed because doing so is based on beliefs and emotions that originated in the limbic system (“I feel that”…) and are neither precise nor accurate.⁶ Teaching our youth in the school system how to think (eg, the science of logic and history of science) vs what to think (ie, indoctrination) is a key to healthy cognitive development. Furthermore, children need to have the time, space, and opportunities (learning moments) to develop this capacity. It is not until approximately age 16 that abstract thinking capabilities are developed. Cognitive dissonance can be eliminated by reducing the valence of the conflicting beliefs or by removing the conflicting attitude or behavior.

As parents and as mental health professionals, we should carry the necessary burden of responsibility to prevent the risk of “lost childhood” due to parental emotional zeal and righteousness that lead to early exposure to damaging adversity. We cannot afford to turn our children into exploitable tools (ie, toy soldiers) in conflicts they do not fully grasp.

Editor’s note: Readers’ Forum is a department for correspondence from readers that is not in response to articles published in Current Psychiatry . All submissions to Readers’ Forum undergo peer review and are subject to editing for length and style. For more information, contact letters@currentpsychiatry.com.

Childhood and adolescence are periods with marked psychobehavioral development of the brain. The sense of self, identity, and role are established. This process is not without risk because brain regions governing reward, impulsivity, and sensation-seeking are relatively more developed and influential than higher-order cognitive regions regulating behavioral inhibition, decision-making, and planning, which continue to mature into one’s early to mid-20s. Consequently, while the developing brain is “under construction” by forging new pathways and taking advantage of its immense neuroplasticity, it is also prone to psychological insults under exposure to stressful events, attitudes, and behaviors, including those that can arise in the family.¹

Most people would agree that there is no stronger emotion than parental love. The origins of this powerful biobehavioral bonding with a child have been attributed to maternal release of oxytocin, known colloquially as the “love hormone,” during the birthing process, and to both biological parents experiencing psychosocial attachment with their infant. Therefore, common sense dictates that parents would do anything to protect their offspring, and that no parent would deliberately behave in a manner that harms their child.

Common sense notwithstanding, reports of both child neglect and abuse are common. States have established agencies to protect children from their own parents. The answers to the question “Whose kids are they?” and under what circumstances the state has the authority to warn or reprimand parents, or even temporarily or permanently separate minors from their parents, are complex and vary by state.

In this commentary, we describe harmful actions committed by parents with the intention of protecting the impressionable minds of their children from malevolent forces or intrusive and unhealthy ideas. Second, we examine how to protect a minor from parental actions that are well-meaning but potentially harmful.

Parent-child communication

Delusional family interactions. Originally described in 1877 as “folie à deux,”² shared madness is an extreme and uncommon parental psychiatric condition harmful to a child’s mental health. It is primarily characterized by parental-initiated delusions shared with the child that are typically persecutory and attributed to danger from vengeful folks or grandiose in nature. The question of whether the “folie” or “madness” is contagious arises due to the propensity of the child to adopt these delusions under an imposed insular or restrictive environment. Separating the child from the environment dominated by the delusional adult usually is sufficient to reverse the symptoms due to reality testing.

Normative familial communication. In contrary to a delusional familial interaction, normative family traditions and values are a unifying psychosocial force and a source of bonding and loyalty from an early age. A ubiquitous example is the support of a local sports team, and the emotional turmoil associated with the team’s wins and losses, accompanied by “hating” a rival. These family rituals are commonly devoid of emotional negative consequences for an impressionable young mind unless the child is exposed to unsportsmanlike emotional, verbal, or aggressive behavior by an adult at home in front of the television or in the stands at a game.

Continue to: Unfortunately...

Unfortunately, the “love-hate” dichotomy rooted in family-generated traditions of loyalty is becoming more evident in today’s turbulent sociopolitical environment. Children and young adolescents are not prepared to cope with the stressful effects of repeated exposure to intense conflictual events at home when parents adopt opposing sociopolitical ideologies. Furthermore, a parent might intentionally expose their child to emotionally conflictual circumstances in the name of a perceived value that might create and exacerbate stress, fear, and self-loathing. Ironically, by doing what a parent believes is right for their child, they might be transforming the child without their consent into a variant of a “toy soldier by proxy.” Such a child is a tool expected to follow the parental pathway and belief system without questioning, or even having the cognitive ability to do so, given their ongoing bio-behavioral and moral developmental phase.³

This new normative exposure to conflictual situations at the will of the parent is not only limited to watching them remotely but also may include participating in what is meant to be a peaceful protest or march. As we all witnessed in 2020, such events can easily deteriorate into unsafe environments rife with lawlessness and uncontrolled violence. This has included clashes between opposing groups who are matched in zeal and conviction, as well as opposition to or endangerment by law enforcement personnel trying to restore order by force. This is not where a responsible parent should take their child. Furthermore, there is the danger of loss of privacy of children exposed by media following their participation in public activity. This may lead to hate mail as that would further confuse and jeopardize a peaceful lifestyle, which is highly desirable for a developing child.

Cognitive dissonance. Have these parents temporarily allowed the limbic system to trump the restraints of the prefrontal cortex, as exhibited by an impulsive and risky behavior driven by poor insight? Have these parents thoughtfully weighed the balance between the merit of a child’s exposure to such conflictual circumstances and the peril of negative emotional consequences? This is illustrated by a mother who has been taking her preadolescent son to demonstrations regularly because “I want him to see how democracy works.”

Might this be a case of cognitive dissonance (CD) that amounts to unwitting mental child abuse if it happens repeatedly? According to the CD theory, there is a tendency to seek consistency between cognitions (eg, beliefs, opinions) and attitudes or behaviors. Inconsistency between these variables is termed “dissonance.”^4,5 The importance attached to the dissonant belief affects the severity of the dissonance. The dissonance occurs when a parent must choose between 2 incompatible beliefs or actions. A classic demonstration of CD is when an adult requests that an adolescent follows his instructions (eg, “do not smoke or drink alcohol”), yet the adult does not act accordingly (eg, they smoke or drink). Role modeling demonstrated by such a discrepancy is a cause of confusion in the child. In terms of this article, the CD is between what the parent believes is an important learning experience by exercising the perceived right to pass to the child the parental value system vs compromising the protection of the child by exposing them to the potential negative consequences of a risky situation.

What can parents and therapists do?

Usually, parents mean well. It is important to communicate to parents the importance of refraining from forcing their children to join their battles. Calculating risks based on an intuitive approach is flawed because doing so is based on beliefs and emotions that originated in the limbic system (“I feel that”…) and are neither precise nor accurate.⁶ Teaching our youth in the school system how to think (eg, the science of logic and history of science) vs what to think (ie, indoctrination) is a key to healthy cognitive development. Furthermore, children need to have the time, space, and opportunities (learning moments) to develop this capacity. It is not until approximately age 16 that abstract thinking capabilities are developed. Cognitive dissonance can be eliminated by reducing the valence of the conflicting beliefs or by removing the conflicting attitude or behavior.

As parents and as mental health professionals, we should carry the necessary burden of responsibility to prevent the risk of “lost childhood” due to parental emotional zeal and righteousness that lead to early exposure to damaging adversity. We cannot afford to turn our children into exploitable tools (ie, toy soldiers) in conflicts they do not fully grasp.

Editor’s note: Readers’ Forum is a department for correspondence from readers that is not in response to articles published in Current Psychiatry . All submissions to Readers’ Forum undergo peer review and are subject to editing for length and style. For more information, contact letters@currentpsychiatry.com.

It was the late 1970s. She arrived by limousine; an attractive young woman, “Jasmine,” daughter of one of the richest men in the country. She was wearing a low-cut silk blouse and was adorned with an abundance of jewelry: large earrings, a necklace, and rings on nearly every finger. She smiled broadly when I introduced myself, shook her hand, and ushered her into my office.

She moved quickly and spoke in a rapid and pressured manner. She complained of poor sleep, mood swings, and racing thoughts. I began to ask her questions. “Have you used cocaine recently?” “What about Ritalin or amphetamines?” “Do you take prednisone or any other steroids?” “Do you have thyroid disease?” “Do you or anyone in your family have a history of manic depressive illness? Who? Have they ever required hospitalization for its treatment?”

“Well, doctor, what do you think?” she asked.

“I think that you probably have manic depressive illness and that you are currently having a manic episode. You should go into the hospital and begin treatment with lithium.”

“Who is the authority on this illness?” she asked.

“…The US authority or the world authority?” I replied.

“The world authority” she answered.

“Probably Professor Mogens Schou in Copenhagen,” I said.

“I’ll go see what he thinks,” she responded.

“Okay, you do that,” I replied.

When she left, I thought, “What a grandiose young woman, I doubt I’ll hear from her again.”

Continue to: Three days...

Three days later I received an unusual phone call.

“Dr. Jaffe, this is the long-distance operator, will you hold for Dr. Schou?”

“Of course,” I replied.

“Dr. Jaffe, I’m here with your patient, a charming young woman. I told her that I am in complete agreement with your diagnosis and treatment plan. She will be flying home tomorrow.”

A few days after she arrived home, I had Jasmine hospitalized under my care at one of the local psychiatric units. She stabilized nicely on lithium and tolerated it well. She remained there for about 3 weeks and was then discharged. I began seeing her in my office for weekly visits. After a few months we started meeting every 2 weeks, and eventually monthly.

She was doing well. Her mood swings were now mild and infrequent. Her sleep had normalized. Most important, she felt a lot more in control of her life.

Jasmine offered me a small window into the world of the super-rich and powerful. Basically, what I learned was that they are just like the rest of us, only more so. All the money provides both the opportunity to do a lot more good as well as to get into a lot more trouble. When a middle-class person gets manic and goes on a spending spree, they may blow a few hundred dollars on lottery tickets and perhaps a thousand dollars on clothing or gifts they don’t need. When the very rich do this, they buy airplanes, Ferraris, and vacation homes.

Jasmine and her siblings were often pestered—usually by acquaintances, but sometimes friends—for favors, usually loans, jobs, or introductions to other famous or powerful people. Jasmine turned out to be a lovely young woman, kind, generous, loyal to her friends and with a fine sense of humor. Getting to know her well helped dispel some of my prejudices about the adult children of the super-rich. I had incorrectly assumed that she would be quite spoiled and entitled.

After working together for approximately 2 years, we said our goodbyes because I was moving to a different part of the country. She thanked me for helping her get well. I asked her if there was anything in particular that she found most helpful. She surprised me when she answered so quickly.

“Yes. When you come from a very wealthy family, most people want something from you. You never wanted anything from me except my honesty” she said.

I thanked Jasmine for her gift.

Editor’s note: Readers’ Forum is a department for correspondence from readers that is not in response to articles published in Current Psychiatry . All submissions to Readers’ Forum undergo peer review and are subject to editing for length and style. For more information, contact letters@currentpsychiatry.com.

It was the late 1970s. She arrived by limousine; an attractive young woman, “Jasmine,” daughter of one of the richest men in the country. She was wearing a low-cut silk blouse and was adorned with an abundance of jewelry: large earrings, a necklace, and rings on nearly every finger. She smiled broadly when I introduced myself, shook her hand, and ushered her into my office.

She moved quickly and spoke in a rapid and pressured manner. She complained of poor sleep, mood swings, and racing thoughts. I began to ask her questions. “Have you used cocaine recently?” “What about Ritalin or amphetamines?” “Do you take prednisone or any other steroids?” “Do you have thyroid disease?” “Do you or anyone in your family have a history of manic depressive illness? Who? Have they ever required hospitalization for its treatment?”

“Well, doctor, what do you think?” she asked.

“I think that you probably have manic depressive illness and that you are currently having a manic episode. You should go into the hospital and begin treatment with lithium.”

“Who is the authority on this illness?” she asked.

“…The US authority or the world authority?” I replied.

“The world authority” she answered.

“Probably Professor Mogens Schou in Copenhagen,” I said.

“I’ll go see what he thinks,” she responded.

“Okay, you do that,” I replied.

When she left, I thought, “What a grandiose young woman, I doubt I’ll hear from her again.”

Continue to: Three days...

Three days later I received an unusual phone call.

“Dr. Jaffe, this is the long-distance operator, will you hold for Dr. Schou?”

“Of course,” I replied.

“Dr. Jaffe, I’m here with your patient, a charming young woman. I told her that I am in complete agreement with your diagnosis and treatment plan. She will be flying home tomorrow.”

A few days after she arrived home, I had Jasmine hospitalized under my care at one of the local psychiatric units. She stabilized nicely on lithium and tolerated it well. She remained there for about 3 weeks and was then discharged. I began seeing her in my office for weekly visits. After a few months we started meeting every 2 weeks, and eventually monthly.

She was doing well. Her mood swings were now mild and infrequent. Her sleep had normalized. Most important, she felt a lot more in control of her life.

Jasmine offered me a small window into the world of the super-rich and powerful. Basically, what I learned was that they are just like the rest of us, only more so. All the money provides both the opportunity to do a lot more good as well as to get into a lot more trouble. When a middle-class person gets manic and goes on a spending spree, they may blow a few hundred dollars on lottery tickets and perhaps a thousand dollars on clothing or gifts they don’t need. When the very rich do this, they buy airplanes, Ferraris, and vacation homes.

Jasmine and her siblings were often pestered—usually by acquaintances, but sometimes friends—for favors, usually loans, jobs, or introductions to other famous or powerful people. Jasmine turned out to be a lovely young woman, kind, generous, loyal to her friends and with a fine sense of humor. Getting to know her well helped dispel some of my prejudices about the adult children of the super-rich. I had incorrectly assumed that she would be quite spoiled and entitled.

After working together for approximately 2 years, we said our goodbyes because I was moving to a different part of the country. She thanked me for helping her get well. I asked her if there was anything in particular that she found most helpful. She surprised me when she answered so quickly.

“Yes. When you come from a very wealthy family, most people want something from you. You never wanted anything from me except my honesty” she said.

I thanked Jasmine for her gift.

Editor’s note: Readers’ Forum is a department for correspondence from readers that is not in response to articles published in Current Psychiatry . All submissions to Readers’ Forum undergo peer review and are subject to editing for length and style. For more information, contact letters@currentpsychiatry.com.

It was the late 1970s. She arrived by limousine; an attractive young woman, “Jasmine,” daughter of one of the richest men in the country. She was wearing a low-cut silk blouse and was adorned with an abundance of jewelry: large earrings, a necklace, and rings on nearly every finger. She smiled broadly when I introduced myself, shook her hand, and ushered her into my office.

She moved quickly and spoke in a rapid and pressured manner. She complained of poor sleep, mood swings, and racing thoughts. I began to ask her questions. “Have you used cocaine recently?” “What about Ritalin or amphetamines?” “Do you take prednisone or any other steroids?” “Do you have thyroid disease?” “Do you or anyone in your family have a history of manic depressive illness? Who? Have they ever required hospitalization for its treatment?”

“Well, doctor, what do you think?” she asked.

“I think that you probably have manic depressive illness and that you are currently having a manic episode. You should go into the hospital and begin treatment with lithium.”

“Who is the authority on this illness?” she asked.

“…The US authority or the world authority?” I replied.

“The world authority” she answered.

“Probably Professor Mogens Schou in Copenhagen,” I said.

“I’ll go see what he thinks,” she responded.

“Okay, you do that,” I replied.

When she left, I thought, “What a grandiose young woman, I doubt I’ll hear from her again.”

Continue to: Three days...

Three days later I received an unusual phone call.

“Dr. Jaffe, this is the long-distance operator, will you hold for Dr. Schou?”

“Of course,” I replied.

“Dr. Jaffe, I’m here with your patient, a charming young woman. I told her that I am in complete agreement with your diagnosis and treatment plan. She will be flying home tomorrow.”

A few days after she arrived home, I had Jasmine hospitalized under my care at one of the local psychiatric units. She stabilized nicely on lithium and tolerated it well. She remained there for about 3 weeks and was then discharged. I began seeing her in my office for weekly visits. After a few months we started meeting every 2 weeks, and eventually monthly.

She was doing well. Her mood swings were now mild and infrequent. Her sleep had normalized. Most important, she felt a lot more in control of her life.

Jasmine offered me a small window into the world of the super-rich and powerful. Basically, what I learned was that they are just like the rest of us, only more so. All the money provides both the opportunity to do a lot more good as well as to get into a lot more trouble. When a middle-class person gets manic and goes on a spending spree, they may blow a few hundred dollars on lottery tickets and perhaps a thousand dollars on clothing or gifts they don’t need. When the very rich do this, they buy airplanes, Ferraris, and vacation homes.

Jasmine and her siblings were often pestered—usually by acquaintances, but sometimes friends—for favors, usually loans, jobs, or introductions to other famous or powerful people. Jasmine turned out to be a lovely young woman, kind, generous, loyal to her friends and with a fine sense of humor. Getting to know her well helped dispel some of my prejudices about the adult children of the super-rich. I had incorrectly assumed that she would be quite spoiled and entitled.

After working together for approximately 2 years, we said our goodbyes because I was moving to a different part of the country. She thanked me for helping her get well. I asked her if there was anything in particular that she found most helpful. She surprised me when she answered so quickly.

“Yes. When you come from a very wealthy family, most people want something from you. You never wanted anything from me except my honesty” she said.

I thanked Jasmine for her gift.

The October issue of GI & Hepatology News marks the first of my tenure as Editor in Chief, accompanied by a talented group of associate editors that truly reflect the spirit and diversity of the AGA. Since its inaugural issue in January 2007, the newspaper has evolved into a trusted source of clinically relevant updates on emerging practice trends and technological advances. I am honored to serve as the fourth editor of GIHN, building on the strong foundation set by former editors Charles J. Lightdale, MD, AGAF; Colin W. Howden, MD, AGAF; and most recently John I. Allen, MD, MBA, AGAF. Each of them has played an instrumental role in the publication’s growth and success over the past 15 years.

GIHN is unique among AGA’s flagship publications in that it is designed to bring together content from a variety of sources, including innovative scientific research from leading academic journals, practice management updates, and information regarding emerging policy initiatives impacting frontline GI practice. It also provides a platform to highlight AGA’s important work on behalf of its members. My goal as EIC is to continue to curate high-yield content that has the potential to directly impact how we manage our patients and practices. Several new initiatives are planned, which I am excited to introduce over the next few months. My door is always open, and I welcome your feedback about how GIHN can best serve the needs of AGA’s diverse membership in both academics and community practice.

Highlights of this month’s issue include updates on a unique multidisciplinary collaboration designed to promote a coordinated response among health care providers in caring for patients with NAFLD/NASH and AGA’s Clinical Practice Update on dysplasia management in patients with IBD. If you haven’t already, please consider nominating yourself or a colleague for an AGA committee appointment – the deadline is Nov. 1, and this is a fantastic way to contribute to the national dialogue on important issues affecting frontline GI practice.

Megan A. Adams, MD, JD, MSc

The October issue of GI & Hepatology News marks the first of my tenure as Editor in Chief, accompanied by a talented group of associate editors that truly reflect the spirit and diversity of the AGA. Since its inaugural issue in January 2007, the newspaper has evolved into a trusted source of clinically relevant updates on emerging practice trends and technological advances. I am honored to serve as the fourth editor of GIHN, building on the strong foundation set by former editors Charles J. Lightdale, MD, AGAF; Colin W. Howden, MD, AGAF; and most recently John I. Allen, MD, MBA, AGAF. Each of them has played an instrumental role in the publication’s growth and success over the past 15 years.

GIHN is unique among AGA’s flagship publications in that it is designed to bring together content from a variety of sources, including innovative scientific research from leading academic journals, practice management updates, and information regarding emerging policy initiatives impacting frontline GI practice. It also provides a platform to highlight AGA’s important work on behalf of its members. My goal as EIC is to continue to curate high-yield content that has the potential to directly impact how we manage our patients and practices. Several new initiatives are planned, which I am excited to introduce over the next few months. My door is always open, and I welcome your feedback about how GIHN can best serve the needs of AGA’s diverse membership in both academics and community practice.

Highlights of this month’s issue include updates on a unique multidisciplinary collaboration designed to promote a coordinated response among health care providers in caring for patients with NAFLD/NASH and AGA’s Clinical Practice Update on dysplasia management in patients with IBD. If you haven’t already, please consider nominating yourself or a colleague for an AGA committee appointment – the deadline is Nov. 1, and this is a fantastic way to contribute to the national dialogue on important issues affecting frontline GI practice.

Megan A. Adams, MD, JD, MSc

The October issue of GI & Hepatology News marks the first of my tenure as Editor in Chief, accompanied by a talented group of associate editors that truly reflect the spirit and diversity of the AGA. Since its inaugural issue in January 2007, the newspaper has evolved into a trusted source of clinically relevant updates on emerging practice trends and technological advances. I am honored to serve as the fourth editor of GIHN, building on the strong foundation set by former editors Charles J. Lightdale, MD, AGAF; Colin W. Howden, MD, AGAF; and most recently John I. Allen, MD, MBA, AGAF. Each of them has played an instrumental role in the publication’s growth and success over the past 15 years.

GIHN is unique among AGA’s flagship publications in that it is designed to bring together content from a variety of sources, including innovative scientific research from leading academic journals, practice management updates, and information regarding emerging policy initiatives impacting frontline GI practice. It also provides a platform to highlight AGA’s important work on behalf of its members. My goal as EIC is to continue to curate high-yield content that has the potential to directly impact how we manage our patients and practices. Several new initiatives are planned, which I am excited to introduce over the next few months. My door is always open, and I welcome your feedback about how GIHN can best serve the needs of AGA’s diverse membership in both academics and community practice.

Highlights of this month’s issue include updates on a unique multidisciplinary collaboration designed to promote a coordinated response among health care providers in caring for patients with NAFLD/NASH and AGA’s Clinical Practice Update on dysplasia management in patients with IBD. If you haven’t already, please consider nominating yourself or a colleague for an AGA committee appointment – the deadline is Nov. 1, and this is a fantastic way to contribute to the national dialogue on important issues affecting frontline GI practice.

Megan A. Adams, MD, JD, MSc

Benjamin Cooper, MD, Director of Proton Therapy at NYU Langone Health, discusses how physicians who treat patients with non-small cell lung cancer (NSCLC) can use genetic profiling results to select effective therapy. Although the current list of therapies is not applicable to all genetic mutations, there are approved treatments for several biomarkers and agents targeting other biomarkers are in clinical trials. 

Dr. Cooper explains that biomarkers in NSCLC either boost the immune system’s capability to destroy oncogenes or they block driver and escape mutations that advance disease. 

Immunotherapies that target either PD-1 or PD-L1 are now mainstays of NSCLC treatment. To gauge whether these therapies have potential effectiveness for a given patient, oncologists test for the presence of PD-L1 in the tumor. Higher expression of PD-L1 indicates stronger potential response to therapy. 

Dr. Cooper then turns to a discussion of oncogenic driver mutations, focusing on EGFR, ALK, ROS1, BRAF, NTRK, RET, MET, KRAS, and HER2. Although there are hundreds of oncogenic driver mutations, not all are currently actionable. Effective therapy options have been available for EGFR, ALK, and BRAF for more than a decade, and treatments for other drivers such as NTRK, MET, KRAS, and HER2 have shown promising results in recent trials. 

-- 

Benjamin Cooper, MD is an Assistant Professor, Department of Radiation Oncology, Director, Proton Therapy Services, NYU Grossman School of Medicine,  

New York, New York 

Benjamin Cooper, MD, has disclosed the following relevant financial relationships: 

Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: AstraZeneca. 

Benjamin Cooper, MD, Director of Proton Therapy at NYU Langone Health, discusses how physicians who treat patients with non-small cell lung cancer (NSCLC) can use genetic profiling results to select effective therapy. Although the current list of therapies is not applicable to all genetic mutations, there are approved treatments for several biomarkers and agents targeting other biomarkers are in clinical trials. 

Dr. Cooper explains that biomarkers in NSCLC either boost the immune system’s capability to destroy oncogenes or they block driver and escape mutations that advance disease. 

Immunotherapies that target either PD-1 or PD-L1 are now mainstays of NSCLC treatment. To gauge whether these therapies have potential effectiveness for a given patient, oncologists test for the presence of PD-L1 in the tumor. Higher expression of PD-L1 indicates stronger potential response to therapy. 

Dr. Cooper then turns to a discussion of oncogenic driver mutations, focusing on EGFR, ALK, ROS1, BRAF, NTRK, RET, MET, KRAS, and HER2. Although there are hundreds of oncogenic driver mutations, not all are currently actionable. Effective therapy options have been available for EGFR, ALK, and BRAF for more than a decade, and treatments for other drivers such as NTRK, MET, KRAS, and HER2 have shown promising results in recent trials. 

-- 

Benjamin Cooper, MD is an Assistant Professor, Department of Radiation Oncology, Director, Proton Therapy Services, NYU Grossman School of Medicine,  

New York, New York 

Benjamin Cooper, MD, has disclosed the following relevant financial relationships: 

Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: AstraZeneca. 

Benjamin Cooper, MD, Director of Proton Therapy at NYU Langone Health, discusses how physicians who treat patients with non-small cell lung cancer (NSCLC) can use genetic profiling results to select effective therapy. Although the current list of therapies is not applicable to all genetic mutations, there are approved treatments for several biomarkers and agents targeting other biomarkers are in clinical trials. 

Dr. Cooper explains that biomarkers in NSCLC either boost the immune system’s capability to destroy oncogenes or they block driver and escape mutations that advance disease. 

Immunotherapies that target either PD-1 or PD-L1 are now mainstays of NSCLC treatment. To gauge whether these therapies have potential effectiveness for a given patient, oncologists test for the presence of PD-L1 in the tumor. Higher expression of PD-L1 indicates stronger potential response to therapy. 

Dr. Cooper then turns to a discussion of oncogenic driver mutations, focusing on EGFR, ALK, ROS1, BRAF, NTRK, RET, MET, KRAS, and HER2. Although there are hundreds of oncogenic driver mutations, not all are currently actionable. Effective therapy options have been available for EGFR, ALK, and BRAF for more than a decade, and treatments for other drivers such as NTRK, MET, KRAS, and HER2 have shown promising results in recent trials. 

-- 

Benjamin Cooper, MD is an Assistant Professor, Department of Radiation Oncology, Director, Proton Therapy Services, NYU Grossman School of Medicine,  

New York, New York 

Benjamin Cooper, MD, has disclosed the following relevant financial relationships: 

Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: AstraZeneca. 

Dr. Ponni V. Perumalswami is an Associate Professor of Internal Medicine in the Division of Gastroenterology and Hepatology at the University of Michigan; Ann Arbor VA Healthcare System. Dr. Perumalswami's areas of clinical interest include cirrhosis, acute/chronic liver diseases and liver transplantation. Her research program focuses on community outreach for hepatitis B and C screening and linking patients to care. 

Q: For patients with liver disease who live in underserved and vulnerable communities, what barriers to that care are more prominent or at the primary systemic-level?

Dr. Perumalswami: I think a major barrier has been our approach to thinking about these barriers, so I'm glad you are asking this question in terms of what the systemic-level barriers are rather than, for example, patient-level barriers. I'll use viral hepatitis as an example in terms of liver-disease care. I think for a very long time we've placed an unfair, onus on patients, leaving them to find their own care and to navigate existing system-level barriers such as language proficiency, health literacy, lack of insurance, and long distances to access specialists by themselves. This “do-it-yourself” approach has created a systemic-level barrier to finding specialists, and it remains a major problem. We would do a better job of improving access to care by re-thinking all barriers to care as system-and provider-level barriers rather than patient-level barriers because it is often the case that solutions that address systems barriers can address these issues.

Many specialists, like myself, are often geographically clustered at tertiary care and urban academic centers but the reality is that patients who are at risk for living with liver disease live all over, including rural areas, where fewer specialists practice. But advancements in treatments of certain liver diseases, such as hepatitis C virus (HCV), have made it possible for frontline community providers to treat patients. Expanding these patients' treatment options, in large part, is dependent on payer policy changes to allow treatment by non-specialists, reducing the cost of treatment and giving frontline workers the support they need so that they are more confident to offer treatment while differentiating the occasional patient who may need referral to a specialist.

Cost is also a systemic-level barrier for our underserved patients with liver disease and comes in many forms. Barriers related to cost include lack or type of insurance, traveling distances which also entails a cost for time (i.e. loss of wages, caregiver support), and cost of treatments. There are certain restrictions on HCV treatments that designate who can administer them and at what point in disease progression the therapy be introduced. These restrictions have been arbitrarily set by payers for treatments like direct-acting antivirals (DAA) and unfortunately dictate "when they can be obtained" and "who can prescribe them." Instead, we should spend time and effort to determine how we can have more providers practicing in different spaces, who might be equipped and motivated to provide treatment, and do it safely and easily.

Another barrier I will mention is the lack of integrated care for patients with certain liver diseases within healthcare systems. Notable examples include integrated care for those with alcohol-associated liver disease and viral hepatitis, who often have co-occurring mental health issues and substance use, addiction, or opioid use disorders. We need to think through how we can get integrated treatment and care to these patients, instead of making them come to us as individual specialists. By integrating medical care into behavioral health practices or other treatment settings, and perhaps by considering nontraditional treatment modalities, we can overcome barriers to care that are all too often siloed.

The last thing that I will mention with regards to patient-level barriers is that liver diseases and their care by providers has been very stigmatized, particularly for patients with underlying mental health and/or addiction disorders. These patients do not always feel comfortable coming to see clinicians in their practices so we must recognize that our offices may be stigmatized places for some patients with liver disease. Because of this, it is vital to think about how we can integrate care into trusted spaces for patient populations who might be at risk or are living with liver disease.

Q: What aspects of these barriers have you focused on to improve screening and links to care in communities at risk?

Dr. Perumalswami: A lot of my work is focused on patients in populations who are at risk for viral hepatitis and on screening them, educating them, and linking them to care in their communities. The challenge in successfully treating patients with a liver disease is that most liver diseases remain silent until they've progressed to a very advanced stage. Certain populations are at a higher risk for contracting these diseases compared to others. For example, with hepatitis B virus, we know that foreign-born populations have a higher infection rate, and how and when they seek care might be very different in terms of being symptom-driven versus preventive care as a result of cultural factors around health seeking behaviors. Our team has attempted to take a more proactive approach; first, to understand who might be at risk, and second, to try to bring screening to trusted places where patients can easily access care. We have found this proactive approach to be very successful in terms of identifying people who are not yet diagnosed with liver disease and then linking them into care.

The first step is knowing which populations you want to target with respect to individual types of liver disease, then working with community partners to bring screening out into the community. Obviously, the challenging part is getting people linked into care. As stated previously, many liver diseases in their earlier stages stay silent and manifest without symptoms, thus why it is vital to offer at-risk patients testing or screening. 

The next step is to raise patient awareness and provide education as to why it is important to seek care; to get a thorough evaluation in terms of the extent of the liver disease and how to best manage and treat it, long term. For example, we have found that care coordination works very well with patients living with HCV. For patients with hepatitis B, we have found that culturally informed patient navigation services are very helpful, so we work with peers in the community who speak the same language and who come from the same communities as the patients identified as at-risk. This combined strategy of testing and then linking to care has been very successful.

I will say an important part of the care-coordination piece is addressing the competing priorities that patients have in their lives. For example, if they need housing, we refer them to housing services; if they have food insecurities, we try to address the need. Once you address their basic determinants of health, you have established a basis for trust while helping patients contend with important competing priorities. This way, your team has enabled potential patients to prioritize and engage in health care.

Q: How have you integrated HCV treatment into harm reduction and opioid use disorder settings?

Dr. Perumalswami: I am fortunate to be involved with a program here in Michigan whose goal is to increase HCV treatment through an open access, HCV consultation program through the Michigan Opioid Collaborative. The premise is to find motivated, interested providers who want to learn how to offer HCV treatment to patients in their communities; the majority of these providers are in rural parts of Michigan. In this setting, we are working with frontline medical personnel in the community, many of whom are either addiction providers or are offering opioid use disorder treatment, and who are also seeing HCV patients. We have set up an open-case consulting program where providers can submit cases for review with guidance from hepatologists. Attendance is optional and we meet for an hour, every other week and we talk through cases in more detail as a group. The result is that the providers have reported that they feel less isolated doing this as a team, having a place to discuss cases and work through practical challenges that can arise with this patient base. While HCV treatment advances have made great strides, many providers want reassurance or guidance in terms how to implement these programs so as a group, we walk through a few cases, demonstrate how to check for drug-drug interactions and how to perform fibrosis assessments. After these providers go through this training, they become more comfortable giving treatment on their own.

The second project, which I have also been fortunate to be involved in, is led by my colleague Dr. Jeffrey Weiss at Mount Sinai Hospital and is located at a syringe exchange program in a Brooklyn, New York. Here, patients attend receive in-person and/or telemedicine-based HCV treatment, which is a new model of care for us. While it has produced a different set of challenges in terms of engaging and bringing treatment to patients in a new space, it has been a great way to meet our objectives of helping patients to be treated where they are comfortable accessing care and services.

Q: Has the pandemic created any new challenges in treating at risk or special populations?

Dr. Perumalswami: The pandemic presented many new challenges. The primary impact that COVID-19 has had on our patients has been with the disruption in care; particularly for those patients who already found it challenging to seek and receive care. For patients who benefitted from following a routine, other pandemic-related challenges were the restrictions placed on our practices, and the reduced hours patients had to contend with access services and treatments at places such as syringe exchange programs or methadone programs.

Many of our patients have expressed feeling isolated as they are not able to get the same type of support that they were previously receiving. The decreases in viral hepatitis outreach, in screening in the community, and in practices resulted in a decrease in diagnosis and treatment.

We have also heard numerous discussions with regards to better reimbursements for phone call and telehealth sessions, but we must recognize that those things are not accessible to all patients. Many of our most vulnerable populations, do not have working phones, stable housing, or smart devices to access telehealth, so while there have been technological advances that can provide access to care and better reimbursement procedures, there are still many limitations that our patients are facing.

(AGA applauds researchers who are working to raise our awareness of health disparities in digestive diseases. AGA is committed to addressing this important societal issue head on. Learn more about AGA’s commitment through the AGA Equity Project).

Dr. Ponni V. Perumalswami is an Associate Professor of Internal Medicine in the Division of Gastroenterology and Hepatology at the University of Michigan; Ann Arbor VA Healthcare System. Dr. Perumalswami's areas of clinical interest include cirrhosis, acute/chronic liver diseases and liver transplantation. Her research program focuses on community outreach for hepatitis B and C screening and linking patients to care. 

Q: For patients with liver disease who live in underserved and vulnerable communities, what barriers to that care are more prominent or at the primary systemic-level?

Dr. Perumalswami: I think a major barrier has been our approach to thinking about these barriers, so I'm glad you are asking this question in terms of what the systemic-level barriers are rather than, for example, patient-level barriers. I'll use viral hepatitis as an example in terms of liver-disease care. I think for a very long time we've placed an unfair, onus on patients, leaving them to find their own care and to navigate existing system-level barriers such as language proficiency, health literacy, lack of insurance, and long distances to access specialists by themselves. This “do-it-yourself” approach has created a systemic-level barrier to finding specialists, and it remains a major problem. We would do a better job of improving access to care by re-thinking all barriers to care as system-and provider-level barriers rather than patient-level barriers because it is often the case that solutions that address systems barriers can address these issues.

Many specialists, like myself, are often geographically clustered at tertiary care and urban academic centers but the reality is that patients who are at risk for living with liver disease live all over, including rural areas, where fewer specialists practice. But advancements in treatments of certain liver diseases, such as hepatitis C virus (HCV), have made it possible for frontline community providers to treat patients. Expanding these patients' treatment options, in large part, is dependent on payer policy changes to allow treatment by non-specialists, reducing the cost of treatment and giving frontline workers the support they need so that they are more confident to offer treatment while differentiating the occasional patient who may need referral to a specialist.

Cost is also a systemic-level barrier for our underserved patients with liver disease and comes in many forms. Barriers related to cost include lack or type of insurance, traveling distances which also entails a cost for time (i.e. loss of wages, caregiver support), and cost of treatments. There are certain restrictions on HCV treatments that designate who can administer them and at what point in disease progression the therapy be introduced. These restrictions have been arbitrarily set by payers for treatments like direct-acting antivirals (DAA) and unfortunately dictate "when they can be obtained" and "who can prescribe them." Instead, we should spend time and effort to determine how we can have more providers practicing in different spaces, who might be equipped and motivated to provide treatment, and do it safely and easily.

Another barrier I will mention is the lack of integrated care for patients with certain liver diseases within healthcare systems. Notable examples include integrated care for those with alcohol-associated liver disease and viral hepatitis, who often have co-occurring mental health issues and substance use, addiction, or opioid use disorders. We need to think through how we can get integrated treatment and care to these patients, instead of making them come to us as individual specialists. By integrating medical care into behavioral health practices or other treatment settings, and perhaps by considering nontraditional treatment modalities, we can overcome barriers to care that are all too often siloed.

The last thing that I will mention with regards to patient-level barriers is that liver diseases and their care by providers has been very stigmatized, particularly for patients with underlying mental health and/or addiction disorders. These patients do not always feel comfortable coming to see clinicians in their practices so we must recognize that our offices may be stigmatized places for some patients with liver disease. Because of this, it is vital to think about how we can integrate care into trusted spaces for patient populations who might be at risk or are living with liver disease.

Q: What aspects of these barriers have you focused on to improve screening and links to care in communities at risk?

Dr. Perumalswami: A lot of my work is focused on patients in populations who are at risk for viral hepatitis and on screening them, educating them, and linking them to care in their communities. The challenge in successfully treating patients with a liver disease is that most liver diseases remain silent until they've progressed to a very advanced stage. Certain populations are at a higher risk for contracting these diseases compared to others. For example, with hepatitis B virus, we know that foreign-born populations have a higher infection rate, and how and when they seek care might be very different in terms of being symptom-driven versus preventive care as a result of cultural factors around health seeking behaviors. Our team has attempted to take a more proactive approach; first, to understand who might be at risk, and second, to try to bring screening to trusted places where patients can easily access care. We have found this proactive approach to be very successful in terms of identifying people who are not yet diagnosed with liver disease and then linking them into care.

The first step is knowing which populations you want to target with respect to individual types of liver disease, then working with community partners to bring screening out into the community. Obviously, the challenging part is getting people linked into care. As stated previously, many liver diseases in their earlier stages stay silent and manifest without symptoms, thus why it is vital to offer at-risk patients testing or screening. 

The next step is to raise patient awareness and provide education as to why it is important to seek care; to get a thorough evaluation in terms of the extent of the liver disease and how to best manage and treat it, long term. For example, we have found that care coordination works very well with patients living with HCV. For patients with hepatitis B, we have found that culturally informed patient navigation services are very helpful, so we work with peers in the community who speak the same language and who come from the same communities as the patients identified as at-risk. This combined strategy of testing and then linking to care has been very successful.

I will say an important part of the care-coordination piece is addressing the competing priorities that patients have in their lives. For example, if they need housing, we refer them to housing services; if they have food insecurities, we try to address the need. Once you address their basic determinants of health, you have established a basis for trust while helping patients contend with important competing priorities. This way, your team has enabled potential patients to prioritize and engage in health care.

Q: How have you integrated HCV treatment into harm reduction and opioid use disorder settings?

Dr. Perumalswami: I am fortunate to be involved with a program here in Michigan whose goal is to increase HCV treatment through an open access, HCV consultation program through the Michigan Opioid Collaborative. The premise is to find motivated, interested providers who want to learn how to offer HCV treatment to patients in their communities; the majority of these providers are in rural parts of Michigan. In this setting, we are working with frontline medical personnel in the community, many of whom are either addiction providers or are offering opioid use disorder treatment, and who are also seeing HCV patients. We have set up an open-case consulting program where providers can submit cases for review with guidance from hepatologists. Attendance is optional and we meet for an hour, every other week and we talk through cases in more detail as a group. The result is that the providers have reported that they feel less isolated doing this as a team, having a place to discuss cases and work through practical challenges that can arise with this patient base. While HCV treatment advances have made great strides, many providers want reassurance or guidance in terms how to implement these programs so as a group, we walk through a few cases, demonstrate how to check for drug-drug interactions and how to perform fibrosis assessments. After these providers go through this training, they become more comfortable giving treatment on their own.

The second project, which I have also been fortunate to be involved in, is led by my colleague Dr. Jeffrey Weiss at Mount Sinai Hospital and is located at a syringe exchange program in a Brooklyn, New York. Here, patients attend receive in-person and/or telemedicine-based HCV treatment, which is a new model of care for us. While it has produced a different set of challenges in terms of engaging and bringing treatment to patients in a new space, it has been a great way to meet our objectives of helping patients to be treated where they are comfortable accessing care and services.

Q: Has the pandemic created any new challenges in treating at risk or special populations?

Dr. Perumalswami: The pandemic presented many new challenges. The primary impact that COVID-19 has had on our patients has been with the disruption in care; particularly for those patients who already found it challenging to seek and receive care. For patients who benefitted from following a routine, other pandemic-related challenges were the restrictions placed on our practices, and the reduced hours patients had to contend with access services and treatments at places such as syringe exchange programs or methadone programs.

Many of our patients have expressed feeling isolated as they are not able to get the same type of support that they were previously receiving. The decreases in viral hepatitis outreach, in screening in the community, and in practices resulted in a decrease in diagnosis and treatment.

We have also heard numerous discussions with regards to better reimbursements for phone call and telehealth sessions, but we must recognize that those things are not accessible to all patients. Many of our most vulnerable populations, do not have working phones, stable housing, or smart devices to access telehealth, so while there have been technological advances that can provide access to care and better reimbursement procedures, there are still many limitations that our patients are facing.

(AGA applauds researchers who are working to raise our awareness of health disparities in digestive diseases. AGA is committed to addressing this important societal issue head on. Learn more about AGA’s commitment through the AGA Equity Project).

Dr. Ponni V. Perumalswami is an Associate Professor of Internal Medicine in the Division of Gastroenterology and Hepatology at the University of Michigan; Ann Arbor VA Healthcare System. Dr. Perumalswami's areas of clinical interest include cirrhosis, acute/chronic liver diseases and liver transplantation. Her research program focuses on community outreach for hepatitis B and C screening and linking patients to care. 

Q: For patients with liver disease who live in underserved and vulnerable communities, what barriers to that care are more prominent or at the primary systemic-level?

Dr. Perumalswami: I think a major barrier has been our approach to thinking about these barriers, so I'm glad you are asking this question in terms of what the systemic-level barriers are rather than, for example, patient-level barriers. I'll use viral hepatitis as an example in terms of liver-disease care. I think for a very long time we've placed an unfair, onus on patients, leaving them to find their own care and to navigate existing system-level barriers such as language proficiency, health literacy, lack of insurance, and long distances to access specialists by themselves. This “do-it-yourself” approach has created a systemic-level barrier to finding specialists, and it remains a major problem. We would do a better job of improving access to care by re-thinking all barriers to care as system-and provider-level barriers rather than patient-level barriers because it is often the case that solutions that address systems barriers can address these issues.

Many specialists, like myself, are often geographically clustered at tertiary care and urban academic centers but the reality is that patients who are at risk for living with liver disease live all over, including rural areas, where fewer specialists practice. But advancements in treatments of certain liver diseases, such as hepatitis C virus (HCV), have made it possible for frontline community providers to treat patients. Expanding these patients' treatment options, in large part, is dependent on payer policy changes to allow treatment by non-specialists, reducing the cost of treatment and giving frontline workers the support they need so that they are more confident to offer treatment while differentiating the occasional patient who may need referral to a specialist.

Cost is also a systemic-level barrier for our underserved patients with liver disease and comes in many forms. Barriers related to cost include lack or type of insurance, traveling distances which also entails a cost for time (i.e. loss of wages, caregiver support), and cost of treatments. There are certain restrictions on HCV treatments that designate who can administer them and at what point in disease progression the therapy be introduced. These restrictions have been arbitrarily set by payers for treatments like direct-acting antivirals (DAA) and unfortunately dictate "when they can be obtained" and "who can prescribe them." Instead, we should spend time and effort to determine how we can have more providers practicing in different spaces, who might be equipped and motivated to provide treatment, and do it safely and easily.

Another barrier I will mention is the lack of integrated care for patients with certain liver diseases within healthcare systems. Notable examples include integrated care for those with alcohol-associated liver disease and viral hepatitis, who often have co-occurring mental health issues and substance use, addiction, or opioid use disorders. We need to think through how we can get integrated treatment and care to these patients, instead of making them come to us as individual specialists. By integrating medical care into behavioral health practices or other treatment settings, and perhaps by considering nontraditional treatment modalities, we can overcome barriers to care that are all too often siloed.

The last thing that I will mention with regards to patient-level barriers is that liver diseases and their care by providers has been very stigmatized, particularly for patients with underlying mental health and/or addiction disorders. These patients do not always feel comfortable coming to see clinicians in their practices so we must recognize that our offices may be stigmatized places for some patients with liver disease. Because of this, it is vital to think about how we can integrate care into trusted spaces for patient populations who might be at risk or are living with liver disease.

Q: What aspects of these barriers have you focused on to improve screening and links to care in communities at risk?

Dr. Perumalswami: A lot of my work is focused on patients in populations who are at risk for viral hepatitis and on screening them, educating them, and linking them to care in their communities. The challenge in successfully treating patients with a liver disease is that most liver diseases remain silent until they've progressed to a very advanced stage. Certain populations are at a higher risk for contracting these diseases compared to others. For example, with hepatitis B virus, we know that foreign-born populations have a higher infection rate, and how and when they seek care might be very different in terms of being symptom-driven versus preventive care as a result of cultural factors around health seeking behaviors. Our team has attempted to take a more proactive approach; first, to understand who might be at risk, and second, to try to bring screening to trusted places where patients can easily access care. We have found this proactive approach to be very successful in terms of identifying people who are not yet diagnosed with liver disease and then linking them into care.

The first step is knowing which populations you want to target with respect to individual types of liver disease, then working with community partners to bring screening out into the community. Obviously, the challenging part is getting people linked into care. As stated previously, many liver diseases in their earlier stages stay silent and manifest without symptoms, thus why it is vital to offer at-risk patients testing or screening. 

The next step is to raise patient awareness and provide education as to why it is important to seek care; to get a thorough evaluation in terms of the extent of the liver disease and how to best manage and treat it, long term. For example, we have found that care coordination works very well with patients living with HCV. For patients with hepatitis B, we have found that culturally informed patient navigation services are very helpful, so we work with peers in the community who speak the same language and who come from the same communities as the patients identified as at-risk. This combined strategy of testing and then linking to care has been very successful.

I will say an important part of the care-coordination piece is addressing the competing priorities that patients have in their lives. For example, if they need housing, we refer them to housing services; if they have food insecurities, we try to address the need. Once you address their basic determinants of health, you have established a basis for trust while helping patients contend with important competing priorities. This way, your team has enabled potential patients to prioritize and engage in health care.

Q: How have you integrated HCV treatment into harm reduction and opioid use disorder settings?

Dr. Perumalswami: I am fortunate to be involved with a program here in Michigan whose goal is to increase HCV treatment through an open access, HCV consultation program through the Michigan Opioid Collaborative. The premise is to find motivated, interested providers who want to learn how to offer HCV treatment to patients in their communities; the majority of these providers are in rural parts of Michigan. In this setting, we are working with frontline medical personnel in the community, many of whom are either addiction providers or are offering opioid use disorder treatment, and who are also seeing HCV patients. We have set up an open-case consulting program where providers can submit cases for review with guidance from hepatologists. Attendance is optional and we meet for an hour, every other week and we talk through cases in more detail as a group. The result is that the providers have reported that they feel less isolated doing this as a team, having a place to discuss cases and work through practical challenges that can arise with this patient base. While HCV treatment advances have made great strides, many providers want reassurance or guidance in terms how to implement these programs so as a group, we walk through a few cases, demonstrate how to check for drug-drug interactions and how to perform fibrosis assessments. After these providers go through this training, they become more comfortable giving treatment on their own.

The second project, which I have also been fortunate to be involved in, is led by my colleague Dr. Jeffrey Weiss at Mount Sinai Hospital and is located at a syringe exchange program in a Brooklyn, New York. Here, patients attend receive in-person and/or telemedicine-based HCV treatment, which is a new model of care for us. While it has produced a different set of challenges in terms of engaging and bringing treatment to patients in a new space, it has been a great way to meet our objectives of helping patients to be treated where they are comfortable accessing care and services.

Q: Has the pandemic created any new challenges in treating at risk or special populations?

Dr. Perumalswami: The pandemic presented many new challenges. The primary impact that COVID-19 has had on our patients has been with the disruption in care; particularly for those patients who already found it challenging to seek and receive care. For patients who benefitted from following a routine, other pandemic-related challenges were the restrictions placed on our practices, and the reduced hours patients had to contend with access services and treatments at places such as syringe exchange programs or methadone programs.

Many of our patients have expressed feeling isolated as they are not able to get the same type of support that they were previously receiving. The decreases in viral hepatitis outreach, in screening in the community, and in practices resulted in a decrease in diagnosis and treatment.

We have also heard numerous discussions with regards to better reimbursements for phone call and telehealth sessions, but we must recognize that those things are not accessible to all patients. Many of our most vulnerable populations, do not have working phones, stable housing, or smart devices to access telehealth, so while there have been technological advances that can provide access to care and better reimbursement procedures, there are still many limitations that our patients are facing.

(AGA applauds researchers who are working to raise our awareness of health disparities in digestive diseases. AGA is committed to addressing this important societal issue head on. Learn more about AGA’s commitment through the AGA Equity Project).