Obsessive-Compulsive Disorder

Mothers with obsessive-compulsive disorder (OCD) are more likely to have adverse pregnancy, delivery, and neonatal outcomes than are those without the disorder, according to new research.

In an observational study that followed almost 3 million pregnancies in two countries over 20 years, children of women with OCD were at increased risk for low Apgar score at 5 minutes in Sweden (adjusted risk ratio [aRR], 1.62) and British Columbia, Canada (aRR, 2.30). The risks for adverse outcomes were greater among women with OCD who were taking serotonin reuptake inhibitors (SRIs), compared with those who were not.

“To me, the most relevant things to consider are the clinical implications of these findings,” lead author Lorena Fernández de la Cruz, PhD, principal researcher at Karolinska Institute in Stockholm, told this news organization. She noted that some of the outcomes, such as preeclampsia, can be prevented or improved with collaboration among clinicians and increased monitoring.

The study was published online in JAMA Network Open.
 

Increased risk

OCD affects roughly 1%-3% of the population. Although it is sometimes seen as a mild psychiatric disorder, OCD entails a range of adverse outcomes, and this research suggests that the adverse outcomes extend to maternal health, Dr. Fernández de la Cruz stressed.

The researchers drew data from population registers in Sweden and British Columbia for all singleton births over a roughly 20-year period ending in 2019, with subcohorts identified by formal OCD diagnosis and exposure to SRIs within 30 days before conception. Statistical analyses were performed on a range of pregnancy, delivery, and neonatal outcomes.

In an analysis adjusted for common risk factors such as age, BMI, and smoking, Swedish women with OCD had elevated risk for several adverse outcomes, including a 40% increased risk for gestational diabetes. In British Columbia, fewer adverse pregnancy outcomes for women were associated with an OCD diagnosis.

The study, which also tracked neonatal outcomes, found that infants of mothers with OCD in both Sweden and British Columbia had higher rates of preterm birth (Sweden: aRR, 1.33; BC: aRR, 1.58), low birth weight (Sweden: aRR, 1.28; BC: aRR, 1.40), and neonatal respiratory distress (Sweden: aRR, 1.63; BC: aRR, 1.47).

These results, the authors say, show a need for more monitoring of maternal OCD and collaboration among obstetricians and psychologists. “All this evidence shows that OCD should be detected and treated so that adverse outcomes can be prevented or properly handled,” said Dr. Fernández de la Cruz.
 

SRI medication

SRIs are frequently used to treat OCD. The subclass of selective SRIs, which includes common antidepressants, has been associated with worsened pregnancy outcomes, but it remains unclear whether all SRIs increase pregnancy risks.

To understand the role of SRIs better in this study, the authors compared the outcomes for women taking SRIs and those who were not prescribed the medication, which is a novel aspect of the study, according to Dr. Fernández de la Cruz. Women who took the medication were at greater risk for several adverse outcomes, although all women with an OCD diagnosis were at higher risk than were those without the condition. The investigators hope to continue studying the role of OCD medication during pregnancy in more detail.

The rates of SRI use varied between the two cohorts: 81% of Canadian patients took the medication, compared with 37% of Swedish patients. The disparate rates, along with other clinical practices, may have contributed to differences in outcomes for the two cohorts.

It is also important to bear in mind, however, that patients taking the medication tend to have more severe cases of OCD, said Dr. Fernández de la Cruz. Thus, the increased risk may or may not result from the medication itself. “It is important to understand that there may be other variables besides medication explaining why one group had higher risks than the other,” she said.
 

‘Multifactorial’ reasons

In addition to medication, other factors may play a role in the association between OCD and adverse pregnancy and neonatal outcomes, including genetics, lifestyle, and psychiatric comorbidities. The authors addressed some of these potential confounders in additional analyses, including sister and cousin comparisons in the Swedish arm of the study, which found weakened associations, compared with population wide statistics.

Commenting on the research, Benicio Frey, PhD, professor of psychiatry and behavioral neurosciences at McMaster University in Hamilton, Ont., said that acknowledging these confounding factors is a strength of the study. Psychiatric conditions such as depression and anxiety are common among patients with OCD. Of the patients with OCD in this study, 72% and 51% had other psychiatric diagnoses in Sweden and British Columbia, respectively. About 7% of the women without OCD had one of these conditions.

However, Dr. Frey said that the effect of adjusting for psychiatric comorbidities on some outcomes should be stated more clearly. “I see a clear difference,” he said. The relative risk for gestational diabetes among the Swedish cohort, for example, drops from a 40% increased risk to 19% increased when adjusted for mood and anxiety disorders. 

Regardless of the cause, the results are important and demonstrate a need to provide additional care for pregnant women with psychiatric conditions, said Dr. Frey. “The important take-home message for policymakers and health care providers is to make sure that they assess for OCD and then monitor those individuals very closely. What I would suggest as a caution is that the reasons behind it are multifactorial.”

The study was supported by the Swedish Research Council for Health, Working Life, and Welfare and by the Canadian Institute of Health Research. Dr. Fernández de la Cruz and Dr. Frey reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Mothers with obsessive-compulsive disorder (OCD) are more likely to have adverse pregnancy, delivery, and neonatal outcomes than are those without the disorder, according to new research.

In an observational study that followed almost 3 million pregnancies in two countries over 20 years, children of women with OCD were at increased risk for low Apgar score at 5 minutes in Sweden (adjusted risk ratio [aRR], 1.62) and British Columbia, Canada (aRR, 2.30). The risks for adverse outcomes were greater among women with OCD who were taking serotonin reuptake inhibitors (SRIs), compared with those who were not.

“To me, the most relevant things to consider are the clinical implications of these findings,” lead author Lorena Fernández de la Cruz, PhD, principal researcher at Karolinska Institute in Stockholm, told this news organization. She noted that some of the outcomes, such as preeclampsia, can be prevented or improved with collaboration among clinicians and increased monitoring.

The study was published online in JAMA Network Open.
 

Increased risk

OCD affects roughly 1%-3% of the population. Although it is sometimes seen as a mild psychiatric disorder, OCD entails a range of adverse outcomes, and this research suggests that the adverse outcomes extend to maternal health, Dr. Fernández de la Cruz stressed.

The researchers drew data from population registers in Sweden and British Columbia for all singleton births over a roughly 20-year period ending in 2019, with subcohorts identified by formal OCD diagnosis and exposure to SRIs within 30 days before conception. Statistical analyses were performed on a range of pregnancy, delivery, and neonatal outcomes.

In an analysis adjusted for common risk factors such as age, BMI, and smoking, Swedish women with OCD had elevated risk for several adverse outcomes, including a 40% increased risk for gestational diabetes. In British Columbia, fewer adverse pregnancy outcomes for women were associated with an OCD diagnosis.

The study, which also tracked neonatal outcomes, found that infants of mothers with OCD in both Sweden and British Columbia had higher rates of preterm birth (Sweden: aRR, 1.33; BC: aRR, 1.58), low birth weight (Sweden: aRR, 1.28; BC: aRR, 1.40), and neonatal respiratory distress (Sweden: aRR, 1.63; BC: aRR, 1.47).

These results, the authors say, show a need for more monitoring of maternal OCD and collaboration among obstetricians and psychologists. “All this evidence shows that OCD should be detected and treated so that adverse outcomes can be prevented or properly handled,” said Dr. Fernández de la Cruz.
 

SRI medication

SRIs are frequently used to treat OCD. The subclass of selective SRIs, which includes common antidepressants, has been associated with worsened pregnancy outcomes, but it remains unclear whether all SRIs increase pregnancy risks.

To understand the role of SRIs better in this study, the authors compared the outcomes for women taking SRIs and those who were not prescribed the medication, which is a novel aspect of the study, according to Dr. Fernández de la Cruz. Women who took the medication were at greater risk for several adverse outcomes, although all women with an OCD diagnosis were at higher risk than were those without the condition. The investigators hope to continue studying the role of OCD medication during pregnancy in more detail.

The rates of SRI use varied between the two cohorts: 81% of Canadian patients took the medication, compared with 37% of Swedish patients. The disparate rates, along with other clinical practices, may have contributed to differences in outcomes for the two cohorts.

It is also important to bear in mind, however, that patients taking the medication tend to have more severe cases of OCD, said Dr. Fernández de la Cruz. Thus, the increased risk may or may not result from the medication itself. “It is important to understand that there may be other variables besides medication explaining why one group had higher risks than the other,” she said.
 

‘Multifactorial’ reasons

In addition to medication, other factors may play a role in the association between OCD and adverse pregnancy and neonatal outcomes, including genetics, lifestyle, and psychiatric comorbidities. The authors addressed some of these potential confounders in additional analyses, including sister and cousin comparisons in the Swedish arm of the study, which found weakened associations, compared with population wide statistics.

Commenting on the research, Benicio Frey, PhD, professor of psychiatry and behavioral neurosciences at McMaster University in Hamilton, Ont., said that acknowledging these confounding factors is a strength of the study. Psychiatric conditions such as depression and anxiety are common among patients with OCD. Of the patients with OCD in this study, 72% and 51% had other psychiatric diagnoses in Sweden and British Columbia, respectively. About 7% of the women without OCD had one of these conditions.

However, Dr. Frey said that the effect of adjusting for psychiatric comorbidities on some outcomes should be stated more clearly. “I see a clear difference,” he said. The relative risk for gestational diabetes among the Swedish cohort, for example, drops from a 40% increased risk to 19% increased when adjusted for mood and anxiety disorders. 

Regardless of the cause, the results are important and demonstrate a need to provide additional care for pregnant women with psychiatric conditions, said Dr. Frey. “The important take-home message for policymakers and health care providers is to make sure that they assess for OCD and then monitor those individuals very closely. What I would suggest as a caution is that the reasons behind it are multifactorial.”

The study was supported by the Swedish Research Council for Health, Working Life, and Welfare and by the Canadian Institute of Health Research. Dr. Fernández de la Cruz and Dr. Frey reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Mothers with obsessive-compulsive disorder (OCD) are more likely to have adverse pregnancy, delivery, and neonatal outcomes than are those without the disorder, according to new research.

In an observational study that followed almost 3 million pregnancies in two countries over 20 years, children of women with OCD were at increased risk for low Apgar score at 5 minutes in Sweden (adjusted risk ratio [aRR], 1.62) and British Columbia, Canada (aRR, 2.30). The risks for adverse outcomes were greater among women with OCD who were taking serotonin reuptake inhibitors (SRIs), compared with those who were not.

“To me, the most relevant things to consider are the clinical implications of these findings,” lead author Lorena Fernández de la Cruz, PhD, principal researcher at Karolinska Institute in Stockholm, told this news organization. She noted that some of the outcomes, such as preeclampsia, can be prevented or improved with collaboration among clinicians and increased monitoring.

The study was published online in JAMA Network Open.
 

Increased risk

OCD affects roughly 1%-3% of the population. Although it is sometimes seen as a mild psychiatric disorder, OCD entails a range of adverse outcomes, and this research suggests that the adverse outcomes extend to maternal health, Dr. Fernández de la Cruz stressed.

The researchers drew data from population registers in Sweden and British Columbia for all singleton births over a roughly 20-year period ending in 2019, with subcohorts identified by formal OCD diagnosis and exposure to SRIs within 30 days before conception. Statistical analyses were performed on a range of pregnancy, delivery, and neonatal outcomes.

In an analysis adjusted for common risk factors such as age, BMI, and smoking, Swedish women with OCD had elevated risk for several adverse outcomes, including a 40% increased risk for gestational diabetes. In British Columbia, fewer adverse pregnancy outcomes for women were associated with an OCD diagnosis.

The study, which also tracked neonatal outcomes, found that infants of mothers with OCD in both Sweden and British Columbia had higher rates of preterm birth (Sweden: aRR, 1.33; BC: aRR, 1.58), low birth weight (Sweden: aRR, 1.28; BC: aRR, 1.40), and neonatal respiratory distress (Sweden: aRR, 1.63; BC: aRR, 1.47).

These results, the authors say, show a need for more monitoring of maternal OCD and collaboration among obstetricians and psychologists. “All this evidence shows that OCD should be detected and treated so that adverse outcomes can be prevented or properly handled,” said Dr. Fernández de la Cruz.
 

SRI medication

SRIs are frequently used to treat OCD. The subclass of selective SRIs, which includes common antidepressants, has been associated with worsened pregnancy outcomes, but it remains unclear whether all SRIs increase pregnancy risks.

To understand the role of SRIs better in this study, the authors compared the outcomes for women taking SRIs and those who were not prescribed the medication, which is a novel aspect of the study, according to Dr. Fernández de la Cruz. Women who took the medication were at greater risk for several adverse outcomes, although all women with an OCD diagnosis were at higher risk than were those without the condition. The investigators hope to continue studying the role of OCD medication during pregnancy in more detail.

The rates of SRI use varied between the two cohorts: 81% of Canadian patients took the medication, compared with 37% of Swedish patients. The disparate rates, along with other clinical practices, may have contributed to differences in outcomes for the two cohorts.

It is also important to bear in mind, however, that patients taking the medication tend to have more severe cases of OCD, said Dr. Fernández de la Cruz. Thus, the increased risk may or may not result from the medication itself. “It is important to understand that there may be other variables besides medication explaining why one group had higher risks than the other,” she said.
 

‘Multifactorial’ reasons

In addition to medication, other factors may play a role in the association between OCD and adverse pregnancy and neonatal outcomes, including genetics, lifestyle, and psychiatric comorbidities. The authors addressed some of these potential confounders in additional analyses, including sister and cousin comparisons in the Swedish arm of the study, which found weakened associations, compared with population wide statistics.

Commenting on the research, Benicio Frey, PhD, professor of psychiatry and behavioral neurosciences at McMaster University in Hamilton, Ont., said that acknowledging these confounding factors is a strength of the study. Psychiatric conditions such as depression and anxiety are common among patients with OCD. Of the patients with OCD in this study, 72% and 51% had other psychiatric diagnoses in Sweden and British Columbia, respectively. About 7% of the women without OCD had one of these conditions.

However, Dr. Frey said that the effect of adjusting for psychiatric comorbidities on some outcomes should be stated more clearly. “I see a clear difference,” he said. The relative risk for gestational diabetes among the Swedish cohort, for example, drops from a 40% increased risk to 19% increased when adjusted for mood and anxiety disorders. 

Regardless of the cause, the results are important and demonstrate a need to provide additional care for pregnant women with psychiatric conditions, said Dr. Frey. “The important take-home message for policymakers and health care providers is to make sure that they assess for OCD and then monitor those individuals very closely. What I would suggest as a caution is that the reasons behind it are multifactorial.”

The study was supported by the Swedish Research Council for Health, Working Life, and Welfare and by the Canadian Institute of Health Research. Dr. Fernández de la Cruz and Dr. Frey reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

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

Neuromodulation treatments

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

Box

Electroconvulsive therapy

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

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

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

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

Transcranial magnetic stimulation

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

Continue to: An unintended outcome...

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

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

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

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

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

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

Continue to: Transcranial direct current stimulation

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

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

Deep brain stimulation

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

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

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

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

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

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

Vagus nerve stimulation

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

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

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

Cranial electrical stimulation

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

Continue to: Other neuromodulation techniques

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

Acupuncture

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

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

Challenges and complications

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

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

Bottom Line

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

Related Resources

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

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

Neuromodulation treatments

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

Box

Electroconvulsive therapy

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

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

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

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

Transcranial magnetic stimulation

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

Continue to: An unintended outcome...

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

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

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

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

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

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

Continue to: Transcranial direct current stimulation

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

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

Deep brain stimulation

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

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

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

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

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

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

Vagus nerve stimulation

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

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

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

Cranial electrical stimulation

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

Continue to: Other neuromodulation techniques

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

Acupuncture

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

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

Challenges and complications

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

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

Bottom Line

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

Related Resources

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

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

Neuromodulation treatments

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

Box

Electroconvulsive therapy

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

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

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

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

Transcranial magnetic stimulation

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

Continue to: An unintended outcome...

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

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

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

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

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

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

Continue to: Transcranial direct current stimulation

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

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

Deep brain stimulation

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

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

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

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

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

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

Vagus nerve stimulation

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

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

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

Cranial electrical stimulation

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

Continue to: Other neuromodulation techniques

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

Acupuncture

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

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

Challenges and complications

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

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

Bottom Line

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

Related Resources

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

The explosion of interest in interventional psychiatry is highlighted by 2 recent reviews published in Current Psychiatry.^1,2 While this is clearly desirable, the rate of growth has created problems. Expansion of interventional modalities has outpaced the training and education of our residents and practicing psychiatrists.

Psychiatry’s failure to address these changes would be a dire error, as psychiatrists could lose control of our field’s advances and growth. But this creates an even larger question: what are the next steps we need to take? We believe interventional psychiatry must be recognized as its own psychiatric subspeciality, receive greater emphasis in psychiatry residency training, and be subject to standardization by professional organizations.

Psychiatry has incorporated procedures into patient care for almost 100 years, starting with electroconvulsive therapy (ECT) and insulin shock therapy in the 1930s.^3,4 However, in the last 10 years, the rapid expansion of FDA approvals of neuromodulation procedures to treat psychiatric conditions (including vagus nerve stimulation in 2005, transcranial magnetic stimulation [TMS] in 2008, and the device exception granted for the use of deep brain stimulation in 2009) has produced the moniker “interventional psychiatry” for this unofficial psychiatric subspeciality.^5,6

If we are to establish interventional psychiatry as a recognized subspeciality, it is important to create a universally accepted definition. We propose the term refer to therapeutic techniques or processes that may or may not be invasive but require special training to perform. Additionally, interventional psychiatry should include even minimally invasive procedures, such as ketamine infusions, medication implants, long-acting injectable (LAI) medications, and processes that require a Risk Evaluation and Mitigation Strategy (REMS), such as those utilized with clozapine, esketamine, or olanzapine for extended-release injectable suspension⁷ (see “Risk Evaluation and Mitigation Strategy programs: How they can be improved”). The proportions of clinicians who prescribe clozapine (7%)⁸ or LAIs (32.1% to 77.7%, depending on the patient population being treated)^9,10 is evidence that the interventional nature of these treatments creates obstacles to their use.

This vacuum of adequate training among psychiatrists has caused interventional psychiatry to grow beyond the confines of the psychiatric field. In most metropolitan areas of the United States, there are clinicians who focus on a specific interventional treatment, such as ketamine infusions or TMS administration. The creation of these specialized clinics has frequently been pioneered by nonpsychiatrists, such as anesthesiologists. This may be attributed to these clinicians’ level of comfort with procedures, or because they possess an infrastructure within their practice that facilitates delivery of the services. In certain states with independent-practice laws, midlevel clinicians are granted permission to open these clinics. However, having nonpsychiatrists provide these treatments to patients with complex psychiatric disorders without psychiatrist involvement makes it less likely that the appropriateness of treatment will be determined, or that the treatment will be incorporated into the patient’s overall biopsychosocial treatment plan.

A gap in training

There is evidence the growth of interventional psychiatry has exceeded the capacity of the current training infrastructure to provide trainees with adequate exposure to these procedures. The Accreditation Council for Graduate Medical Education requires that psychiatry residents be trained in the indications for and use of ECT and neuromodulation therapies but does not provide any specifics about how this training should occur,¹¹ and the Psychiatry Milestones do not indicate how competency in these therapies can be achieved.¹² Most trainees have exposure to some interventional treatments, such as ECT or clozapine administration, during residency. However, in 1 survey, only 63% of residents had prescribed clozapine, and 83% indicated they wanted additional experience.¹³ In a survey of 91 training programs, 75% stated that ECT was required of residents, but 37% estimated that a typical resident would participate in <10 treatments.¹⁴ Even more surprising, 27% estimated that the typical resident would care for <5 patients receiving ECT.¹⁴

Addressing the changing role of interventional practices in our field must occur on multiple levels, starting with a core curriculum during residency training, expanded learning opportunities for residents with a specific interest in interventional psychiatry, and, most important, a formal interventional psychiatry fellowship leading to certification from the American Board of Medical Specialties.^5,6 There are growing numbers of 1-year fellowship programs that offer extensive experiences in neuromodulation and novel pharma­cologic treatment and may produce the next generation of leaders in this field. However, training in interventional psychiatry techniques for practicing psychiatrists wishing to expand their treatment offerings is generally quite limited.

Oversight of interventional psychiatry training should be performed by peers. Therefore, creation of an interventional psychiatry society, or a work group within a larger organization, is necessary. While much of this already exists, it is fragmented into associations focused on unique aspects of interventional psychiatry, such as just ECT (eg, International Society for ECT and Neurostimulation), just TMS (eg, Clinical TMS Society), or just ketamine (eg, the American Society of Ketamine Physicians). Despite disparate foci, the goal would be for all to unite into a parent interventional organization that can face these challenges. These organizations have already united a core of individual interventional psychiatrists who can lead psychiatry into the future. They can provide input into guidelines, minimal standards, procedures, protocols, and outcome measures. They also can address any ethical issues that may arise with the use of more invasive treatments.

Change, especially the monumental changes in practice that accompany interventional psychiatry, is both exciting and intimidating. However, certain “growing pains” along the way require urgent consideration. Ultimately, as a field, we either adapt to change or get left behind.

The explosion of interest in interventional psychiatry is highlighted by 2 recent reviews published in Current Psychiatry.^1,2 While this is clearly desirable, the rate of growth has created problems. Expansion of interventional modalities has outpaced the training and education of our residents and practicing psychiatrists.

Psychiatry’s failure to address these changes would be a dire error, as psychiatrists could lose control of our field’s advances and growth. But this creates an even larger question: what are the next steps we need to take? We believe interventional psychiatry must be recognized as its own psychiatric subspeciality, receive greater emphasis in psychiatry residency training, and be subject to standardization by professional organizations.

Psychiatry has incorporated procedures into patient care for almost 100 years, starting with electroconvulsive therapy (ECT) and insulin shock therapy in the 1930s.^3,4 However, in the last 10 years, the rapid expansion of FDA approvals of neuromodulation procedures to treat psychiatric conditions (including vagus nerve stimulation in 2005, transcranial magnetic stimulation [TMS] in 2008, and the device exception granted for the use of deep brain stimulation in 2009) has produced the moniker “interventional psychiatry” for this unofficial psychiatric subspeciality.^5,6

If we are to establish interventional psychiatry as a recognized subspeciality, it is important to create a universally accepted definition. We propose the term refer to therapeutic techniques or processes that may or may not be invasive but require special training to perform. Additionally, interventional psychiatry should include even minimally invasive procedures, such as ketamine infusions, medication implants, long-acting injectable (LAI) medications, and processes that require a Risk Evaluation and Mitigation Strategy (REMS), such as those utilized with clozapine, esketamine, or olanzapine for extended-release injectable suspension⁷ (see “Risk Evaluation and Mitigation Strategy programs: How they can be improved”). The proportions of clinicians who prescribe clozapine (7%)⁸ or LAIs (32.1% to 77.7%, depending on the patient population being treated)^9,10 is evidence that the interventional nature of these treatments creates obstacles to their use.

This vacuum of adequate training among psychiatrists has caused interventional psychiatry to grow beyond the confines of the psychiatric field. In most metropolitan areas of the United States, there are clinicians who focus on a specific interventional treatment, such as ketamine infusions or TMS administration. The creation of these specialized clinics has frequently been pioneered by nonpsychiatrists, such as anesthesiologists. This may be attributed to these clinicians’ level of comfort with procedures, or because they possess an infrastructure within their practice that facilitates delivery of the services. In certain states with independent-practice laws, midlevel clinicians are granted permission to open these clinics. However, having nonpsychiatrists provide these treatments to patients with complex psychiatric disorders without psychiatrist involvement makes it less likely that the appropriateness of treatment will be determined, or that the treatment will be incorporated into the patient’s overall biopsychosocial treatment plan.

A gap in training

There is evidence the growth of interventional psychiatry has exceeded the capacity of the current training infrastructure to provide trainees with adequate exposure to these procedures. The Accreditation Council for Graduate Medical Education requires that psychiatry residents be trained in the indications for and use of ECT and neuromodulation therapies but does not provide any specifics about how this training should occur,¹¹ and the Psychiatry Milestones do not indicate how competency in these therapies can be achieved.¹² Most trainees have exposure to some interventional treatments, such as ECT or clozapine administration, during residency. However, in 1 survey, only 63% of residents had prescribed clozapine, and 83% indicated they wanted additional experience.¹³ In a survey of 91 training programs, 75% stated that ECT was required of residents, but 37% estimated that a typical resident would participate in <10 treatments.¹⁴ Even more surprising, 27% estimated that the typical resident would care for <5 patients receiving ECT.¹⁴

Addressing the changing role of interventional practices in our field must occur on multiple levels, starting with a core curriculum during residency training, expanded learning opportunities for residents with a specific interest in interventional psychiatry, and, most important, a formal interventional psychiatry fellowship leading to certification from the American Board of Medical Specialties.^5,6 There are growing numbers of 1-year fellowship programs that offer extensive experiences in neuromodulation and novel pharma­cologic treatment and may produce the next generation of leaders in this field. However, training in interventional psychiatry techniques for practicing psychiatrists wishing to expand their treatment offerings is generally quite limited.

Oversight of interventional psychiatry training should be performed by peers. Therefore, creation of an interventional psychiatry society, or a work group within a larger organization, is necessary. While much of this already exists, it is fragmented into associations focused on unique aspects of interventional psychiatry, such as just ECT (eg, International Society for ECT and Neurostimulation), just TMS (eg, Clinical TMS Society), or just ketamine (eg, the American Society of Ketamine Physicians). Despite disparate foci, the goal would be for all to unite into a parent interventional organization that can face these challenges. These organizations have already united a core of individual interventional psychiatrists who can lead psychiatry into the future. They can provide input into guidelines, minimal standards, procedures, protocols, and outcome measures. They also can address any ethical issues that may arise with the use of more invasive treatments.

Change, especially the monumental changes in practice that accompany interventional psychiatry, is both exciting and intimidating. However, certain “growing pains” along the way require urgent consideration. Ultimately, as a field, we either adapt to change or get left behind.

The explosion of interest in interventional psychiatry is highlighted by 2 recent reviews published in Current Psychiatry.^1,2 While this is clearly desirable, the rate of growth has created problems. Expansion of interventional modalities has outpaced the training and education of our residents and practicing psychiatrists.

Psychiatry’s failure to address these changes would be a dire error, as psychiatrists could lose control of our field’s advances and growth. But this creates an even larger question: what are the next steps we need to take? We believe interventional psychiatry must be recognized as its own psychiatric subspeciality, receive greater emphasis in psychiatry residency training, and be subject to standardization by professional organizations.

Psychiatry has incorporated procedures into patient care for almost 100 years, starting with electroconvulsive therapy (ECT) and insulin shock therapy in the 1930s.^3,4 However, in the last 10 years, the rapid expansion of FDA approvals of neuromodulation procedures to treat psychiatric conditions (including vagus nerve stimulation in 2005, transcranial magnetic stimulation [TMS] in 2008, and the device exception granted for the use of deep brain stimulation in 2009) has produced the moniker “interventional psychiatry” for this unofficial psychiatric subspeciality.^5,6

If we are to establish interventional psychiatry as a recognized subspeciality, it is important to create a universally accepted definition. We propose the term refer to therapeutic techniques or processes that may or may not be invasive but require special training to perform. Additionally, interventional psychiatry should include even minimally invasive procedures, such as ketamine infusions, medication implants, long-acting injectable (LAI) medications, and processes that require a Risk Evaluation and Mitigation Strategy (REMS), such as those utilized with clozapine, esketamine, or olanzapine for extended-release injectable suspension⁷ (see “Risk Evaluation and Mitigation Strategy programs: How they can be improved”). The proportions of clinicians who prescribe clozapine (7%)⁸ or LAIs (32.1% to 77.7%, depending on the patient population being treated)^9,10 is evidence that the interventional nature of these treatments creates obstacles to their use.

This vacuum of adequate training among psychiatrists has caused interventional psychiatry to grow beyond the confines of the psychiatric field. In most metropolitan areas of the United States, there are clinicians who focus on a specific interventional treatment, such as ketamine infusions or TMS administration. The creation of these specialized clinics has frequently been pioneered by nonpsychiatrists, such as anesthesiologists. This may be attributed to these clinicians’ level of comfort with procedures, or because they possess an infrastructure within their practice that facilitates delivery of the services. In certain states with independent-practice laws, midlevel clinicians are granted permission to open these clinics. However, having nonpsychiatrists provide these treatments to patients with complex psychiatric disorders without psychiatrist involvement makes it less likely that the appropriateness of treatment will be determined, or that the treatment will be incorporated into the patient’s overall biopsychosocial treatment plan.

A gap in training

There is evidence the growth of interventional psychiatry has exceeded the capacity of the current training infrastructure to provide trainees with adequate exposure to these procedures. The Accreditation Council for Graduate Medical Education requires that psychiatry residents be trained in the indications for and use of ECT and neuromodulation therapies but does not provide any specifics about how this training should occur,¹¹ and the Psychiatry Milestones do not indicate how competency in these therapies can be achieved.¹² Most trainees have exposure to some interventional treatments, such as ECT or clozapine administration, during residency. However, in 1 survey, only 63% of residents had prescribed clozapine, and 83% indicated they wanted additional experience.¹³ In a survey of 91 training programs, 75% stated that ECT was required of residents, but 37% estimated that a typical resident would participate in <10 treatments.¹⁴ Even more surprising, 27% estimated that the typical resident would care for <5 patients receiving ECT.¹⁴

Addressing the changing role of interventional practices in our field must occur on multiple levels, starting with a core curriculum during residency training, expanded learning opportunities for residents with a specific interest in interventional psychiatry, and, most important, a formal interventional psychiatry fellowship leading to certification from the American Board of Medical Specialties.^5,6 There are growing numbers of 1-year fellowship programs that offer extensive experiences in neuromodulation and novel pharma­cologic treatment and may produce the next generation of leaders in this field. However, training in interventional psychiatry techniques for practicing psychiatrists wishing to expand their treatment offerings is generally quite limited.

Oversight of interventional psychiatry training should be performed by peers. Therefore, creation of an interventional psychiatry society, or a work group within a larger organization, is necessary. While much of this already exists, it is fragmented into associations focused on unique aspects of interventional psychiatry, such as just ECT (eg, International Society for ECT and Neurostimulation), just TMS (eg, Clinical TMS Society), or just ketamine (eg, the American Society of Ketamine Physicians). Despite disparate foci, the goal would be for all to unite into a parent interventional organization that can face these challenges. These organizations have already united a core of individual interventional psychiatrists who can lead psychiatry into the future. They can provide input into guidelines, minimal standards, procedures, protocols, and outcome measures. They also can address any ethical issues that may arise with the use of more invasive treatments.

Change, especially the monumental changes in practice that accompany interventional psychiatry, is both exciting and intimidating. However, certain “growing pains” along the way require urgent consideration. Ultimately, as a field, we either adapt to change or get left behind.

The Department of Health & Human Services has issued an advisory to help medical professionals better recognize the mental health symptoms that may come with long COVID.

The nine mental health symptoms highlighted in the advisory are fatigue; cognitive impairment, including brain fog; anxiety; depression; obsessive-compulsive disorder; sleep disorders; PTSD; psychotic disorder; and start of a substance use disorder.

The advisory noted that social factors can contribute to the mental health problems for racial and ethnic minorities; people with limited access to health care; people who already have behavioral health conditions and physical disabilities; and people who are lesbian, gay, bisexual, transgender, queer, or intersex.

“Long COVID has a range of burdensome physical symptoms and can take a toll on a person’s mental health. It can be very challenging for a person, whether they are impacted themselves, or they are a caregiver for someone who is affected,” Health and Human Services Secretary Xavier Becerra said in a statement. “This advisory helps to raise awareness, especially among primary care practitioners and clinicians who are often the ones treating patients with long COVID.”

The department says about 10% of people infected with COVID have at least one long COVID symptom. Physical symptoms include dizziness, stomach upset, heart palpitations, issues with sexual desire or capacity, loss of smell or taste, thirst, chronic coughing, chest pain, and abnormal movements. 

“We know that people living with long COVID need help today, and providers need help understanding what long COVID is and how to treat it,” Admiral Rachel Levine, MD, assistant secretary for health, said in the statement. “This advisory helps bridge that gap for the behavioral health impacts of long COVID.”

A version of this article first appeared on WebMD.com.

The Department of Health & Human Services has issued an advisory to help medical professionals better recognize the mental health symptoms that may come with long COVID.

The nine mental health symptoms highlighted in the advisory are fatigue; cognitive impairment, including brain fog; anxiety; depression; obsessive-compulsive disorder; sleep disorders; PTSD; psychotic disorder; and start of a substance use disorder.

The advisory noted that social factors can contribute to the mental health problems for racial and ethnic minorities; people with limited access to health care; people who already have behavioral health conditions and physical disabilities; and people who are lesbian, gay, bisexual, transgender, queer, or intersex.

“Long COVID has a range of burdensome physical symptoms and can take a toll on a person’s mental health. It can be very challenging for a person, whether they are impacted themselves, or they are a caregiver for someone who is affected,” Health and Human Services Secretary Xavier Becerra said in a statement. “This advisory helps to raise awareness, especially among primary care practitioners and clinicians who are often the ones treating patients with long COVID.”

The department says about 10% of people infected with COVID have at least one long COVID symptom. Physical symptoms include dizziness, stomach upset, heart palpitations, issues with sexual desire or capacity, loss of smell or taste, thirst, chronic coughing, chest pain, and abnormal movements. 

“We know that people living with long COVID need help today, and providers need help understanding what long COVID is and how to treat it,” Admiral Rachel Levine, MD, assistant secretary for health, said in the statement. “This advisory helps bridge that gap for the behavioral health impacts of long COVID.”

A version of this article first appeared on WebMD.com.

The Department of Health & Human Services has issued an advisory to help medical professionals better recognize the mental health symptoms that may come with long COVID.

The nine mental health symptoms highlighted in the advisory are fatigue; cognitive impairment, including brain fog; anxiety; depression; obsessive-compulsive disorder; sleep disorders; PTSD; psychotic disorder; and start of a substance use disorder.

The advisory noted that social factors can contribute to the mental health problems for racial and ethnic minorities; people with limited access to health care; people who already have behavioral health conditions and physical disabilities; and people who are lesbian, gay, bisexual, transgender, queer, or intersex.

“Long COVID has a range of burdensome physical symptoms and can take a toll on a person’s mental health. It can be very challenging for a person, whether they are impacted themselves, or they are a caregiver for someone who is affected,” Health and Human Services Secretary Xavier Becerra said in a statement. “This advisory helps to raise awareness, especially among primary care practitioners and clinicians who are often the ones treating patients with long COVID.”

The department says about 10% of people infected with COVID have at least one long COVID symptom. Physical symptoms include dizziness, stomach upset, heart palpitations, issues with sexual desire or capacity, loss of smell or taste, thirst, chronic coughing, chest pain, and abnormal movements. 

“We know that people living with long COVID need help today, and providers need help understanding what long COVID is and how to treat it,” Admiral Rachel Levine, MD, assistant secretary for health, said in the statement. “This advisory helps bridge that gap for the behavioral health impacts of long COVID.”

A version of this article first appeared on WebMD.com.

Primary care providers (PCPs) are addressing an increasing number of mental health visits, requiring collaborative and innovative approaches to providing psychiatric care.

This growth in the number of patients needing behavioral health–related care is likely driven by multiple factors, including a shortage of mental health care providers, an increasing incidence of psychiatric illness, and destigmatization of mental health in general, suggested Swetha P. Iruku, MD, MPH, associate professor of family medicine and community health at the University of Pennsylvania and Penn Medicine family physician in Philadelphia.

The Centers for Disease Control and Prevention noted that “the COVID-19 pandemic has been associated with mental health challenges related to the morbidity and mortality caused by the disease and to mitigation activities, including the impact of physical distancing and stay-at-home orders,” in a Morbidity and Mortality Weekly Report.

From June 24 to 30, 2020, U.S. adults reported considerably elevated adverse mental health conditions associated with COVID-19, and symptoms of anxiety disorder and depressive disorder climbed during the months of April through June of the same year, compared with the same period in 2019, they wrote.

Even before the pandemic got underway, multiple studies of national data published this year suggested mental issues were on the rise in the United States. For example, the proportion of adult patient visits to primary care providers that addressed mental health concerns rose from 10.7% to 15.9% from 2006 to 2018, according to research published in Health Affairs. Plus, the number and proportion of pediatric acute care hospitalizations because of mental health diagnoses increased significantly between 2009 and 2019, according to a paper published in JAMA.

“I truly believe that we can’t, as primary care physicians, take care of someone’s physical health without also taking care of their mental health,” Dr. Iruku said in an interview. “It’s all intertwined.”

To rise to this challenge, PCPs first need a collaborative mindset, she suggested, as well as familiarity with available resources, both locally and virtually.

This article examines strategies for managing mental illness in primary care, outlines clinical resources, and reviews related educational opportunities.

In addition, clinical pearls are shared by Dr. Iruku and five other clinicians who provide or have provided mental health care to primary care patients or work in close collaboration with a primary care practice, including a clinical psychologist, a nurse practitioner licensed in psychiatric health, a pediatrician, and a licensed clinical social worker.
 

Build a network

Most of the providers interviewed cited the importance of collaboration in mental health care, particularly for complex cases.

“I would recommend [that primary care providers get] to know the psychiatric providers [in their area],” said Jessica Viton, DNP, FNP, PMHNP, who delivers mental health care through a community-based primary care practice in Colorado which she requested remain anonymous.

Dr. Iruku suggested making an in-person connection first, if possible.

“So much of what we do is ‘see one, do one, teach one,’ so learn a little bit, then go off and trial,” she said. “[It can be valuable] having someone in your back pocket that you can contact in the case of an emergency, or in a situation where you just don’t know how to tackle it.”
 

Screen for depression and anxiety

William J. Sieber, PhD, a clinical psychologist, director of integrated behavioral health, and professor in the department of family medicine and public health and the department of psychiatry at the University of California, San Diego, said primary care providers should screen all adult patients for depression and anxiety with the Patient Health Questionnaire (PHQ-9) and General Anxiety Disorder Assessment (GAD-7), respectively.

To save time, he suggested a cascading approach.

“In primary care, everybody’s in a hurry,” Dr. Sieber said. “[With the cascading approach,] the first two items [from each questionnaire] are given, and if a person endorses either of those items … then they are asked to complete the other items.”

Jennifer Mullally, MD, a pediatrician at Sanford Health in Fargo, N.D., uses this cascading approach to depression and anxiety screening with all her patients aged 13-18. For younger kids, she screens only those who present with signs or symptoms of mental health issues, or if the parent shares a concern.

This approach differs slightly from U.S. Preventive Services Task Force recommendations, which suggest screening for anxiety in patients aged 8-18 years and depression in patients aged 12-18 years.
 

Use other screening tools only as needed

Dr. Sieber, the research director for the division of family medicine at UC San Diego, collaborates regularly with primary care providers via hallway consultations, by sharing cases, and through providing oversight of psychiatric care at 13 primary care practices within the UC San Diego network. He recommended against routine screening beyond depression and anxiety in the primary care setting.

“There are a lot of screening tools,” Dr. Sieber said. “It depends on what you’re presented with. The challenge in primary care is you’re going to see all kinds of things. It’s not like running a depression clinic.”

Other than the PHQ-9 and GAD-7, he suggested primary care providers establish familiarity with screening tools for posttraumatic stress disorder and attention-deficit/hyperactivity disorder, noting again that these should be used only when one of the conditions is already suspected.

Dr. Mullally follows a similar approach with her pediatric population. In addition to the GAD-7, she investigates whether a patient has anxiety with the Screen for Child Anxiety Related Disorders (SCARED). For depression, she couples the PHQ-9 with the Columbia Suicide Severity Rating Scale.

While additional screening tools like these are readily available online, Dr. Viton suggested that they should be employed only if the provider is trained to interpret and respond to those findings, and only if they know which tool to use, and when.

For example, she has recently observed PCPs diagnosing adults with ADHD using a three-question test, when in fact a full-length, standardized instrument should be administered by a provider with necessary training.

She also pointed out that bipolar disorder continues to be underdiagnosed, possibly because of providers detecting depression using a questionnaire like the PHQ-9, while failing to inquire about manic episodes.
 

Leverage online resources

If depression is confirmed, Dr. Iruku often directs the patient to the Mayo Clinic Depression Medication Choice Decision Aid. This website steers patients through medication options based on their answers to a questionnaire. Choices are listed alongside possible adverse effects.

For clinician use, Dr. Iruku recommended The Waco Guide to Psychopharmacology in Primary Care, which aids clinical decision-making for mental illness and substance abuse. The app processes case details to suggest first-, second-, and third-line pharmacotherapies, as well as modifications based on patient needs.

Even with tools like these, however, a referral may be needed.

“[Primary care providers] may not be the best fit for what the patient is looking for, from a mental health or behavioral standpoint,” Dr. Sieber said.

In this case, he encourages patients to visit Psychology Today, a “quite popular portal” that helps patients locate a suitable provider based on location, insurance, driving radius, and mental health concern. This usually generates 10-20 options, Dr. Sieber said, although results can vary.

“It may be discouraging, because maybe only three [providers] pop up based on your criteria, and the closest one is miles away,” he said.
 

Consider virtual support

If no local psychiatric help is available, Dr. Sieber suggested virtual support, highlighting that “it’s much easier now than it was 3 or 4 years ago” to connect patients with external mental health care.

But this strategy should be reserved for cases of actual need instead of pure convenience, cautioned Dr. Viton, who noted that virtual visits may fail to capture the nuance of an in-person meeting, as body language, mode of dress, and other clues can provide insights into mental health status.

“Occasionally, I think you do have to have an in-person visit, especially when you’re developing a rapport with someone,” Dr. Viton said.

Claire McArdle, a licensed clinical social worker in Fort Collins, Colo., noted that virtual care from an outside provider may also impede the collaboration needed to effectively address mental illness.

In her 11 years in primary care at Associates in Family Medicine, Ms. McArdle had countless interactions with colleagues seeking support when managing a complex case. “I’m coaching providers, front desk staff, and nursing staff on how to interact with patients [with] behavioral health needs,” she said, citing the multitude of nonmedical factors that need to be considered, such as family relationships and patient preferences.

These unscheduled conversations with colleagues throughout the day are impossible to have when sharing a case with an unknown, remote peer.

Ms. McArdle speaks from experience. She recently resigned from Associates in Family Medicine to start her own private therapy practice after her former employer was acquired by VillageMD, a national provider that terminated employment of most other social workers in the practice and began outsourcing mental health care to Mindoula Health, a virtual provider.

Dr. Sieber offered a similar perspective on in-person collaboration as the psychiatric specialist at his center. He routinely offers on-site support for both providers and patients, serving as “another set of eyes and ears” when there is a concern about patient safety or directly managing care when a patient is hospitalized for mental illness.

While virtual solutions may fall short of in-person management, they can offer care at a scale and cost impossible through traditional practice.

This could even be free. Zero-cost, automated software now allows individuals who are uninsured or unable to afford care at least one avenue to manage their mental health concerns.

For example, Bliss is a free, 8-session, interactive online therapy program for depression that was created by the Centre for Interactive Mental Health Solutions. The program offers a tool for monitoring mood and quizzes to test understanding of personal mental health management, among other features.

More advanced programs are emerging as artificial intelligence (AI) enables dialogues between humans and machines. This is the case with Woebot, an app that asks the user about their mood throughout the day, and responds with evidence-based strategies for managing concerns, all for free at press time.
 

Keep learning

A range of educational options and professional resources are available for primary care providers who would like to improve their knowledge of mental health care. These include formal fellowships in primary care psychiatry/behavioral health integration, free mental health webinars, and various other opportunities.

Eric Eschweiler, DNP, APRN, FNP-C, PHN, completed the University of California, Irvine, Train New Trainers (TNT) Primary Care Psychiatry (PCP) Fellowship in 2016, when he was working as a solo nurse practitioner.

“I was drowning in practice,” said Dr. Eschweiler, director of nursing and public health outreach services at Riverside-San Bernardino County Indian Health, Grand Terrace, Calif., in an interview. “I was a solo NP. There was no physician on site. We were seeing a lot of [individuals with] schizoaffective [disorder] in downtown San Bernardino, the homeless, unhoused – a lot of substance use. I felt I needed to have the skills to be able to treat them effectively. That’s what the fellowship did.”

The skills Dr. Eschweiler learned from participating in his fellowship allowed him to manage more cases of mental illness without need for referral. When a referral was needed for a complex or severe case, he had the confidence to bridge care and collaborate more effectively with psychiatric specialists.

“It was awesome, because we were able to communicate using the same language,” Dr. Eschweiler said of these collaborations. “It’s [about] talking that same language, starting those initial treatments, and then moving forward with specialty care, and vice versa. [Psychiatric specialists] would send me patients that needed medical care because of the types of medications they were taking. And I was then very well aware of those side effects and other issues that might come up from those treatments. So it’s a two-way street.”

Dr. Eschweiler was so impressed by his fellowship that he has since ushered multiple providers through the program since transitioning to an administrative role as director of nursing.

In Fargo, where psychiatric care is sparse and wait times for referral can be months long, Dr. Mullally, like Dr. Eschweiler, knew that she needed more training in mental health.

“I don’t feel like we get enough training in residency,” Dr. Mullally said. “So you do need to look at your options for further CME.”

Out of several CME courses she has taken to further her understanding of pediatric psychiatry, Dr. Mullally recommended The Reach Institute above all others, as their courses involve in-depth discussions and valuable handouts, particularly for medication selection.

“I think that a lot of the other CMEs tend to involve a lot more PowerPoint presentations,” Dr. Mullally said. “And you don’t necessarily leave with a lot of good documents. I still use my Reach handouts. I have them sitting right next to me. I use them every single day.”

Providers interested in The Reach Institute, however, should be prepared to invest both time and money, she added, citing a 2-3 day commitment, and calling it “not cheap.” To overcome these barriers, she suggested that providers get their institution to support their attendance.

For a lighter commitment, Dr. Iruku recommended the American Academy of Family Physicians CME portal, as this offers 13 online, accredited courses covering a range of topics, from adolescent health to substance abuse disorders.

Dr. Sieber suggested that primary care providers join the Collaborative Family Healthcare Association, which aims to integrate physical and behavioral health in routine practice. CFHA, of which he is a member, offers a “bevy of different resources” for interested providers, including a conference in Phoenix this October.

The interviewees disclosed no conflicts of interest.

Primary care providers (PCPs) are addressing an increasing number of mental health visits, requiring collaborative and innovative approaches to providing psychiatric care.

This growth in the number of patients needing behavioral health–related care is likely driven by multiple factors, including a shortage of mental health care providers, an increasing incidence of psychiatric illness, and destigmatization of mental health in general, suggested Swetha P. Iruku, MD, MPH, associate professor of family medicine and community health at the University of Pennsylvania and Penn Medicine family physician in Philadelphia.

The Centers for Disease Control and Prevention noted that “the COVID-19 pandemic has been associated with mental health challenges related to the morbidity and mortality caused by the disease and to mitigation activities, including the impact of physical distancing and stay-at-home orders,” in a Morbidity and Mortality Weekly Report.

From June 24 to 30, 2020, U.S. adults reported considerably elevated adverse mental health conditions associated with COVID-19, and symptoms of anxiety disorder and depressive disorder climbed during the months of April through June of the same year, compared with the same period in 2019, they wrote.

Even before the pandemic got underway, multiple studies of national data published this year suggested mental issues were on the rise in the United States. For example, the proportion of adult patient visits to primary care providers that addressed mental health concerns rose from 10.7% to 15.9% from 2006 to 2018, according to research published in Health Affairs. Plus, the number and proportion of pediatric acute care hospitalizations because of mental health diagnoses increased significantly between 2009 and 2019, according to a paper published in JAMA.

“I truly believe that we can’t, as primary care physicians, take care of someone’s physical health without also taking care of their mental health,” Dr. Iruku said in an interview. “It’s all intertwined.”

To rise to this challenge, PCPs first need a collaborative mindset, she suggested, as well as familiarity with available resources, both locally and virtually.

This article examines strategies for managing mental illness in primary care, outlines clinical resources, and reviews related educational opportunities.

In addition, clinical pearls are shared by Dr. Iruku and five other clinicians who provide or have provided mental health care to primary care patients or work in close collaboration with a primary care practice, including a clinical psychologist, a nurse practitioner licensed in psychiatric health, a pediatrician, and a licensed clinical social worker.
 

Build a network

Most of the providers interviewed cited the importance of collaboration in mental health care, particularly for complex cases.

“I would recommend [that primary care providers get] to know the psychiatric providers [in their area],” said Jessica Viton, DNP, FNP, PMHNP, who delivers mental health care through a community-based primary care practice in Colorado which she requested remain anonymous.

Dr. Iruku suggested making an in-person connection first, if possible.

“So much of what we do is ‘see one, do one, teach one,’ so learn a little bit, then go off and trial,” she said. “[It can be valuable] having someone in your back pocket that you can contact in the case of an emergency, or in a situation where you just don’t know how to tackle it.”
 

Screen for depression and anxiety

William J. Sieber, PhD, a clinical psychologist, director of integrated behavioral health, and professor in the department of family medicine and public health and the department of psychiatry at the University of California, San Diego, said primary care providers should screen all adult patients for depression and anxiety with the Patient Health Questionnaire (PHQ-9) and General Anxiety Disorder Assessment (GAD-7), respectively.

To save time, he suggested a cascading approach.

“In primary care, everybody’s in a hurry,” Dr. Sieber said. “[With the cascading approach,] the first two items [from each questionnaire] are given, and if a person endorses either of those items … then they are asked to complete the other items.”

Jennifer Mullally, MD, a pediatrician at Sanford Health in Fargo, N.D., uses this cascading approach to depression and anxiety screening with all her patients aged 13-18. For younger kids, she screens only those who present with signs or symptoms of mental health issues, or if the parent shares a concern.

This approach differs slightly from U.S. Preventive Services Task Force recommendations, which suggest screening for anxiety in patients aged 8-18 years and depression in patients aged 12-18 years.
 

Use other screening tools only as needed

Dr. Sieber, the research director for the division of family medicine at UC San Diego, collaborates regularly with primary care providers via hallway consultations, by sharing cases, and through providing oversight of psychiatric care at 13 primary care practices within the UC San Diego network. He recommended against routine screening beyond depression and anxiety in the primary care setting.

“There are a lot of screening tools,” Dr. Sieber said. “It depends on what you’re presented with. The challenge in primary care is you’re going to see all kinds of things. It’s not like running a depression clinic.”

Other than the PHQ-9 and GAD-7, he suggested primary care providers establish familiarity with screening tools for posttraumatic stress disorder and attention-deficit/hyperactivity disorder, noting again that these should be used only when one of the conditions is already suspected.

Dr. Mullally follows a similar approach with her pediatric population. In addition to the GAD-7, she investigates whether a patient has anxiety with the Screen for Child Anxiety Related Disorders (SCARED). For depression, she couples the PHQ-9 with the Columbia Suicide Severity Rating Scale.

While additional screening tools like these are readily available online, Dr. Viton suggested that they should be employed only if the provider is trained to interpret and respond to those findings, and only if they know which tool to use, and when.

For example, she has recently observed PCPs diagnosing adults with ADHD using a three-question test, when in fact a full-length, standardized instrument should be administered by a provider with necessary training.

She also pointed out that bipolar disorder continues to be underdiagnosed, possibly because of providers detecting depression using a questionnaire like the PHQ-9, while failing to inquire about manic episodes.
 

Leverage online resources

If depression is confirmed, Dr. Iruku often directs the patient to the Mayo Clinic Depression Medication Choice Decision Aid. This website steers patients through medication options based on their answers to a questionnaire. Choices are listed alongside possible adverse effects.

For clinician use, Dr. Iruku recommended The Waco Guide to Psychopharmacology in Primary Care, which aids clinical decision-making for mental illness and substance abuse. The app processes case details to suggest first-, second-, and third-line pharmacotherapies, as well as modifications based on patient needs.

Even with tools like these, however, a referral may be needed.

“[Primary care providers] may not be the best fit for what the patient is looking for, from a mental health or behavioral standpoint,” Dr. Sieber said.

In this case, he encourages patients to visit Psychology Today, a “quite popular portal” that helps patients locate a suitable provider based on location, insurance, driving radius, and mental health concern. This usually generates 10-20 options, Dr. Sieber said, although results can vary.

“It may be discouraging, because maybe only three [providers] pop up based on your criteria, and the closest one is miles away,” he said.
 

Consider virtual support

If no local psychiatric help is available, Dr. Sieber suggested virtual support, highlighting that “it’s much easier now than it was 3 or 4 years ago” to connect patients with external mental health care.

But this strategy should be reserved for cases of actual need instead of pure convenience, cautioned Dr. Viton, who noted that virtual visits may fail to capture the nuance of an in-person meeting, as body language, mode of dress, and other clues can provide insights into mental health status.

“Occasionally, I think you do have to have an in-person visit, especially when you’re developing a rapport with someone,” Dr. Viton said.

Claire McArdle, a licensed clinical social worker in Fort Collins, Colo., noted that virtual care from an outside provider may also impede the collaboration needed to effectively address mental illness.

In her 11 years in primary care at Associates in Family Medicine, Ms. McArdle had countless interactions with colleagues seeking support when managing a complex case. “I’m coaching providers, front desk staff, and nursing staff on how to interact with patients [with] behavioral health needs,” she said, citing the multitude of nonmedical factors that need to be considered, such as family relationships and patient preferences.

These unscheduled conversations with colleagues throughout the day are impossible to have when sharing a case with an unknown, remote peer.

Ms. McArdle speaks from experience. She recently resigned from Associates in Family Medicine to start her own private therapy practice after her former employer was acquired by VillageMD, a national provider that terminated employment of most other social workers in the practice and began outsourcing mental health care to Mindoula Health, a virtual provider.

Dr. Sieber offered a similar perspective on in-person collaboration as the psychiatric specialist at his center. He routinely offers on-site support for both providers and patients, serving as “another set of eyes and ears” when there is a concern about patient safety or directly managing care when a patient is hospitalized for mental illness.

While virtual solutions may fall short of in-person management, they can offer care at a scale and cost impossible through traditional practice.

This could even be free. Zero-cost, automated software now allows individuals who are uninsured or unable to afford care at least one avenue to manage their mental health concerns.

For example, Bliss is a free, 8-session, interactive online therapy program for depression that was created by the Centre for Interactive Mental Health Solutions. The program offers a tool for monitoring mood and quizzes to test understanding of personal mental health management, among other features.

More advanced programs are emerging as artificial intelligence (AI) enables dialogues between humans and machines. This is the case with Woebot, an app that asks the user about their mood throughout the day, and responds with evidence-based strategies for managing concerns, all for free at press time.
 

Keep learning

A range of educational options and professional resources are available for primary care providers who would like to improve their knowledge of mental health care. These include formal fellowships in primary care psychiatry/behavioral health integration, free mental health webinars, and various other opportunities.

Eric Eschweiler, DNP, APRN, FNP-C, PHN, completed the University of California, Irvine, Train New Trainers (TNT) Primary Care Psychiatry (PCP) Fellowship in 2016, when he was working as a solo nurse practitioner.

“I was drowning in practice,” said Dr. Eschweiler, director of nursing and public health outreach services at Riverside-San Bernardino County Indian Health, Grand Terrace, Calif., in an interview. “I was a solo NP. There was no physician on site. We were seeing a lot of [individuals with] schizoaffective [disorder] in downtown San Bernardino, the homeless, unhoused – a lot of substance use. I felt I needed to have the skills to be able to treat them effectively. That’s what the fellowship did.”

The skills Dr. Eschweiler learned from participating in his fellowship allowed him to manage more cases of mental illness without need for referral. When a referral was needed for a complex or severe case, he had the confidence to bridge care and collaborate more effectively with psychiatric specialists.

“It was awesome, because we were able to communicate using the same language,” Dr. Eschweiler said of these collaborations. “It’s [about] talking that same language, starting those initial treatments, and then moving forward with specialty care, and vice versa. [Psychiatric specialists] would send me patients that needed medical care because of the types of medications they were taking. And I was then very well aware of those side effects and other issues that might come up from those treatments. So it’s a two-way street.”

Dr. Eschweiler was so impressed by his fellowship that he has since ushered multiple providers through the program since transitioning to an administrative role as director of nursing.

In Fargo, where psychiatric care is sparse and wait times for referral can be months long, Dr. Mullally, like Dr. Eschweiler, knew that she needed more training in mental health.

“I don’t feel like we get enough training in residency,” Dr. Mullally said. “So you do need to look at your options for further CME.”

Out of several CME courses she has taken to further her understanding of pediatric psychiatry, Dr. Mullally recommended The Reach Institute above all others, as their courses involve in-depth discussions and valuable handouts, particularly for medication selection.

“I think that a lot of the other CMEs tend to involve a lot more PowerPoint presentations,” Dr. Mullally said. “And you don’t necessarily leave with a lot of good documents. I still use my Reach handouts. I have them sitting right next to me. I use them every single day.”

Providers interested in The Reach Institute, however, should be prepared to invest both time and money, she added, citing a 2-3 day commitment, and calling it “not cheap.” To overcome these barriers, she suggested that providers get their institution to support their attendance.

For a lighter commitment, Dr. Iruku recommended the American Academy of Family Physicians CME portal, as this offers 13 online, accredited courses covering a range of topics, from adolescent health to substance abuse disorders.

Dr. Sieber suggested that primary care providers join the Collaborative Family Healthcare Association, which aims to integrate physical and behavioral health in routine practice. CFHA, of which he is a member, offers a “bevy of different resources” for interested providers, including a conference in Phoenix this October.

The interviewees disclosed no conflicts of interest.

Primary care providers (PCPs) are addressing an increasing number of mental health visits, requiring collaborative and innovative approaches to providing psychiatric care.

This growth in the number of patients needing behavioral health–related care is likely driven by multiple factors, including a shortage of mental health care providers, an increasing incidence of psychiatric illness, and destigmatization of mental health in general, suggested Swetha P. Iruku, MD, MPH, associate professor of family medicine and community health at the University of Pennsylvania and Penn Medicine family physician in Philadelphia.

The Centers for Disease Control and Prevention noted that “the COVID-19 pandemic has been associated with mental health challenges related to the morbidity and mortality caused by the disease and to mitigation activities, including the impact of physical distancing and stay-at-home orders,” in a Morbidity and Mortality Weekly Report.

From June 24 to 30, 2020, U.S. adults reported considerably elevated adverse mental health conditions associated with COVID-19, and symptoms of anxiety disorder and depressive disorder climbed during the months of April through June of the same year, compared with the same period in 2019, they wrote.

Even before the pandemic got underway, multiple studies of national data published this year suggested mental issues were on the rise in the United States. For example, the proportion of adult patient visits to primary care providers that addressed mental health concerns rose from 10.7% to 15.9% from 2006 to 2018, according to research published in Health Affairs. Plus, the number and proportion of pediatric acute care hospitalizations because of mental health diagnoses increased significantly between 2009 and 2019, according to a paper published in JAMA.

“I truly believe that we can’t, as primary care physicians, take care of someone’s physical health without also taking care of their mental health,” Dr. Iruku said in an interview. “It’s all intertwined.”

To rise to this challenge, PCPs first need a collaborative mindset, she suggested, as well as familiarity with available resources, both locally and virtually.

This article examines strategies for managing mental illness in primary care, outlines clinical resources, and reviews related educational opportunities.

In addition, clinical pearls are shared by Dr. Iruku and five other clinicians who provide or have provided mental health care to primary care patients or work in close collaboration with a primary care practice, including a clinical psychologist, a nurse practitioner licensed in psychiatric health, a pediatrician, and a licensed clinical social worker.
 

Build a network

Most of the providers interviewed cited the importance of collaboration in mental health care, particularly for complex cases.

“I would recommend [that primary care providers get] to know the psychiatric providers [in their area],” said Jessica Viton, DNP, FNP, PMHNP, who delivers mental health care through a community-based primary care practice in Colorado which she requested remain anonymous.

Dr. Iruku suggested making an in-person connection first, if possible.

“So much of what we do is ‘see one, do one, teach one,’ so learn a little bit, then go off and trial,” she said. “[It can be valuable] having someone in your back pocket that you can contact in the case of an emergency, or in a situation where you just don’t know how to tackle it.”
 

Screen for depression and anxiety

William J. Sieber, PhD, a clinical psychologist, director of integrated behavioral health, and professor in the department of family medicine and public health and the department of psychiatry at the University of California, San Diego, said primary care providers should screen all adult patients for depression and anxiety with the Patient Health Questionnaire (PHQ-9) and General Anxiety Disorder Assessment (GAD-7), respectively.

To save time, he suggested a cascading approach.

“In primary care, everybody’s in a hurry,” Dr. Sieber said. “[With the cascading approach,] the first two items [from each questionnaire] are given, and if a person endorses either of those items … then they are asked to complete the other items.”

Jennifer Mullally, MD, a pediatrician at Sanford Health in Fargo, N.D., uses this cascading approach to depression and anxiety screening with all her patients aged 13-18. For younger kids, she screens only those who present with signs or symptoms of mental health issues, or if the parent shares a concern.

This approach differs slightly from U.S. Preventive Services Task Force recommendations, which suggest screening for anxiety in patients aged 8-18 years and depression in patients aged 12-18 years.
 

Use other screening tools only as needed

Dr. Sieber, the research director for the division of family medicine at UC San Diego, collaborates regularly with primary care providers via hallway consultations, by sharing cases, and through providing oversight of psychiatric care at 13 primary care practices within the UC San Diego network. He recommended against routine screening beyond depression and anxiety in the primary care setting.

“There are a lot of screening tools,” Dr. Sieber said. “It depends on what you’re presented with. The challenge in primary care is you’re going to see all kinds of things. It’s not like running a depression clinic.”

Other than the PHQ-9 and GAD-7, he suggested primary care providers establish familiarity with screening tools for posttraumatic stress disorder and attention-deficit/hyperactivity disorder, noting again that these should be used only when one of the conditions is already suspected.

Dr. Mullally follows a similar approach with her pediatric population. In addition to the GAD-7, she investigates whether a patient has anxiety with the Screen for Child Anxiety Related Disorders (SCARED). For depression, she couples the PHQ-9 with the Columbia Suicide Severity Rating Scale.

While additional screening tools like these are readily available online, Dr. Viton suggested that they should be employed only if the provider is trained to interpret and respond to those findings, and only if they know which tool to use, and when.

For example, she has recently observed PCPs diagnosing adults with ADHD using a three-question test, when in fact a full-length, standardized instrument should be administered by a provider with necessary training.

She also pointed out that bipolar disorder continues to be underdiagnosed, possibly because of providers detecting depression using a questionnaire like the PHQ-9, while failing to inquire about manic episodes.
 

Leverage online resources

If depression is confirmed, Dr. Iruku often directs the patient to the Mayo Clinic Depression Medication Choice Decision Aid. This website steers patients through medication options based on their answers to a questionnaire. Choices are listed alongside possible adverse effects.

For clinician use, Dr. Iruku recommended The Waco Guide to Psychopharmacology in Primary Care, which aids clinical decision-making for mental illness and substance abuse. The app processes case details to suggest first-, second-, and third-line pharmacotherapies, as well as modifications based on patient needs.

Even with tools like these, however, a referral may be needed.

“[Primary care providers] may not be the best fit for what the patient is looking for, from a mental health or behavioral standpoint,” Dr. Sieber said.

In this case, he encourages patients to visit Psychology Today, a “quite popular portal” that helps patients locate a suitable provider based on location, insurance, driving radius, and mental health concern. This usually generates 10-20 options, Dr. Sieber said, although results can vary.

“It may be discouraging, because maybe only three [providers] pop up based on your criteria, and the closest one is miles away,” he said.
 

Consider virtual support

If no local psychiatric help is available, Dr. Sieber suggested virtual support, highlighting that “it’s much easier now than it was 3 or 4 years ago” to connect patients with external mental health care.

But this strategy should be reserved for cases of actual need instead of pure convenience, cautioned Dr. Viton, who noted that virtual visits may fail to capture the nuance of an in-person meeting, as body language, mode of dress, and other clues can provide insights into mental health status.

“Occasionally, I think you do have to have an in-person visit, especially when you’re developing a rapport with someone,” Dr. Viton said.

Claire McArdle, a licensed clinical social worker in Fort Collins, Colo., noted that virtual care from an outside provider may also impede the collaboration needed to effectively address mental illness.

In her 11 years in primary care at Associates in Family Medicine, Ms. McArdle had countless interactions with colleagues seeking support when managing a complex case. “I’m coaching providers, front desk staff, and nursing staff on how to interact with patients [with] behavioral health needs,” she said, citing the multitude of nonmedical factors that need to be considered, such as family relationships and patient preferences.

These unscheduled conversations with colleagues throughout the day are impossible to have when sharing a case with an unknown, remote peer.

Ms. McArdle speaks from experience. She recently resigned from Associates in Family Medicine to start her own private therapy practice after her former employer was acquired by VillageMD, a national provider that terminated employment of most other social workers in the practice and began outsourcing mental health care to Mindoula Health, a virtual provider.

Dr. Sieber offered a similar perspective on in-person collaboration as the psychiatric specialist at his center. He routinely offers on-site support for both providers and patients, serving as “another set of eyes and ears” when there is a concern about patient safety or directly managing care when a patient is hospitalized for mental illness.

While virtual solutions may fall short of in-person management, they can offer care at a scale and cost impossible through traditional practice.

This could even be free. Zero-cost, automated software now allows individuals who are uninsured or unable to afford care at least one avenue to manage their mental health concerns.

For example, Bliss is a free, 8-session, interactive online therapy program for depression that was created by the Centre for Interactive Mental Health Solutions. The program offers a tool for monitoring mood and quizzes to test understanding of personal mental health management, among other features.

More advanced programs are emerging as artificial intelligence (AI) enables dialogues between humans and machines. This is the case with Woebot, an app that asks the user about their mood throughout the day, and responds with evidence-based strategies for managing concerns, all for free at press time.
 

Keep learning

A range of educational options and professional resources are available for primary care providers who would like to improve their knowledge of mental health care. These include formal fellowships in primary care psychiatry/behavioral health integration, free mental health webinars, and various other opportunities.

Eric Eschweiler, DNP, APRN, FNP-C, PHN, completed the University of California, Irvine, Train New Trainers (TNT) Primary Care Psychiatry (PCP) Fellowship in 2016, when he was working as a solo nurse practitioner.

“I was drowning in practice,” said Dr. Eschweiler, director of nursing and public health outreach services at Riverside-San Bernardino County Indian Health, Grand Terrace, Calif., in an interview. “I was a solo NP. There was no physician on site. We were seeing a lot of [individuals with] schizoaffective [disorder] in downtown San Bernardino, the homeless, unhoused – a lot of substance use. I felt I needed to have the skills to be able to treat them effectively. That’s what the fellowship did.”

The skills Dr. Eschweiler learned from participating in his fellowship allowed him to manage more cases of mental illness without need for referral. When a referral was needed for a complex or severe case, he had the confidence to bridge care and collaborate more effectively with psychiatric specialists.

“It was awesome, because we were able to communicate using the same language,” Dr. Eschweiler said of these collaborations. “It’s [about] talking that same language, starting those initial treatments, and then moving forward with specialty care, and vice versa. [Psychiatric specialists] would send me patients that needed medical care because of the types of medications they were taking. And I was then very well aware of those side effects and other issues that might come up from those treatments. So it’s a two-way street.”

Dr. Eschweiler was so impressed by his fellowship that he has since ushered multiple providers through the program since transitioning to an administrative role as director of nursing.

In Fargo, where psychiatric care is sparse and wait times for referral can be months long, Dr. Mullally, like Dr. Eschweiler, knew that she needed more training in mental health.

“I don’t feel like we get enough training in residency,” Dr. Mullally said. “So you do need to look at your options for further CME.”

Out of several CME courses she has taken to further her understanding of pediatric psychiatry, Dr. Mullally recommended The Reach Institute above all others, as their courses involve in-depth discussions and valuable handouts, particularly for medication selection.

“I think that a lot of the other CMEs tend to involve a lot more PowerPoint presentations,” Dr. Mullally said. “And you don’t necessarily leave with a lot of good documents. I still use my Reach handouts. I have them sitting right next to me. I use them every single day.”

Providers interested in The Reach Institute, however, should be prepared to invest both time and money, she added, citing a 2-3 day commitment, and calling it “not cheap.” To overcome these barriers, she suggested that providers get their institution to support their attendance.

For a lighter commitment, Dr. Iruku recommended the American Academy of Family Physicians CME portal, as this offers 13 online, accredited courses covering a range of topics, from adolescent health to substance abuse disorders.

Dr. Sieber suggested that primary care providers join the Collaborative Family Healthcare Association, which aims to integrate physical and behavioral health in routine practice. CFHA, of which he is a member, offers a “bevy of different resources” for interested providers, including a conference in Phoenix this October.

The interviewees disclosed no conflicts of interest.

A large proportion of U.S. adults who are prescribed schedule II stimulants are simultaneously receiving other CNS-active agents including benzodiazepines, opioids, and antidepressants – a potentially dangerous practice.

Investigators analyzed prescription drug claims for over 9.1 million U.S. adults over a 1-year period and found that 276,223 (3%) had used a schedule II stimulant, such as methylphenidate and amphetamines, during that time. Of these 276,223 patients, 45% combined these agents with one or more additional CNS-active drugs and almost 25% were simultaneously using two or more additional CNS-active drugs.

Close to half of the stimulant users were taking an antidepressant, while close to one-third filled prescriptions for anxiolytic/sedative/hypnotic meditations, and one-fifth received opioid prescriptions.

The widespread, often off-label use of these stimulants in combination therapy with antidepressants, anxiolytics, opioids, and other psychoactive drugs, “reveals new patterns of utilization beyond the approved use of stimulants as monotherapy for ADHD, but because there are so few studies of these kinds of combination therapy, both the advantages and additional risks [of this type of prescribing] remain unknown,” study investigator Thomas J. Moore, AB, faculty associate in epidemiology, Johns Hopkins Bloomberg School of Public Health and Johns Hopkins Medicine, Baltimore, told this news organization.

The study was published online in BMJ Open.
 

‘Dangerous’ substances

Amphetamines and methylphenidate are CNS stimulants that have been in use for almost a century. Like opioids and barbiturates, they’re considered “dangerous” and classified as schedule II Controlled Substances because of their high potential for abuse.

Over many years, these stimulants have been used for multiple purposes, including nasal congestion, narcolepsy, appetite suppression, binge eating, depression, senile behavior, lethargy, and ADHD, the researchers note.

Observational studies suggest medical use of these agents has been increasing in the United States. The investigators conducted previous research that revealed a 79% increase from 2013 to 2018 in the number of adults who self-report their use. The current study, said Mr. Moore, explores how these stimulants are being used.

For the study, data was extracted from the MarketScan 2019 and 2020 Commercial Claims and Encounters Databases, focusing on 9.1 million adults aged 19-64 years who were continuously enrolled in an included commercial benefit plan from Oct. 1, 2019 to Dec. 31, 2020.

The primary outcome consisted of an outpatient prescription claim, service date, and days’ supply for the CNS-active drugs.

The researchers defined “combination-2” therapy as 60 or more days of combination treatment with a schedule II stimulant and at least one additional CNS-active drug. “Combination-3” therapy was defined as the addition of at least two additional CNS-active drugs.

The researchers used service date and days’ supply to examine the number of stimulant and other CNS-active drugs for each of the days of 2020.

CNS-active drug classes included antidepressants, anxiolytics/sedatives/hypnotics, antipsychotics, opioids, anticonvulsants, and other CNS-active drugs.
 

Prescribing cascade

Of the total number of adults enrolled, 3% (n = 276,223) were taking schedule II stimulants during 2020, with a median of 8 (interquartile range, 4-11) prescriptions. These drugs provided 227 (IQR, 110-322) treatment days of exposure.

Among those taking stimulants 45.5% combined the use of at least one additional CNS-active drug for a median of 213 (IQR, 126-301) treatment days; and 24.3% used at least two additional CNS-active drugs for a median of 182 (IQR, 108-276) days.

“Clinicians should beware of the prescribing cascade. Sometimes it begins with an antidepressant that causes too much sedation, so a stimulant gets added, which leads to insomnia, so alprazolam gets added to the mix,” Mr. Moore said.

He cautioned that this “leaves a patient with multiple drugs, all with discontinuation effects of different kinds and clashing effects.”

These new findings, the investigators note, “add new public health concerns to those raised by our previous study. ... this more-detailed profile reveals several new patterns.”

Most patients become “long-term users” once treatment has started, with 75% continuing for a 1-year period.

“This underscores the possible risks of nonmedical use and dependence that have warranted the classification of these drugs as having high potential for psychological or physical dependence and their prominent appearance in toxicology drug rankings of fatal overdose cases,” they write.

They note that the data “do not indicate which intervention may have come first – a stimulant added to compensate for excess sedation from the benzodiazepine, or the alprazolam added to calm excessive CNS stimulation and/or insomnia from the stimulants or other drugs.”

Several limitations cited by the authors include the fact that, although the population encompassed 9.1 million people, it “may not represent all commercially insured adults,” and it doesn’t include people who aren’t covered by commercial insurance.

Moreover, the MarketScan dataset included up to four diagnosis codes for each outpatient and emergency department encounter; therefore, it was not possible to directly link the diagnoses to specific prescription drug claims, and thus the diagnoses were not evaluated.

“Since many providers will not accept a drug claim for a schedule II stimulant without an on-label diagnosis of ADHD,” the authors suspect that “large numbers of this diagnosis were present.”
 

Complex prescribing regimens

Mark Olfson, MD, MPH, professor of psychiatry, medicine, and law and professor of epidemiology, Columbia University Irving Medical Center, New York, said the report “highlights the pharmacological complexity of adults who are treated with stimulants.”

Columbia University

Dr. Olfson, who is a research psychiatrist at the New York State Psychiatric Institute, New York, and was not involved with the study, observed there is “evidence to support stimulants as an adjunctive therapy for treatment-resistant unipolar depression in older adults.”

However, he added, “this indication is unlikely to fully explain the high proportion of nonelderly, stimulant-treated adults who also receive antidepressants.”

These new findings “call for research to increase our understanding of the clinical contexts that motivate these complex prescribing regimens as well as their effectiveness and safety,” said Dr. Olfson.

The authors have not declared a specific grant for this research from any funding agency in the public, commercial, or not-for-profit sectors. Mr. Moore declares no relevant financial relationships. Coauthor G. Caleb Alexander, MD, is past chair and a current member of the Food and Drug Administration’s Peripheral and Central Nervous System Advisory Committee; is a cofounding principal and equity holder in Monument Analytics, a health care consultancy whose clients include the life sciences industry as well as plaintiffs in opioid litigation, for whom he has served as a paid expert witness; and is a past member of OptumRx’s National P&T Committee. Dr. Olfson declares no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A large proportion of U.S. adults who are prescribed schedule II stimulants are simultaneously receiving other CNS-active agents including benzodiazepines, opioids, and antidepressants – a potentially dangerous practice.

Investigators analyzed prescription drug claims for over 9.1 million U.S. adults over a 1-year period and found that 276,223 (3%) had used a schedule II stimulant, such as methylphenidate and amphetamines, during that time. Of these 276,223 patients, 45% combined these agents with one or more additional CNS-active drugs and almost 25% were simultaneously using two or more additional CNS-active drugs.

Close to half of the stimulant users were taking an antidepressant, while close to one-third filled prescriptions for anxiolytic/sedative/hypnotic meditations, and one-fifth received opioid prescriptions.

The widespread, often off-label use of these stimulants in combination therapy with antidepressants, anxiolytics, opioids, and other psychoactive drugs, “reveals new patterns of utilization beyond the approved use of stimulants as monotherapy for ADHD, but because there are so few studies of these kinds of combination therapy, both the advantages and additional risks [of this type of prescribing] remain unknown,” study investigator Thomas J. Moore, AB, faculty associate in epidemiology, Johns Hopkins Bloomberg School of Public Health and Johns Hopkins Medicine, Baltimore, told this news organization.

The study was published online in BMJ Open.
 

‘Dangerous’ substances

Amphetamines and methylphenidate are CNS stimulants that have been in use for almost a century. Like opioids and barbiturates, they’re considered “dangerous” and classified as schedule II Controlled Substances because of their high potential for abuse.

Over many years, these stimulants have been used for multiple purposes, including nasal congestion, narcolepsy, appetite suppression, binge eating, depression, senile behavior, lethargy, and ADHD, the researchers note.

Observational studies suggest medical use of these agents has been increasing in the United States. The investigators conducted previous research that revealed a 79% increase from 2013 to 2018 in the number of adults who self-report their use. The current study, said Mr. Moore, explores how these stimulants are being used.

For the study, data was extracted from the MarketScan 2019 and 2020 Commercial Claims and Encounters Databases, focusing on 9.1 million adults aged 19-64 years who were continuously enrolled in an included commercial benefit plan from Oct. 1, 2019 to Dec. 31, 2020.

The primary outcome consisted of an outpatient prescription claim, service date, and days’ supply for the CNS-active drugs.

The researchers defined “combination-2” therapy as 60 or more days of combination treatment with a schedule II stimulant and at least one additional CNS-active drug. “Combination-3” therapy was defined as the addition of at least two additional CNS-active drugs.

The researchers used service date and days’ supply to examine the number of stimulant and other CNS-active drugs for each of the days of 2020.

CNS-active drug classes included antidepressants, anxiolytics/sedatives/hypnotics, antipsychotics, opioids, anticonvulsants, and other CNS-active drugs.
 

Prescribing cascade

Of the total number of adults enrolled, 3% (n = 276,223) were taking schedule II stimulants during 2020, with a median of 8 (interquartile range, 4-11) prescriptions. These drugs provided 227 (IQR, 110-322) treatment days of exposure.

Among those taking stimulants 45.5% combined the use of at least one additional CNS-active drug for a median of 213 (IQR, 126-301) treatment days; and 24.3% used at least two additional CNS-active drugs for a median of 182 (IQR, 108-276) days.

“Clinicians should beware of the prescribing cascade. Sometimes it begins with an antidepressant that causes too much sedation, so a stimulant gets added, which leads to insomnia, so alprazolam gets added to the mix,” Mr. Moore said.

He cautioned that this “leaves a patient with multiple drugs, all with discontinuation effects of different kinds and clashing effects.”

These new findings, the investigators note, “add new public health concerns to those raised by our previous study. ... this more-detailed profile reveals several new patterns.”

Most patients become “long-term users” once treatment has started, with 75% continuing for a 1-year period.

“This underscores the possible risks of nonmedical use and dependence that have warranted the classification of these drugs as having high potential for psychological or physical dependence and their prominent appearance in toxicology drug rankings of fatal overdose cases,” they write.

They note that the data “do not indicate which intervention may have come first – a stimulant added to compensate for excess sedation from the benzodiazepine, or the alprazolam added to calm excessive CNS stimulation and/or insomnia from the stimulants or other drugs.”

Several limitations cited by the authors include the fact that, although the population encompassed 9.1 million people, it “may not represent all commercially insured adults,” and it doesn’t include people who aren’t covered by commercial insurance.

Moreover, the MarketScan dataset included up to four diagnosis codes for each outpatient and emergency department encounter; therefore, it was not possible to directly link the diagnoses to specific prescription drug claims, and thus the diagnoses were not evaluated.

“Since many providers will not accept a drug claim for a schedule II stimulant without an on-label diagnosis of ADHD,” the authors suspect that “large numbers of this diagnosis were present.”
 

Complex prescribing regimens

Mark Olfson, MD, MPH, professor of psychiatry, medicine, and law and professor of epidemiology, Columbia University Irving Medical Center, New York, said the report “highlights the pharmacological complexity of adults who are treated with stimulants.”

Columbia University

Dr. Olfson, who is a research psychiatrist at the New York State Psychiatric Institute, New York, and was not involved with the study, observed there is “evidence to support stimulants as an adjunctive therapy for treatment-resistant unipolar depression in older adults.”

However, he added, “this indication is unlikely to fully explain the high proportion of nonelderly, stimulant-treated adults who also receive antidepressants.”

These new findings “call for research to increase our understanding of the clinical contexts that motivate these complex prescribing regimens as well as their effectiveness and safety,” said Dr. Olfson.

The authors have not declared a specific grant for this research from any funding agency in the public, commercial, or not-for-profit sectors. Mr. Moore declares no relevant financial relationships. Coauthor G. Caleb Alexander, MD, is past chair and a current member of the Food and Drug Administration’s Peripheral and Central Nervous System Advisory Committee; is a cofounding principal and equity holder in Monument Analytics, a health care consultancy whose clients include the life sciences industry as well as plaintiffs in opioid litigation, for whom he has served as a paid expert witness; and is a past member of OptumRx’s National P&T Committee. Dr. Olfson declares no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A large proportion of U.S. adults who are prescribed schedule II stimulants are simultaneously receiving other CNS-active agents including benzodiazepines, opioids, and antidepressants – a potentially dangerous practice.

Investigators analyzed prescription drug claims for over 9.1 million U.S. adults over a 1-year period and found that 276,223 (3%) had used a schedule II stimulant, such as methylphenidate and amphetamines, during that time. Of these 276,223 patients, 45% combined these agents with one or more additional CNS-active drugs and almost 25% were simultaneously using two or more additional CNS-active drugs.

Close to half of the stimulant users were taking an antidepressant, while close to one-third filled prescriptions for anxiolytic/sedative/hypnotic meditations, and one-fifth received opioid prescriptions.

The widespread, often off-label use of these stimulants in combination therapy with antidepressants, anxiolytics, opioids, and other psychoactive drugs, “reveals new patterns of utilization beyond the approved use of stimulants as monotherapy for ADHD, but because there are so few studies of these kinds of combination therapy, both the advantages and additional risks [of this type of prescribing] remain unknown,” study investigator Thomas J. Moore, AB, faculty associate in epidemiology, Johns Hopkins Bloomberg School of Public Health and Johns Hopkins Medicine, Baltimore, told this news organization.

The study was published online in BMJ Open.
 

‘Dangerous’ substances

Amphetamines and methylphenidate are CNS stimulants that have been in use for almost a century. Like opioids and barbiturates, they’re considered “dangerous” and classified as schedule II Controlled Substances because of their high potential for abuse.

Over many years, these stimulants have been used for multiple purposes, including nasal congestion, narcolepsy, appetite suppression, binge eating, depression, senile behavior, lethargy, and ADHD, the researchers note.

Observational studies suggest medical use of these agents has been increasing in the United States. The investigators conducted previous research that revealed a 79% increase from 2013 to 2018 in the number of adults who self-report their use. The current study, said Mr. Moore, explores how these stimulants are being used.

For the study, data was extracted from the MarketScan 2019 and 2020 Commercial Claims and Encounters Databases, focusing on 9.1 million adults aged 19-64 years who were continuously enrolled in an included commercial benefit plan from Oct. 1, 2019 to Dec. 31, 2020.

The primary outcome consisted of an outpatient prescription claim, service date, and days’ supply for the CNS-active drugs.

The researchers defined “combination-2” therapy as 60 or more days of combination treatment with a schedule II stimulant and at least one additional CNS-active drug. “Combination-3” therapy was defined as the addition of at least two additional CNS-active drugs.

The researchers used service date and days’ supply to examine the number of stimulant and other CNS-active drugs for each of the days of 2020.

CNS-active drug classes included antidepressants, anxiolytics/sedatives/hypnotics, antipsychotics, opioids, anticonvulsants, and other CNS-active drugs.
 

Prescribing cascade

Of the total number of adults enrolled, 3% (n = 276,223) were taking schedule II stimulants during 2020, with a median of 8 (interquartile range, 4-11) prescriptions. These drugs provided 227 (IQR, 110-322) treatment days of exposure.

Among those taking stimulants 45.5% combined the use of at least one additional CNS-active drug for a median of 213 (IQR, 126-301) treatment days; and 24.3% used at least two additional CNS-active drugs for a median of 182 (IQR, 108-276) days.

“Clinicians should beware of the prescribing cascade. Sometimes it begins with an antidepressant that causes too much sedation, so a stimulant gets added, which leads to insomnia, so alprazolam gets added to the mix,” Mr. Moore said.

He cautioned that this “leaves a patient with multiple drugs, all with discontinuation effects of different kinds and clashing effects.”

These new findings, the investigators note, “add new public health concerns to those raised by our previous study. ... this more-detailed profile reveals several new patterns.”

Most patients become “long-term users” once treatment has started, with 75% continuing for a 1-year period.

“This underscores the possible risks of nonmedical use and dependence that have warranted the classification of these drugs as having high potential for psychological or physical dependence and their prominent appearance in toxicology drug rankings of fatal overdose cases,” they write.

They note that the data “do not indicate which intervention may have come first – a stimulant added to compensate for excess sedation from the benzodiazepine, or the alprazolam added to calm excessive CNS stimulation and/or insomnia from the stimulants or other drugs.”

Several limitations cited by the authors include the fact that, although the population encompassed 9.1 million people, it “may not represent all commercially insured adults,” and it doesn’t include people who aren’t covered by commercial insurance.

Moreover, the MarketScan dataset included up to four diagnosis codes for each outpatient and emergency department encounter; therefore, it was not possible to directly link the diagnoses to specific prescription drug claims, and thus the diagnoses were not evaluated.

“Since many providers will not accept a drug claim for a schedule II stimulant without an on-label diagnosis of ADHD,” the authors suspect that “large numbers of this diagnosis were present.”
 

Complex prescribing regimens

Mark Olfson, MD, MPH, professor of psychiatry, medicine, and law and professor of epidemiology, Columbia University Irving Medical Center, New York, said the report “highlights the pharmacological complexity of adults who are treated with stimulants.”

Columbia University

Dr. Olfson, who is a research psychiatrist at the New York State Psychiatric Institute, New York, and was not involved with the study, observed there is “evidence to support stimulants as an adjunctive therapy for treatment-resistant unipolar depression in older adults.”

However, he added, “this indication is unlikely to fully explain the high proportion of nonelderly, stimulant-treated adults who also receive antidepressants.”

These new findings “call for research to increase our understanding of the clinical contexts that motivate these complex prescribing regimens as well as their effectiveness and safety,” said Dr. Olfson.

The authors have not declared a specific grant for this research from any funding agency in the public, commercial, or not-for-profit sectors. Mr. Moore declares no relevant financial relationships. Coauthor G. Caleb Alexander, MD, is past chair and a current member of the Food and Drug Administration’s Peripheral and Central Nervous System Advisory Committee; is a cofounding principal and equity holder in Monument Analytics, a health care consultancy whose clients include the life sciences industry as well as plaintiffs in opioid litigation, for whom he has served as a paid expert witness; and is a past member of OptumRx’s National P&T Committee. Dr. Olfson declares no relevant financial relationships.

A version of this article first appeared on Medscape.com.

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

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

Parenteral medications in psychiatry

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

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

IV administration

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

Ketamine

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

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

Continue to: Ketamine is a schedule...

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

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

Aducanumab and lecanemab

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

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

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

Continue to: Aducanumab and lecanemab are generally...

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

Brexanolone

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

Magnesium

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

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

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

Continue to: The efficacy of oral magnesium...

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

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

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

Scopolamine

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

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

Continue to: Multiple animal studies show...

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

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

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

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

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

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

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

Clomipramine

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

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

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

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

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

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

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

Vortioxetine and citalopram

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

Injections and blocks

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

Stellate ganglion blocks

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

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

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

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

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

Glabellar BT injections

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

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

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

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

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

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

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

Trigger point injections

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

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

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

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

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

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

Bottom Line

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

Related Resources

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

Drug Brand Names

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

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

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

Parenteral medications in psychiatry

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

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

IV administration

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

Ketamine

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

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

Continue to: Ketamine is a schedule...

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

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

Aducanumab and lecanemab

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

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

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

Continue to: Aducanumab and lecanemab are generally...

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

Brexanolone

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

Magnesium

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

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

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

Continue to: The efficacy of oral magnesium...

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

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

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

Scopolamine

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

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

Continue to: Multiple animal studies show...

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

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

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

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

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

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

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

Clomipramine

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

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

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

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

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

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

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

Vortioxetine and citalopram

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

Injections and blocks

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

Stellate ganglion blocks

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

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

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

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

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

Glabellar BT injections

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

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

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

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

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

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

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

Trigger point injections

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

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

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

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

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

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

Bottom Line

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

Related Resources

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

Drug Brand Names

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

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

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

Parenteral medications in psychiatry

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

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

IV administration

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

Ketamine

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

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

Continue to: Ketamine is a schedule...

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

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

Aducanumab and lecanemab

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

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

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

Continue to: Aducanumab and lecanemab are generally...

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

Brexanolone

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

Magnesium

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

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

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

Continue to: The efficacy of oral magnesium...

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

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

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

Scopolamine

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

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

Continue to: Multiple animal studies show...

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

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

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

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

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

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

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

Clomipramine

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

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

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

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

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

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

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

Vortioxetine and citalopram

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

Injections and blocks

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

Stellate ganglion blocks

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

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

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

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

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

Glabellar BT injections

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

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

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

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

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

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

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

Trigger point injections

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

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

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

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

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

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

Bottom Line

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

Related Resources

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

Drug Brand Names

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

Memantine, a drug typically used to treat symptoms of Alzheimer’s disease, is linked to a significant reduction in symptoms of trichotillomania and skin-picking disorder, new research shows.

Results from the double-blind, placebo-controlled trial showed that 61% of participants who received memantine were “much or very much improved,” versus 8% in the placebo group.

“Memantine was far more effective than placebo,” lead investigator Jon Grant, MD, MPH, professor of psychiatry and behavioral neuroscience at the University of Chicago, said in an interview. “However, while subjects responded favorably, that didn’t necessarily mean there were no symptoms.”

The study was published online  in the American Journal of Psychiatry.
 

Underrecognized, disabling

The investigators noted that trichotillomania and skin-picking disorder are underrecognized and are often disabling conditions. However, the researchers pointed out that with prevalence rates of 1.7% for trichotillomania and 2.1% for skin-picking disorder, they are not uncommon.

Behavioral therapy that attempts to reverse these habits is considered first-line treatment, but trained therapists are difficult to find. In addition, the investigators wrote that currently, there are no Food and Drug Administration–approved medications for either disorder, and pharmacologic clinical trials are relatively uncommon.

The existing data from double-blind, placebo-controlled studies support the use of the antipsychotic olanzapine, the tricyclic antidepressant clomipramine, and the supplement N-acetyl-L-cysteine (NAC). Dr. Grant also noted that previous drug trials involving patients with trichotillomania have been very short in duration.

Prior research has implicated the glutamate system in repetitive motor habits and the urges that drive them. Memantine, a glutamate receptor antagonist, targets excessive glutamatergic drive. To investigate whether this medication may be beneficial for patients with trichotillomania and skin-picking disorders, the investigators conducted a randomized placebo-controlled trial.

The study included 100 adults (86 women; mean age, 31.4) with trichotillomania, skin-picking disorder, or both; participants received memantine (n = 55) or placebo (n = 45) for 8 weeks; they received memantine 10 mg or placebo for the first 2 weeks, then 20 mg for the next 6 weeks.

The researchers, who were blinded to assignment, assessed participants every 2 weeks using the National Institute of Mental Health Trichotillomania Symptom Severity Scale, which was modified to include questions for skin-picking disorder.

The team also tracked symptoms and behaviors using additional scales, including the Sheehan Disability Scale and the Clinical Global Impressions severity scale.

At the study’s conclusion, 79 patients remained. Of those, 26 of the 43 participants in the memantine group were “very much” or “much” improved (61%), versus 3 of 36 (8%) in the placebo group. (P < .0001)

Six participants in the memantine group experienced complete remission of symptoms, compared with one in the placebo group. There were no differences between the study groups in terms of adverse events.

Study limitations included the relatively short length of the trial for what should be considered a chronic disease, as well as the inclusion of only mildly to moderately symptomatic participants.

Dr. Grant said that he would like to study how memantine works in combination with behavioral therapy.
 

‘Two great options’

Katharine Phillips, MD, professor of psychiatry at Weill Cornell Medicine, New York, said she has been using memantine for “quite some time” to treat her patients with skin-picking disorder, adding that she uses higher doses of the drug than were tested in the study.

She noted that both NAC and memantine affect glutamate, an amino acid in the brain that is likely involved in repetitive physical or motor habits, such as hair pulling and skin picking.

“The good news is that we have two great options” for the treatment of trichotillomania and skin-picking disorder, said Dr. Phillips, and that both are easy to tolerate.

Future research should focus on longer trials of memantine and at higher doses, as well as other glutamate modulators, she said.

The study was funded by departmental research funds at the University of Chicago. Dr. Grant reported receiving research funding from Biohaven Pharmaceuticals and Janssen, as well as yearly compensation from Springer Publishing for his role as editor-in-chief of the Journal of Gambling Studies. He has also received royalties from American Psychiatric Publishing, McGraw Hill, Oxford University Press, and WW Norton. Dr. Phillips reported receiving royalties from American Psychiatric Publishing and an honorarium from the Merck Manual.

A version of this article first appeared on Medscape.com.

Memantine, a drug typically used to treat symptoms of Alzheimer’s disease, is linked to a significant reduction in symptoms of trichotillomania and skin-picking disorder, new research shows.

Results from the double-blind, placebo-controlled trial showed that 61% of participants who received memantine were “much or very much improved,” versus 8% in the placebo group.

“Memantine was far more effective than placebo,” lead investigator Jon Grant, MD, MPH, professor of psychiatry and behavioral neuroscience at the University of Chicago, said in an interview. “However, while subjects responded favorably, that didn’t necessarily mean there were no symptoms.”

The study was published online  in the American Journal of Psychiatry.
 

Underrecognized, disabling

The investigators noted that trichotillomania and skin-picking disorder are underrecognized and are often disabling conditions. However, the researchers pointed out that with prevalence rates of 1.7% for trichotillomania and 2.1% for skin-picking disorder, they are not uncommon.

Behavioral therapy that attempts to reverse these habits is considered first-line treatment, but trained therapists are difficult to find. In addition, the investigators wrote that currently, there are no Food and Drug Administration–approved medications for either disorder, and pharmacologic clinical trials are relatively uncommon.

The existing data from double-blind, placebo-controlled studies support the use of the antipsychotic olanzapine, the tricyclic antidepressant clomipramine, and the supplement N-acetyl-L-cysteine (NAC). Dr. Grant also noted that previous drug trials involving patients with trichotillomania have been very short in duration.

Prior research has implicated the glutamate system in repetitive motor habits and the urges that drive them. Memantine, a glutamate receptor antagonist, targets excessive glutamatergic drive. To investigate whether this medication may be beneficial for patients with trichotillomania and skin-picking disorders, the investigators conducted a randomized placebo-controlled trial.

The study included 100 adults (86 women; mean age, 31.4) with trichotillomania, skin-picking disorder, or both; participants received memantine (n = 55) or placebo (n = 45) for 8 weeks; they received memantine 10 mg or placebo for the first 2 weeks, then 20 mg for the next 6 weeks.

The researchers, who were blinded to assignment, assessed participants every 2 weeks using the National Institute of Mental Health Trichotillomania Symptom Severity Scale, which was modified to include questions for skin-picking disorder.

The team also tracked symptoms and behaviors using additional scales, including the Sheehan Disability Scale and the Clinical Global Impressions severity scale.

At the study’s conclusion, 79 patients remained. Of those, 26 of the 43 participants in the memantine group were “very much” or “much” improved (61%), versus 3 of 36 (8%) in the placebo group. (P < .0001)

Six participants in the memantine group experienced complete remission of symptoms, compared with one in the placebo group. There were no differences between the study groups in terms of adverse events.

Study limitations included the relatively short length of the trial for what should be considered a chronic disease, as well as the inclusion of only mildly to moderately symptomatic participants.

Dr. Grant said that he would like to study how memantine works in combination with behavioral therapy.
 

‘Two great options’

Katharine Phillips, MD, professor of psychiatry at Weill Cornell Medicine, New York, said she has been using memantine for “quite some time” to treat her patients with skin-picking disorder, adding that she uses higher doses of the drug than were tested in the study.

She noted that both NAC and memantine affect glutamate, an amino acid in the brain that is likely involved in repetitive physical or motor habits, such as hair pulling and skin picking.

“The good news is that we have two great options” for the treatment of trichotillomania and skin-picking disorder, said Dr. Phillips, and that both are easy to tolerate.

Future research should focus on longer trials of memantine and at higher doses, as well as other glutamate modulators, she said.

The study was funded by departmental research funds at the University of Chicago. Dr. Grant reported receiving research funding from Biohaven Pharmaceuticals and Janssen, as well as yearly compensation from Springer Publishing for his role as editor-in-chief of the Journal of Gambling Studies. He has also received royalties from American Psychiatric Publishing, McGraw Hill, Oxford University Press, and WW Norton. Dr. Phillips reported receiving royalties from American Psychiatric Publishing and an honorarium from the Merck Manual.

A version of this article first appeared on Medscape.com.

Memantine, a drug typically used to treat symptoms of Alzheimer’s disease, is linked to a significant reduction in symptoms of trichotillomania and skin-picking disorder, new research shows.

Results from the double-blind, placebo-controlled trial showed that 61% of participants who received memantine were “much or very much improved,” versus 8% in the placebo group.

“Memantine was far more effective than placebo,” lead investigator Jon Grant, MD, MPH, professor of psychiatry and behavioral neuroscience at the University of Chicago, said in an interview. “However, while subjects responded favorably, that didn’t necessarily mean there were no symptoms.”

The study was published online  in the American Journal of Psychiatry.
 

Underrecognized, disabling

The investigators noted that trichotillomania and skin-picking disorder are underrecognized and are often disabling conditions. However, the researchers pointed out that with prevalence rates of 1.7% for trichotillomania and 2.1% for skin-picking disorder, they are not uncommon.

Behavioral therapy that attempts to reverse these habits is considered first-line treatment, but trained therapists are difficult to find. In addition, the investigators wrote that currently, there are no Food and Drug Administration–approved medications for either disorder, and pharmacologic clinical trials are relatively uncommon.

The existing data from double-blind, placebo-controlled studies support the use of the antipsychotic olanzapine, the tricyclic antidepressant clomipramine, and the supplement N-acetyl-L-cysteine (NAC). Dr. Grant also noted that previous drug trials involving patients with trichotillomania have been very short in duration.

Prior research has implicated the glutamate system in repetitive motor habits and the urges that drive them. Memantine, a glutamate receptor antagonist, targets excessive glutamatergic drive. To investigate whether this medication may be beneficial for patients with trichotillomania and skin-picking disorders, the investigators conducted a randomized placebo-controlled trial.

The study included 100 adults (86 women; mean age, 31.4) with trichotillomania, skin-picking disorder, or both; participants received memantine (n = 55) or placebo (n = 45) for 8 weeks; they received memantine 10 mg or placebo for the first 2 weeks, then 20 mg for the next 6 weeks.

The researchers, who were blinded to assignment, assessed participants every 2 weeks using the National Institute of Mental Health Trichotillomania Symptom Severity Scale, which was modified to include questions for skin-picking disorder.

The team also tracked symptoms and behaviors using additional scales, including the Sheehan Disability Scale and the Clinical Global Impressions severity scale.

At the study’s conclusion, 79 patients remained. Of those, 26 of the 43 participants in the memantine group were “very much” or “much” improved (61%), versus 3 of 36 (8%) in the placebo group. (P < .0001)

Six participants in the memantine group experienced complete remission of symptoms, compared with one in the placebo group. There were no differences between the study groups in terms of adverse events.

Study limitations included the relatively short length of the trial for what should be considered a chronic disease, as well as the inclusion of only mildly to moderately symptomatic participants.

Dr. Grant said that he would like to study how memantine works in combination with behavioral therapy.
 

‘Two great options’

Katharine Phillips, MD, professor of psychiatry at Weill Cornell Medicine, New York, said she has been using memantine for “quite some time” to treat her patients with skin-picking disorder, adding that she uses higher doses of the drug than were tested in the study.

She noted that both NAC and memantine affect glutamate, an amino acid in the brain that is likely involved in repetitive physical or motor habits, such as hair pulling and skin picking.

“The good news is that we have two great options” for the treatment of trichotillomania and skin-picking disorder, said Dr. Phillips, and that both are easy to tolerate.

Future research should focus on longer trials of memantine and at higher doses, as well as other glutamate modulators, she said.

The study was funded by departmental research funds at the University of Chicago. Dr. Grant reported receiving research funding from Biohaven Pharmaceuticals and Janssen, as well as yearly compensation from Springer Publishing for his role as editor-in-chief of the Journal of Gambling Studies. He has also received royalties from American Psychiatric Publishing, McGraw Hill, Oxford University Press, and WW Norton. Dr. Phillips reported receiving royalties from American Psychiatric Publishing and an honorarium from the Merck Manual.

A version of this article first appeared on Medscape.com.

Obsessive-compulsive disorder (OCD) is transmitted from parent to child mostly through genetics and not the way a child is raised, new research suggests.

This finding from a large, register-based study is particularly surprising because results from previous studies of major depression and anxiety disorder have shown a significant effect of parenting and a child’s home environment on the risk for these disorders, the investigators noted.

While the results likely won’t change patient treatment, one expert said it could alleviate concerns of some parents with OCD who fear that witnessing their obsessive behaviors might put their children at higher risk for the disorder.

“The evidence is consistent with the idea that the psychological transmission of OCD from parent to child, if it exists, is really pretty weak,” lead author Kenneth S. Kendler, MD, professor of psychiatry and director of the Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, said in an interview.

The findings were published online in JAMA Psychiatry.
 

Family analysis

The study is the first to include adoptive parents in an analysis of OCD transmission, which allowed investigators to answer the nature versus nurture question that is often difficult to decipher.

Working with Swedish population registries, researchers identified more than 2.4 million offspring. Of these, 27,141 individuals (1.1%) had a lifetime diagnosis of OCD.

Families were divided into four types: intact families, with kids who lived at home with their biological parents from birth to at least age 15 years; families with kids who never lived with their biological father; families with children who did not live with their biological fathers between birth and age 15 years but who lived with a stepfather for at least 10 of those years; and families with children who were adopted before the age of 5 by people with no biological connection to the child.

After analyzing data from all parent-child relationships, researchers found that genes plus rearing (odds ratio, 3.94; 95% confidence interval, 3.58-4.33) and genes only (OR, 3.34; 95% CI, 2.27-4.93) were significantly more likely to be correlated to transmission of OCD from parent to offspring than rearing alone. Rearing only (OR, 1.4; 95% CI, 0.45-4.39) was not significantly correlated with OCD transmission

“It appears from our data that the only substantial transmission that occurs is in the genes parents transmit, not by the modeling of behavior,” Dr. Kendler said.

“There’s an idea that you can learn some things from your parents from psychopathology, but we didn’t see that kids picked that up much in the case of OCD,” he added.

However, there was one outlier: Children raised by stepparents or adoptive parents with an anxiety disorder had a greater risk of developing OCD.

Given the lack of evidence of a strong rearing effect in other analyses, Dr. Kendler noted that this rogue finding could be caused by an underpowered sample; the researchers plan to study the data further.

“Psychiatric disorders, like many other conditions, are often correlated with neighboring conditions,” he said. “Our study would suggest that some of the molecular genetic variants between OCD and generalized anxiety disorder or other anxiety disorders would be shared, but some would be unique.”
 

Answers an old question

In a comment, Jon Grant, JD, MD, MPH, professor of psychiatry and director of the Addictive, Compulsive, and Impulsive Disorders Research Lab at the University of Chicago, said the findings fill an important gap in what is known about OCD.

“I think the findings are really answering this old question of: ‘Is OCD due to the rearing patterns in a family versus genetics?’ This was able to get at that information showing that it’s virtually all due to genetics within families, and that’s really good to know,” said Dr. Grant, who was not a part of the study.

He was also struck by the finding of a strong genetic relationship between OCD and generalized anxiety disorder (GAD).

While identifying that OCD and GAD are genetically linked likely won’t change clinical care, “I think it at least allows clinicians to know when we see that comorbidity that it may be much more genetically linked in the case of GAD,” Dr. Grant said.

The study was funded by the Swedish Research Council, as well as Avtal om Läkarutbildning och Forskning funding from Region Skåne. Dr. Kendler and Dr. Grant reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Obsessive-compulsive disorder (OCD) is transmitted from parent to child mostly through genetics and not the way a child is raised, new research suggests.

This finding from a large, register-based study is particularly surprising because results from previous studies of major depression and anxiety disorder have shown a significant effect of parenting and a child’s home environment on the risk for these disorders, the investigators noted.

While the results likely won’t change patient treatment, one expert said it could alleviate concerns of some parents with OCD who fear that witnessing their obsessive behaviors might put their children at higher risk for the disorder.

“The evidence is consistent with the idea that the psychological transmission of OCD from parent to child, if it exists, is really pretty weak,” lead author Kenneth S. Kendler, MD, professor of psychiatry and director of the Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, said in an interview.

The findings were published online in JAMA Psychiatry.
 

Family analysis

The study is the first to include adoptive parents in an analysis of OCD transmission, which allowed investigators to answer the nature versus nurture question that is often difficult to decipher.

Working with Swedish population registries, researchers identified more than 2.4 million offspring. Of these, 27,141 individuals (1.1%) had a lifetime diagnosis of OCD.

Families were divided into four types: intact families, with kids who lived at home with their biological parents from birth to at least age 15 years; families with kids who never lived with their biological father; families with children who did not live with their biological fathers between birth and age 15 years but who lived with a stepfather for at least 10 of those years; and families with children who were adopted before the age of 5 by people with no biological connection to the child.

After analyzing data from all parent-child relationships, researchers found that genes plus rearing (odds ratio, 3.94; 95% confidence interval, 3.58-4.33) and genes only (OR, 3.34; 95% CI, 2.27-4.93) were significantly more likely to be correlated to transmission of OCD from parent to offspring than rearing alone. Rearing only (OR, 1.4; 95% CI, 0.45-4.39) was not significantly correlated with OCD transmission

“It appears from our data that the only substantial transmission that occurs is in the genes parents transmit, not by the modeling of behavior,” Dr. Kendler said.

“There’s an idea that you can learn some things from your parents from psychopathology, but we didn’t see that kids picked that up much in the case of OCD,” he added.

However, there was one outlier: Children raised by stepparents or adoptive parents with an anxiety disorder had a greater risk of developing OCD.

Given the lack of evidence of a strong rearing effect in other analyses, Dr. Kendler noted that this rogue finding could be caused by an underpowered sample; the researchers plan to study the data further.

“Psychiatric disorders, like many other conditions, are often correlated with neighboring conditions,” he said. “Our study would suggest that some of the molecular genetic variants between OCD and generalized anxiety disorder or other anxiety disorders would be shared, but some would be unique.”
 

Answers an old question

In a comment, Jon Grant, JD, MD, MPH, professor of psychiatry and director of the Addictive, Compulsive, and Impulsive Disorders Research Lab at the University of Chicago, said the findings fill an important gap in what is known about OCD.

“I think the findings are really answering this old question of: ‘Is OCD due to the rearing patterns in a family versus genetics?’ This was able to get at that information showing that it’s virtually all due to genetics within families, and that’s really good to know,” said Dr. Grant, who was not a part of the study.

He was also struck by the finding of a strong genetic relationship between OCD and generalized anxiety disorder (GAD).

While identifying that OCD and GAD are genetically linked likely won’t change clinical care, “I think it at least allows clinicians to know when we see that comorbidity that it may be much more genetically linked in the case of GAD,” Dr. Grant said.

The study was funded by the Swedish Research Council, as well as Avtal om Läkarutbildning och Forskning funding from Region Skåne. Dr. Kendler and Dr. Grant reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Obsessive-compulsive disorder (OCD) is transmitted from parent to child mostly through genetics and not the way a child is raised, new research suggests.

This finding from a large, register-based study is particularly surprising because results from previous studies of major depression and anxiety disorder have shown a significant effect of parenting and a child’s home environment on the risk for these disorders, the investigators noted.

While the results likely won’t change patient treatment, one expert said it could alleviate concerns of some parents with OCD who fear that witnessing their obsessive behaviors might put their children at higher risk for the disorder.

“The evidence is consistent with the idea that the psychological transmission of OCD from parent to child, if it exists, is really pretty weak,” lead author Kenneth S. Kendler, MD, professor of psychiatry and director of the Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, said in an interview.

The findings were published online in JAMA Psychiatry.
 

Family analysis

The study is the first to include adoptive parents in an analysis of OCD transmission, which allowed investigators to answer the nature versus nurture question that is often difficult to decipher.

Working with Swedish population registries, researchers identified more than 2.4 million offspring. Of these, 27,141 individuals (1.1%) had a lifetime diagnosis of OCD.

Families were divided into four types: intact families, with kids who lived at home with their biological parents from birth to at least age 15 years; families with kids who never lived with their biological father; families with children who did not live with their biological fathers between birth and age 15 years but who lived with a stepfather for at least 10 of those years; and families with children who were adopted before the age of 5 by people with no biological connection to the child.

After analyzing data from all parent-child relationships, researchers found that genes plus rearing (odds ratio, 3.94; 95% confidence interval, 3.58-4.33) and genes only (OR, 3.34; 95% CI, 2.27-4.93) were significantly more likely to be correlated to transmission of OCD from parent to offspring than rearing alone. Rearing only (OR, 1.4; 95% CI, 0.45-4.39) was not significantly correlated with OCD transmission

“It appears from our data that the only substantial transmission that occurs is in the genes parents transmit, not by the modeling of behavior,” Dr. Kendler said.

“There’s an idea that you can learn some things from your parents from psychopathology, but we didn’t see that kids picked that up much in the case of OCD,” he added.

However, there was one outlier: Children raised by stepparents or adoptive parents with an anxiety disorder had a greater risk of developing OCD.

Given the lack of evidence of a strong rearing effect in other analyses, Dr. Kendler noted that this rogue finding could be caused by an underpowered sample; the researchers plan to study the data further.

“Psychiatric disorders, like many other conditions, are often correlated with neighboring conditions,” he said. “Our study would suggest that some of the molecular genetic variants between OCD and generalized anxiety disorder or other anxiety disorders would be shared, but some would be unique.”
 

Answers an old question

In a comment, Jon Grant, JD, MD, MPH, professor of psychiatry and director of the Addictive, Compulsive, and Impulsive Disorders Research Lab at the University of Chicago, said the findings fill an important gap in what is known about OCD.

“I think the findings are really answering this old question of: ‘Is OCD due to the rearing patterns in a family versus genetics?’ This was able to get at that information showing that it’s virtually all due to genetics within families, and that’s really good to know,” said Dr. Grant, who was not a part of the study.

He was also struck by the finding of a strong genetic relationship between OCD and generalized anxiety disorder (GAD).

While identifying that OCD and GAD are genetically linked likely won’t change clinical care, “I think it at least allows clinicians to know when we see that comorbidity that it may be much more genetically linked in the case of GAD,” Dr. Grant said.

The study was funded by the Swedish Research Council, as well as Avtal om Läkarutbildning och Forskning funding from Region Skåne. Dr. Kendler and Dr. Grant reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A network of neural connections is linked to six psychiatric disorders: schizophrenia, bipolar disorder (BD), depression, addiction, obsessive-compulsive disorder (OCD), and anxiety, new research shows.

Investigators used coordinate and lesion network mapping to assess whether there was a shared brain network common to multiple psychiatric disorders. In a meta-analysis of almost 200 studies encompassing more than 15,000 individuals, they found that atrophy coordinates across these six psychiatric conditions all mapped to a common brain network.

Moreover, lesion damage to this network in patients with penetrating head trauma correlated with the number of psychiatric illnesses that the patients were diagnosed with post trauma.

The findings have “bigger-picture potential implications,” lead author Joseph Taylor, MD, PhD, medical director of transcranial magnetic stimulation at Brigham and Women’s Hospital’s Center for Brain Circuit Therapeutics, Boston, told this news organization.

“In psychiatry, we talk about symptoms and define our disorders based on symptom checklists, which are fairly reliable but don’t have neurobiological underpinnings,” said Dr. Taylor, who is also an associate psychiatrist in Brigham’s department of psychiatry.

By contrast, “in neurology, we ask: ‘Where is the lesion?’ Studying brain networks could potentially help us diagnose and treat people with psychiatric illness more effectively, just as we treat neurological disorders,” he added.

The findings were published online in Nature Human Behavior.
 

Beyond symptom checklists

Dr. Taylor noted that, in the field of psychiatry, “we often study disorders in isolation,” such as generalized anxiety disorder and major depressive disorder.

“But what see clinically is that half of patients meet the criteria for more than one psychiatric disorder,” he said. “It can be difficult to diagnose and treat these patients, and there are worse treatment outcomes.”

There is also a “discrepancy” between how these disorders are studied (one at a time) and how patients are treated in clinic, Dr. Taylor noted. And there is increasing evidence that psychiatric disorders may share a common neurobiology.

This “highlights the possibility of potentially developing transdiagnostic treatments based on common neurobiology, not just symptom checklists,” Dr. Taylor said.

Prior work “has attempted to map abnormalities to common brain regions rather than to a common brain network,” the investigators wrote. Moreover, “prior studies have rarely tested specificity by comparing psychiatric disorders to other brain disorders.”

In the current study, the researchers used “morphometric brain lesion datasets coupled with a wiring diagram of the human brain to derive a convergent brain network for psychiatric illness.”

They analyzed four large published datasets. Dataset 1 was sourced from an activation likelihood estimation meta-analysis (ALE) of whole-brain voxel-based studies that compared patients with psychiatric disorders such as schizophrenia, BD, depression, addiction, OCD, and anxiety to healthy controls (n = 193 studies; 15,892 individuals in total).

Dataset 2 was drawn from published neuroimaging studies involving patients with Alzheimer’s disease (AD) and other neurodegenerative conditions (n = 72 studies). They reported coordinates regarding which patients with these disorders had more atrophy compared with control persons.

Dataset 3 was sourced from the Vietnam Head Injury study, which followed veterans with and those without penetrating head injuries (n = 194 veterans with injuries). Dataset 4 was sourced from published neurosurgical ablation coordinates for depression.
 

Shared neurobiology

Upon analyzing dataset 1, the researchers found decreased gray matter in the bilateral anterior insula, dorsal anterior cingulate cortex, dorsomedial prefrontal cortex, thalamus, amygdala, hippocampus, and parietal operculum – findings that are “consistent with prior work.”

However, fewer than 35% of the studies contributed to any single cluster; and no cluster was specific to psychiatric versus neurodegenerative coordinates (drawn from dataset 2).

On the other hand, coordinate network mapping yielded “more statistically robust” (P < .001) results, which were found in 85% of the studies. “Psychiatric atrophy coordinates were functionally connected to the same network of brain regions,” the researchers reported.

This network was defined by two types of connectivity, positive and negative.

“The topography of this transdiagnostic network was independent of the statistical threshold and specific to psychiatric (vs. neurodegenerative) disorders, with the strongest peak occurring in the posterior parietal cortex (Brodmann Area 7) near the intraparietal sulcus,” the investigators wrote.

When lesions from dataset 3 were overlaid onto the ALE map and the transdiagnostic network in order to evaluate whether damage to either map correlated with number of post-lesion psychiatric diagnosis, results showed no evidence of a correlation between psychiatric comorbidity and damage on the ALE map (Pearson r, 0.02; P = .766).

However, when the same approach was applied to the transdiagnostic network, a statistically significant correlation was found between psychiatric comorbidity and lesion damage (Pearson r, –0.21; P = .01). A multiple regression model showed that the transdiagnostic, but not the ALE, network “independently predicted the number of post-lesion psychiatric diagnoses” (P = .003 vs. P = .1), the investigators reported.

All four neurosurgical ablative targets for psychiatric disorders found on analysis of dataset 4 “intersected” and aligned with the transdiagnostic network.

“The study does not immediately impact clinical practice, but it would be helpful for practicing clinicians to know that psychiatric disorders commonly co-occur and might share common neurobiology and a convergent brain network,” Dr. Taylor said.

“Future work based on our findings could potentially influence clinical trials and clinical practice, especially in the area of brain stimulation,” he added.
 

‘Exciting new targets’

In a comment, Desmond Oathes, PhD, associate director, Center for Neuromodulation and Stress, University of Pennsylvania, Philadelphia, said the “next step in the science is to combine individual brain imaging, aka, ‘individualized connectomes,’ with these promising group maps to determine something meaningful at the individual patient level.”

Dr. Oathes, who is also a faculty clinician at the Center for the Treatment and Study of Anxiety and was not involved with the study, noted that an open question is whether the brain volume abnormalities/atrophy “can be changed with treatment and in what direction.”

A “strong take-home message from this paper is that brain volume measures from single coordinates are noisy as measures of psychiatric abnormality, whereas network effects seem to be especially sensitive for capturing these effects,” Dr. Oathes said.

The “abnormal networks across these disorders do not fit easily into well-known networks from healthy participants. However, they map well onto other databases relevant to psychiatric disorders and offer exciting new potential targets for prospective treatment studies,” he added.

The investigators received no specific funding for this work. Dr. Taylor reported no relevant financial relationships. Dr. Oathes reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A network of neural connections is linked to six psychiatric disorders: schizophrenia, bipolar disorder (BD), depression, addiction, obsessive-compulsive disorder (OCD), and anxiety, new research shows.

Investigators used coordinate and lesion network mapping to assess whether there was a shared brain network common to multiple psychiatric disorders. In a meta-analysis of almost 200 studies encompassing more than 15,000 individuals, they found that atrophy coordinates across these six psychiatric conditions all mapped to a common brain network.

Moreover, lesion damage to this network in patients with penetrating head trauma correlated with the number of psychiatric illnesses that the patients were diagnosed with post trauma.

The findings have “bigger-picture potential implications,” lead author Joseph Taylor, MD, PhD, medical director of transcranial magnetic stimulation at Brigham and Women’s Hospital’s Center for Brain Circuit Therapeutics, Boston, told this news organization.

“In psychiatry, we talk about symptoms and define our disorders based on symptom checklists, which are fairly reliable but don’t have neurobiological underpinnings,” said Dr. Taylor, who is also an associate psychiatrist in Brigham’s department of psychiatry.

By contrast, “in neurology, we ask: ‘Where is the lesion?’ Studying brain networks could potentially help us diagnose and treat people with psychiatric illness more effectively, just as we treat neurological disorders,” he added.

The findings were published online in Nature Human Behavior.
 

Beyond symptom checklists

Dr. Taylor noted that, in the field of psychiatry, “we often study disorders in isolation,” such as generalized anxiety disorder and major depressive disorder.

“But what see clinically is that half of patients meet the criteria for more than one psychiatric disorder,” he said. “It can be difficult to diagnose and treat these patients, and there are worse treatment outcomes.”

There is also a “discrepancy” between how these disorders are studied (one at a time) and how patients are treated in clinic, Dr. Taylor noted. And there is increasing evidence that psychiatric disorders may share a common neurobiology.

This “highlights the possibility of potentially developing transdiagnostic treatments based on common neurobiology, not just symptom checklists,” Dr. Taylor said.

Prior work “has attempted to map abnormalities to common brain regions rather than to a common brain network,” the investigators wrote. Moreover, “prior studies have rarely tested specificity by comparing psychiatric disorders to other brain disorders.”

In the current study, the researchers used “morphometric brain lesion datasets coupled with a wiring diagram of the human brain to derive a convergent brain network for psychiatric illness.”

They analyzed four large published datasets. Dataset 1 was sourced from an activation likelihood estimation meta-analysis (ALE) of whole-brain voxel-based studies that compared patients with psychiatric disorders such as schizophrenia, BD, depression, addiction, OCD, and anxiety to healthy controls (n = 193 studies; 15,892 individuals in total).

Dataset 2 was drawn from published neuroimaging studies involving patients with Alzheimer’s disease (AD) and other neurodegenerative conditions (n = 72 studies). They reported coordinates regarding which patients with these disorders had more atrophy compared with control persons.

Dataset 3 was sourced from the Vietnam Head Injury study, which followed veterans with and those without penetrating head injuries (n = 194 veterans with injuries). Dataset 4 was sourced from published neurosurgical ablation coordinates for depression.
 

Shared neurobiology

Upon analyzing dataset 1, the researchers found decreased gray matter in the bilateral anterior insula, dorsal anterior cingulate cortex, dorsomedial prefrontal cortex, thalamus, amygdala, hippocampus, and parietal operculum – findings that are “consistent with prior work.”

However, fewer than 35% of the studies contributed to any single cluster; and no cluster was specific to psychiatric versus neurodegenerative coordinates (drawn from dataset 2).

On the other hand, coordinate network mapping yielded “more statistically robust” (P < .001) results, which were found in 85% of the studies. “Psychiatric atrophy coordinates were functionally connected to the same network of brain regions,” the researchers reported.

This network was defined by two types of connectivity, positive and negative.

“The topography of this transdiagnostic network was independent of the statistical threshold and specific to psychiatric (vs. neurodegenerative) disorders, with the strongest peak occurring in the posterior parietal cortex (Brodmann Area 7) near the intraparietal sulcus,” the investigators wrote.

When lesions from dataset 3 were overlaid onto the ALE map and the transdiagnostic network in order to evaluate whether damage to either map correlated with number of post-lesion psychiatric diagnosis, results showed no evidence of a correlation between psychiatric comorbidity and damage on the ALE map (Pearson r, 0.02; P = .766).

However, when the same approach was applied to the transdiagnostic network, a statistically significant correlation was found between psychiatric comorbidity and lesion damage (Pearson r, –0.21; P = .01). A multiple regression model showed that the transdiagnostic, but not the ALE, network “independently predicted the number of post-lesion psychiatric diagnoses” (P = .003 vs. P = .1), the investigators reported.

All four neurosurgical ablative targets for psychiatric disorders found on analysis of dataset 4 “intersected” and aligned with the transdiagnostic network.

“The study does not immediately impact clinical practice, but it would be helpful for practicing clinicians to know that psychiatric disorders commonly co-occur and might share common neurobiology and a convergent brain network,” Dr. Taylor said.

“Future work based on our findings could potentially influence clinical trials and clinical practice, especially in the area of brain stimulation,” he added.
 

‘Exciting new targets’

In a comment, Desmond Oathes, PhD, associate director, Center for Neuromodulation and Stress, University of Pennsylvania, Philadelphia, said the “next step in the science is to combine individual brain imaging, aka, ‘individualized connectomes,’ with these promising group maps to determine something meaningful at the individual patient level.”

Dr. Oathes, who is also a faculty clinician at the Center for the Treatment and Study of Anxiety and was not involved with the study, noted that an open question is whether the brain volume abnormalities/atrophy “can be changed with treatment and in what direction.”

A “strong take-home message from this paper is that brain volume measures from single coordinates are noisy as measures of psychiatric abnormality, whereas network effects seem to be especially sensitive for capturing these effects,” Dr. Oathes said.

The “abnormal networks across these disorders do not fit easily into well-known networks from healthy participants. However, they map well onto other databases relevant to psychiatric disorders and offer exciting new potential targets for prospective treatment studies,” he added.

The investigators received no specific funding for this work. Dr. Taylor reported no relevant financial relationships. Dr. Oathes reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A network of neural connections is linked to six psychiatric disorders: schizophrenia, bipolar disorder (BD), depression, addiction, obsessive-compulsive disorder (OCD), and anxiety, new research shows.

Investigators used coordinate and lesion network mapping to assess whether there was a shared brain network common to multiple psychiatric disorders. In a meta-analysis of almost 200 studies encompassing more than 15,000 individuals, they found that atrophy coordinates across these six psychiatric conditions all mapped to a common brain network.

Moreover, lesion damage to this network in patients with penetrating head trauma correlated with the number of psychiatric illnesses that the patients were diagnosed with post trauma.

The findings have “bigger-picture potential implications,” lead author Joseph Taylor, MD, PhD, medical director of transcranial magnetic stimulation at Brigham and Women’s Hospital’s Center for Brain Circuit Therapeutics, Boston, told this news organization.

“In psychiatry, we talk about symptoms and define our disorders based on symptom checklists, which are fairly reliable but don’t have neurobiological underpinnings,” said Dr. Taylor, who is also an associate psychiatrist in Brigham’s department of psychiatry.

By contrast, “in neurology, we ask: ‘Where is the lesion?’ Studying brain networks could potentially help us diagnose and treat people with psychiatric illness more effectively, just as we treat neurological disorders,” he added.

The findings were published online in Nature Human Behavior.
 

Beyond symptom checklists

Dr. Taylor noted that, in the field of psychiatry, “we often study disorders in isolation,” such as generalized anxiety disorder and major depressive disorder.

“But what see clinically is that half of patients meet the criteria for more than one psychiatric disorder,” he said. “It can be difficult to diagnose and treat these patients, and there are worse treatment outcomes.”

There is also a “discrepancy” between how these disorders are studied (one at a time) and how patients are treated in clinic, Dr. Taylor noted. And there is increasing evidence that psychiatric disorders may share a common neurobiology.

This “highlights the possibility of potentially developing transdiagnostic treatments based on common neurobiology, not just symptom checklists,” Dr. Taylor said.

Prior work “has attempted to map abnormalities to common brain regions rather than to a common brain network,” the investigators wrote. Moreover, “prior studies have rarely tested specificity by comparing psychiatric disorders to other brain disorders.”

In the current study, the researchers used “morphometric brain lesion datasets coupled with a wiring diagram of the human brain to derive a convergent brain network for psychiatric illness.”

They analyzed four large published datasets. Dataset 1 was sourced from an activation likelihood estimation meta-analysis (ALE) of whole-brain voxel-based studies that compared patients with psychiatric disorders such as schizophrenia, BD, depression, addiction, OCD, and anxiety to healthy controls (n = 193 studies; 15,892 individuals in total).

Dataset 2 was drawn from published neuroimaging studies involving patients with Alzheimer’s disease (AD) and other neurodegenerative conditions (n = 72 studies). They reported coordinates regarding which patients with these disorders had more atrophy compared with control persons.

Dataset 3 was sourced from the Vietnam Head Injury study, which followed veterans with and those without penetrating head injuries (n = 194 veterans with injuries). Dataset 4 was sourced from published neurosurgical ablation coordinates for depression.
 

Shared neurobiology

Upon analyzing dataset 1, the researchers found decreased gray matter in the bilateral anterior insula, dorsal anterior cingulate cortex, dorsomedial prefrontal cortex, thalamus, amygdala, hippocampus, and parietal operculum – findings that are “consistent with prior work.”

However, fewer than 35% of the studies contributed to any single cluster; and no cluster was specific to psychiatric versus neurodegenerative coordinates (drawn from dataset 2).

On the other hand, coordinate network mapping yielded “more statistically robust” (P < .001) results, which were found in 85% of the studies. “Psychiatric atrophy coordinates were functionally connected to the same network of brain regions,” the researchers reported.

This network was defined by two types of connectivity, positive and negative.

“The topography of this transdiagnostic network was independent of the statistical threshold and specific to psychiatric (vs. neurodegenerative) disorders, with the strongest peak occurring in the posterior parietal cortex (Brodmann Area 7) near the intraparietal sulcus,” the investigators wrote.

When lesions from dataset 3 were overlaid onto the ALE map and the transdiagnostic network in order to evaluate whether damage to either map correlated with number of post-lesion psychiatric diagnosis, results showed no evidence of a correlation between psychiatric comorbidity and damage on the ALE map (Pearson r, 0.02; P = .766).

However, when the same approach was applied to the transdiagnostic network, a statistically significant correlation was found between psychiatric comorbidity and lesion damage (Pearson r, –0.21; P = .01). A multiple regression model showed that the transdiagnostic, but not the ALE, network “independently predicted the number of post-lesion psychiatric diagnoses” (P = .003 vs. P = .1), the investigators reported.

All four neurosurgical ablative targets for psychiatric disorders found on analysis of dataset 4 “intersected” and aligned with the transdiagnostic network.

“The study does not immediately impact clinical practice, but it would be helpful for practicing clinicians to know that psychiatric disorders commonly co-occur and might share common neurobiology and a convergent brain network,” Dr. Taylor said.

“Future work based on our findings could potentially influence clinical trials and clinical practice, especially in the area of brain stimulation,” he added.
 

‘Exciting new targets’

In a comment, Desmond Oathes, PhD, associate director, Center for Neuromodulation and Stress, University of Pennsylvania, Philadelphia, said the “next step in the science is to combine individual brain imaging, aka, ‘individualized connectomes,’ with these promising group maps to determine something meaningful at the individual patient level.”

Dr. Oathes, who is also a faculty clinician at the Center for the Treatment and Study of Anxiety and was not involved with the study, noted that an open question is whether the brain volume abnormalities/atrophy “can be changed with treatment and in what direction.”

A “strong take-home message from this paper is that brain volume measures from single coordinates are noisy as measures of psychiatric abnormality, whereas network effects seem to be especially sensitive for capturing these effects,” Dr. Oathes said.

The “abnormal networks across these disorders do not fit easily into well-known networks from healthy participants. However, they map well onto other databases relevant to psychiatric disorders and offer exciting new potential targets for prospective treatment studies,” he added.

The investigators received no specific funding for this work. Dr. Taylor reported no relevant financial relationships. Dr. Oathes reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.