Mental Health

The U.S. Preventive Services Task Force on Apr. 12 posted draft recommendations on screening for depression and anxiety in children and adolescents.

For the first time, the USPSTF is recommending screening children ages 8 and older for anxiety.

It also recommended screening children ages 12 and older for depression, which was consistent with the USPSTF’s prior recommendations on the topic.

These B-grade draft recommendations are for children and teens who are not showing signs or symptoms of these conditions. The task force emphasized that anyone who has concerns about or shows signs of these conditions should be connected to care.

Task force member Martha Kubik, PhD, RN, a professor with George Mason University, Fairfax, Va, said in a statement: “Fortunately, we found that screening older children for anxiety and depression is effective in identifying these conditions so children and teens can be connected to the support they need.”

The group cited in its recommendation on anxiety the 2018-2019 National Survey of Children’s Health, which found that 7.8% of children and adolescents ages 3-17 years had a current anxiety disorder. It also noted that the National Survey on LGBTQ Youth Mental Health found that 72% of LGBTQ youth and 77% of transgender and nonbinary youth described general anxiety disorder symptoms.

“Anxiety disorders in childhood and adolescence are associated with an increased likelihood of a future anxiety disorder or depression,” the task force authors wrote.

They highlighted that “the prevalence of anxiety in Black youth may be evolving.” Previously, studies had suggested that young Black people may have had lower rates of mental health disorders, compared with their White counterparts.

“However, recent cohorts of Black children or adolescents have reported a higher prevalence of anxiety disorders than in the past,” the authors wrote.

Joanna Quigley, MD, clinical associate professor and associate medical director for child & adolescent services at the University of Michigan, Ann Arbor, said in an interview she was not surprised the USPSTF recommended screening for anxiety starting at age 8.

That’s when parents and providers see anxiety disorders begin to present or become more problematic, she said.

“It’s also acknowledging the importance of prevention,” she said. “The sooner we can identify these challenges for kids, the sooner we can intervene and have better outcomes for that child across their lifespan.”

Screening gets providers and families in the habit of thinking about these concerns when a child or adolescent comes in for another kind of visit, Dr. Quigley said. Chest pains in a well-child check, for example, may trigger thoughts to consider anxiety later if the child is brought in for a cardiac check for chest pains.

“It creates a culture of awareness that is important as well,” Dr. Quigley said. “I think part of what the task force is trying to do is saying that identifying anxiety can be a precursor to what could turn out to be related to depression or related to ADHD and factors we think about when we think about suicide risk as well.

“We’re seeing an increase in suicide in the younger age group as well, which is a huge concern, “ she noted.

Dr. Quigley said, if these recommendations are adopted after the comment period, pediatricians and family practice providers will likely be doing most of the screening for anxiety, but there may also be a role for the screening in pediatric subspecialty care, such as those treating children with chronic illness and in specialized mental health care.

She added: “This builds on the national conversation going on about the mental health crisis, declared a national emergency in the fall. This deserves attention in continuing the momentum.”
 

Factors that may signal higher risk for depression

While the USPSTF recommends screening for major depressive disorder in all adolescents aged 12 years and older, the USPSTF notes that several risk factors might help identify those at higher risk.

Markers for higher risk include a combination of factors such as a family history of depression, prior episode of depression, and other mental health or behavioral problems.

“Other psychosocial risk factors include childhood abuse or neglect, exposure to traumatic events, bullying (either as perpetrators or as victims), adverse life events, early exposure to stress, maltreatment, and an insecure parental relationship,” the task force authors wrote.

There was limited evidence, however, on the benefits and harms of screening children younger than 8 for anxiety and screening kids younger than 12 for depression.
 

Not enough evidence for suicide risk screening

The authors of the recommendations acknowledged that, while suicide is a leading cause of death for older children and teens, evidence is still too sparse to make recommendations regarding screening for suicide risk in those without signs or symptoms at any age.

They also explained that evidence is lacking and inconsistent on the effectiveness of treatment (psychotherapy, pharmacotherapy, or collaborative care) for suicide risk in improving outcomes in children and adolescents.

Comments on the USPSTF recommendations may be submitted until May 9, 2022. The USPSTF topic leads review all comments, revise the draft recommendations, put them to a vote by the full task force, and then post the final versions to the website.

The task force authors and Dr. Quigley reported no financial disclosures.

The U.S. Preventive Services Task Force on Apr. 12 posted draft recommendations on screening for depression and anxiety in children and adolescents.

For the first time, the USPSTF is recommending screening children ages 8 and older for anxiety.

It also recommended screening children ages 12 and older for depression, which was consistent with the USPSTF’s prior recommendations on the topic.

These B-grade draft recommendations are for children and teens who are not showing signs or symptoms of these conditions. The task force emphasized that anyone who has concerns about or shows signs of these conditions should be connected to care.

Task force member Martha Kubik, PhD, RN, a professor with George Mason University, Fairfax, Va, said in a statement: “Fortunately, we found that screening older children for anxiety and depression is effective in identifying these conditions so children and teens can be connected to the support they need.”

The group cited in its recommendation on anxiety the 2018-2019 National Survey of Children’s Health, which found that 7.8% of children and adolescents ages 3-17 years had a current anxiety disorder. It also noted that the National Survey on LGBTQ Youth Mental Health found that 72% of LGBTQ youth and 77% of transgender and nonbinary youth described general anxiety disorder symptoms.

“Anxiety disorders in childhood and adolescence are associated with an increased likelihood of a future anxiety disorder or depression,” the task force authors wrote.

They highlighted that “the prevalence of anxiety in Black youth may be evolving.” Previously, studies had suggested that young Black people may have had lower rates of mental health disorders, compared with their White counterparts.

“However, recent cohorts of Black children or adolescents have reported a higher prevalence of anxiety disorders than in the past,” the authors wrote.

Joanna Quigley, MD, clinical associate professor and associate medical director for child & adolescent services at the University of Michigan, Ann Arbor, said in an interview she was not surprised the USPSTF recommended screening for anxiety starting at age 8.

That’s when parents and providers see anxiety disorders begin to present or become more problematic, she said.

“It’s also acknowledging the importance of prevention,” she said. “The sooner we can identify these challenges for kids, the sooner we can intervene and have better outcomes for that child across their lifespan.”

Screening gets providers and families in the habit of thinking about these concerns when a child or adolescent comes in for another kind of visit, Dr. Quigley said. Chest pains in a well-child check, for example, may trigger thoughts to consider anxiety later if the child is brought in for a cardiac check for chest pains.

“It creates a culture of awareness that is important as well,” Dr. Quigley said. “I think part of what the task force is trying to do is saying that identifying anxiety can be a precursor to what could turn out to be related to depression or related to ADHD and factors we think about when we think about suicide risk as well.

“We’re seeing an increase in suicide in the younger age group as well, which is a huge concern, “ she noted.

Dr. Quigley said, if these recommendations are adopted after the comment period, pediatricians and family practice providers will likely be doing most of the screening for anxiety, but there may also be a role for the screening in pediatric subspecialty care, such as those treating children with chronic illness and in specialized mental health care.

She added: “This builds on the national conversation going on about the mental health crisis, declared a national emergency in the fall. This deserves attention in continuing the momentum.”
 

Factors that may signal higher risk for depression

While the USPSTF recommends screening for major depressive disorder in all adolescents aged 12 years and older, the USPSTF notes that several risk factors might help identify those at higher risk.

Markers for higher risk include a combination of factors such as a family history of depression, prior episode of depression, and other mental health or behavioral problems.

“Other psychosocial risk factors include childhood abuse or neglect, exposure to traumatic events, bullying (either as perpetrators or as victims), adverse life events, early exposure to stress, maltreatment, and an insecure parental relationship,” the task force authors wrote.

There was limited evidence, however, on the benefits and harms of screening children younger than 8 for anxiety and screening kids younger than 12 for depression.
 

Not enough evidence for suicide risk screening

The authors of the recommendations acknowledged that, while suicide is a leading cause of death for older children and teens, evidence is still too sparse to make recommendations regarding screening for suicide risk in those without signs or symptoms at any age.

They also explained that evidence is lacking and inconsistent on the effectiveness of treatment (psychotherapy, pharmacotherapy, or collaborative care) for suicide risk in improving outcomes in children and adolescents.

Comments on the USPSTF recommendations may be submitted until May 9, 2022. The USPSTF topic leads review all comments, revise the draft recommendations, put them to a vote by the full task force, and then post the final versions to the website.

The task force authors and Dr. Quigley reported no financial disclosures.

The U.S. Preventive Services Task Force on Apr. 12 posted draft recommendations on screening for depression and anxiety in children and adolescents.

For the first time, the USPSTF is recommending screening children ages 8 and older for anxiety.

It also recommended screening children ages 12 and older for depression, which was consistent with the USPSTF’s prior recommendations on the topic.

These B-grade draft recommendations are for children and teens who are not showing signs or symptoms of these conditions. The task force emphasized that anyone who has concerns about or shows signs of these conditions should be connected to care.

Task force member Martha Kubik, PhD, RN, a professor with George Mason University, Fairfax, Va, said in a statement: “Fortunately, we found that screening older children for anxiety and depression is effective in identifying these conditions so children and teens can be connected to the support they need.”

The group cited in its recommendation on anxiety the 2018-2019 National Survey of Children’s Health, which found that 7.8% of children and adolescents ages 3-17 years had a current anxiety disorder. It also noted that the National Survey on LGBTQ Youth Mental Health found that 72% of LGBTQ youth and 77% of transgender and nonbinary youth described general anxiety disorder symptoms.

“Anxiety disorders in childhood and adolescence are associated with an increased likelihood of a future anxiety disorder or depression,” the task force authors wrote.

They highlighted that “the prevalence of anxiety in Black youth may be evolving.” Previously, studies had suggested that young Black people may have had lower rates of mental health disorders, compared with their White counterparts.

“However, recent cohorts of Black children or adolescents have reported a higher prevalence of anxiety disorders than in the past,” the authors wrote.

Joanna Quigley, MD, clinical associate professor and associate medical director for child & adolescent services at the University of Michigan, Ann Arbor, said in an interview she was not surprised the USPSTF recommended screening for anxiety starting at age 8.

That’s when parents and providers see anxiety disorders begin to present or become more problematic, she said.

“It’s also acknowledging the importance of prevention,” she said. “The sooner we can identify these challenges for kids, the sooner we can intervene and have better outcomes for that child across their lifespan.”

Screening gets providers and families in the habit of thinking about these concerns when a child or adolescent comes in for another kind of visit, Dr. Quigley said. Chest pains in a well-child check, for example, may trigger thoughts to consider anxiety later if the child is brought in for a cardiac check for chest pains.

“It creates a culture of awareness that is important as well,” Dr. Quigley said. “I think part of what the task force is trying to do is saying that identifying anxiety can be a precursor to what could turn out to be related to depression or related to ADHD and factors we think about when we think about suicide risk as well.

“We’re seeing an increase in suicide in the younger age group as well, which is a huge concern, “ she noted.

Dr. Quigley said, if these recommendations are adopted after the comment period, pediatricians and family practice providers will likely be doing most of the screening for anxiety, but there may also be a role for the screening in pediatric subspecialty care, such as those treating children with chronic illness and in specialized mental health care.

She added: “This builds on the national conversation going on about the mental health crisis, declared a national emergency in the fall. This deserves attention in continuing the momentum.”
 

Factors that may signal higher risk for depression

While the USPSTF recommends screening for major depressive disorder in all adolescents aged 12 years and older, the USPSTF notes that several risk factors might help identify those at higher risk.

Markers for higher risk include a combination of factors such as a family history of depression, prior episode of depression, and other mental health or behavioral problems.

“Other psychosocial risk factors include childhood abuse or neglect, exposure to traumatic events, bullying (either as perpetrators or as victims), adverse life events, early exposure to stress, maltreatment, and an insecure parental relationship,” the task force authors wrote.

There was limited evidence, however, on the benefits and harms of screening children younger than 8 for anxiety and screening kids younger than 12 for depression.
 

Not enough evidence for suicide risk screening

The authors of the recommendations acknowledged that, while suicide is a leading cause of death for older children and teens, evidence is still too sparse to make recommendations regarding screening for suicide risk in those without signs or symptoms at any age.

They also explained that evidence is lacking and inconsistent on the effectiveness of treatment (psychotherapy, pharmacotherapy, or collaborative care) for suicide risk in improving outcomes in children and adolescents.

Comments on the USPSTF recommendations may be submitted until May 9, 2022. The USPSTF topic leads review all comments, revise the draft recommendations, put them to a vote by the full task force, and then post the final versions to the website.

The task force authors and Dr. Quigley reported no financial disclosures.

THE CASE

James R* is a 30-year-old man who presented for a primary care walk-in visit due to dizziness, 2 days after he visited an emergency department (ED) for the same concern. He reported episodic symptoms lasting seconds to minutes, specifically when lying down. He said he had not fallen or experienced other physical trauma, did not have blurred vision or hearing loss, and was taking no medications. He also reported panic attacks, during which he experienced palpitations, trembling, paresthesia, and fear of dying. He stated that dizziness did not occur exclusively during panic episodes. His medical history was significant for hypertension; however, he reported significant anxiety related to medical visits. All home blood pressure readings he reported were within normal limits. 

Upon examination, the patient had a blood pressure reading of 142/90 mm Hg and no evidence of nystagmus at rest. A neurologic exam was normal and a Dix-Hallpike maneuver reproduced subjective vertigo without nystagmus. Laboratory findings from the patient’s ED visit were negative for troponin and drug use, and blood oxygenation levels were within normal limits. At the time of this current visit, an electrocardiogram was unremarkable, with the exception of some tachycardia.

The presumptive diagnosis was benign paroxysmal positional vertigo (BPPV). An Epley maneuver was performed in the clinic and resulted in minimal symptom improvement. The physician taught Mr. R how to perform the Epley maneuver himself, prescribed a short course of meclizine, and referred him to the integrated mental health care service to address his panic attacks and anxiety.

Over the next few months, Mr. R continued to report significant distress about the dizzy spells, which persisted even after performing the Epley maneuver, and he reported that the meclizine was causing worsening vertigo. He received an ear-nose-and-throat consultation and cognitive behavioral therapy (CBT)–based consultation/interventions. He also reported avoiding multiple activities due to concerns about his dizziness.

● How would you proceed with this patient?

*The patient’s name and other personally identifying information have been changed to protect his identity.

Somatic symptom disorder (SSD) is characterized by one or more physical symptoms associated with “excessive thoughts, feelings, or behaviors that result in distress and/or functional impairment.”¹ Individuals with SSD are preoccupied with symptom-related severity, experience high symptom-related anxiety, or devote significant time and energy to the symptoms or heath concerns. With a diagnosis of SSD, physical symptoms experienced by the patient may or may not be medically explained. The same symptom need not be continuously present as long as the overall symptomatic presentation lasts 6 months or longer.

The specifier “with predominant pain” is used when pain dominates the presentation.¹ Estimated prevalence of SSD in primary care ranges from 5% to 35%.² The true scope of SSD is difficult to assess accurately since research tends to focus on medically unexplained symptoms, rather than excessive symptom-related concerns. Furthermore, terms such as “medically unexplained symptoms” and “functional syndromes” (including fibromyalgia and irritable bowel syndrome) are frequently used when describing SSD.³

One or more factors may contribute to unexplained symptoms: limitations of medical procedures and techniques, partial clinical information, patients’ inability to follow management recommendations, challenges in differential diagnostics, and access-to-care limitations preventing regular care and appropriate diagnostic work up.

What’s important to remember is that it’s the patient’s reaction to physical symptoms, rather than the presence of symptoms per se, that defines SSD.

Considerations in the differential diagnosis

When making a diagnosis of SSD, symptoms cannot:⁴

• be feigned or deliberately produced as in malingering or factitious disorder.
• result from physiologic effects of a substance (eg, intoxication, withdrawal, or adverse medication effects).
• constitute somatic delusions, as occur in psychotic disorders.
• constitute symptoms or deficits affecting voluntary motor or sensory function that are better explained by neurologic, medical, or psychiatric conditions (consider conversion disorder).
• be preoccupations with physical appearance flaws, as in body dysmorphic disorder.
• be accounted for by an anxiety disorder (eg, palpitations associated with panic attacks).

Continue to: Illness anxiety disorder...

Illness anxiety disorder is also characterized by significant health-related concerns; however, physical symptoms are either mild or absent.

Ongoing elevated screening scores for anxiety and depression refractory to interventions may signal somatic symptom disorder.

Possible causes of SSD are varied and complex, including genetic and biological factors, family dynamics, behavioral modeling/learning, personality traits, difficulties with emotional regulation, and awareness.⁵ Patients may present with ongoing requests for symptom explanations, feelings of helplessness, fear of having concerns dismissed, and low motivation for change.³

Aids in supporting a diagnosis of SSD

It’s not appropriate to rely solely on questionnaires to make the diagnosis of SSD. However, brief screening tools are a time-efficient way to capture patients’ experiences and perceptions.⁶ Along with other components of clinical evaluation, brief symptom screens can both support the diagnosis and help in longitudinal symptom assessment.

Patient Health Questionnaire-15 (PHQ-15), developed for self-report screening in primary care, has desirable psychometric properties including appropriate internal reliability; convergent validity with measures of functional status, disability days, and symptom-related burden; and discriminant validity from measures of depressive symptoms.⁷ The PHQ-15 is an open access tool that is available in several languages. The respondent is asked to rate the extent of being bothered by a range of medical symptoms in the proceeding 4 weeks. Total scores range from 0 to 30, with higher scores indicating greater symptom aggravation. Cutoffs of 5, 10, and 15 correspond to mild, moderate, and severe symptom levels.⁸

Somatic Symptom Disorder - B Criteria Scale (SSD-12) aims to capture SSD symptoms in line with Diagnostic and Statistical Manual of Mental Disorders (DSM-5) diagnostic criteria. It assesses cognitive, affective, and behavioral aspects of SSD.⁹ The SSD-12 is copyrighted and its use requires registration and purchase. Cutoffs by age and gender are available. SSD-12 has demonstrated appropriate reliability and validity.⁹

Continue to: Structured Clinical Interview for DSM Disorders

Structured Clinical Interview for DSM Disorders (SCID)^10,11 is perhaps the most rigorous differential diagnostic tool. However, SCID administration requires training and skill; time for administration and cost of the materials may be prohibitive in primary care.

CBT is empirically supported as a treatment approach to medically unexplained symptoms and somatic symptom disorder.

Finally, SSD symptoms are highly associated with depression and anxiety. Ongoing elevated screening scores for anxiety and depression refractory to interventions may indicate the possibility of overlooked SSD. Furthermore, use of SSD screening tools with anxiety and depression screening tools can provide a more comprehensive picture of impairment, as well as symptom progress.

Treatment: Avoid a split approach

Diagnosing and treating SSD can be challenging for physicians who focus on biomedically based approaches in patient care. Additional tests, studies, and prescriptions are likely to fuel (rather than pacify) patients’ concerns, as such steps divert attention from the underlying psychological needs and mechanisms which maintain SSD. Avoid using a split biopsychosocial approach—ie, beginning the inquiry and treatment planning from a biomedical perspective, and then falling back on psychosocial formulation when treatment efforts have been ineffective. Such an approach leads to understandable patient dissatisfaction and can be interpreted by them as the caregiver suggesting that physical symptoms are “all in [their] head.”¹²

These 4 tips can help

1. Use a biopsychosocial formulation when initiating treatment. Be familiar with biopsychosocial factors in SSD and develop a narrative for discussing this formulation with patients. For example: “Mr. R, we are going to use the following [medical tests/studies/medications] to understand the cause of your symptoms and better manage them. We also need to think about the role of stress and distress in your symptoms because these can also be at play with dizziness.” This may be particularly beneficial for a functional disorder, such as chronic pain. Incorporating patient education resources is an important step toward shared understanding (see Hunter Integrated Pain Service for chronic pain educational videos; www.tga.gov.au/chronic-pain-­management-video-resource-brainman¹³).

2. Combine education about pathophysiology with patient-centered interviewing. Significant SSD symptom improvements were noted following a single 30-minute educational session, while motivational interviewing techniques were used to probe patients’ concerns.²

Continue to: Maintain professionalism and good clinical practice

3. Maintain professionalism and good clinical practice. Consider SSD a medical matter and address it accordingly: explore concerns fully, provide evidence-based responses, communicate empathy, and employ objective management strategies.¹⁴

4. Do not overlook the value of the relationship. A recent systematic review concluded that the relationship between the patient and care provider was central to the success of the interventions for symptom reduction.¹⁵

A controversial approach. Pharmacotherapy for SSD is controversial. While several trials of antidepressants and St. John’s wort have been positive and some authors have stated that all classes of antidepressants are effective for SSD, others maintain that questions regarding dosing, treatment duration, and sustainability of improvement have not been sufficiently addressed in research.^16,17

Coordination of care issues

Primary care continues to be the de facto mental health system, and specialty services may be unavailable or declined by patients.¹⁸ CBT delivered in person or online is empirically supported as a treatment approach to medically unexplained symptoms and SSD.^17,19-22

A recent meta-analysis of randomized controlled trials published by Jing and colleagues²³ reported that CBT was effective for SSD symptom reduction, and that treatment gains were maintained 3 to 12 months post treatment. However, concerns about the practical implementation of CBT in primary care were raised because CBT was not shown to be effective in improving social functioning or reducing the number of medical visits. Symptom improvement was maximized with longer durations of treatment (> 10 sessions) and greater session lengths (> 50 minutes). Additionally, Abbass and colleagues²⁴ brought up several methodologic (sampling and analysis) concerns related to Jing et al’s work.

Continue to: Overally, CBT's effect sizes...

Overall, CBT’s effect sizes are small, and patients who are open to biopsychosocial explanations for their symptoms and to receiving psychological services may differ from most patients seen in primary care practices.²¹ Furthermore, mental health providers may hesitate to diagnose SSD because they are concerned about missing a somatic illness.³ Therefore, when coordinating care with mental health providers, it may be beneficial to discuss the treatment approach, assess familiarity with the SSD diagnosis, and closely coordinate and collaborate on the treatment plan.

While physicians cannot be expected to function as psychotherapists, an understanding of CBT and techniques for SSD treatment can be beneficial. Integrated mental health services may hold promise in addressing SSD in primary care. Onsite availability of a behavioral health provider competent in providing evidence-based care can target SSD symptoms and support both patients and physicians.

THE CASE

Mr. R’s treatment course included multiple primary care appointments (scheduled and walk in), ED visits, and specialist visits (ENT/­vestibular rehabilitation). He sought care as symptoms intensified, lasted longer, or occurred in new circumstances. He reported persistent fear of the symptoms and anxiety that serious medical causes had been overlooked. He also described distress associated with vertigo and his anxiety sensitivity (anxiety about being anxious).

While physicians cannot be expected to function as psychotherapists, an understanding of CBT and techniques for somatic symptom disorder treatment can be beneficial.

The behavioral health consultant (BHC; psychologist) and physician talked to the patient about the biopsychosocial antecedents of his condition and the factors that perpetuate the anxiety and stress response. The BHC described the fight/flight/freeze response to the patient and explained its role in the physiologic stress response associated with somatic symptoms and panic. Educational materials (videos and handouts) were also provided to the patient to further illustrate these concepts. The BHC also discussed the role of interoceptive and situational avoidance and active coping (eg, engaging in safe activities); taught the patient relaxation and grounding techniques; and used cognitive disputation aimed at challenging catastrophic symptom interpretations.

The BHC and the patient’s physician established joint treatment goals that included improving functioning, promoting active coping, and decreasing distress associated with symptoms. After the initial medical and BHC visits, both vertigo and anxiety symptoms appeared to abate somewhat, but symptoms have been ongoing and distress and impairment have been variable. The patient’s family physician and BHC continue to work with him to optimize the care plan and treatment goals.

CORRESPONDENCE
Nataliya Pilipenko, PhD, ABPP, Center for Family and Community Medicine, Columbia University Vagelos College of Physicians and Surgeons, 630 West 168th Street, New York, NY 10032; np2615@cumc.columbia.edu

ACKNOWLEDGEMENT
The author thanks Dr. Molly Warren for her collaboration and guidance.

THE CASE

James R* is a 30-year-old man who presented for a primary care walk-in visit due to dizziness, 2 days after he visited an emergency department (ED) for the same concern. He reported episodic symptoms lasting seconds to minutes, specifically when lying down. He said he had not fallen or experienced other physical trauma, did not have blurred vision or hearing loss, and was taking no medications. He also reported panic attacks, during which he experienced palpitations, trembling, paresthesia, and fear of dying. He stated that dizziness did not occur exclusively during panic episodes. His medical history was significant for hypertension; however, he reported significant anxiety related to medical visits. All home blood pressure readings he reported were within normal limits. 

Upon examination, the patient had a blood pressure reading of 142/90 mm Hg and no evidence of nystagmus at rest. A neurologic exam was normal and a Dix-Hallpike maneuver reproduced subjective vertigo without nystagmus. Laboratory findings from the patient’s ED visit were negative for troponin and drug use, and blood oxygenation levels were within normal limits. At the time of this current visit, an electrocardiogram was unremarkable, with the exception of some tachycardia.

The presumptive diagnosis was benign paroxysmal positional vertigo (BPPV). An Epley maneuver was performed in the clinic and resulted in minimal symptom improvement. The physician taught Mr. R how to perform the Epley maneuver himself, prescribed a short course of meclizine, and referred him to the integrated mental health care service to address his panic attacks and anxiety.

Over the next few months, Mr. R continued to report significant distress about the dizzy spells, which persisted even after performing the Epley maneuver, and he reported that the meclizine was causing worsening vertigo. He received an ear-nose-and-throat consultation and cognitive behavioral therapy (CBT)–based consultation/interventions. He also reported avoiding multiple activities due to concerns about his dizziness.

● How would you proceed with this patient?

*The patient’s name and other personally identifying information have been changed to protect his identity.

Somatic symptom disorder (SSD) is characterized by one or more physical symptoms associated with “excessive thoughts, feelings, or behaviors that result in distress and/or functional impairment.”¹ Individuals with SSD are preoccupied with symptom-related severity, experience high symptom-related anxiety, or devote significant time and energy to the symptoms or heath concerns. With a diagnosis of SSD, physical symptoms experienced by the patient may or may not be medically explained. The same symptom need not be continuously present as long as the overall symptomatic presentation lasts 6 months or longer.

The specifier “with predominant pain” is used when pain dominates the presentation.¹ Estimated prevalence of SSD in primary care ranges from 5% to 35%.² The true scope of SSD is difficult to assess accurately since research tends to focus on medically unexplained symptoms, rather than excessive symptom-related concerns. Furthermore, terms such as “medically unexplained symptoms” and “functional syndromes” (including fibromyalgia and irritable bowel syndrome) are frequently used when describing SSD.³

One or more factors may contribute to unexplained symptoms: limitations of medical procedures and techniques, partial clinical information, patients’ inability to follow management recommendations, challenges in differential diagnostics, and access-to-care limitations preventing regular care and appropriate diagnostic work up.

What’s important to remember is that it’s the patient’s reaction to physical symptoms, rather than the presence of symptoms per se, that defines SSD.

Considerations in the differential diagnosis

When making a diagnosis of SSD, symptoms cannot:⁴

• be feigned or deliberately produced as in malingering or factitious disorder.
• result from physiologic effects of a substance (eg, intoxication, withdrawal, or adverse medication effects).
• constitute somatic delusions, as occur in psychotic disorders.
• constitute symptoms or deficits affecting voluntary motor or sensory function that are better explained by neurologic, medical, or psychiatric conditions (consider conversion disorder).
• be preoccupations with physical appearance flaws, as in body dysmorphic disorder.
• be accounted for by an anxiety disorder (eg, palpitations associated with panic attacks).

Continue to: Illness anxiety disorder...

Illness anxiety disorder is also characterized by significant health-related concerns; however, physical symptoms are either mild or absent.

Ongoing elevated screening scores for anxiety and depression refractory to interventions may signal somatic symptom disorder.

Possible causes of SSD are varied and complex, including genetic and biological factors, family dynamics, behavioral modeling/learning, personality traits, difficulties with emotional regulation, and awareness.⁵ Patients may present with ongoing requests for symptom explanations, feelings of helplessness, fear of having concerns dismissed, and low motivation for change.³

Aids in supporting a diagnosis of SSD

It’s not appropriate to rely solely on questionnaires to make the diagnosis of SSD. However, brief screening tools are a time-efficient way to capture patients’ experiences and perceptions.⁶ Along with other components of clinical evaluation, brief symptom screens can both support the diagnosis and help in longitudinal symptom assessment.

Patient Health Questionnaire-15 (PHQ-15), developed for self-report screening in primary care, has desirable psychometric properties including appropriate internal reliability; convergent validity with measures of functional status, disability days, and symptom-related burden; and discriminant validity from measures of depressive symptoms.⁷ The PHQ-15 is an open access tool that is available in several languages. The respondent is asked to rate the extent of being bothered by a range of medical symptoms in the proceeding 4 weeks. Total scores range from 0 to 30, with higher scores indicating greater symptom aggravation. Cutoffs of 5, 10, and 15 correspond to mild, moderate, and severe symptom levels.⁸

Somatic Symptom Disorder - B Criteria Scale (SSD-12) aims to capture SSD symptoms in line with Diagnostic and Statistical Manual of Mental Disorders (DSM-5) diagnostic criteria. It assesses cognitive, affective, and behavioral aspects of SSD.⁹ The SSD-12 is copyrighted and its use requires registration and purchase. Cutoffs by age and gender are available. SSD-12 has demonstrated appropriate reliability and validity.⁹

Continue to: Structured Clinical Interview for DSM Disorders

Structured Clinical Interview for DSM Disorders (SCID)^10,11 is perhaps the most rigorous differential diagnostic tool. However, SCID administration requires training and skill; time for administration and cost of the materials may be prohibitive in primary care.

CBT is empirically supported as a treatment approach to medically unexplained symptoms and somatic symptom disorder.

Finally, SSD symptoms are highly associated with depression and anxiety. Ongoing elevated screening scores for anxiety and depression refractory to interventions may indicate the possibility of overlooked SSD. Furthermore, use of SSD screening tools with anxiety and depression screening tools can provide a more comprehensive picture of impairment, as well as symptom progress.

Treatment: Avoid a split approach

Diagnosing and treating SSD can be challenging for physicians who focus on biomedically based approaches in patient care. Additional tests, studies, and prescriptions are likely to fuel (rather than pacify) patients’ concerns, as such steps divert attention from the underlying psychological needs and mechanisms which maintain SSD. Avoid using a split biopsychosocial approach—ie, beginning the inquiry and treatment planning from a biomedical perspective, and then falling back on psychosocial formulation when treatment efforts have been ineffective. Such an approach leads to understandable patient dissatisfaction and can be interpreted by them as the caregiver suggesting that physical symptoms are “all in [their] head.”¹²

These 4 tips can help

1. Use a biopsychosocial formulation when initiating treatment. Be familiar with biopsychosocial factors in SSD and develop a narrative for discussing this formulation with patients. For example: “Mr. R, we are going to use the following [medical tests/studies/medications] to understand the cause of your symptoms and better manage them. We also need to think about the role of stress and distress in your symptoms because these can also be at play with dizziness.” This may be particularly beneficial for a functional disorder, such as chronic pain. Incorporating patient education resources is an important step toward shared understanding (see Hunter Integrated Pain Service for chronic pain educational videos; www.tga.gov.au/chronic-pain-­management-video-resource-brainman¹³).

2. Combine education about pathophysiology with patient-centered interviewing. Significant SSD symptom improvements were noted following a single 30-minute educational session, while motivational interviewing techniques were used to probe patients’ concerns.²

Continue to: Maintain professionalism and good clinical practice

3. Maintain professionalism and good clinical practice. Consider SSD a medical matter and address it accordingly: explore concerns fully, provide evidence-based responses, communicate empathy, and employ objective management strategies.¹⁴

4. Do not overlook the value of the relationship. A recent systematic review concluded that the relationship between the patient and care provider was central to the success of the interventions for symptom reduction.¹⁵

A controversial approach. Pharmacotherapy for SSD is controversial. While several trials of antidepressants and St. John’s wort have been positive and some authors have stated that all classes of antidepressants are effective for SSD, others maintain that questions regarding dosing, treatment duration, and sustainability of improvement have not been sufficiently addressed in research.^16,17

Coordination of care issues

Primary care continues to be the de facto mental health system, and specialty services may be unavailable or declined by patients.¹⁸ CBT delivered in person or online is empirically supported as a treatment approach to medically unexplained symptoms and SSD.^17,19-22

A recent meta-analysis of randomized controlled trials published by Jing and colleagues²³ reported that CBT was effective for SSD symptom reduction, and that treatment gains were maintained 3 to 12 months post treatment. However, concerns about the practical implementation of CBT in primary care were raised because CBT was not shown to be effective in improving social functioning or reducing the number of medical visits. Symptom improvement was maximized with longer durations of treatment (> 10 sessions) and greater session lengths (> 50 minutes). Additionally, Abbass and colleagues²⁴ brought up several methodologic (sampling and analysis) concerns related to Jing et al’s work.

Continue to: Overally, CBT's effect sizes...

Overall, CBT’s effect sizes are small, and patients who are open to biopsychosocial explanations for their symptoms and to receiving psychological services may differ from most patients seen in primary care practices.²¹ Furthermore, mental health providers may hesitate to diagnose SSD because they are concerned about missing a somatic illness.³ Therefore, when coordinating care with mental health providers, it may be beneficial to discuss the treatment approach, assess familiarity with the SSD diagnosis, and closely coordinate and collaborate on the treatment plan.

While physicians cannot be expected to function as psychotherapists, an understanding of CBT and techniques for SSD treatment can be beneficial. Integrated mental health services may hold promise in addressing SSD in primary care. Onsite availability of a behavioral health provider competent in providing evidence-based care can target SSD symptoms and support both patients and physicians.

THE CASE

Mr. R’s treatment course included multiple primary care appointments (scheduled and walk in), ED visits, and specialist visits (ENT/­vestibular rehabilitation). He sought care as symptoms intensified, lasted longer, or occurred in new circumstances. He reported persistent fear of the symptoms and anxiety that serious medical causes had been overlooked. He also described distress associated with vertigo and his anxiety sensitivity (anxiety about being anxious).

While physicians cannot be expected to function as psychotherapists, an understanding of CBT and techniques for somatic symptom disorder treatment can be beneficial.

The behavioral health consultant (BHC; psychologist) and physician talked to the patient about the biopsychosocial antecedents of his condition and the factors that perpetuate the anxiety and stress response. The BHC described the fight/flight/freeze response to the patient and explained its role in the physiologic stress response associated with somatic symptoms and panic. Educational materials (videos and handouts) were also provided to the patient to further illustrate these concepts. The BHC also discussed the role of interoceptive and situational avoidance and active coping (eg, engaging in safe activities); taught the patient relaxation and grounding techniques; and used cognitive disputation aimed at challenging catastrophic symptom interpretations.

The BHC and the patient’s physician established joint treatment goals that included improving functioning, promoting active coping, and decreasing distress associated with symptoms. After the initial medical and BHC visits, both vertigo and anxiety symptoms appeared to abate somewhat, but symptoms have been ongoing and distress and impairment have been variable. The patient’s family physician and BHC continue to work with him to optimize the care plan and treatment goals.

CORRESPONDENCE
Nataliya Pilipenko, PhD, ABPP, Center for Family and Community Medicine, Columbia University Vagelos College of Physicians and Surgeons, 630 West 168th Street, New York, NY 10032; np2615@cumc.columbia.edu

ACKNOWLEDGEMENT
The author thanks Dr. Molly Warren for her collaboration and guidance.

THE CASE

James R* is a 30-year-old man who presented for a primary care walk-in visit due to dizziness, 2 days after he visited an emergency department (ED) for the same concern. He reported episodic symptoms lasting seconds to minutes, specifically when lying down. He said he had not fallen or experienced other physical trauma, did not have blurred vision or hearing loss, and was taking no medications. He also reported panic attacks, during which he experienced palpitations, trembling, paresthesia, and fear of dying. He stated that dizziness did not occur exclusively during panic episodes. His medical history was significant for hypertension; however, he reported significant anxiety related to medical visits. All home blood pressure readings he reported were within normal limits. 

Upon examination, the patient had a blood pressure reading of 142/90 mm Hg and no evidence of nystagmus at rest. A neurologic exam was normal and a Dix-Hallpike maneuver reproduced subjective vertigo without nystagmus. Laboratory findings from the patient’s ED visit were negative for troponin and drug use, and blood oxygenation levels were within normal limits. At the time of this current visit, an electrocardiogram was unremarkable, with the exception of some tachycardia.

The presumptive diagnosis was benign paroxysmal positional vertigo (BPPV). An Epley maneuver was performed in the clinic and resulted in minimal symptom improvement. The physician taught Mr. R how to perform the Epley maneuver himself, prescribed a short course of meclizine, and referred him to the integrated mental health care service to address his panic attacks and anxiety.

Over the next few months, Mr. R continued to report significant distress about the dizzy spells, which persisted even after performing the Epley maneuver, and he reported that the meclizine was causing worsening vertigo. He received an ear-nose-and-throat consultation and cognitive behavioral therapy (CBT)–based consultation/interventions. He also reported avoiding multiple activities due to concerns about his dizziness.

● How would you proceed with this patient?

*The patient’s name and other personally identifying information have been changed to protect his identity.

Somatic symptom disorder (SSD) is characterized by one or more physical symptoms associated with “excessive thoughts, feelings, or behaviors that result in distress and/or functional impairment.”¹ Individuals with SSD are preoccupied with symptom-related severity, experience high symptom-related anxiety, or devote significant time and energy to the symptoms or heath concerns. With a diagnosis of SSD, physical symptoms experienced by the patient may or may not be medically explained. The same symptom need not be continuously present as long as the overall symptomatic presentation lasts 6 months or longer.

The specifier “with predominant pain” is used when pain dominates the presentation.¹ Estimated prevalence of SSD in primary care ranges from 5% to 35%.² The true scope of SSD is difficult to assess accurately since research tends to focus on medically unexplained symptoms, rather than excessive symptom-related concerns. Furthermore, terms such as “medically unexplained symptoms” and “functional syndromes” (including fibromyalgia and irritable bowel syndrome) are frequently used when describing SSD.³

One or more factors may contribute to unexplained symptoms: limitations of medical procedures and techniques, partial clinical information, patients’ inability to follow management recommendations, challenges in differential diagnostics, and access-to-care limitations preventing regular care and appropriate diagnostic work up.

What’s important to remember is that it’s the patient’s reaction to physical symptoms, rather than the presence of symptoms per se, that defines SSD.

Considerations in the differential diagnosis

When making a diagnosis of SSD, symptoms cannot:⁴

• be feigned or deliberately produced as in malingering or factitious disorder.
• result from physiologic effects of a substance (eg, intoxication, withdrawal, or adverse medication effects).
• constitute somatic delusions, as occur in psychotic disorders.
• constitute symptoms or deficits affecting voluntary motor or sensory function that are better explained by neurologic, medical, or psychiatric conditions (consider conversion disorder).
• be preoccupations with physical appearance flaws, as in body dysmorphic disorder.
• be accounted for by an anxiety disorder (eg, palpitations associated with panic attacks).

Continue to: Illness anxiety disorder...

Illness anxiety disorder is also characterized by significant health-related concerns; however, physical symptoms are either mild or absent.

Ongoing elevated screening scores for anxiety and depression refractory to interventions may signal somatic symptom disorder.

Possible causes of SSD are varied and complex, including genetic and biological factors, family dynamics, behavioral modeling/learning, personality traits, difficulties with emotional regulation, and awareness.⁵ Patients may present with ongoing requests for symptom explanations, feelings of helplessness, fear of having concerns dismissed, and low motivation for change.³

Aids in supporting a diagnosis of SSD

It’s not appropriate to rely solely on questionnaires to make the diagnosis of SSD. However, brief screening tools are a time-efficient way to capture patients’ experiences and perceptions.⁶ Along with other components of clinical evaluation, brief symptom screens can both support the diagnosis and help in longitudinal symptom assessment.

Patient Health Questionnaire-15 (PHQ-15), developed for self-report screening in primary care, has desirable psychometric properties including appropriate internal reliability; convergent validity with measures of functional status, disability days, and symptom-related burden; and discriminant validity from measures of depressive symptoms.⁷ The PHQ-15 is an open access tool that is available in several languages. The respondent is asked to rate the extent of being bothered by a range of medical symptoms in the proceeding 4 weeks. Total scores range from 0 to 30, with higher scores indicating greater symptom aggravation. Cutoffs of 5, 10, and 15 correspond to mild, moderate, and severe symptom levels.⁸

Somatic Symptom Disorder - B Criteria Scale (SSD-12) aims to capture SSD symptoms in line with Diagnostic and Statistical Manual of Mental Disorders (DSM-5) diagnostic criteria. It assesses cognitive, affective, and behavioral aspects of SSD.⁹ The SSD-12 is copyrighted and its use requires registration and purchase. Cutoffs by age and gender are available. SSD-12 has demonstrated appropriate reliability and validity.⁹

Continue to: Structured Clinical Interview for DSM Disorders

Structured Clinical Interview for DSM Disorders (SCID)^10,11 is perhaps the most rigorous differential diagnostic tool. However, SCID administration requires training and skill; time for administration and cost of the materials may be prohibitive in primary care.

CBT is empirically supported as a treatment approach to medically unexplained symptoms and somatic symptom disorder.

Finally, SSD symptoms are highly associated with depression and anxiety. Ongoing elevated screening scores for anxiety and depression refractory to interventions may indicate the possibility of overlooked SSD. Furthermore, use of SSD screening tools with anxiety and depression screening tools can provide a more comprehensive picture of impairment, as well as symptom progress.

Treatment: Avoid a split approach

Diagnosing and treating SSD can be challenging for physicians who focus on biomedically based approaches in patient care. Additional tests, studies, and prescriptions are likely to fuel (rather than pacify) patients’ concerns, as such steps divert attention from the underlying psychological needs and mechanisms which maintain SSD. Avoid using a split biopsychosocial approach—ie, beginning the inquiry and treatment planning from a biomedical perspective, and then falling back on psychosocial formulation when treatment efforts have been ineffective. Such an approach leads to understandable patient dissatisfaction and can be interpreted by them as the caregiver suggesting that physical symptoms are “all in [their] head.”¹²

These 4 tips can help

1. Use a biopsychosocial formulation when initiating treatment. Be familiar with biopsychosocial factors in SSD and develop a narrative for discussing this formulation with patients. For example: “Mr. R, we are going to use the following [medical tests/studies/medications] to understand the cause of your symptoms and better manage them. We also need to think about the role of stress and distress in your symptoms because these can also be at play with dizziness.” This may be particularly beneficial for a functional disorder, such as chronic pain. Incorporating patient education resources is an important step toward shared understanding (see Hunter Integrated Pain Service for chronic pain educational videos; www.tga.gov.au/chronic-pain-­management-video-resource-brainman¹³).

2. Combine education about pathophysiology with patient-centered interviewing. Significant SSD symptom improvements were noted following a single 30-minute educational session, while motivational interviewing techniques were used to probe patients’ concerns.²

Continue to: Maintain professionalism and good clinical practice

3. Maintain professionalism and good clinical practice. Consider SSD a medical matter and address it accordingly: explore concerns fully, provide evidence-based responses, communicate empathy, and employ objective management strategies.¹⁴

4. Do not overlook the value of the relationship. A recent systematic review concluded that the relationship between the patient and care provider was central to the success of the interventions for symptom reduction.¹⁵

A controversial approach. Pharmacotherapy for SSD is controversial. While several trials of antidepressants and St. John’s wort have been positive and some authors have stated that all classes of antidepressants are effective for SSD, others maintain that questions regarding dosing, treatment duration, and sustainability of improvement have not been sufficiently addressed in research.^16,17

Coordination of care issues

Primary care continues to be the de facto mental health system, and specialty services may be unavailable or declined by patients.¹⁸ CBT delivered in person or online is empirically supported as a treatment approach to medically unexplained symptoms and SSD.^17,19-22

A recent meta-analysis of randomized controlled trials published by Jing and colleagues²³ reported that CBT was effective for SSD symptom reduction, and that treatment gains were maintained 3 to 12 months post treatment. However, concerns about the practical implementation of CBT in primary care were raised because CBT was not shown to be effective in improving social functioning or reducing the number of medical visits. Symptom improvement was maximized with longer durations of treatment (> 10 sessions) and greater session lengths (> 50 minutes). Additionally, Abbass and colleagues²⁴ brought up several methodologic (sampling and analysis) concerns related to Jing et al’s work.

Continue to: Overally, CBT's effect sizes...

Overall, CBT’s effect sizes are small, and patients who are open to biopsychosocial explanations for their symptoms and to receiving psychological services may differ from most patients seen in primary care practices.²¹ Furthermore, mental health providers may hesitate to diagnose SSD because they are concerned about missing a somatic illness.³ Therefore, when coordinating care with mental health providers, it may be beneficial to discuss the treatment approach, assess familiarity with the SSD diagnosis, and closely coordinate and collaborate on the treatment plan.

While physicians cannot be expected to function as psychotherapists, an understanding of CBT and techniques for SSD treatment can be beneficial. Integrated mental health services may hold promise in addressing SSD in primary care. Onsite availability of a behavioral health provider competent in providing evidence-based care can target SSD symptoms and support both patients and physicians.

THE CASE

Mr. R’s treatment course included multiple primary care appointments (scheduled and walk in), ED visits, and specialist visits (ENT/­vestibular rehabilitation). He sought care as symptoms intensified, lasted longer, or occurred in new circumstances. He reported persistent fear of the symptoms and anxiety that serious medical causes had been overlooked. He also described distress associated with vertigo and his anxiety sensitivity (anxiety about being anxious).

While physicians cannot be expected to function as psychotherapists, an understanding of CBT and techniques for somatic symptom disorder treatment can be beneficial.

The behavioral health consultant (BHC; psychologist) and physician talked to the patient about the biopsychosocial antecedents of his condition and the factors that perpetuate the anxiety and stress response. The BHC described the fight/flight/freeze response to the patient and explained its role in the physiologic stress response associated with somatic symptoms and panic. Educational materials (videos and handouts) were also provided to the patient to further illustrate these concepts. The BHC also discussed the role of interoceptive and situational avoidance and active coping (eg, engaging in safe activities); taught the patient relaxation and grounding techniques; and used cognitive disputation aimed at challenging catastrophic symptom interpretations.

The BHC and the patient’s physician established joint treatment goals that included improving functioning, promoting active coping, and decreasing distress associated with symptoms. After the initial medical and BHC visits, both vertigo and anxiety symptoms appeared to abate somewhat, but symptoms have been ongoing and distress and impairment have been variable. The patient’s family physician and BHC continue to work with him to optimize the care plan and treatment goals.

CORRESPONDENCE
Nataliya Pilipenko, PhD, ABPP, Center for Family and Community Medicine, Columbia University Vagelos College of Physicians and Surgeons, 630 West 168th Street, New York, NY 10032; np2615@cumc.columbia.edu

ACKNOWLEDGEMENT
The author thanks Dr. Molly Warren for her collaboration and guidance.

Benzodiazepines (BZDs) and Z-hypnotics have been available for decades, yet uncertainties about their use remain. They are prescribed and overprescribed most often for anxiety and insomnia, for which they have value but also the potential for significant adverse consequences, notably physiologic dependence. Use of these agents should be limited, and planned deprescribing is a fundamental aspect of prescribing.

A brief history. BZDs are a subset of benzodiazepine receptor agonists (BZRAs), which enhance the inhibitory effect of centrally acting γ-amino butyric acid (GABA) at the GABA_A receptor through allosteric modulation. In 1960, the first BZD, chlordiazepoxide, was marketed for clinical use, and as other agents in the class became available, BZDs supplanted the more toxic barbiturates, another BZRA subset (TABLE 1). By the late 1970s, BZDs had risen to the top of most prescribed medications, with one agent in particular—diazepam (Valium)—earning a reputation as “mother’s little helper,” a phrase derived from a Rolling Stones' song with that title produced in 1966.¹

With recognition of the problems associated with BZDs, their popularity diminished somewhat but remained high. BZDs were listed under Schedule IV by the Drug Enforcement Administration in 1975 due to the risk for addiction, and on the American Geriatrics Society Beers Criteria list in 1991 because of significant adverse consequences in the elderly. Researchers began to question their use as early as the 1970s, and the landmark Ashton Manual, guidance for patients and clinicians alike, was published in 2002.²

Currently, there are 14 BZDs approved by the Food and Drug Administration (FDA) as well as 3 Z-hypnotics, termed such as they include the letter “z” in their generic names (TABLE 1). In recent years, BZD prescribing has risen; a 2019 study found that 1 of 8 American adults reported using a BZD in the previous year.³

Limited benefits of benzodiazepine receptor agonists

BZRAs can be of benefit in a limited range of medical conditions, including some for which they are first-line considerations. (See TABLE 2 for a list of indications for BZDs.) They are most often prescribed for anxiety and insomnia, although they are not first-line treatments for these conditions and should be prescribed only when symptoms limit a patient’s daily functioning.

BZRAs are not intended for long-term use. In recent decades, the percentage of patients prescribed BZRAs has doubled, and more than 80% of these patients indicate usage for more than 6 months.⁴ Evidence, however, does not support long-term daily use.

Observation periods in most studies are far shorter than the number of years over which BZDs are actually prescribed, and flawed research methodology has introduced the risk of bias. Specifically, the generalizability of reported outcomes must be qualified, since efficacy trials performed under ideal study conditions (eg, exclusion criteria to minimize confounders) differ from circumstances seen in clinical practice. Conclusions are also limited by the inherent bias of pharmaceutical industry sponsorship and unavailability of unpublished trials that may have demonstrated unfavorable results.

Continue to: Insomnia

Insomnia, a current (past 30 days) complaint in more than 40% of US adults, is associated with a variety of symptoms.⁵ About 20% of adults have an insomnia disorder, defined as a predominant problem for at least 1 month involving sleep initiation, maintenance, or nonrestorative sleep along with daytime function-limiting fatigue.⁵ Meta-­analyses indicate BZRAs can reduce sleep latency (BZDs, by 4 minutes; Z-hypnotics, 22 minutes) and may increase sleep duration (BZDs, 62 minutes per limited data; Z-hypnotics, data insufficient).^6,7 Definitive evidence for long-term (> 2-4 weeks) BZD benefit is lacking, and cognitive behavioral therapy for insomnia (CBT-I) is well established as first-line treatment yielding improvements that may last at least 18 months after completion of therapy. ^8,9

Although CBT-I is generally provided by behavioral health specialists, elements of CBT-I and sleep hygiene measures can be effectively used by primary care clinicians.¹⁰ Data indicate other nonpharmacologic interventions are also effective,¹¹ including acceptance and commitment therapy,¹² meditation,¹³ and acupuncture.¹⁴

Episodic fear and anxiety are universal and essential for survival. Fear is an alarm warning of an immediate hazard. Anxiety (the emotion) paired with worry (the thought) relate to a perceived future threat. Transient (state) anxiety should not be suppressed altogether if self-management can curb its intensity and thereby allow effective problem engagement. However, when individuals are incapacitated by crisis anxiety or sporadic specific phobias such as flight anxiety, episodic BZDs do have a role.

Ongoing anxiety is a more complex treatment situation. Obsessive-compulsive disorder and posttraumatic stress disorder are no longer categorized as anxiety disorders, but they often involve anxiety. Here, BZDs have no indication aside from exceptional acute crisis presentations. Anxiety disorders are defined by a core persistent (trait) anxiety disproportionate to the actual threat, limited daily functioning, and more than 6 months’ duration. One of 3 Americans older than 13 years meet the criteria for anxiety in their lifetime; 1 of 5 meet the criteria in any single year.¹⁵

BZDs are effective in treating anxiety disorders in the short term (2-4 weeks)^2,16,17; however, benefit may fade over time.^18-21 For some individuals, data suggest BZDs themselves might actually generate anxiety, as evidenced by reduced symptom intensity following discontinuation.^22,23 Recommended first-line medications for anxiety disorders include certain antidepressants and pregabalin, which exhibit efficacy similar to that of BZDs.²⁴ Mindfulness and various psychotherapies have value, as well.¹⁶ Among the latter, CBT is considered first line with benefit comparable to BZDs in the short term; yet unlike BZDs, CBT gains can last 12 months or longer after the conclusion of therapy. ^25,26 Because there may be a delay between the start of CBT and the onset of benefit, BZDs, which work quickly, may be used to bridge functionally impaired patients in the short term.

Continue to: Risks with benzodiazepine receptor agonists

Risks with benzodiazepine receptor agonists

Harms from BZRA use are common, tempering their utility. Sedation, dyscognition, and psychomotor impairments are often seen upon initiation of BZRA use. These adverse effects can—although not always—improve with continuous BZRA exposure, an effect known as tolerance, which is due to neuropharmacologic adaptation. 

Cognitive issues include problems with memory, judgment, and decision making. These may be unrecognized or, if noted, attributed to other issues such as aging, and may become clear only when BZRAs are discontinued. Anterograde amnesia and parasomnias occur less often.

Psychomotor impairment can result in falls, fractures, and other injuries, especially in the elderly. Decrements in mood, including emergent depression and paradoxical anxiety, can occur. Some individuals experience disinhibition that is expressed through irritability, agitation, aggression, and violence.

Misuse of BZRAs is not unusual and can be related to dosing errors or attempts to ease intrusive symptoms. Nonmedical use almost always occurs in the context of an underlying use disorder, whereby BZRAs serve to amplify euphoria or ameliorate withdrawal from opioids or alcohol. Addiction per se, which entails BZRA craving and compulsive use leading to adverse consequences, is unusual.

BZRAs are associated with increased mortality, including all-cause mortality and suicide. They are respiratory depressants, although when taken alone in excess rarely result in death. They are, however, strongly implicated in opioid-related overdose fatalities, as their presence has been identified in 1 of 3 such decedents.²⁷

Continue to: Physiologic dependence with BZRAs

 

 

Physiologic dependence with BZRAs

Among the more important adverse outcomes with ongoing BZRA exposure is physiologic dependence. This occurs primarily because of neuroadaptation of GABA_A and glutaminergic receptors, but dependence probably also involves changes in the adenosine A_2A, serotonergic, and peripheral benzodiazepine receptors, the latter being present on mitochondrial membranes. The hypothalamic-pituitary-adrenal axis also appears to be involved.

Physiologic dependence is expressed through BZRA tolerance and characteristic physical and psychological symptoms upon withdrawal. Tolerance refers to a reduced effect with continued substance exposure or the need for an increased dose to get the same effect. Drug withdrawal can result in manifestations distinctive to addiction-prone substances, as well as to some medications without addiction liability, such as corticosteroids and antidepressants. Tolerance and withdrawal are not applicable criteria in the diagnosis of sedative-hypnotic use disorder when BZRAs are prescribed.²⁸

Withdrawal. Reported prevalence of BZRA physiologic dependence differs according to populations studied, criteria used, and the deprescribing process employed. Some researchers have found rates of one-third and others exceeding one-half among individuals using BZRAs for longer than a month.^23,29Physiologic dependence has also been seen in those exposed for as little as 1 week and at usual or even low dosages.^30,31 Moderate-to-severe withdrawal symptoms occur in 10% to 44% of BZRA users, and an estimated 10% to 15% have protracted (months, years, indefinite) symptoms that may fluctuate unpredictably and seem peculiar, bizarre, or unrelated to BZRA neuropharmacology.^2,32,33 The extent and severity of withdrawal can be striking, as highlighted in qualitative research of individuals seeking support and assistance in online communities.³⁴

Deprescribing BZRAs

Because benefits are limited and adverse outcomes including physiologic dependence are common, it is recommended that clinicians urge deprescribing of BZRAs for any patient taking them consistently for more than 1 month. Published deprescribing investigations and guidance are insufficient, heterogenous, and confusing. Still, some approaches can work well, and success rates as high as 80% have been achieved among the elderly, for example.³⁵ Brief interventions such as providing individualized advice, support, and management are effective.^36,37 Abrupt discontinuation is inappropriate and can be life threatening.³⁸ Forced cessation is also inappropriate unless significant respiratory depression is identified.

Physiologic dependence with benzodiazepine receptor agonists has been seen in those exposed for as little as 1 week and at usual or even low dosages.

The Ashton Manual is a useful guide, readable by patients. Proceed with tapering slowly at a rate led by the patient’s response.^2,39 Avoid discrediting patients’ reports of unusual withdrawal symptoms, as this can lead to misdiagnosis (eg, somatic symptom disorder) or ineffective treatment (eg, addiction recovery approaches). Adding CBT to tapering improves outcomes, and adjunctive medications may be helpful, although not without their own problems.²⁹ Consistent support of patients by others involved in treatment (prescriber, pharmacist, behavioral health specialists, peer coach, significant others) is essential. Complex challenges generally resolve through authentic listening and response but may require referral to others with necessary skills and experience. Complete cessation may take 12 to 18 months (or longer). Even if complete cessation is not possible, the least dose necessary can be achieved.

CORRESPONDENCE
Steven Wright, MD, 1975 Ashland Mine Road, Ashland, OR 97520; sleighwright@gmail.com

Benzodiazepines (BZDs) and Z-hypnotics have been available for decades, yet uncertainties about their use remain. They are prescribed and overprescribed most often for anxiety and insomnia, for which they have value but also the potential for significant adverse consequences, notably physiologic dependence. Use of these agents should be limited, and planned deprescribing is a fundamental aspect of prescribing.

A brief history. BZDs are a subset of benzodiazepine receptor agonists (BZRAs), which enhance the inhibitory effect of centrally acting γ-amino butyric acid (GABA) at the GABA_A receptor through allosteric modulation. In 1960, the first BZD, chlordiazepoxide, was marketed for clinical use, and as other agents in the class became available, BZDs supplanted the more toxic barbiturates, another BZRA subset (TABLE 1). By the late 1970s, BZDs had risen to the top of most prescribed medications, with one agent in particular—diazepam (Valium)—earning a reputation as “mother’s little helper,” a phrase derived from a Rolling Stones' song with that title produced in 1966.¹

With recognition of the problems associated with BZDs, their popularity diminished somewhat but remained high. BZDs were listed under Schedule IV by the Drug Enforcement Administration in 1975 due to the risk for addiction, and on the American Geriatrics Society Beers Criteria list in 1991 because of significant adverse consequences in the elderly. Researchers began to question their use as early as the 1970s, and the landmark Ashton Manual, guidance for patients and clinicians alike, was published in 2002.²

Currently, there are 14 BZDs approved by the Food and Drug Administration (FDA) as well as 3 Z-hypnotics, termed such as they include the letter “z” in their generic names (TABLE 1). In recent years, BZD prescribing has risen; a 2019 study found that 1 of 8 American adults reported using a BZD in the previous year.³

Limited benefits of benzodiazepine receptor agonists

BZRAs can be of benefit in a limited range of medical conditions, including some for which they are first-line considerations. (See TABLE 2 for a list of indications for BZDs.) They are most often prescribed for anxiety and insomnia, although they are not first-line treatments for these conditions and should be prescribed only when symptoms limit a patient’s daily functioning.

BZRAs are not intended for long-term use. In recent decades, the percentage of patients prescribed BZRAs has doubled, and more than 80% of these patients indicate usage for more than 6 months.⁴ Evidence, however, does not support long-term daily use.

Observation periods in most studies are far shorter than the number of years over which BZDs are actually prescribed, and flawed research methodology has introduced the risk of bias. Specifically, the generalizability of reported outcomes must be qualified, since efficacy trials performed under ideal study conditions (eg, exclusion criteria to minimize confounders) differ from circumstances seen in clinical practice. Conclusions are also limited by the inherent bias of pharmaceutical industry sponsorship and unavailability of unpublished trials that may have demonstrated unfavorable results.

Continue to: Insomnia

Insomnia, a current (past 30 days) complaint in more than 40% of US adults, is associated with a variety of symptoms.⁵ About 20% of adults have an insomnia disorder, defined as a predominant problem for at least 1 month involving sleep initiation, maintenance, or nonrestorative sleep along with daytime function-limiting fatigue.⁵ Meta-­analyses indicate BZRAs can reduce sleep latency (BZDs, by 4 minutes; Z-hypnotics, 22 minutes) and may increase sleep duration (BZDs, 62 minutes per limited data; Z-hypnotics, data insufficient).^6,7 Definitive evidence for long-term (> 2-4 weeks) BZD benefit is lacking, and cognitive behavioral therapy for insomnia (CBT-I) is well established as first-line treatment yielding improvements that may last at least 18 months after completion of therapy. ^8,9

Although CBT-I is generally provided by behavioral health specialists, elements of CBT-I and sleep hygiene measures can be effectively used by primary care clinicians.¹⁰ Data indicate other nonpharmacologic interventions are also effective,¹¹ including acceptance and commitment therapy,¹² meditation,¹³ and acupuncture.¹⁴

Episodic fear and anxiety are universal and essential for survival. Fear is an alarm warning of an immediate hazard. Anxiety (the emotion) paired with worry (the thought) relate to a perceived future threat. Transient (state) anxiety should not be suppressed altogether if self-management can curb its intensity and thereby allow effective problem engagement. However, when individuals are incapacitated by crisis anxiety or sporadic specific phobias such as flight anxiety, episodic BZDs do have a role.

Ongoing anxiety is a more complex treatment situation. Obsessive-compulsive disorder and posttraumatic stress disorder are no longer categorized as anxiety disorders, but they often involve anxiety. Here, BZDs have no indication aside from exceptional acute crisis presentations. Anxiety disorders are defined by a core persistent (trait) anxiety disproportionate to the actual threat, limited daily functioning, and more than 6 months’ duration. One of 3 Americans older than 13 years meet the criteria for anxiety in their lifetime; 1 of 5 meet the criteria in any single year.¹⁵

BZDs are effective in treating anxiety disorders in the short term (2-4 weeks)^2,16,17; however, benefit may fade over time.^18-21 For some individuals, data suggest BZDs themselves might actually generate anxiety, as evidenced by reduced symptom intensity following discontinuation.^22,23 Recommended first-line medications for anxiety disorders include certain antidepressants and pregabalin, which exhibit efficacy similar to that of BZDs.²⁴ Mindfulness and various psychotherapies have value, as well.¹⁶ Among the latter, CBT is considered first line with benefit comparable to BZDs in the short term; yet unlike BZDs, CBT gains can last 12 months or longer after the conclusion of therapy. ^25,26 Because there may be a delay between the start of CBT and the onset of benefit, BZDs, which work quickly, may be used to bridge functionally impaired patients in the short term.

Continue to: Risks with benzodiazepine receptor agonists

Risks with benzodiazepine receptor agonists

Harms from BZRA use are common, tempering their utility. Sedation, dyscognition, and psychomotor impairments are often seen upon initiation of BZRA use. These adverse effects can—although not always—improve with continuous BZRA exposure, an effect known as tolerance, which is due to neuropharmacologic adaptation. 

Cognitive issues include problems with memory, judgment, and decision making. These may be unrecognized or, if noted, attributed to other issues such as aging, and may become clear only when BZRAs are discontinued. Anterograde amnesia and parasomnias occur less often.

Psychomotor impairment can result in falls, fractures, and other injuries, especially in the elderly. Decrements in mood, including emergent depression and paradoxical anxiety, can occur. Some individuals experience disinhibition that is expressed through irritability, agitation, aggression, and violence.

Misuse of BZRAs is not unusual and can be related to dosing errors or attempts to ease intrusive symptoms. Nonmedical use almost always occurs in the context of an underlying use disorder, whereby BZRAs serve to amplify euphoria or ameliorate withdrawal from opioids or alcohol. Addiction per se, which entails BZRA craving and compulsive use leading to adverse consequences, is unusual.

BZRAs are associated with increased mortality, including all-cause mortality and suicide. They are respiratory depressants, although when taken alone in excess rarely result in death. They are, however, strongly implicated in opioid-related overdose fatalities, as their presence has been identified in 1 of 3 such decedents.²⁷

Continue to: Physiologic dependence with BZRAs

 

 

Physiologic dependence with BZRAs

Among the more important adverse outcomes with ongoing BZRA exposure is physiologic dependence. This occurs primarily because of neuroadaptation of GABA_A and glutaminergic receptors, but dependence probably also involves changes in the adenosine A_2A, serotonergic, and peripheral benzodiazepine receptors, the latter being present on mitochondrial membranes. The hypothalamic-pituitary-adrenal axis also appears to be involved.

Physiologic dependence is expressed through BZRA tolerance and characteristic physical and psychological symptoms upon withdrawal. Tolerance refers to a reduced effect with continued substance exposure or the need for an increased dose to get the same effect. Drug withdrawal can result in manifestations distinctive to addiction-prone substances, as well as to some medications without addiction liability, such as corticosteroids and antidepressants. Tolerance and withdrawal are not applicable criteria in the diagnosis of sedative-hypnotic use disorder when BZRAs are prescribed.²⁸

Withdrawal. Reported prevalence of BZRA physiologic dependence differs according to populations studied, criteria used, and the deprescribing process employed. Some researchers have found rates of one-third and others exceeding one-half among individuals using BZRAs for longer than a month.^23,29Physiologic dependence has also been seen in those exposed for as little as 1 week and at usual or even low dosages.^30,31 Moderate-to-severe withdrawal symptoms occur in 10% to 44% of BZRA users, and an estimated 10% to 15% have protracted (months, years, indefinite) symptoms that may fluctuate unpredictably and seem peculiar, bizarre, or unrelated to BZRA neuropharmacology.^2,32,33 The extent and severity of withdrawal can be striking, as highlighted in qualitative research of individuals seeking support and assistance in online communities.³⁴

Deprescribing BZRAs

Because benefits are limited and adverse outcomes including physiologic dependence are common, it is recommended that clinicians urge deprescribing of BZRAs for any patient taking them consistently for more than 1 month. Published deprescribing investigations and guidance are insufficient, heterogenous, and confusing. Still, some approaches can work well, and success rates as high as 80% have been achieved among the elderly, for example.³⁵ Brief interventions such as providing individualized advice, support, and management are effective.^36,37 Abrupt discontinuation is inappropriate and can be life threatening.³⁸ Forced cessation is also inappropriate unless significant respiratory depression is identified.

Physiologic dependence with benzodiazepine receptor agonists has been seen in those exposed for as little as 1 week and at usual or even low dosages.

The Ashton Manual is a useful guide, readable by patients. Proceed with tapering slowly at a rate led by the patient’s response.^2,39 Avoid discrediting patients’ reports of unusual withdrawal symptoms, as this can lead to misdiagnosis (eg, somatic symptom disorder) or ineffective treatment (eg, addiction recovery approaches). Adding CBT to tapering improves outcomes, and adjunctive medications may be helpful, although not without their own problems.²⁹ Consistent support of patients by others involved in treatment (prescriber, pharmacist, behavioral health specialists, peer coach, significant others) is essential. Complex challenges generally resolve through authentic listening and response but may require referral to others with necessary skills and experience. Complete cessation may take 12 to 18 months (or longer). Even if complete cessation is not possible, the least dose necessary can be achieved.

CORRESPONDENCE
Steven Wright, MD, 1975 Ashland Mine Road, Ashland, OR 97520; sleighwright@gmail.com

Benzodiazepines (BZDs) and Z-hypnotics have been available for decades, yet uncertainties about their use remain. They are prescribed and overprescribed most often for anxiety and insomnia, for which they have value but also the potential for significant adverse consequences, notably physiologic dependence. Use of these agents should be limited, and planned deprescribing is a fundamental aspect of prescribing.

A brief history. BZDs are a subset of benzodiazepine receptor agonists (BZRAs), which enhance the inhibitory effect of centrally acting γ-amino butyric acid (GABA) at the GABA_A receptor through allosteric modulation. In 1960, the first BZD, chlordiazepoxide, was marketed for clinical use, and as other agents in the class became available, BZDs supplanted the more toxic barbiturates, another BZRA subset (TABLE 1). By the late 1970s, BZDs had risen to the top of most prescribed medications, with one agent in particular—diazepam (Valium)—earning a reputation as “mother’s little helper,” a phrase derived from a Rolling Stones' song with that title produced in 1966.¹

With recognition of the problems associated with BZDs, their popularity diminished somewhat but remained high. BZDs were listed under Schedule IV by the Drug Enforcement Administration in 1975 due to the risk for addiction, and on the American Geriatrics Society Beers Criteria list in 1991 because of significant adverse consequences in the elderly. Researchers began to question their use as early as the 1970s, and the landmark Ashton Manual, guidance for patients and clinicians alike, was published in 2002.²

Currently, there are 14 BZDs approved by the Food and Drug Administration (FDA) as well as 3 Z-hypnotics, termed such as they include the letter “z” in their generic names (TABLE 1). In recent years, BZD prescribing has risen; a 2019 study found that 1 of 8 American adults reported using a BZD in the previous year.³

Limited benefits of benzodiazepine receptor agonists

BZRAs can be of benefit in a limited range of medical conditions, including some for which they are first-line considerations. (See TABLE 2 for a list of indications for BZDs.) They are most often prescribed for anxiety and insomnia, although they are not first-line treatments for these conditions and should be prescribed only when symptoms limit a patient’s daily functioning.

BZRAs are not intended for long-term use. In recent decades, the percentage of patients prescribed BZRAs has doubled, and more than 80% of these patients indicate usage for more than 6 months.⁴ Evidence, however, does not support long-term daily use.

Observation periods in most studies are far shorter than the number of years over which BZDs are actually prescribed, and flawed research methodology has introduced the risk of bias. Specifically, the generalizability of reported outcomes must be qualified, since efficacy trials performed under ideal study conditions (eg, exclusion criteria to minimize confounders) differ from circumstances seen in clinical practice. Conclusions are also limited by the inherent bias of pharmaceutical industry sponsorship and unavailability of unpublished trials that may have demonstrated unfavorable results.

Continue to: Insomnia

Insomnia, a current (past 30 days) complaint in more than 40% of US adults, is associated with a variety of symptoms.⁵ About 20% of adults have an insomnia disorder, defined as a predominant problem for at least 1 month involving sleep initiation, maintenance, or nonrestorative sleep along with daytime function-limiting fatigue.⁵ Meta-­analyses indicate BZRAs can reduce sleep latency (BZDs, by 4 minutes; Z-hypnotics, 22 minutes) and may increase sleep duration (BZDs, 62 minutes per limited data; Z-hypnotics, data insufficient).^6,7 Definitive evidence for long-term (> 2-4 weeks) BZD benefit is lacking, and cognitive behavioral therapy for insomnia (CBT-I) is well established as first-line treatment yielding improvements that may last at least 18 months after completion of therapy. ^8,9

Although CBT-I is generally provided by behavioral health specialists, elements of CBT-I and sleep hygiene measures can be effectively used by primary care clinicians.¹⁰ Data indicate other nonpharmacologic interventions are also effective,¹¹ including acceptance and commitment therapy,¹² meditation,¹³ and acupuncture.¹⁴

Episodic fear and anxiety are universal and essential for survival. Fear is an alarm warning of an immediate hazard. Anxiety (the emotion) paired with worry (the thought) relate to a perceived future threat. Transient (state) anxiety should not be suppressed altogether if self-management can curb its intensity and thereby allow effective problem engagement. However, when individuals are incapacitated by crisis anxiety or sporadic specific phobias such as flight anxiety, episodic BZDs do have a role.

Ongoing anxiety is a more complex treatment situation. Obsessive-compulsive disorder and posttraumatic stress disorder are no longer categorized as anxiety disorders, but they often involve anxiety. Here, BZDs have no indication aside from exceptional acute crisis presentations. Anxiety disorders are defined by a core persistent (trait) anxiety disproportionate to the actual threat, limited daily functioning, and more than 6 months’ duration. One of 3 Americans older than 13 years meet the criteria for anxiety in their lifetime; 1 of 5 meet the criteria in any single year.¹⁵

BZDs are effective in treating anxiety disorders in the short term (2-4 weeks)^2,16,17; however, benefit may fade over time.^18-21 For some individuals, data suggest BZDs themselves might actually generate anxiety, as evidenced by reduced symptom intensity following discontinuation.^22,23 Recommended first-line medications for anxiety disorders include certain antidepressants and pregabalin, which exhibit efficacy similar to that of BZDs.²⁴ Mindfulness and various psychotherapies have value, as well.¹⁶ Among the latter, CBT is considered first line with benefit comparable to BZDs in the short term; yet unlike BZDs, CBT gains can last 12 months or longer after the conclusion of therapy. ^25,26 Because there may be a delay between the start of CBT and the onset of benefit, BZDs, which work quickly, may be used to bridge functionally impaired patients in the short term.

Continue to: Risks with benzodiazepine receptor agonists

Risks with benzodiazepine receptor agonists

Harms from BZRA use are common, tempering their utility. Sedation, dyscognition, and psychomotor impairments are often seen upon initiation of BZRA use. These adverse effects can—although not always—improve with continuous BZRA exposure, an effect known as tolerance, which is due to neuropharmacologic adaptation. 

Cognitive issues include problems with memory, judgment, and decision making. These may be unrecognized or, if noted, attributed to other issues such as aging, and may become clear only when BZRAs are discontinued. Anterograde amnesia and parasomnias occur less often.

Psychomotor impairment can result in falls, fractures, and other injuries, especially in the elderly. Decrements in mood, including emergent depression and paradoxical anxiety, can occur. Some individuals experience disinhibition that is expressed through irritability, agitation, aggression, and violence.

Misuse of BZRAs is not unusual and can be related to dosing errors or attempts to ease intrusive symptoms. Nonmedical use almost always occurs in the context of an underlying use disorder, whereby BZRAs serve to amplify euphoria or ameliorate withdrawal from opioids or alcohol. Addiction per se, which entails BZRA craving and compulsive use leading to adverse consequences, is unusual.

BZRAs are associated with increased mortality, including all-cause mortality and suicide. They are respiratory depressants, although when taken alone in excess rarely result in death. They are, however, strongly implicated in opioid-related overdose fatalities, as their presence has been identified in 1 of 3 such decedents.²⁷

Continue to: Physiologic dependence with BZRAs

 

 

Physiologic dependence with BZRAs

Among the more important adverse outcomes with ongoing BZRA exposure is physiologic dependence. This occurs primarily because of neuroadaptation of GABA_A and glutaminergic receptors, but dependence probably also involves changes in the adenosine A_2A, serotonergic, and peripheral benzodiazepine receptors, the latter being present on mitochondrial membranes. The hypothalamic-pituitary-adrenal axis also appears to be involved.

Physiologic dependence is expressed through BZRA tolerance and characteristic physical and psychological symptoms upon withdrawal. Tolerance refers to a reduced effect with continued substance exposure or the need for an increased dose to get the same effect. Drug withdrawal can result in manifestations distinctive to addiction-prone substances, as well as to some medications without addiction liability, such as corticosteroids and antidepressants. Tolerance and withdrawal are not applicable criteria in the diagnosis of sedative-hypnotic use disorder when BZRAs are prescribed.²⁸

Withdrawal. Reported prevalence of BZRA physiologic dependence differs according to populations studied, criteria used, and the deprescribing process employed. Some researchers have found rates of one-third and others exceeding one-half among individuals using BZRAs for longer than a month.^23,29Physiologic dependence has also been seen in those exposed for as little as 1 week and at usual or even low dosages.^30,31 Moderate-to-severe withdrawal symptoms occur in 10% to 44% of BZRA users, and an estimated 10% to 15% have protracted (months, years, indefinite) symptoms that may fluctuate unpredictably and seem peculiar, bizarre, or unrelated to BZRA neuropharmacology.^2,32,33 The extent and severity of withdrawal can be striking, as highlighted in qualitative research of individuals seeking support and assistance in online communities.³⁴

Deprescribing BZRAs

Because benefits are limited and adverse outcomes including physiologic dependence are common, it is recommended that clinicians urge deprescribing of BZRAs for any patient taking them consistently for more than 1 month. Published deprescribing investigations and guidance are insufficient, heterogenous, and confusing. Still, some approaches can work well, and success rates as high as 80% have been achieved among the elderly, for example.³⁵ Brief interventions such as providing individualized advice, support, and management are effective.^36,37 Abrupt discontinuation is inappropriate and can be life threatening.³⁸ Forced cessation is also inappropriate unless significant respiratory depression is identified.

Physiologic dependence with benzodiazepine receptor agonists has been seen in those exposed for as little as 1 week and at usual or even low dosages.

The Ashton Manual is a useful guide, readable by patients. Proceed with tapering slowly at a rate led by the patient’s response.^2,39 Avoid discrediting patients’ reports of unusual withdrawal symptoms, as this can lead to misdiagnosis (eg, somatic symptom disorder) or ineffective treatment (eg, addiction recovery approaches). Adding CBT to tapering improves outcomes, and adjunctive medications may be helpful, although not without their own problems.²⁹ Consistent support of patients by others involved in treatment (prescriber, pharmacist, behavioral health specialists, peer coach, significant others) is essential. Complex challenges generally resolve through authentic listening and response but may require referral to others with necessary skills and experience. Complete cessation may take 12 to 18 months (or longer). Even if complete cessation is not possible, the least dose necessary can be achieved.

CORRESPONDENCE
Steven Wright, MD, 1975 Ashland Mine Road, Ashland, OR 97520; sleighwright@gmail.com

An analysis at a large academic health system suggests that universal screening might help to reduce problematic disparities in depression treatment.  

The study began soon after the U.S. Preventive Services Task Force recommended depression screening for all adults in 2016. The task force based this recommendation on evidence that people who are screened and treated experience fewer debilitating symptoms.

In the new research, the investigators analyzed electronic health record data following a rollout of a universal depression screening program at the University of California, San Francisco. The researchers found that the overall rate of depression screening doubled at six primary care practices over a little more than 2 years, reaching nearly 90%. The investigators presented the data April 9 at the Society of General Internal Medicine 2022 Annual Meeting in Orlando.

Meanwhile, screening disparities diminished for men, older individuals, racial and ethnic minorities, and people with language barriers – all groups that are undertreated for depression.

“It shows that if a health system is really invested, it can achieve really high depression screening,” primary investigator Maria Garcia, MD, MPH, co-director of UCSF’s Multiethnic Health Equity Research Center, told this news organization.
 

Methods for identifying depression

The health system assigned medical assistants to administer annual screening using a validated tool, the Patient Health Questionnaire-2 (PHQ-2). A “yes” response to either of its two questions triggered a longer questionnaire, the PHQ-9, used to diagnose and guide treatment.

Screening forms were available in multiple languages. Medical assistants received training on the importance of identifying depression in undertreated groups, and a banner was inserted in the electronic health record to indicate a screening was due, Dr. Garcia said.

During the rollout, a committee was assigned to monitor screening rates and adjust strategies to target disparities.

Dr. Garcia and fellow researchers calculated the likelihood of a patient being screened starting in September 2017 – when a field for depression screening status was added to the system’s electronic health record – until the rollout was completed on Dec. 31, 2019.
 

Screening disparities narrowed for all groups studied

The screening rate for patients who had a primary care visit increased from 40.5% to 88.8%. Early on, patients with language barriers were less likely to be screened than English-speaking White individuals (odds ratios, 0.55-0.59). Men were less likely to be screened than women (OR, 0.82; 95% confidence interval, 0.78-0.86), and the likelihood of being screened decreased as people got older. By 2019, screening disparities had narrowed for all groups and were only statistically significant for men (OR, 0.87; 95% CI, 0.81-0.93).

Ian Kronish, MD, MPH, a general internist and associate professor of medicine at Columbia University, New York, called the increases “impressive,” adding that the data show universal depression screening is possible in a system that serves a diverse population.

Dr. Kronish, who was not involved in this study, noted that other research indicates screening does not result in a significant reduction in depressive symptoms in the overall population. He found this to be the case in a trial he led, which focused on patients with recent cardiac events, for example.

“Given all the effort that is going into depression screening and the inclusion of depression screening as a quality metric, we need definitive randomized clinical trials testing whether depression screening leads to increased treatment uptake and, importantly, improved depressive symptoms and quality of life,” he said.

Dr. Garcia acknowledged that more work needs to be done to address treatment barriers, such as language and lack of insurance, and assess whether greater recognition of depressive symptoms in underserved groups can lead to effective treatment. “But this is an important step to know that universal depression screening narrowed disparities in screening over time,” she added.

Dr. Garcia and Dr. Kronish have disclosed no relevant financial relationships.

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

An analysis at a large academic health system suggests that universal screening might help to reduce problematic disparities in depression treatment.  

The study began soon after the U.S. Preventive Services Task Force recommended depression screening for all adults in 2016. The task force based this recommendation on evidence that people who are screened and treated experience fewer debilitating symptoms.

In the new research, the investigators analyzed electronic health record data following a rollout of a universal depression screening program at the University of California, San Francisco. The researchers found that the overall rate of depression screening doubled at six primary care practices over a little more than 2 years, reaching nearly 90%. The investigators presented the data April 9 at the Society of General Internal Medicine 2022 Annual Meeting in Orlando.

Meanwhile, screening disparities diminished for men, older individuals, racial and ethnic minorities, and people with language barriers – all groups that are undertreated for depression.

“It shows that if a health system is really invested, it can achieve really high depression screening,” primary investigator Maria Garcia, MD, MPH, co-director of UCSF’s Multiethnic Health Equity Research Center, told this news organization.
 

Methods for identifying depression

The health system assigned medical assistants to administer annual screening using a validated tool, the Patient Health Questionnaire-2 (PHQ-2). A “yes” response to either of its two questions triggered a longer questionnaire, the PHQ-9, used to diagnose and guide treatment.

Screening forms were available in multiple languages. Medical assistants received training on the importance of identifying depression in undertreated groups, and a banner was inserted in the electronic health record to indicate a screening was due, Dr. Garcia said.

During the rollout, a committee was assigned to monitor screening rates and adjust strategies to target disparities.

Dr. Garcia and fellow researchers calculated the likelihood of a patient being screened starting in September 2017 – when a field for depression screening status was added to the system’s electronic health record – until the rollout was completed on Dec. 31, 2019.
 

Screening disparities narrowed for all groups studied

The screening rate for patients who had a primary care visit increased from 40.5% to 88.8%. Early on, patients with language barriers were less likely to be screened than English-speaking White individuals (odds ratios, 0.55-0.59). Men were less likely to be screened than women (OR, 0.82; 95% confidence interval, 0.78-0.86), and the likelihood of being screened decreased as people got older. By 2019, screening disparities had narrowed for all groups and were only statistically significant for men (OR, 0.87; 95% CI, 0.81-0.93).

Ian Kronish, MD, MPH, a general internist and associate professor of medicine at Columbia University, New York, called the increases “impressive,” adding that the data show universal depression screening is possible in a system that serves a diverse population.

Dr. Kronish, who was not involved in this study, noted that other research indicates screening does not result in a significant reduction in depressive symptoms in the overall population. He found this to be the case in a trial he led, which focused on patients with recent cardiac events, for example.

“Given all the effort that is going into depression screening and the inclusion of depression screening as a quality metric, we need definitive randomized clinical trials testing whether depression screening leads to increased treatment uptake and, importantly, improved depressive symptoms and quality of life,” he said.

Dr. Garcia acknowledged that more work needs to be done to address treatment barriers, such as language and lack of insurance, and assess whether greater recognition of depressive symptoms in underserved groups can lead to effective treatment. “But this is an important step to know that universal depression screening narrowed disparities in screening over time,” she added.

Dr. Garcia and Dr. Kronish have disclosed no relevant financial relationships.

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

An analysis at a large academic health system suggests that universal screening might help to reduce problematic disparities in depression treatment.  

The study began soon after the U.S. Preventive Services Task Force recommended depression screening for all adults in 2016. The task force based this recommendation on evidence that people who are screened and treated experience fewer debilitating symptoms.

In the new research, the investigators analyzed electronic health record data following a rollout of a universal depression screening program at the University of California, San Francisco. The researchers found that the overall rate of depression screening doubled at six primary care practices over a little more than 2 years, reaching nearly 90%. The investigators presented the data April 9 at the Society of General Internal Medicine 2022 Annual Meeting in Orlando.

Meanwhile, screening disparities diminished for men, older individuals, racial and ethnic minorities, and people with language barriers – all groups that are undertreated for depression.

“It shows that if a health system is really invested, it can achieve really high depression screening,” primary investigator Maria Garcia, MD, MPH, co-director of UCSF’s Multiethnic Health Equity Research Center, told this news organization.
 

Methods for identifying depression

The health system assigned medical assistants to administer annual screening using a validated tool, the Patient Health Questionnaire-2 (PHQ-2). A “yes” response to either of its two questions triggered a longer questionnaire, the PHQ-9, used to diagnose and guide treatment.

Screening forms were available in multiple languages. Medical assistants received training on the importance of identifying depression in undertreated groups, and a banner was inserted in the electronic health record to indicate a screening was due, Dr. Garcia said.

During the rollout, a committee was assigned to monitor screening rates and adjust strategies to target disparities.

Dr. Garcia and fellow researchers calculated the likelihood of a patient being screened starting in September 2017 – when a field for depression screening status was added to the system’s electronic health record – until the rollout was completed on Dec. 31, 2019.
 

Screening disparities narrowed for all groups studied

The screening rate for patients who had a primary care visit increased from 40.5% to 88.8%. Early on, patients with language barriers were less likely to be screened than English-speaking White individuals (odds ratios, 0.55-0.59). Men were less likely to be screened than women (OR, 0.82; 95% confidence interval, 0.78-0.86), and the likelihood of being screened decreased as people got older. By 2019, screening disparities had narrowed for all groups and were only statistically significant for men (OR, 0.87; 95% CI, 0.81-0.93).

Ian Kronish, MD, MPH, a general internist and associate professor of medicine at Columbia University, New York, called the increases “impressive,” adding that the data show universal depression screening is possible in a system that serves a diverse population.

Dr. Kronish, who was not involved in this study, noted that other research indicates screening does not result in a significant reduction in depressive symptoms in the overall population. He found this to be the case in a trial he led, which focused on patients with recent cardiac events, for example.

“Given all the effort that is going into depression screening and the inclusion of depression screening as a quality metric, we need definitive randomized clinical trials testing whether depression screening leads to increased treatment uptake and, importantly, improved depressive symptoms and quality of life,” he said.

Dr. Garcia acknowledged that more work needs to be done to address treatment barriers, such as language and lack of insurance, and assess whether greater recognition of depressive symptoms in underserved groups can lead to effective treatment. “But this is an important step to know that universal depression screening narrowed disparities in screening over time,” she added.

Dr. Garcia and Dr. Kronish have disclosed no relevant financial relationships.

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

The Food and Drug Administration has approved dexmedetomidine (Igalmi, BioXcel Therapeutics) sublingual film for the acute treatment of agitation associated with schizophrenia or bipolar I or II disorder in adults.

This is the first FDA-approved, orally dissolving, self-administered sublingual treatment for this indication. With a demonstrated onset of action as early as 20 minutes, it shows a high response rate in patients at both 120-mcg and 180-mcg doses.

Olivier Le Moal/Getty Images

An estimated 7.3 million individuals in the United States are diagnosed with schizophrenia or bipolar disorders, and up to one-quarter of them experience episodes of agitation that can occur 10-17 times annually. These episodes represent a significant burden for patients, caregivers, and the health care system.

“There are large numbers of patients who experience agitation associated with schizophrenia and bipolar disorders, and this condition has been a long-standing challenge for health care professionals to treat,” said John Krystal, MD, the Robert L. McNeil Jr. Professor of Translational Research and chair of the department of psychiatry at Yale University, New Haven, Conn.

“The approval of Igalmi, a self-administered film with a desirable onset of action, represents a milestone moment. It provides health care teams with an innovative tool to help control agitation. As clinicians, we welcome this much-needed new oral treatment option,” he added.

“Igalmi is the first new acute treatment for schizophrenia or bipolar disorder–associated agitation in nearly a decade and represents a differentiated approach to helping patients manage this difficult and debilitating symptom,” said Vimal Mehta, PhD, CEO of BioXcel Therapeutics.

The FDA approval of Igalmi is based on data from two pivotal randomized, double-blinded, placebo-controlled, parallel-group, phase 3 trials that evaluated Igalmi for the acute treatment of agitation associated with schizophrenia (SERENITY I) or bipolar I or II disorder (SERENITY II).

The most common adverse reactions (incidence ≥5% and at least twice the rate of placebo) were somnolence, paresthesia or oral hypoesthesia, dizziness, dry mouth, hypotension, and orthostatic hypotension. All adverse drug reactions were mild to moderate in severity. While Igalmi was not associated with any treatment-related serious adverse effects in phase 3 studies, it may cause notable side effects, including hypotension, orthostatic hypotension, bradycardia, QT interval prolongation, and somnolence.

As previously reported by this news organization, data from the phase 3 SERENITY II trial that evaluated Igalmi in bipolar disorders were published in JAMA.

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

The Food and Drug Administration has approved dexmedetomidine (Igalmi, BioXcel Therapeutics) sublingual film for the acute treatment of agitation associated with schizophrenia or bipolar I or II disorder in adults.

This is the first FDA-approved, orally dissolving, self-administered sublingual treatment for this indication. With a demonstrated onset of action as early as 20 minutes, it shows a high response rate in patients at both 120-mcg and 180-mcg doses.

Olivier Le Moal/Getty Images

An estimated 7.3 million individuals in the United States are diagnosed with schizophrenia or bipolar disorders, and up to one-quarter of them experience episodes of agitation that can occur 10-17 times annually. These episodes represent a significant burden for patients, caregivers, and the health care system.

“There are large numbers of patients who experience agitation associated with schizophrenia and bipolar disorders, and this condition has been a long-standing challenge for health care professionals to treat,” said John Krystal, MD, the Robert L. McNeil Jr. Professor of Translational Research and chair of the department of psychiatry at Yale University, New Haven, Conn.

“The approval of Igalmi, a self-administered film with a desirable onset of action, represents a milestone moment. It provides health care teams with an innovative tool to help control agitation. As clinicians, we welcome this much-needed new oral treatment option,” he added.

“Igalmi is the first new acute treatment for schizophrenia or bipolar disorder–associated agitation in nearly a decade and represents a differentiated approach to helping patients manage this difficult and debilitating symptom,” said Vimal Mehta, PhD, CEO of BioXcel Therapeutics.

The FDA approval of Igalmi is based on data from two pivotal randomized, double-blinded, placebo-controlled, parallel-group, phase 3 trials that evaluated Igalmi for the acute treatment of agitation associated with schizophrenia (SERENITY I) or bipolar I or II disorder (SERENITY II).

The most common adverse reactions (incidence ≥5% and at least twice the rate of placebo) were somnolence, paresthesia or oral hypoesthesia, dizziness, dry mouth, hypotension, and orthostatic hypotension. All adverse drug reactions were mild to moderate in severity. While Igalmi was not associated with any treatment-related serious adverse effects in phase 3 studies, it may cause notable side effects, including hypotension, orthostatic hypotension, bradycardia, QT interval prolongation, and somnolence.

As previously reported by this news organization, data from the phase 3 SERENITY II trial that evaluated Igalmi in bipolar disorders were published in JAMA.

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

The Food and Drug Administration has approved dexmedetomidine (Igalmi, BioXcel Therapeutics) sublingual film for the acute treatment of agitation associated with schizophrenia or bipolar I or II disorder in adults.

This is the first FDA-approved, orally dissolving, self-administered sublingual treatment for this indication. With a demonstrated onset of action as early as 20 minutes, it shows a high response rate in patients at both 120-mcg and 180-mcg doses.

Olivier Le Moal/Getty Images

An estimated 7.3 million individuals in the United States are diagnosed with schizophrenia or bipolar disorders, and up to one-quarter of them experience episodes of agitation that can occur 10-17 times annually. These episodes represent a significant burden for patients, caregivers, and the health care system.

“There are large numbers of patients who experience agitation associated with schizophrenia and bipolar disorders, and this condition has been a long-standing challenge for health care professionals to treat,” said John Krystal, MD, the Robert L. McNeil Jr. Professor of Translational Research and chair of the department of psychiatry at Yale University, New Haven, Conn.

“The approval of Igalmi, a self-administered film with a desirable onset of action, represents a milestone moment. It provides health care teams with an innovative tool to help control agitation. As clinicians, we welcome this much-needed new oral treatment option,” he added.

“Igalmi is the first new acute treatment for schizophrenia or bipolar disorder–associated agitation in nearly a decade and represents a differentiated approach to helping patients manage this difficult and debilitating symptom,” said Vimal Mehta, PhD, CEO of BioXcel Therapeutics.

The FDA approval of Igalmi is based on data from two pivotal randomized, double-blinded, placebo-controlled, parallel-group, phase 3 trials that evaluated Igalmi for the acute treatment of agitation associated with schizophrenia (SERENITY I) or bipolar I or II disorder (SERENITY II).

The most common adverse reactions (incidence ≥5% and at least twice the rate of placebo) were somnolence, paresthesia or oral hypoesthesia, dizziness, dry mouth, hypotension, and orthostatic hypotension. All adverse drug reactions were mild to moderate in severity. While Igalmi was not associated with any treatment-related serious adverse effects in phase 3 studies, it may cause notable side effects, including hypotension, orthostatic hypotension, bradycardia, QT interval prolongation, and somnolence.

As previously reported by this news organization, data from the phase 3 SERENITY II trial that evaluated Igalmi in bipolar disorders were published in JAMA.

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

Physically fit children have a greater ability to concentrate and better health-related quality of life (HRQOL), according to a new study.

The findings of the German study involving more than 6,500 kids emphasize the importance of cardiorespiratory health in childhood, and support physical fitness initiatives in schools, according to lead author Katharina Köble, MSc, of the Technical University of Munich (Germany), and colleagues.

“Recent studies show that only a few children meet the recommendations of physical activity,” the investigators wrote in Journal of Clinical Medicine.

While the health benefits of physical activity are clearly documented, Ms. Köble and colleagues noted that typical measures of activity, such as accelerometers or self-reported questionnaires, are suboptimal research tools.

“Physical fitness is a more objective parameter to quantify when evaluating health promotion,” the investigators wrote. “Furthermore, cardiorespiratory fitness as part of physical fitness is more strongly related to risk factors of cardiovascular disease than physical activity.”

According to the investigators, physical fitness has also been linked with better concentration and HRQOL, but never in the same population of children.

The new study aimed to address this knowledge gap by assessing 6,533 healthy children aged 6-10 years, approximately half boys and half girls. Associations between physical fitness, concentration, and HRQOL were evaluated using multiple linear regression analysis in participants aged 9-10 years.

Physical fitness was measured using a series of challenges, including curl-ups (pull-ups with palms facing body), push-ups, standing long jump, handgrip strength measurement, and Progressive Aerobic Cardiovascular Endurance Run (PACER). Performing the multistage shuttle run, PACER, “requires participants to maintain the pace set by an audio signal, which progressively increases the intensity every minute.” Results of the PACER test were used to estimate VO_2max.

Concentration was measured using the d2-R test, “a paper-pencil cancellation test, where subjects have to cross out all ‘d’ letters with two dashes under a time limit.”

HRQOL was evaluated with the KINDL questionnaire, which covers emotional well-being, physical well-being, everyday functioning (school), friends, family, and self-esteem.

Analysis showed that physical fitness improved with age (P < .001), except for VO_2max in girls (P = .129). Concentration also improved with age (P < .001), while HRQOL did not (P = .179).

Among children aged 9-10 years, VO_2max scores were strongly associated with both HRQOL (P < .001) and concentration (P < .001).

“VO_2max was found to be one of the main factors influencing concentration levels and HRQOL dimensions in primary school children,” the investigators wrote. “Physical fitness, especially cardiorespiratory performance, should therefore be promoted more specifically in school settings to support the promotion of an overall healthy lifestyle in children and adolescents.”
 

Findings are having a real-word impact, according to researcher

In an interview, Ms. Köble noted that the findings are already having a real-world impact.

“We continued data assessment in the long-term and specifically adapted prevention programs in school to the needs of the school children we identified in our study,” she said. “Schools are partially offering specific movement and nutrition classes now.”

In addition, Ms. Köble and colleagues plan on educating teachers about the “urgent need for sufficient physical activity.”

“Academic performance should be considered as an additional health factor in future studies, as well as screen time and eating patterns, as all those variables showed interactions with physical fitness and concentration. In a subanalysis, we showed that children with better physical fitness and concentration values were those who usually went to higher education secondary schools,” they wrote.
 

VO_2max did not correlate with BMI

Gregory Weaver, MD, a pediatrician at Cleveland Clinic Children’s, voiced some concerns about the reliability of the findings. He noted that VO_2max did not correlate with body mass index or other measures of physical fitness, and that using the PACER test to estimate VO_2max may have skewed the association between physical fitness and concentration.

“It is quite conceivable that children who can maintain the focus to perform maximally on this test will also do well on other tests of attention/concentration,” Dr. Weaver said. “Most children I know would have a very difficult time performing a physical fitness test which requires them to match a recorded pace that slowly increases overtime. I’m not an expert in the area, but it is my understanding that usually VO_2max tests involve a treadmill which allows investigators to have complete control over pace.”

Dr. Weaver concluded that more work is needed to determine if physical fitness interventions can have a positive impact on HRQOL and concentration.

“I think the authors of this study attempted to ask an important question about the possible association between physical fitness and concentration among school aged children,” Dr. Weaver said in an interview. “But what is even more vital are studies demonstrating that a change in modifiable health factors like nutrition, physical fitness, or the built environment can improve quality of life. I was hoping the authors would show that an improvement in VO_2max over time resulted in an improvement in concentration. Frustratingly, that is not what this article demonstrates.”

The investigators and Dr. Weaver reported no conflicts of interest.

Physically fit children have a greater ability to concentrate and better health-related quality of life (HRQOL), according to a new study.

The findings of the German study involving more than 6,500 kids emphasize the importance of cardiorespiratory health in childhood, and support physical fitness initiatives in schools, according to lead author Katharina Köble, MSc, of the Technical University of Munich (Germany), and colleagues.

“Recent studies show that only a few children meet the recommendations of physical activity,” the investigators wrote in Journal of Clinical Medicine.

While the health benefits of physical activity are clearly documented, Ms. Köble and colleagues noted that typical measures of activity, such as accelerometers or self-reported questionnaires, are suboptimal research tools.

“Physical fitness is a more objective parameter to quantify when evaluating health promotion,” the investigators wrote. “Furthermore, cardiorespiratory fitness as part of physical fitness is more strongly related to risk factors of cardiovascular disease than physical activity.”

According to the investigators, physical fitness has also been linked with better concentration and HRQOL, but never in the same population of children.

The new study aimed to address this knowledge gap by assessing 6,533 healthy children aged 6-10 years, approximately half boys and half girls. Associations between physical fitness, concentration, and HRQOL were evaluated using multiple linear regression analysis in participants aged 9-10 years.

Physical fitness was measured using a series of challenges, including curl-ups (pull-ups with palms facing body), push-ups, standing long jump, handgrip strength measurement, and Progressive Aerobic Cardiovascular Endurance Run (PACER). Performing the multistage shuttle run, PACER, “requires participants to maintain the pace set by an audio signal, which progressively increases the intensity every minute.” Results of the PACER test were used to estimate VO_2max.

Concentration was measured using the d2-R test, “a paper-pencil cancellation test, where subjects have to cross out all ‘d’ letters with two dashes under a time limit.”

HRQOL was evaluated with the KINDL questionnaire, which covers emotional well-being, physical well-being, everyday functioning (school), friends, family, and self-esteem.

Analysis showed that physical fitness improved with age (P < .001), except for VO_2max in girls (P = .129). Concentration also improved with age (P < .001), while HRQOL did not (P = .179).

Among children aged 9-10 years, VO_2max scores were strongly associated with both HRQOL (P < .001) and concentration (P < .001).

“VO_2max was found to be one of the main factors influencing concentration levels and HRQOL dimensions in primary school children,” the investigators wrote. “Physical fitness, especially cardiorespiratory performance, should therefore be promoted more specifically in school settings to support the promotion of an overall healthy lifestyle in children and adolescents.”
 

Findings are having a real-word impact, according to researcher

In an interview, Ms. Köble noted that the findings are already having a real-world impact.

“We continued data assessment in the long-term and specifically adapted prevention programs in school to the needs of the school children we identified in our study,” she said. “Schools are partially offering specific movement and nutrition classes now.”

In addition, Ms. Köble and colleagues plan on educating teachers about the “urgent need for sufficient physical activity.”

“Academic performance should be considered as an additional health factor in future studies, as well as screen time and eating patterns, as all those variables showed interactions with physical fitness and concentration. In a subanalysis, we showed that children with better physical fitness and concentration values were those who usually went to higher education secondary schools,” they wrote.
 

VO_2max did not correlate with BMI

Gregory Weaver, MD, a pediatrician at Cleveland Clinic Children’s, voiced some concerns about the reliability of the findings. He noted that VO_2max did not correlate with body mass index or other measures of physical fitness, and that using the PACER test to estimate VO_2max may have skewed the association between physical fitness and concentration.

“It is quite conceivable that children who can maintain the focus to perform maximally on this test will also do well on other tests of attention/concentration,” Dr. Weaver said. “Most children I know would have a very difficult time performing a physical fitness test which requires them to match a recorded pace that slowly increases overtime. I’m not an expert in the area, but it is my understanding that usually VO_2max tests involve a treadmill which allows investigators to have complete control over pace.”

Dr. Weaver concluded that more work is needed to determine if physical fitness interventions can have a positive impact on HRQOL and concentration.

“I think the authors of this study attempted to ask an important question about the possible association between physical fitness and concentration among school aged children,” Dr. Weaver said in an interview. “But what is even more vital are studies demonstrating that a change in modifiable health factors like nutrition, physical fitness, or the built environment can improve quality of life. I was hoping the authors would show that an improvement in VO_2max over time resulted in an improvement in concentration. Frustratingly, that is not what this article demonstrates.”

The investigators and Dr. Weaver reported no conflicts of interest.

Physically fit children have a greater ability to concentrate and better health-related quality of life (HRQOL), according to a new study.

The findings of the German study involving more than 6,500 kids emphasize the importance of cardiorespiratory health in childhood, and support physical fitness initiatives in schools, according to lead author Katharina Köble, MSc, of the Technical University of Munich (Germany), and colleagues.

“Recent studies show that only a few children meet the recommendations of physical activity,” the investigators wrote in Journal of Clinical Medicine.

While the health benefits of physical activity are clearly documented, Ms. Köble and colleagues noted that typical measures of activity, such as accelerometers or self-reported questionnaires, are suboptimal research tools.

“Physical fitness is a more objective parameter to quantify when evaluating health promotion,” the investigators wrote. “Furthermore, cardiorespiratory fitness as part of physical fitness is more strongly related to risk factors of cardiovascular disease than physical activity.”

According to the investigators, physical fitness has also been linked with better concentration and HRQOL, but never in the same population of children.

The new study aimed to address this knowledge gap by assessing 6,533 healthy children aged 6-10 years, approximately half boys and half girls. Associations between physical fitness, concentration, and HRQOL were evaluated using multiple linear regression analysis in participants aged 9-10 years.

Physical fitness was measured using a series of challenges, including curl-ups (pull-ups with palms facing body), push-ups, standing long jump, handgrip strength measurement, and Progressive Aerobic Cardiovascular Endurance Run (PACER). Performing the multistage shuttle run, PACER, “requires participants to maintain the pace set by an audio signal, which progressively increases the intensity every minute.” Results of the PACER test were used to estimate VO_2max.

Concentration was measured using the d2-R test, “a paper-pencil cancellation test, where subjects have to cross out all ‘d’ letters with two dashes under a time limit.”

HRQOL was evaluated with the KINDL questionnaire, which covers emotional well-being, physical well-being, everyday functioning (school), friends, family, and self-esteem.

Analysis showed that physical fitness improved with age (P < .001), except for VO_2max in girls (P = .129). Concentration also improved with age (P < .001), while HRQOL did not (P = .179).

Among children aged 9-10 years, VO_2max scores were strongly associated with both HRQOL (P < .001) and concentration (P < .001).

“VO_2max was found to be one of the main factors influencing concentration levels and HRQOL dimensions in primary school children,” the investigators wrote. “Physical fitness, especially cardiorespiratory performance, should therefore be promoted more specifically in school settings to support the promotion of an overall healthy lifestyle in children and adolescents.”
 

Findings are having a real-word impact, according to researcher

In an interview, Ms. Köble noted that the findings are already having a real-world impact.

“We continued data assessment in the long-term and specifically adapted prevention programs in school to the needs of the school children we identified in our study,” she said. “Schools are partially offering specific movement and nutrition classes now.”

In addition, Ms. Köble and colleagues plan on educating teachers about the “urgent need for sufficient physical activity.”

“Academic performance should be considered as an additional health factor in future studies, as well as screen time and eating patterns, as all those variables showed interactions with physical fitness and concentration. In a subanalysis, we showed that children with better physical fitness and concentration values were those who usually went to higher education secondary schools,” they wrote.
 

VO_2max did not correlate with BMI

Gregory Weaver, MD, a pediatrician at Cleveland Clinic Children’s, voiced some concerns about the reliability of the findings. He noted that VO_2max did not correlate with body mass index or other measures of physical fitness, and that using the PACER test to estimate VO_2max may have skewed the association between physical fitness and concentration.

“It is quite conceivable that children who can maintain the focus to perform maximally on this test will also do well on other tests of attention/concentration,” Dr. Weaver said. “Most children I know would have a very difficult time performing a physical fitness test which requires them to match a recorded pace that slowly increases overtime. I’m not an expert in the area, but it is my understanding that usually VO_2max tests involve a treadmill which allows investigators to have complete control over pace.”

Dr. Weaver concluded that more work is needed to determine if physical fitness interventions can have a positive impact on HRQOL and concentration.

“I think the authors of this study attempted to ask an important question about the possible association between physical fitness and concentration among school aged children,” Dr. Weaver said in an interview. “But what is even more vital are studies demonstrating that a change in modifiable health factors like nutrition, physical fitness, or the built environment can improve quality of life. I was hoping the authors would show that an improvement in VO_2max over time resulted in an improvement in concentration. Frustratingly, that is not what this article demonstrates.”

The investigators and Dr. Weaver reported no conflicts of interest.

Physical exercise offers preventative and therapeutic benefits for a range of chronic health conditions, including cardiovascular disease, type 2 diabetes mellitus, Alzheimer disease, and depression.^1,2 Exercise has been well studied for its antidepressant effects, its ability to reduce risk of aging-related dementia, and favorable effects on a range of cognitive functions.² Lesser evidence exists regarding the impact of exercise on other mental health concerns. Therefore, an accurate understanding of whether physical exercise may ameliorate other conditions is important.

A small meta-analysis by Rosenbaum and colleagues found that exercise interventions were superior to control conditions for symptom reduction in study participants with posttraumatic stress disorder (PTSD).³ This meta-analysis included 4 randomized clinical trials representing 200 cases. The trial included a variety of physical activities (eg, yoga, aerobic, and strength-building exercises) and control conditions, and participants recruited from online, community, inpatient, and outpatient settings. The standardized mean difference (SMD) produced by the analysis indicated a small-to-medium effect (Hedges g, -0.35), with the authors reporting no evidence of publication bias, although an assessment of potential bias associated with individual trial design characteristics was not conducted. Of note, a meta-analysis by Watts and colleagues found that effect sizes for PTSD treatments tend to be smaller in veteran populations.⁴ Therefore, how much the mean effect size estimate in the study is applicable to veterans with PTSD is unknown.³

Veterans represent a unique subpopulation in which PTSD is common, although no meta-analysis yet published has synthesized the effects of exercise interventions from trials of veterans with PTSD.⁵ A recent systematic review by Whitworth and Ciccolo concluded that exercise may be associated with reduced risk of PTSD, a briefer course of PTSD symptoms, and/or reduced sleep- and depression-related difficulties.⁶ However, that review primarily included observational, cross-sectional, and qualitative works. No trials included in our meta-analysis were included in that review.⁶

Evidence-based psychotherapies like cognitive processing therapy and prolonged exposure have been shown to be effective for treating PTSD in veterans; however, these modalities are accompanied by high rates of dropout (eg, 40-60%), thereby limiting their clinical utility.⁷ The use of complementary and alternative approaches for treatment in the United States has increased in recent years, and exercise represents an important complementary treatment option.⁸ In a study by Baldwin and colleagues, nearly 50% of veterans reported using complementary or alternative approaches, and veterans with PTSD were among those likely to use such approaches.⁹ However, current studies of the effects of exercise interventions on PTSD symptom reduction are mostly small and varied, making determinations difficult regarding the potential utility of exercise for treating this condition in veterans.

Literature Search

No previous research has synthesized the literature on the effects of exercise on PTSD in the veteran population. The current meta-analysis aims to provide a synthesis of systematically selected studies on this topic to determine whether exercise-based interventions are effective at reducing veterans’ symptoms of PTSD. Our hypothesis was that, when used as a primary or adjuvant intervention for PTSD, physical exercise would be associated with a reduction of PTSD symptom scale scores. We planned a priori to produce separate estimates for single-arm and multi-arm trials. We also wanted to conduct a careful risk of bias assessment—or evaluation of study features that may have systematically influenced results—for included trials, not only to provide context for interpretation of results, but also to inform suggestions for research to advance this field of inquiry.¹⁰

Methods

This study was preregistered on PROSPERO and followed PRISMA guidelines for meta-analyses and systematic reviews.¹¹ Supplementary materials, such as the PRISMA checklist, study data, and funnel plots, are available online (doi.org/10.6084/m9.figshare.c.5618437.v1). Conference abstracts were omitted due to a lack of necessary information. We decided early in the planning process to include both randomized and single-arm trials, expecting the number of completed studies in the area of exercise for PTSD symptom reduction in veterans, and particularly randomized trials of such, would be relatively small.

Studies were included if they met the following criteria: (1) the study was a single- or multi-arm interventional trial; (2) participants were veterans; (3) participants had a current diagnosis of PTSD or exhibited subthreshold PTSD symptoms, as established by authors of the individual studies and supported by a structured clinical interview, semistructured interview, or elevated scores on PTSD symptom self-report measures; (4) the study included an intervention in which exercise (physical activity that is planned, structured, repetitive, and purposive in the sense that improvement or maintenance of physical fitness or health is an objective) was the primary component; (5) PTSD symptom severity was by a clinician-rated or self-report measure; and (6) the study was published in a peer-reviewed journal.¹² Studies were excluded if means, standard deviations, and sample sizes were not available or the full text of the study was not available in English.

Data Collection

Data were extracted from included studies using custom forms and included the following information based on PRISMA guidelines: (1) study design characteristics; (2) intervention details; and (3) PTSD outcome information.¹¹ PTSD symptom severity was the primary outcome of interest. Outcome data were included if they were derived from a measure of PTSD symptoms—equivalency across measures was assumed for meta-analyses. Potential study bias for each outcome was evaluated using the ROBINS-I and Cochrane Collaboration’s RoB 2 tools for single-arm and multi-arm trials, respectively.^13,14 These tools evaluate domains related to the design, conduct, and analysis of studies that are associated with bias (ie, systematic error in findings, such as under- or overestimation of results).¹⁰ Examples include how well authors performed and concealed randomization procedures, addressed missing data, and measured study outcomes.^13,14 The risk of bias (eg, low, moderate, serious) associated with each domain is rated and, based on the domain ratings, each study is then given an overall rating regarding how much risk influences bias.^13,14 Broadly, lower risk of bias corresponds to higher confidence in the validity of results.

Finally, 4 authors (associated with 2 single- and 2 multi-arm studies) were contacted and asked to provide further information. Data for 1 additional multi-arm study were obtained from these communications and included in the final study selection.¹⁵ These authors were also asked for information about any unpublished works of which they were aware, although no additional works were identified.

Statistical Analyses

Analyses were performed with R Studio R 3.6.0 software.¹⁶ An SMD (also known as Hedges g) was calculated for each study outcome: for single-arm trials, this was the SMD between pre- and postintervention scores, whereas for multi-arm trials, this was the SMD between postintervention outcome scores across groups. CIs for each SMD were calculated using a standard normal distribution. Combined SMDs were estimated separately for single- and multi-arm studies, using random-effects meta-analyses. In order to include multiple relevant outcomes from a single trial (ie, for studies using multiple PTSD symptom measures), robust variance estimation was used.¹⁷ Precision was used to weight SMDs.

Correlations between pre- and postintervention scores were not available for 1 single-arm study.¹⁸ A correlation coefficient of 0.8 was imputed to calculate the standard error of the of the SMDs for the Clinician-Administered PTSD Scale (CAPS) and the PTSD Checklist (PCL), as this value is consistent with past findings regarding the test-retest reliability of these measures.^19-22 A sensitivity analysis, using several alternative correlational values, revealed that the choice of correlation coefficient did not impact the overall results of the meta-analysis.

I² was used to evaluate between-study heterogeneity. Values of I² > 25%, 50%, and 75% were selected to reflect low, moderate, and high heterogeneity, respectively, in accordance with guidelines described by Higgins and colleagues.²³ Potential publication bias was assessed via funnel plot and Egger test.²⁴ Finally, although collection of depressive symptom scores was proposed as a secondary outcome in the study protocol, such data were available only for 1 multi-arm study. As a result, this outcome was not evaluated.

Results

Six studies with 101 total participants were included in the single-arm analyses (Table 1).^18,25-29 Participants consisted of veterans with chronic pain, post-9/11 veterans, female veterans of childbearing age, veterans with a history of trauma therapy, and other veterans. Types of exercise included moderate aerobic exercise and yoga. PTSD symptom measures included the CAPS and the PCL (PCL-5 or PCL-M versions). Reported financial sources for included studies included federal grant funding, nonprofit material support, outside organization support, use of US Department of Veterans Affairs (VA) resources, and no reported financial support.

With respect to individual studies, Shivakumar and colleagues found that completion of an aerobic exercise program was associated with reduced scores on 2 different PTSD symptom scales (PCL and CAPS) in 16 women veterans.¹⁸ A trauma-informed yoga intervention study with 18 participants by Cushing and colleagues demonstrated veteran participation to be associated with large reductions in PTSD, anxiety, and depression scale scores.²⁵ In a study with 34 veterans, Chopin and colleagues found that a trauma-informed yoga intervention was associated with a statistically significant reduction in PTSD symptoms, as did a study by Zaccari and colleagues with 17 veterans.^26,29 Justice and Brems also found some evidence that trauma-informed yoga interventions helped PTSD symptoms in a small sample of 4 veterans, although these results were not quantitatively analyzed.²⁷ In contrast, a small pilot study (n = 12) by Staples and colleagues testing a biweekly, 6-week yoga program did not show a significant effect on PTSD symptoms.²⁸

Three studies with 217 total veteran participants were included in the multi-arm analyses (Table 2).^15,30,31 As all multi-arm trials incorporated randomization, they will be referred to as randomized controlled trials (RCTs). On contact, Davis and colleagues provided veteran-specific results for their trial; as such, our data differ from those within the published article.¹⁵ Participants from all included studies were veterans currently experiencing symptoms of PTSD. Types of exercise included yoga and combined methods (eg, aerobic and strength training).^15,30,31 PTSD symptom measures included the CAPS or the PCL-5.^15,30,31 Reported financial sources for included studies included federal grant funding, as well as nonprofit support, private donations, and VA and Department of Defense resources.

Davis and colleagues conducted a recently concluded RCT with > 130 veteran participants and found that a novel manualized yoga program was superior to an attention control in reducing PTSD symptom scale scores for veterans.¹⁵ Goldstein and colleagues found that a program consisting of both aerobic and resistance exercises reduced PTSD symptoms to a greater extent than a waitlist control condition, with 47 veterans randomized in this trial.³⁰ Likewise, Hall and colleagues conducted a pilot RCT in which an intervention that integrated exercise and cognitive behavioral techniques was compared to a waitlist control condition.³¹ For the 48 veterans included in the analyses, the authors reported greater PTSD symptom reduction associated with integrated exercise than that of the control condition; however, the study was not powered to detect statistically significant differences between groups.

Bias Assessment

Results for the risk of bias assessments can be viewed in Tables 3 and 4. For single-arm studies, overall risk of bias was serious for all included trials. Serious risk of bias was found in 2 domains: confounding, due to a lack of accounting for potential preexisting baseline trends (eg, regression to the mean) that could have impacted study results; and measurement, due to the use of a self-report symptom measure (PCL) or CAPS with unblinded assessors. Multiple studies also showed moderate risk in the missing data domain due to participant dropout without appropriate analytic methods to address potential bias.

For RCTs, overall risk of bias ranged from some concerns to high risk. High risk of bias was found in 1 domain, measurement of outcome, due to use of a self-report symptom measure (PCL) with unblinded groups.³¹ The other 2 studies all had some concern of bias in at least 1 of the following domains: randomization, missing data, and measurement of outcome.

Pooled Standardized Mean Differences

Meta-analytic results can be viewed in Figure 2. The pooled SMD for the 6 single-arm studies was -0.60 (df = 4.41, 95% CI, -1.08 to -0.12, P = .03), indicating a statistically significant reduction in PTSD symptoms over the course of an exercise intervention. Combining SMDs for the 3 included RCTs revealed a pooled SMD of -0.40 (df = 1.57, 95% CI, -0.86 to 0.06, P = .06), indicating that exercise did not result in a statistically significant reduction in PTSD symptoms compared with control conditions.

Publication Bias and Heterogeneity

Visual inspection funnel plots and Egger test did not suggest the presence of publication bias for RCTs (t = 1.21, df = 2, P = .35) or single-arm studies (t = -0.36, df = 5, P = .73).

Single-arm studies displayed a high degree of heterogeneity (I² = 81.5%). Including sample size or exercise duration as variables in meta-regressions did not reduce heterogeneity (I² = 85.2% and I² = 83.8%, respectively). Performing a subgroup analysis only on studies using yoga as an intervention also did not reduce heterogeneity (I² = 79.2%). Due to the small number of studies, no further exploration of heterogeneity was conducted on single-arm studies. RCTs did not display any heterogeneity (I² = 0%).

Discussion

Our report represents an early synthesis of the first prospective studies of physical exercise interventions for PTSD in veterans. Results from meta-analyses of 6 single-arm studies (101 participants) and 3 RCTs (217 participants) provide early evidence that exercise may reduce PTSD symptoms in veterans. Yoga was the most common form of exercise used in single-arm studies, whereas RCTs used a wider range of interventions. The pooled SMD of -0.60 for single-arm longitudinal studies suggest a medium decrease in PTSD symptoms for veterans who engage in exercise interventions. Analysis of the RCTs supported this finding, with a pooled SMD of -0.40 reflecting a small-to-medium effect of exercise on PTSD symptoms over control conditions, although this result did not achieve statistical significance. Of note, while the nonsignificant finding for RCTs may have been due to insufficient power caused by the limited number of included studies, possibly exercise was not more efficacious than were the control conditions.

Although RCTs represented a variety of exercise types, PTSD symptom measures, and veteran subgroups, statistical results were not indicative of heterogeneity. However, only the largest and most comprehensive study of exercise for PTSD in veterans to date by Davis and colleagues had a statistically significant SMD.¹⁵ Of note, one of the other 2 RCTs displayed an SMD of a similar magnitude, but this study had a much smaller sample size and was underpowered to detect significance.³⁰ Additionally, risk of bias assessments for single-arm studies and RCTs revealed study characteristics that suggest possible inflation of absolute effect sizes for individual studies. Therefore, the pooled SMDs we report are interpretable but may exceed the true effect of exercise for PTSD symptom reduction in veterans.

Limitations

The present study has several important limitations. First, few studies were found that met the broad eligibility criteria and those that did often had a small sample size. Besides highlighting a gap in the extant research, the limited studies available for meta-analysis means that caution must be taken when interpreting results. Fortunately, this issue will likely resolve once additional studies investigating the impact of exercise on PTSD symptoms in veterans are available for synthesis.

Relatedly, the included study interventions varied considerably, both in the types of exercise used and the characteristics of the exercises (eg, frequency, duration, and intensity), which is relevant as different exercise modalities are associated with differential physical effects.³³ Including such a mixture of exercises may have given an incomplete picture of their potential therapeutic effects. Also, none of the RCTs compared exercise against first-line treatments for PTSD, such as prolonged exposure or cognitive processing therapy, which would have provided further insight into the role exercise could play in clinical settings.⁷

Another limitation is the elevated risk of bias found in most studies, particularly present in the longitudinal single-arm studies, all of which were rated at serious risk. For instance, no single-arm study controlled for preexisting baseline trends: without such (and lacking a comparison control group like in RCTs), it is possible that the observed effects were due to extraneous factors, rather than the exercise intervention. Although not as severe, the multi-arm RCTs also displayed at least moderate risk of bias. Therefore, SMDs may have been overestimated for each group of studies.

Finally, the results of the single-arm meta-analysis displayed high statistical heterogeneity, reducing the generalizability of the results. One possible cause of this heterogeneity may have been the yoga interventions, as a separate analysis removing the only nonyoga study did not reduce heterogeneity. This result was surprising, as the included yoga interventions seemed similar across studies. While the presence of high heterogeneity does require some caution when applying these results to outside interventions, the present study made use of random-effects meta-analysis, a technique that incorporates study heterogeneity into the statistical model, thereby strengthening the findings compared with that of a traditional fixed-effects approach.¹⁰

Future Steps

Several future steps are warranted to improve knowledge of exercise as a treatment for PTSD in veterans and in the general population. With current meta-analyses limited to small numbers of studies, additional studies of the efficacy of exercise for treating PTSD could help in several ways. A larger pool of studies would enable future meta-analyses to explore related questions, such as those regarding the impact of exercise on quality of life or depressive symptom reduction among veterans with PTSD. A greater number of studies also would enable meta-analysts to explore potentially critical moderators. For example, the duration, frequency, or type of exercise may moderate the effect of exercise on PTSD symptom reduction. Moderators related to patient or study design characteristics also should be explored in future studies.

Future work also should evaluate the impact that specific features of exercise regimens have on PTSD. Knowing whether the type or structure of exercise affects its clinical use would be invaluable in developing and implementing efficient exercise-based interventions. For example, if facilitated exercise was found to be significantly more effective at reducing PTSD symptoms than exercise completed independently, the development of exercise intervention programs in the VA and other facilities that commonly treat PTSD may be warranted. Additionally, it may be useful to identify specific mechanisms through which exercise reduces PTSD symptoms. For example, in addition to its beneficial biological effects, exercise also promotes psychological health through behavioral activation and alterations within reinforcement/reward systems, suggesting that exercise regularity may be more important than intensity.^34,35 Understanding which mechanisms contribute most to change will aid in the development of more efficient interventions.

Given that veterans are demonstrating considerable interest in complementary and alternative PTSD treatments, it is critical that researchers focus on high-quality randomized tests of these interventions. Therefore, in addition to greater quality of exercise intervention studies, future efforts should be focused on RCTs that are designed in such a way as to limit potential introduction of bias. For example, assessment data should be completed by blinded assessors using standardized measures, and analyses should account for missing data and unequal participant attrition between groups. Ideally, pre-intervention trends across multiple baseline datapoints also would be collected in single-arm studies to avoid confounding related to regression to the mean. It is also recommended that future meta-analyses use risk of bias assessments and consider how the results of such assessments may impact the interpretation of results.

Conclusions

Findings from both single-arm studies and RCTs suggest possible benefit of exercise on PTSD symptom reduction, although confirmation of findings is needed. No study found increased symptoms following exercise intervention. Thus, it is reasonable to consider physical exercise, such as yoga, as an adjunct, whole-health consistent treatment. HCPs working with veterans with past traumatic experiences should consider incorporating exercise into patient care. Enhanced educational efforts emphasizing the psychotherapeutic impact of exercise may also have value for the veteran population. Furthermore, the current risk of bias assessments highlights the need for additional high-quality RCTs evaluating the specific impact of exercise on PTSD symptom reduction in veterans. In particular, this field of inquiry would benefit from larger samples and design characteristics to reduce bias (eg, blinding when possible, use of CAPS vs only self-report symptom measures, reducing problematic attrition, corrections for missing data, etc).

Acknowledgments

This research is the result of work supported with resources and the use of facilities at the VA Eastern Kansas Healthcare System (Dwight D. Eisenhower VA Medical Center). It was also supported by the Department of Veterans Affairs Office of Academic Affiliations Advanced Fellowship Program in Mental Illness Research and Treatment, as well as the Rocky Mountain Mental Illness Research, Education, and Clinical Center. Since Dr. Reis and Dr. Gaddy are employees of the US Government and contributed to this manuscript as part of their official duties, the work is not subject to US copyright. This study was preregistered on PROSPERO (https://www.crd.york.ac.uk/prospero/; ID: CRD42020153419).

Physical exercise offers preventative and therapeutic benefits for a range of chronic health conditions, including cardiovascular disease, type 2 diabetes mellitus, Alzheimer disease, and depression.^1,2 Exercise has been well studied for its antidepressant effects, its ability to reduce risk of aging-related dementia, and favorable effects on a range of cognitive functions.² Lesser evidence exists regarding the impact of exercise on other mental health concerns. Therefore, an accurate understanding of whether physical exercise may ameliorate other conditions is important.

A small meta-analysis by Rosenbaum and colleagues found that exercise interventions were superior to control conditions for symptom reduction in study participants with posttraumatic stress disorder (PTSD).³ This meta-analysis included 4 randomized clinical trials representing 200 cases. The trial included a variety of physical activities (eg, yoga, aerobic, and strength-building exercises) and control conditions, and participants recruited from online, community, inpatient, and outpatient settings. The standardized mean difference (SMD) produced by the analysis indicated a small-to-medium effect (Hedges g, -0.35), with the authors reporting no evidence of publication bias, although an assessment of potential bias associated with individual trial design characteristics was not conducted. Of note, a meta-analysis by Watts and colleagues found that effect sizes for PTSD treatments tend to be smaller in veteran populations.⁴ Therefore, how much the mean effect size estimate in the study is applicable to veterans with PTSD is unknown.³

Veterans represent a unique subpopulation in which PTSD is common, although no meta-analysis yet published has synthesized the effects of exercise interventions from trials of veterans with PTSD.⁵ A recent systematic review by Whitworth and Ciccolo concluded that exercise may be associated with reduced risk of PTSD, a briefer course of PTSD symptoms, and/or reduced sleep- and depression-related difficulties.⁶ However, that review primarily included observational, cross-sectional, and qualitative works. No trials included in our meta-analysis were included in that review.⁶

Evidence-based psychotherapies like cognitive processing therapy and prolonged exposure have been shown to be effective for treating PTSD in veterans; however, these modalities are accompanied by high rates of dropout (eg, 40-60%), thereby limiting their clinical utility.⁷ The use of complementary and alternative approaches for treatment in the United States has increased in recent years, and exercise represents an important complementary treatment option.⁸ In a study by Baldwin and colleagues, nearly 50% of veterans reported using complementary or alternative approaches, and veterans with PTSD were among those likely to use such approaches.⁹ However, current studies of the effects of exercise interventions on PTSD symptom reduction are mostly small and varied, making determinations difficult regarding the potential utility of exercise for treating this condition in veterans.

Literature Search

No previous research has synthesized the literature on the effects of exercise on PTSD in the veteran population. The current meta-analysis aims to provide a synthesis of systematically selected studies on this topic to determine whether exercise-based interventions are effective at reducing veterans’ symptoms of PTSD. Our hypothesis was that, when used as a primary or adjuvant intervention for PTSD, physical exercise would be associated with a reduction of PTSD symptom scale scores. We planned a priori to produce separate estimates for single-arm and multi-arm trials. We also wanted to conduct a careful risk of bias assessment—or evaluation of study features that may have systematically influenced results—for included trials, not only to provide context for interpretation of results, but also to inform suggestions for research to advance this field of inquiry.¹⁰

Methods

This study was preregistered on PROSPERO and followed PRISMA guidelines for meta-analyses and systematic reviews.¹¹ Supplementary materials, such as the PRISMA checklist, study data, and funnel plots, are available online (doi.org/10.6084/m9.figshare.c.5618437.v1). Conference abstracts were omitted due to a lack of necessary information. We decided early in the planning process to include both randomized and single-arm trials, expecting the number of completed studies in the area of exercise for PTSD symptom reduction in veterans, and particularly randomized trials of such, would be relatively small.

Studies were included if they met the following criteria: (1) the study was a single- or multi-arm interventional trial; (2) participants were veterans; (3) participants had a current diagnosis of PTSD or exhibited subthreshold PTSD symptoms, as established by authors of the individual studies and supported by a structured clinical interview, semistructured interview, or elevated scores on PTSD symptom self-report measures; (4) the study included an intervention in which exercise (physical activity that is planned, structured, repetitive, and purposive in the sense that improvement or maintenance of physical fitness or health is an objective) was the primary component; (5) PTSD symptom severity was by a clinician-rated or self-report measure; and (6) the study was published in a peer-reviewed journal.¹² Studies were excluded if means, standard deviations, and sample sizes were not available or the full text of the study was not available in English.

Data Collection

Data were extracted from included studies using custom forms and included the following information based on PRISMA guidelines: (1) study design characteristics; (2) intervention details; and (3) PTSD outcome information.¹¹ PTSD symptom severity was the primary outcome of interest. Outcome data were included if they were derived from a measure of PTSD symptoms—equivalency across measures was assumed for meta-analyses. Potential study bias for each outcome was evaluated using the ROBINS-I and Cochrane Collaboration’s RoB 2 tools for single-arm and multi-arm trials, respectively.^13,14 These tools evaluate domains related to the design, conduct, and analysis of studies that are associated with bias (ie, systematic error in findings, such as under- or overestimation of results).¹⁰ Examples include how well authors performed and concealed randomization procedures, addressed missing data, and measured study outcomes.^13,14 The risk of bias (eg, low, moderate, serious) associated with each domain is rated and, based on the domain ratings, each study is then given an overall rating regarding how much risk influences bias.^13,14 Broadly, lower risk of bias corresponds to higher confidence in the validity of results.

Finally, 4 authors (associated with 2 single- and 2 multi-arm studies) were contacted and asked to provide further information. Data for 1 additional multi-arm study were obtained from these communications and included in the final study selection.¹⁵ These authors were also asked for information about any unpublished works of which they were aware, although no additional works were identified.

Statistical Analyses

Analyses were performed with R Studio R 3.6.0 software.¹⁶ An SMD (also known as Hedges g) was calculated for each study outcome: for single-arm trials, this was the SMD between pre- and postintervention scores, whereas for multi-arm trials, this was the SMD between postintervention outcome scores across groups. CIs for each SMD were calculated using a standard normal distribution. Combined SMDs were estimated separately for single- and multi-arm studies, using random-effects meta-analyses. In order to include multiple relevant outcomes from a single trial (ie, for studies using multiple PTSD symptom measures), robust variance estimation was used.¹⁷ Precision was used to weight SMDs.

Correlations between pre- and postintervention scores were not available for 1 single-arm study.¹⁸ A correlation coefficient of 0.8 was imputed to calculate the standard error of the of the SMDs for the Clinician-Administered PTSD Scale (CAPS) and the PTSD Checklist (PCL), as this value is consistent with past findings regarding the test-retest reliability of these measures.^19-22 A sensitivity analysis, using several alternative correlational values, revealed that the choice of correlation coefficient did not impact the overall results of the meta-analysis.

I² was used to evaluate between-study heterogeneity. Values of I² > 25%, 50%, and 75% were selected to reflect low, moderate, and high heterogeneity, respectively, in accordance with guidelines described by Higgins and colleagues.²³ Potential publication bias was assessed via funnel plot and Egger test.²⁴ Finally, although collection of depressive symptom scores was proposed as a secondary outcome in the study protocol, such data were available only for 1 multi-arm study. As a result, this outcome was not evaluated.

Results

Six studies with 101 total participants were included in the single-arm analyses (Table 1).^18,25-29 Participants consisted of veterans with chronic pain, post-9/11 veterans, female veterans of childbearing age, veterans with a history of trauma therapy, and other veterans. Types of exercise included moderate aerobic exercise and yoga. PTSD symptom measures included the CAPS and the PCL (PCL-5 or PCL-M versions). Reported financial sources for included studies included federal grant funding, nonprofit material support, outside organization support, use of US Department of Veterans Affairs (VA) resources, and no reported financial support.

With respect to individual studies, Shivakumar and colleagues found that completion of an aerobic exercise program was associated with reduced scores on 2 different PTSD symptom scales (PCL and CAPS) in 16 women veterans.¹⁸ A trauma-informed yoga intervention study with 18 participants by Cushing and colleagues demonstrated veteran participation to be associated with large reductions in PTSD, anxiety, and depression scale scores.²⁵ In a study with 34 veterans, Chopin and colleagues found that a trauma-informed yoga intervention was associated with a statistically significant reduction in PTSD symptoms, as did a study by Zaccari and colleagues with 17 veterans.^26,29 Justice and Brems also found some evidence that trauma-informed yoga interventions helped PTSD symptoms in a small sample of 4 veterans, although these results were not quantitatively analyzed.²⁷ In contrast, a small pilot study (n = 12) by Staples and colleagues testing a biweekly, 6-week yoga program did not show a significant effect on PTSD symptoms.²⁸

Three studies with 217 total veteran participants were included in the multi-arm analyses (Table 2).^15,30,31 As all multi-arm trials incorporated randomization, they will be referred to as randomized controlled trials (RCTs). On contact, Davis and colleagues provided veteran-specific results for their trial; as such, our data differ from those within the published article.¹⁵ Participants from all included studies were veterans currently experiencing symptoms of PTSD. Types of exercise included yoga and combined methods (eg, aerobic and strength training).^15,30,31 PTSD symptom measures included the CAPS or the PCL-5.^15,30,31 Reported financial sources for included studies included federal grant funding, as well as nonprofit support, private donations, and VA and Department of Defense resources.

Davis and colleagues conducted a recently concluded RCT with > 130 veteran participants and found that a novel manualized yoga program was superior to an attention control in reducing PTSD symptom scale scores for veterans.¹⁵ Goldstein and colleagues found that a program consisting of both aerobic and resistance exercises reduced PTSD symptoms to a greater extent than a waitlist control condition, with 47 veterans randomized in this trial.³⁰ Likewise, Hall and colleagues conducted a pilot RCT in which an intervention that integrated exercise and cognitive behavioral techniques was compared to a waitlist control condition.³¹ For the 48 veterans included in the analyses, the authors reported greater PTSD symptom reduction associated with integrated exercise than that of the control condition; however, the study was not powered to detect statistically significant differences between groups.

Bias Assessment

Results for the risk of bias assessments can be viewed in Tables 3 and 4. For single-arm studies, overall risk of bias was serious for all included trials. Serious risk of bias was found in 2 domains: confounding, due to a lack of accounting for potential preexisting baseline trends (eg, regression to the mean) that could have impacted study results; and measurement, due to the use of a self-report symptom measure (PCL) or CAPS with unblinded assessors. Multiple studies also showed moderate risk in the missing data domain due to participant dropout without appropriate analytic methods to address potential bias.

For RCTs, overall risk of bias ranged from some concerns to high risk. High risk of bias was found in 1 domain, measurement of outcome, due to use of a self-report symptom measure (PCL) with unblinded groups.³¹ The other 2 studies all had some concern of bias in at least 1 of the following domains: randomization, missing data, and measurement of outcome.

Pooled Standardized Mean Differences

Meta-analytic results can be viewed in Figure 2. The pooled SMD for the 6 single-arm studies was -0.60 (df = 4.41, 95% CI, -1.08 to -0.12, P = .03), indicating a statistically significant reduction in PTSD symptoms over the course of an exercise intervention. Combining SMDs for the 3 included RCTs revealed a pooled SMD of -0.40 (df = 1.57, 95% CI, -0.86 to 0.06, P = .06), indicating that exercise did not result in a statistically significant reduction in PTSD symptoms compared with control conditions.

Publication Bias and Heterogeneity

Visual inspection funnel plots and Egger test did not suggest the presence of publication bias for RCTs (t = 1.21, df = 2, P = .35) or single-arm studies (t = -0.36, df = 5, P = .73).

Single-arm studies displayed a high degree of heterogeneity (I² = 81.5%). Including sample size or exercise duration as variables in meta-regressions did not reduce heterogeneity (I² = 85.2% and I² = 83.8%, respectively). Performing a subgroup analysis only on studies using yoga as an intervention also did not reduce heterogeneity (I² = 79.2%). Due to the small number of studies, no further exploration of heterogeneity was conducted on single-arm studies. RCTs did not display any heterogeneity (I² = 0%).

Discussion

Our report represents an early synthesis of the first prospective studies of physical exercise interventions for PTSD in veterans. Results from meta-analyses of 6 single-arm studies (101 participants) and 3 RCTs (217 participants) provide early evidence that exercise may reduce PTSD symptoms in veterans. Yoga was the most common form of exercise used in single-arm studies, whereas RCTs used a wider range of interventions. The pooled SMD of -0.60 for single-arm longitudinal studies suggest a medium decrease in PTSD symptoms for veterans who engage in exercise interventions. Analysis of the RCTs supported this finding, with a pooled SMD of -0.40 reflecting a small-to-medium effect of exercise on PTSD symptoms over control conditions, although this result did not achieve statistical significance. Of note, while the nonsignificant finding for RCTs may have been due to insufficient power caused by the limited number of included studies, possibly exercise was not more efficacious than were the control conditions.

Although RCTs represented a variety of exercise types, PTSD symptom measures, and veteran subgroups, statistical results were not indicative of heterogeneity. However, only the largest and most comprehensive study of exercise for PTSD in veterans to date by Davis and colleagues had a statistically significant SMD.¹⁵ Of note, one of the other 2 RCTs displayed an SMD of a similar magnitude, but this study had a much smaller sample size and was underpowered to detect significance.³⁰ Additionally, risk of bias assessments for single-arm studies and RCTs revealed study characteristics that suggest possible inflation of absolute effect sizes for individual studies. Therefore, the pooled SMDs we report are interpretable but may exceed the true effect of exercise for PTSD symptom reduction in veterans.

Limitations

The present study has several important limitations. First, few studies were found that met the broad eligibility criteria and those that did often had a small sample size. Besides highlighting a gap in the extant research, the limited studies available for meta-analysis means that caution must be taken when interpreting results. Fortunately, this issue will likely resolve once additional studies investigating the impact of exercise on PTSD symptoms in veterans are available for synthesis.

Relatedly, the included study interventions varied considerably, both in the types of exercise used and the characteristics of the exercises (eg, frequency, duration, and intensity), which is relevant as different exercise modalities are associated with differential physical effects.³³ Including such a mixture of exercises may have given an incomplete picture of their potential therapeutic effects. Also, none of the RCTs compared exercise against first-line treatments for PTSD, such as prolonged exposure or cognitive processing therapy, which would have provided further insight into the role exercise could play in clinical settings.⁷

Another limitation is the elevated risk of bias found in most studies, particularly present in the longitudinal single-arm studies, all of which were rated at serious risk. For instance, no single-arm study controlled for preexisting baseline trends: without such (and lacking a comparison control group like in RCTs), it is possible that the observed effects were due to extraneous factors, rather than the exercise intervention. Although not as severe, the multi-arm RCTs also displayed at least moderate risk of bias. Therefore, SMDs may have been overestimated for each group of studies.

Finally, the results of the single-arm meta-analysis displayed high statistical heterogeneity, reducing the generalizability of the results. One possible cause of this heterogeneity may have been the yoga interventions, as a separate analysis removing the only nonyoga study did not reduce heterogeneity. This result was surprising, as the included yoga interventions seemed similar across studies. While the presence of high heterogeneity does require some caution when applying these results to outside interventions, the present study made use of random-effects meta-analysis, a technique that incorporates study heterogeneity into the statistical model, thereby strengthening the findings compared with that of a traditional fixed-effects approach.¹⁰

Future Steps

Several future steps are warranted to improve knowledge of exercise as a treatment for PTSD in veterans and in the general population. With current meta-analyses limited to small numbers of studies, additional studies of the efficacy of exercise for treating PTSD could help in several ways. A larger pool of studies would enable future meta-analyses to explore related questions, such as those regarding the impact of exercise on quality of life or depressive symptom reduction among veterans with PTSD. A greater number of studies also would enable meta-analysts to explore potentially critical moderators. For example, the duration, frequency, or type of exercise may moderate the effect of exercise on PTSD symptom reduction. Moderators related to patient or study design characteristics also should be explored in future studies.

Future work also should evaluate the impact that specific features of exercise regimens have on PTSD. Knowing whether the type or structure of exercise affects its clinical use would be invaluable in developing and implementing efficient exercise-based interventions. For example, if facilitated exercise was found to be significantly more effective at reducing PTSD symptoms than exercise completed independently, the development of exercise intervention programs in the VA and other facilities that commonly treat PTSD may be warranted. Additionally, it may be useful to identify specific mechanisms through which exercise reduces PTSD symptoms. For example, in addition to its beneficial biological effects, exercise also promotes psychological health through behavioral activation and alterations within reinforcement/reward systems, suggesting that exercise regularity may be more important than intensity.^34,35 Understanding which mechanisms contribute most to change will aid in the development of more efficient interventions.

Given that veterans are demonstrating considerable interest in complementary and alternative PTSD treatments, it is critical that researchers focus on high-quality randomized tests of these interventions. Therefore, in addition to greater quality of exercise intervention studies, future efforts should be focused on RCTs that are designed in such a way as to limit potential introduction of bias. For example, assessment data should be completed by blinded assessors using standardized measures, and analyses should account for missing data and unequal participant attrition between groups. Ideally, pre-intervention trends across multiple baseline datapoints also would be collected in single-arm studies to avoid confounding related to regression to the mean. It is also recommended that future meta-analyses use risk of bias assessments and consider how the results of such assessments may impact the interpretation of results.

Conclusions

Findings from both single-arm studies and RCTs suggest possible benefit of exercise on PTSD symptom reduction, although confirmation of findings is needed. No study found increased symptoms following exercise intervention. Thus, it is reasonable to consider physical exercise, such as yoga, as an adjunct, whole-health consistent treatment. HCPs working with veterans with past traumatic experiences should consider incorporating exercise into patient care. Enhanced educational efforts emphasizing the psychotherapeutic impact of exercise may also have value for the veteran population. Furthermore, the current risk of bias assessments highlights the need for additional high-quality RCTs evaluating the specific impact of exercise on PTSD symptom reduction in veterans. In particular, this field of inquiry would benefit from larger samples and design characteristics to reduce bias (eg, blinding when possible, use of CAPS vs only self-report symptom measures, reducing problematic attrition, corrections for missing data, etc).

Acknowledgments

This research is the result of work supported with resources and the use of facilities at the VA Eastern Kansas Healthcare System (Dwight D. Eisenhower VA Medical Center). It was also supported by the Department of Veterans Affairs Office of Academic Affiliations Advanced Fellowship Program in Mental Illness Research and Treatment, as well as the Rocky Mountain Mental Illness Research, Education, and Clinical Center. Since Dr. Reis and Dr. Gaddy are employees of the US Government and contributed to this manuscript as part of their official duties, the work is not subject to US copyright. This study was preregistered on PROSPERO (https://www.crd.york.ac.uk/prospero/; ID: CRD42020153419).

Physical exercise offers preventative and therapeutic benefits for a range of chronic health conditions, including cardiovascular disease, type 2 diabetes mellitus, Alzheimer disease, and depression.^1,2 Exercise has been well studied for its antidepressant effects, its ability to reduce risk of aging-related dementia, and favorable effects on a range of cognitive functions.² Lesser evidence exists regarding the impact of exercise on other mental health concerns. Therefore, an accurate understanding of whether physical exercise may ameliorate other conditions is important.

A small meta-analysis by Rosenbaum and colleagues found that exercise interventions were superior to control conditions for symptom reduction in study participants with posttraumatic stress disorder (PTSD).³ This meta-analysis included 4 randomized clinical trials representing 200 cases. The trial included a variety of physical activities (eg, yoga, aerobic, and strength-building exercises) and control conditions, and participants recruited from online, community, inpatient, and outpatient settings. The standardized mean difference (SMD) produced by the analysis indicated a small-to-medium effect (Hedges g, -0.35), with the authors reporting no evidence of publication bias, although an assessment of potential bias associated with individual trial design characteristics was not conducted. Of note, a meta-analysis by Watts and colleagues found that effect sizes for PTSD treatments tend to be smaller in veteran populations.⁴ Therefore, how much the mean effect size estimate in the study is applicable to veterans with PTSD is unknown.³

Veterans represent a unique subpopulation in which PTSD is common, although no meta-analysis yet published has synthesized the effects of exercise interventions from trials of veterans with PTSD.⁵ A recent systematic review by Whitworth and Ciccolo concluded that exercise may be associated with reduced risk of PTSD, a briefer course of PTSD symptoms, and/or reduced sleep- and depression-related difficulties.⁶ However, that review primarily included observational, cross-sectional, and qualitative works. No trials included in our meta-analysis were included in that review.⁶

Evidence-based psychotherapies like cognitive processing therapy and prolonged exposure have been shown to be effective for treating PTSD in veterans; however, these modalities are accompanied by high rates of dropout (eg, 40-60%), thereby limiting their clinical utility.⁷ The use of complementary and alternative approaches for treatment in the United States has increased in recent years, and exercise represents an important complementary treatment option.⁸ In a study by Baldwin and colleagues, nearly 50% of veterans reported using complementary or alternative approaches, and veterans with PTSD were among those likely to use such approaches.⁹ However, current studies of the effects of exercise interventions on PTSD symptom reduction are mostly small and varied, making determinations difficult regarding the potential utility of exercise for treating this condition in veterans.

Literature Search

No previous research has synthesized the literature on the effects of exercise on PTSD in the veteran population. The current meta-analysis aims to provide a synthesis of systematically selected studies on this topic to determine whether exercise-based interventions are effective at reducing veterans’ symptoms of PTSD. Our hypothesis was that, when used as a primary or adjuvant intervention for PTSD, physical exercise would be associated with a reduction of PTSD symptom scale scores. We planned a priori to produce separate estimates for single-arm and multi-arm trials. We also wanted to conduct a careful risk of bias assessment—or evaluation of study features that may have systematically influenced results—for included trials, not only to provide context for interpretation of results, but also to inform suggestions for research to advance this field of inquiry.¹⁰

Methods

This study was preregistered on PROSPERO and followed PRISMA guidelines for meta-analyses and systematic reviews.¹¹ Supplementary materials, such as the PRISMA checklist, study data, and funnel plots, are available online (doi.org/10.6084/m9.figshare.c.5618437.v1). Conference abstracts were omitted due to a lack of necessary information. We decided early in the planning process to include both randomized and single-arm trials, expecting the number of completed studies in the area of exercise for PTSD symptom reduction in veterans, and particularly randomized trials of such, would be relatively small.

Studies were included if they met the following criteria: (1) the study was a single- or multi-arm interventional trial; (2) participants were veterans; (3) participants had a current diagnosis of PTSD or exhibited subthreshold PTSD symptoms, as established by authors of the individual studies and supported by a structured clinical interview, semistructured interview, or elevated scores on PTSD symptom self-report measures; (4) the study included an intervention in which exercise (physical activity that is planned, structured, repetitive, and purposive in the sense that improvement or maintenance of physical fitness or health is an objective) was the primary component; (5) PTSD symptom severity was by a clinician-rated or self-report measure; and (6) the study was published in a peer-reviewed journal.¹² Studies were excluded if means, standard deviations, and sample sizes were not available or the full text of the study was not available in English.

Data Collection

Data were extracted from included studies using custom forms and included the following information based on PRISMA guidelines: (1) study design characteristics; (2) intervention details; and (3) PTSD outcome information.¹¹ PTSD symptom severity was the primary outcome of interest. Outcome data were included if they were derived from a measure of PTSD symptoms—equivalency across measures was assumed for meta-analyses. Potential study bias for each outcome was evaluated using the ROBINS-I and Cochrane Collaboration’s RoB 2 tools for single-arm and multi-arm trials, respectively.^13,14 These tools evaluate domains related to the design, conduct, and analysis of studies that are associated with bias (ie, systematic error in findings, such as under- or overestimation of results).¹⁰ Examples include how well authors performed and concealed randomization procedures, addressed missing data, and measured study outcomes.^13,14 The risk of bias (eg, low, moderate, serious) associated with each domain is rated and, based on the domain ratings, each study is then given an overall rating regarding how much risk influences bias.^13,14 Broadly, lower risk of bias corresponds to higher confidence in the validity of results.

Finally, 4 authors (associated with 2 single- and 2 multi-arm studies) were contacted and asked to provide further information. Data for 1 additional multi-arm study were obtained from these communications and included in the final study selection.¹⁵ These authors were also asked for information about any unpublished works of which they were aware, although no additional works were identified.

Statistical Analyses

Analyses were performed with R Studio R 3.6.0 software.¹⁶ An SMD (also known as Hedges g) was calculated for each study outcome: for single-arm trials, this was the SMD between pre- and postintervention scores, whereas for multi-arm trials, this was the SMD between postintervention outcome scores across groups. CIs for each SMD were calculated using a standard normal distribution. Combined SMDs were estimated separately for single- and multi-arm studies, using random-effects meta-analyses. In order to include multiple relevant outcomes from a single trial (ie, for studies using multiple PTSD symptom measures), robust variance estimation was used.¹⁷ Precision was used to weight SMDs.

Correlations between pre- and postintervention scores were not available for 1 single-arm study.¹⁸ A correlation coefficient of 0.8 was imputed to calculate the standard error of the of the SMDs for the Clinician-Administered PTSD Scale (CAPS) and the PTSD Checklist (PCL), as this value is consistent with past findings regarding the test-retest reliability of these measures.^19-22 A sensitivity analysis, using several alternative correlational values, revealed that the choice of correlation coefficient did not impact the overall results of the meta-analysis.

I² was used to evaluate between-study heterogeneity. Values of I² > 25%, 50%, and 75% were selected to reflect low, moderate, and high heterogeneity, respectively, in accordance with guidelines described by Higgins and colleagues.²³ Potential publication bias was assessed via funnel plot and Egger test.²⁴ Finally, although collection of depressive symptom scores was proposed as a secondary outcome in the study protocol, such data were available only for 1 multi-arm study. As a result, this outcome was not evaluated.

Results

Six studies with 101 total participants were included in the single-arm analyses (Table 1).^18,25-29 Participants consisted of veterans with chronic pain, post-9/11 veterans, female veterans of childbearing age, veterans with a history of trauma therapy, and other veterans. Types of exercise included moderate aerobic exercise and yoga. PTSD symptom measures included the CAPS and the PCL (PCL-5 or PCL-M versions). Reported financial sources for included studies included federal grant funding, nonprofit material support, outside organization support, use of US Department of Veterans Affairs (VA) resources, and no reported financial support.

With respect to individual studies, Shivakumar and colleagues found that completion of an aerobic exercise program was associated with reduced scores on 2 different PTSD symptom scales (PCL and CAPS) in 16 women veterans.¹⁸ A trauma-informed yoga intervention study with 18 participants by Cushing and colleagues demonstrated veteran participation to be associated with large reductions in PTSD, anxiety, and depression scale scores.²⁵ In a study with 34 veterans, Chopin and colleagues found that a trauma-informed yoga intervention was associated with a statistically significant reduction in PTSD symptoms, as did a study by Zaccari and colleagues with 17 veterans.^26,29 Justice and Brems also found some evidence that trauma-informed yoga interventions helped PTSD symptoms in a small sample of 4 veterans, although these results were not quantitatively analyzed.²⁷ In contrast, a small pilot study (n = 12) by Staples and colleagues testing a biweekly, 6-week yoga program did not show a significant effect on PTSD symptoms.²⁸

Three studies with 217 total veteran participants were included in the multi-arm analyses (Table 2).^15,30,31 As all multi-arm trials incorporated randomization, they will be referred to as randomized controlled trials (RCTs). On contact, Davis and colleagues provided veteran-specific results for their trial; as such, our data differ from those within the published article.¹⁵ Participants from all included studies were veterans currently experiencing symptoms of PTSD. Types of exercise included yoga and combined methods (eg, aerobic and strength training).^15,30,31 PTSD symptom measures included the CAPS or the PCL-5.^15,30,31 Reported financial sources for included studies included federal grant funding, as well as nonprofit support, private donations, and VA and Department of Defense resources.

Davis and colleagues conducted a recently concluded RCT with > 130 veteran participants and found that a novel manualized yoga program was superior to an attention control in reducing PTSD symptom scale scores for veterans.¹⁵ Goldstein and colleagues found that a program consisting of both aerobic and resistance exercises reduced PTSD symptoms to a greater extent than a waitlist control condition, with 47 veterans randomized in this trial.³⁰ Likewise, Hall and colleagues conducted a pilot RCT in which an intervention that integrated exercise and cognitive behavioral techniques was compared to a waitlist control condition.³¹ For the 48 veterans included in the analyses, the authors reported greater PTSD symptom reduction associated with integrated exercise than that of the control condition; however, the study was not powered to detect statistically significant differences between groups.

Bias Assessment

Results for the risk of bias assessments can be viewed in Tables 3 and 4. For single-arm studies, overall risk of bias was serious for all included trials. Serious risk of bias was found in 2 domains: confounding, due to a lack of accounting for potential preexisting baseline trends (eg, regression to the mean) that could have impacted study results; and measurement, due to the use of a self-report symptom measure (PCL) or CAPS with unblinded assessors. Multiple studies also showed moderate risk in the missing data domain due to participant dropout without appropriate analytic methods to address potential bias.

For RCTs, overall risk of bias ranged from some concerns to high risk. High risk of bias was found in 1 domain, measurement of outcome, due to use of a self-report symptom measure (PCL) with unblinded groups.³¹ The other 2 studies all had some concern of bias in at least 1 of the following domains: randomization, missing data, and measurement of outcome.

Pooled Standardized Mean Differences

Meta-analytic results can be viewed in Figure 2. The pooled SMD for the 6 single-arm studies was -0.60 (df = 4.41, 95% CI, -1.08 to -0.12, P = .03), indicating a statistically significant reduction in PTSD symptoms over the course of an exercise intervention. Combining SMDs for the 3 included RCTs revealed a pooled SMD of -0.40 (df = 1.57, 95% CI, -0.86 to 0.06, P = .06), indicating that exercise did not result in a statistically significant reduction in PTSD symptoms compared with control conditions.

Publication Bias and Heterogeneity

Visual inspection funnel plots and Egger test did not suggest the presence of publication bias for RCTs (t = 1.21, df = 2, P = .35) or single-arm studies (t = -0.36, df = 5, P = .73).

Single-arm studies displayed a high degree of heterogeneity (I² = 81.5%). Including sample size or exercise duration as variables in meta-regressions did not reduce heterogeneity (I² = 85.2% and I² = 83.8%, respectively). Performing a subgroup analysis only on studies using yoga as an intervention also did not reduce heterogeneity (I² = 79.2%). Due to the small number of studies, no further exploration of heterogeneity was conducted on single-arm studies. RCTs did not display any heterogeneity (I² = 0%).

Discussion

Our report represents an early synthesis of the first prospective studies of physical exercise interventions for PTSD in veterans. Results from meta-analyses of 6 single-arm studies (101 participants) and 3 RCTs (217 participants) provide early evidence that exercise may reduce PTSD symptoms in veterans. Yoga was the most common form of exercise used in single-arm studies, whereas RCTs used a wider range of interventions. The pooled SMD of -0.60 for single-arm longitudinal studies suggest a medium decrease in PTSD symptoms for veterans who engage in exercise interventions. Analysis of the RCTs supported this finding, with a pooled SMD of -0.40 reflecting a small-to-medium effect of exercise on PTSD symptoms over control conditions, although this result did not achieve statistical significance. Of note, while the nonsignificant finding for RCTs may have been due to insufficient power caused by the limited number of included studies, possibly exercise was not more efficacious than were the control conditions.

Although RCTs represented a variety of exercise types, PTSD symptom measures, and veteran subgroups, statistical results were not indicative of heterogeneity. However, only the largest and most comprehensive study of exercise for PTSD in veterans to date by Davis and colleagues had a statistically significant SMD.¹⁵ Of note, one of the other 2 RCTs displayed an SMD of a similar magnitude, but this study had a much smaller sample size and was underpowered to detect significance.³⁰ Additionally, risk of bias assessments for single-arm studies and RCTs revealed study characteristics that suggest possible inflation of absolute effect sizes for individual studies. Therefore, the pooled SMDs we report are interpretable but may exceed the true effect of exercise for PTSD symptom reduction in veterans.

Limitations

The present study has several important limitations. First, few studies were found that met the broad eligibility criteria and those that did often had a small sample size. Besides highlighting a gap in the extant research, the limited studies available for meta-analysis means that caution must be taken when interpreting results. Fortunately, this issue will likely resolve once additional studies investigating the impact of exercise on PTSD symptoms in veterans are available for synthesis.

Relatedly, the included study interventions varied considerably, both in the types of exercise used and the characteristics of the exercises (eg, frequency, duration, and intensity), which is relevant as different exercise modalities are associated with differential physical effects.³³ Including such a mixture of exercises may have given an incomplete picture of their potential therapeutic effects. Also, none of the RCTs compared exercise against first-line treatments for PTSD, such as prolonged exposure or cognitive processing therapy, which would have provided further insight into the role exercise could play in clinical settings.⁷

Another limitation is the elevated risk of bias found in most studies, particularly present in the longitudinal single-arm studies, all of which were rated at serious risk. For instance, no single-arm study controlled for preexisting baseline trends: without such (and lacking a comparison control group like in RCTs), it is possible that the observed effects were due to extraneous factors, rather than the exercise intervention. Although not as severe, the multi-arm RCTs also displayed at least moderate risk of bias. Therefore, SMDs may have been overestimated for each group of studies.

Finally, the results of the single-arm meta-analysis displayed high statistical heterogeneity, reducing the generalizability of the results. One possible cause of this heterogeneity may have been the yoga interventions, as a separate analysis removing the only nonyoga study did not reduce heterogeneity. This result was surprising, as the included yoga interventions seemed similar across studies. While the presence of high heterogeneity does require some caution when applying these results to outside interventions, the present study made use of random-effects meta-analysis, a technique that incorporates study heterogeneity into the statistical model, thereby strengthening the findings compared with that of a traditional fixed-effects approach.¹⁰

Future Steps

Several future steps are warranted to improve knowledge of exercise as a treatment for PTSD in veterans and in the general population. With current meta-analyses limited to small numbers of studies, additional studies of the efficacy of exercise for treating PTSD could help in several ways. A larger pool of studies would enable future meta-analyses to explore related questions, such as those regarding the impact of exercise on quality of life or depressive symptom reduction among veterans with PTSD. A greater number of studies also would enable meta-analysts to explore potentially critical moderators. For example, the duration, frequency, or type of exercise may moderate the effect of exercise on PTSD symptom reduction. Moderators related to patient or study design characteristics also should be explored in future studies.

Future work also should evaluate the impact that specific features of exercise regimens have on PTSD. Knowing whether the type or structure of exercise affects its clinical use would be invaluable in developing and implementing efficient exercise-based interventions. For example, if facilitated exercise was found to be significantly more effective at reducing PTSD symptoms than exercise completed independently, the development of exercise intervention programs in the VA and other facilities that commonly treat PTSD may be warranted. Additionally, it may be useful to identify specific mechanisms through which exercise reduces PTSD symptoms. For example, in addition to its beneficial biological effects, exercise also promotes psychological health through behavioral activation and alterations within reinforcement/reward systems, suggesting that exercise regularity may be more important than intensity.^34,35 Understanding which mechanisms contribute most to change will aid in the development of more efficient interventions.

Given that veterans are demonstrating considerable interest in complementary and alternative PTSD treatments, it is critical that researchers focus on high-quality randomized tests of these interventions. Therefore, in addition to greater quality of exercise intervention studies, future efforts should be focused on RCTs that are designed in such a way as to limit potential introduction of bias. For example, assessment data should be completed by blinded assessors using standardized measures, and analyses should account for missing data and unequal participant attrition between groups. Ideally, pre-intervention trends across multiple baseline datapoints also would be collected in single-arm studies to avoid confounding related to regression to the mean. It is also recommended that future meta-analyses use risk of bias assessments and consider how the results of such assessments may impact the interpretation of results.

Conclusions

Findings from both single-arm studies and RCTs suggest possible benefit of exercise on PTSD symptom reduction, although confirmation of findings is needed. No study found increased symptoms following exercise intervention. Thus, it is reasonable to consider physical exercise, such as yoga, as an adjunct, whole-health consistent treatment. HCPs working with veterans with past traumatic experiences should consider incorporating exercise into patient care. Enhanced educational efforts emphasizing the psychotherapeutic impact of exercise may also have value for the veteran population. Furthermore, the current risk of bias assessments highlights the need for additional high-quality RCTs evaluating the specific impact of exercise on PTSD symptom reduction in veterans. In particular, this field of inquiry would benefit from larger samples and design characteristics to reduce bias (eg, blinding when possible, use of CAPS vs only self-report symptom measures, reducing problematic attrition, corrections for missing data, etc).

Acknowledgments

This research is the result of work supported with resources and the use of facilities at the VA Eastern Kansas Healthcare System (Dwight D. Eisenhower VA Medical Center). It was also supported by the Department of Veterans Affairs Office of Academic Affiliations Advanced Fellowship Program in Mental Illness Research and Treatment, as well as the Rocky Mountain Mental Illness Research, Education, and Clinical Center. Since Dr. Reis and Dr. Gaddy are employees of the US Government and contributed to this manuscript as part of their official duties, the work is not subject to US copyright. This study was preregistered on PROSPERO (https://www.crd.york.ac.uk/prospero/; ID: CRD42020153419).

Trichotillomania is a chronic psychiatric disorder that causes people to repeatedly pull out their own hair. Not only does it result in alopecia with no other underlying causes but it can have significant psychosocial ramifications and rare, but serious, complications. Though the reported prevalence rates are up to approximately 2%, it’s probable that you’ll come upon a patient suffering with this disorder at your practice, if you haven’t already.

To find out more about the best methods for diagnosing and treating this disorder, we spoke with Jon E. Grant, JD, MD, MPH, a leading trichotillomania researcher and part of the department of psychiatry and behavioral neuroscience at the University of Chicago.

Courtesy of Dr. Jon Grant

Defining trichotillomania

What were the earliest descriptions of trichotillomania in medical literature?

The first real discussion of it probably goes back to Hippocrates, but from a modern medical perspective, discussion began in the 19th century with reports from the French dermatologist François Hallopeau.

They didn’t really call them disorders then – it was long before the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) – but they described this in young men who kept pulling their hair for unclear reasons. These early case reports don’t provide a lot of psychological perspective, but they seem consistent with what we see now.

What are the diagnostic criteria for trichotillomania?

The current DSM-5 criteria are recurrent pulling out of hair, an inability to stop it, the pulling resulting in some noticeable thinning or hair loss, and that it causes some level of distress or some type of impairment in functioning.

At what age do most people experience an onset of symptoms?

Generally speaking, it’s in early adolescence, post puberty, around 12-15 years of age. Having said that, we do see children as young as 1-2 years who are pulling their hair, and we occasionally see somebody far older who is doing it for the first time, a sort of geriatric onset.
 

Overlap and differences with other disorders

You’ve written that although trichotillomania is grouped with obsessive-compulsive disorder (OCD) in the DSM-5, the thinking around that has recently shifted. Why is that?

At first, it was noticed that many of these people pulled their hair repetitively in an almost ritualized manner, perhaps every night before bed. That looked like a compulsion of OCD.

When DSM-5 came out in 2013, they grouped it with OCD. Yet people shifted to thinking that it’s kind of a cousin of OCD because it has this compulsive quality but doesn’t really have obsessive thinking that drives it. Many people just pull their hair. They’re not even always aware of it: sometimes yes, sometimes no.

We know that it has some links to OCD. You’ll see more OCD in folks with trichotillomania, but it clearly is not just the same as OCD. One of the biggest pieces of evidence for that is that our first-line treatment for OCD – a selective serotonin reuptake inhibitor antidepressant – does not really help hair pulling.

Having said that, if people are looking for help with trichotillomania, they often are best served by therapists and doctors who have a familiarity with OCD and have kept it on their radar over the past couple of decades.

How does trichotillomania overlap with skin picking disorder, which is another condition that you’ve closely researched?

It does have some overlap with skin picking in the sense that it often seems familial. For example, the mother may pull her hair and child picks their skin.

It also has a fair amount of comorbidity with skin picking. Many people who pull will pick a little bit or did at some point. Many people who pick pulled their hair at some point. It seems closely related to nail biting as well.

Studies have also shown that one of the things that runs in the histories of most families of people with trichotillomania might be substance abuse – alcohol or drug addiction.

All of this has led people to believe that there might be subtypes of trichotillomania: one that’s more like an OCD and one that’s more like an addiction. That’s similar to the debate with other mental health conditions, that there are probably multiple types of depression, multiple types of schizophrenia.

Is there a component of this that could be defined as self-harm?

That’s been its own debate. It doesn’t seem to have the same developmental trajectory that we see with self-harm, or even some of the personality features.

However, there may be a small segment of folks with trichotillomania that might more appropriately fit that category. For example, those with family histories of trauma, higher rates of posttraumatic stress disorder, or borderline personality. But it wouldn’t be the majority.

The problem is, if you look at some of the pediatrician data, they often group picking, pulling, and cutting. I think that’s far too all-inclusive.
 

A gap in clinician education

Are adolescent patients likely to self-report this behavior, or is it something that physicians need to suss out for themselves?

Clearly, if child psychologists, psychiatrists, or pediatricians see young people with patches of alopecia – eyebrows or eyelashes missing, head hair with spots – in addition to a dermatologic assessment, they should simply ask, “Do you pull your hair?”

But it’s interesting that with the internet, young people are much more likely to disclose and actually come forward and tell their parents that they think they have trichotillomania.

I also hear from a lot of the adolescents that they have to educate their doctors about trichotillomania because so often physicians don’t know much about it and will assume that it’s self-injury or just a symptom of anxiety. It’s a little bit of a flip from what we might have seen 20 years ago.

I’ve seen several patients who’ve said, basically, “I’m tired of no professionals seeming to know about this. I shouldn’t have to be educating my doctors about this.” I tell them that I completely agree. It’s a shame because if a doctor doesn’t know about it, then how can they get the appropriate care?

What are the complications that accompany trichotillomania?

A small percentage, maybe about 10%, will ingest their hair, much like people who bite and swallow their fingernails. The concern there is that because hair is nondigestible, it could create an intestinal plug that could rupture and be potentially life-threatening. That makes it all the more important to ask those who pull their hair what they do with the hair once they pull it.

However, with most people, the real problem is with self-esteem. Young people may not want to socialize, go on dates, or do other things they would normally do because of it. In adults, you may find that they’re far more educated than their job allows but don’t want to go to an interview because they don’t want to have somebody sit there and look at them and notice that perhaps they don’t have any eyebrows, or that they’re wearing a wig. Those psychosocial implications are huge for so many people.
 

Treatment options

In a 2021 study, you showed that nearly one-quarter of people with trichotillomania do naturally recover from it. What characteristics do they seem to have?

It’s interesting because we see natural recovery across many mental health problems: alcohol addition, gambling, OCD. The question then becomes why is that some people can seemingly just stop doing a behavior? Can we learn from those people?

We did see that those who naturally recovered were less likely to have some other mental health comorbidities. It seems like when you have other things such as skin picking or OCD plus trichotillomania, that it probably speaks to something that perhaps synergistically is keeping it going. But this is just a first study; learning how to harness and understand it is the next step.

What’s the goal of treating trichotillomania?

The desired goal is zero pulling. The realistic goal is more likely significantly reduced pulling that then leads to greater function in life, greater quality-of-life.

One doesn’t have to go from 100 to 0 in order to do that. I always tell people that maybe every now and then, every few months, when something is going on in life, you might find yourself pulling a hair or two. That’s okay. If you’re not pulling every day and it’s significantly reduced, we’ll call that a success. I think that setting reasonable goals at this point is really important.

And what would the treatment pathway look like for most patients?

The standard approach is probably some type of habit-reversal therapy, of which there have been many variants over the years. It involves doing something different with your hand, identifying the triggers that may set you off, and then doing something in response to those triggers that is not pulling and might neutralize whatever that anxious or stressed feeling is. That could be different with each person.

At this point, there is no drug approved by the U.S. Food and Drug Administration for trichotillomania. Our best approaches have included N-acetylcysteine, a glutamate modulator, which we’ve done research in.

That’s kind of a go-to option for people because its side-effect profile is generally innocuous. The data show that it could be beneficial in many people with very few, if any, side effects. That would be one “medication,” although it’s actually an over-the-counter vitamin. But we’re constantly looking for better and better treatments.

Do you have any final advice for clinicians or researchers?

Given how common it is, I don’t think clinicians should just see it as an innocuous little habit that people should be able to stop on their own. Clinicians should educate themselves about trichotillomania and know where the person should get the appropriate care.

From the research perspective, given the fact that we see this in animals of multiple species – that they overgroom – this seems to be deeply ingrained in us as animals. So when it comes to the underlying neuroscience, people should pay more attention because it probably has a lot to do with our understanding of habit and compulsive behaviors. It arguably can cut across a lot of different behaviors.

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

Trichotillomania is a chronic psychiatric disorder that causes people to repeatedly pull out their own hair. Not only does it result in alopecia with no other underlying causes but it can have significant psychosocial ramifications and rare, but serious, complications. Though the reported prevalence rates are up to approximately 2%, it’s probable that you’ll come upon a patient suffering with this disorder at your practice, if you haven’t already.

To find out more about the best methods for diagnosing and treating this disorder, we spoke with Jon E. Grant, JD, MD, MPH, a leading trichotillomania researcher and part of the department of psychiatry and behavioral neuroscience at the University of Chicago.

Courtesy of Dr. Jon Grant

Defining trichotillomania

What were the earliest descriptions of trichotillomania in medical literature?

The first real discussion of it probably goes back to Hippocrates, but from a modern medical perspective, discussion began in the 19th century with reports from the French dermatologist François Hallopeau.

They didn’t really call them disorders then – it was long before the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) – but they described this in young men who kept pulling their hair for unclear reasons. These early case reports don’t provide a lot of psychological perspective, but they seem consistent with what we see now.

What are the diagnostic criteria for trichotillomania?

The current DSM-5 criteria are recurrent pulling out of hair, an inability to stop it, the pulling resulting in some noticeable thinning or hair loss, and that it causes some level of distress or some type of impairment in functioning.

At what age do most people experience an onset of symptoms?

Generally speaking, it’s in early adolescence, post puberty, around 12-15 years of age. Having said that, we do see children as young as 1-2 years who are pulling their hair, and we occasionally see somebody far older who is doing it for the first time, a sort of geriatric onset.
 

Overlap and differences with other disorders

You’ve written that although trichotillomania is grouped with obsessive-compulsive disorder (OCD) in the DSM-5, the thinking around that has recently shifted. Why is that?

At first, it was noticed that many of these people pulled their hair repetitively in an almost ritualized manner, perhaps every night before bed. That looked like a compulsion of OCD.

When DSM-5 came out in 2013, they grouped it with OCD. Yet people shifted to thinking that it’s kind of a cousin of OCD because it has this compulsive quality but doesn’t really have obsessive thinking that drives it. Many people just pull their hair. They’re not even always aware of it: sometimes yes, sometimes no.

We know that it has some links to OCD. You’ll see more OCD in folks with trichotillomania, but it clearly is not just the same as OCD. One of the biggest pieces of evidence for that is that our first-line treatment for OCD – a selective serotonin reuptake inhibitor antidepressant – does not really help hair pulling.

Having said that, if people are looking for help with trichotillomania, they often are best served by therapists and doctors who have a familiarity with OCD and have kept it on their radar over the past couple of decades.

How does trichotillomania overlap with skin picking disorder, which is another condition that you’ve closely researched?

It does have some overlap with skin picking in the sense that it often seems familial. For example, the mother may pull her hair and child picks their skin.

It also has a fair amount of comorbidity with skin picking. Many people who pull will pick a little bit or did at some point. Many people who pick pulled their hair at some point. It seems closely related to nail biting as well.

Studies have also shown that one of the things that runs in the histories of most families of people with trichotillomania might be substance abuse – alcohol or drug addiction.

All of this has led people to believe that there might be subtypes of trichotillomania: one that’s more like an OCD and one that’s more like an addiction. That’s similar to the debate with other mental health conditions, that there are probably multiple types of depression, multiple types of schizophrenia.

Is there a component of this that could be defined as self-harm?

That’s been its own debate. It doesn’t seem to have the same developmental trajectory that we see with self-harm, or even some of the personality features.

However, there may be a small segment of folks with trichotillomania that might more appropriately fit that category. For example, those with family histories of trauma, higher rates of posttraumatic stress disorder, or borderline personality. But it wouldn’t be the majority.

The problem is, if you look at some of the pediatrician data, they often group picking, pulling, and cutting. I think that’s far too all-inclusive.
 

A gap in clinician education

Are adolescent patients likely to self-report this behavior, or is it something that physicians need to suss out for themselves?

Clearly, if child psychologists, psychiatrists, or pediatricians see young people with patches of alopecia – eyebrows or eyelashes missing, head hair with spots – in addition to a dermatologic assessment, they should simply ask, “Do you pull your hair?”

But it’s interesting that with the internet, young people are much more likely to disclose and actually come forward and tell their parents that they think they have trichotillomania.

I also hear from a lot of the adolescents that they have to educate their doctors about trichotillomania because so often physicians don’t know much about it and will assume that it’s self-injury or just a symptom of anxiety. It’s a little bit of a flip from what we might have seen 20 years ago.

I’ve seen several patients who’ve said, basically, “I’m tired of no professionals seeming to know about this. I shouldn’t have to be educating my doctors about this.” I tell them that I completely agree. It’s a shame because if a doctor doesn’t know about it, then how can they get the appropriate care?

What are the complications that accompany trichotillomania?

A small percentage, maybe about 10%, will ingest their hair, much like people who bite and swallow their fingernails. The concern there is that because hair is nondigestible, it could create an intestinal plug that could rupture and be potentially life-threatening. That makes it all the more important to ask those who pull their hair what they do with the hair once they pull it.

However, with most people, the real problem is with self-esteem. Young people may not want to socialize, go on dates, or do other things they would normally do because of it. In adults, you may find that they’re far more educated than their job allows but don’t want to go to an interview because they don’t want to have somebody sit there and look at them and notice that perhaps they don’t have any eyebrows, or that they’re wearing a wig. Those psychosocial implications are huge for so many people.
 

Treatment options

In a 2021 study, you showed that nearly one-quarter of people with trichotillomania do naturally recover from it. What characteristics do they seem to have?

It’s interesting because we see natural recovery across many mental health problems: alcohol addition, gambling, OCD. The question then becomes why is that some people can seemingly just stop doing a behavior? Can we learn from those people?

We did see that those who naturally recovered were less likely to have some other mental health comorbidities. It seems like when you have other things such as skin picking or OCD plus trichotillomania, that it probably speaks to something that perhaps synergistically is keeping it going. But this is just a first study; learning how to harness and understand it is the next step.

What’s the goal of treating trichotillomania?

The desired goal is zero pulling. The realistic goal is more likely significantly reduced pulling that then leads to greater function in life, greater quality-of-life.

One doesn’t have to go from 100 to 0 in order to do that. I always tell people that maybe every now and then, every few months, when something is going on in life, you might find yourself pulling a hair or two. That’s okay. If you’re not pulling every day and it’s significantly reduced, we’ll call that a success. I think that setting reasonable goals at this point is really important.

And what would the treatment pathway look like for most patients?

The standard approach is probably some type of habit-reversal therapy, of which there have been many variants over the years. It involves doing something different with your hand, identifying the triggers that may set you off, and then doing something in response to those triggers that is not pulling and might neutralize whatever that anxious or stressed feeling is. That could be different with each person.

At this point, there is no drug approved by the U.S. Food and Drug Administration for trichotillomania. Our best approaches have included N-acetylcysteine, a glutamate modulator, which we’ve done research in.

That’s kind of a go-to option for people because its side-effect profile is generally innocuous. The data show that it could be beneficial in many people with very few, if any, side effects. That would be one “medication,” although it’s actually an over-the-counter vitamin. But we’re constantly looking for better and better treatments.

Do you have any final advice for clinicians or researchers?

Given how common it is, I don’t think clinicians should just see it as an innocuous little habit that people should be able to stop on their own. Clinicians should educate themselves about trichotillomania and know where the person should get the appropriate care.

From the research perspective, given the fact that we see this in animals of multiple species – that they overgroom – this seems to be deeply ingrained in us as animals. So when it comes to the underlying neuroscience, people should pay more attention because it probably has a lot to do with our understanding of habit and compulsive behaviors. It arguably can cut across a lot of different behaviors.

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

Trichotillomania is a chronic psychiatric disorder that causes people to repeatedly pull out their own hair. Not only does it result in alopecia with no other underlying causes but it can have significant psychosocial ramifications and rare, but serious, complications. Though the reported prevalence rates are up to approximately 2%, it’s probable that you’ll come upon a patient suffering with this disorder at your practice, if you haven’t already.

To find out more about the best methods for diagnosing and treating this disorder, we spoke with Jon E. Grant, JD, MD, MPH, a leading trichotillomania researcher and part of the department of psychiatry and behavioral neuroscience at the University of Chicago.

Courtesy of Dr. Jon Grant

Defining trichotillomania

What were the earliest descriptions of trichotillomania in medical literature?

The first real discussion of it probably goes back to Hippocrates, but from a modern medical perspective, discussion began in the 19th century with reports from the French dermatologist François Hallopeau.

They didn’t really call them disorders then – it was long before the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) – but they described this in young men who kept pulling their hair for unclear reasons. These early case reports don’t provide a lot of psychological perspective, but they seem consistent with what we see now.

What are the diagnostic criteria for trichotillomania?

The current DSM-5 criteria are recurrent pulling out of hair, an inability to stop it, the pulling resulting in some noticeable thinning or hair loss, and that it causes some level of distress or some type of impairment in functioning.

At what age do most people experience an onset of symptoms?

Generally speaking, it’s in early adolescence, post puberty, around 12-15 years of age. Having said that, we do see children as young as 1-2 years who are pulling their hair, and we occasionally see somebody far older who is doing it for the first time, a sort of geriatric onset.
 

Overlap and differences with other disorders

You’ve written that although trichotillomania is grouped with obsessive-compulsive disorder (OCD) in the DSM-5, the thinking around that has recently shifted. Why is that?

At first, it was noticed that many of these people pulled their hair repetitively in an almost ritualized manner, perhaps every night before bed. That looked like a compulsion of OCD.

When DSM-5 came out in 2013, they grouped it with OCD. Yet people shifted to thinking that it’s kind of a cousin of OCD because it has this compulsive quality but doesn’t really have obsessive thinking that drives it. Many people just pull their hair. They’re not even always aware of it: sometimes yes, sometimes no.

We know that it has some links to OCD. You’ll see more OCD in folks with trichotillomania, but it clearly is not just the same as OCD. One of the biggest pieces of evidence for that is that our first-line treatment for OCD – a selective serotonin reuptake inhibitor antidepressant – does not really help hair pulling.

Having said that, if people are looking for help with trichotillomania, they often are best served by therapists and doctors who have a familiarity with OCD and have kept it on their radar over the past couple of decades.

How does trichotillomania overlap with skin picking disorder, which is another condition that you’ve closely researched?

It does have some overlap with skin picking in the sense that it often seems familial. For example, the mother may pull her hair and child picks their skin.

It also has a fair amount of comorbidity with skin picking. Many people who pull will pick a little bit or did at some point. Many people who pick pulled their hair at some point. It seems closely related to nail biting as well.

Studies have also shown that one of the things that runs in the histories of most families of people with trichotillomania might be substance abuse – alcohol or drug addiction.

All of this has led people to believe that there might be subtypes of trichotillomania: one that’s more like an OCD and one that’s more like an addiction. That’s similar to the debate with other mental health conditions, that there are probably multiple types of depression, multiple types of schizophrenia.

Is there a component of this that could be defined as self-harm?

That’s been its own debate. It doesn’t seem to have the same developmental trajectory that we see with self-harm, or even some of the personality features.

However, there may be a small segment of folks with trichotillomania that might more appropriately fit that category. For example, those with family histories of trauma, higher rates of posttraumatic stress disorder, or borderline personality. But it wouldn’t be the majority.

The problem is, if you look at some of the pediatrician data, they often group picking, pulling, and cutting. I think that’s far too all-inclusive.
 

A gap in clinician education

Are adolescent patients likely to self-report this behavior, or is it something that physicians need to suss out for themselves?

Clearly, if child psychologists, psychiatrists, or pediatricians see young people with patches of alopecia – eyebrows or eyelashes missing, head hair with spots – in addition to a dermatologic assessment, they should simply ask, “Do you pull your hair?”

But it’s interesting that with the internet, young people are much more likely to disclose and actually come forward and tell their parents that they think they have trichotillomania.

I also hear from a lot of the adolescents that they have to educate their doctors about trichotillomania because so often physicians don’t know much about it and will assume that it’s self-injury or just a symptom of anxiety. It’s a little bit of a flip from what we might have seen 20 years ago.

I’ve seen several patients who’ve said, basically, “I’m tired of no professionals seeming to know about this. I shouldn’t have to be educating my doctors about this.” I tell them that I completely agree. It’s a shame because if a doctor doesn’t know about it, then how can they get the appropriate care?

What are the complications that accompany trichotillomania?

A small percentage, maybe about 10%, will ingest their hair, much like people who bite and swallow their fingernails. The concern there is that because hair is nondigestible, it could create an intestinal plug that could rupture and be potentially life-threatening. That makes it all the more important to ask those who pull their hair what they do with the hair once they pull it.

However, with most people, the real problem is with self-esteem. Young people may not want to socialize, go on dates, or do other things they would normally do because of it. In adults, you may find that they’re far more educated than their job allows but don’t want to go to an interview because they don’t want to have somebody sit there and look at them and notice that perhaps they don’t have any eyebrows, or that they’re wearing a wig. Those psychosocial implications are huge for so many people.
 

Treatment options

In a 2021 study, you showed that nearly one-quarter of people with trichotillomania do naturally recover from it. What characteristics do they seem to have?

It’s interesting because we see natural recovery across many mental health problems: alcohol addition, gambling, OCD. The question then becomes why is that some people can seemingly just stop doing a behavior? Can we learn from those people?

We did see that those who naturally recovered were less likely to have some other mental health comorbidities. It seems like when you have other things such as skin picking or OCD plus trichotillomania, that it probably speaks to something that perhaps synergistically is keeping it going. But this is just a first study; learning how to harness and understand it is the next step.

What’s the goal of treating trichotillomania?

The desired goal is zero pulling. The realistic goal is more likely significantly reduced pulling that then leads to greater function in life, greater quality-of-life.

One doesn’t have to go from 100 to 0 in order to do that. I always tell people that maybe every now and then, every few months, when something is going on in life, you might find yourself pulling a hair or two. That’s okay. If you’re not pulling every day and it’s significantly reduced, we’ll call that a success. I think that setting reasonable goals at this point is really important.

And what would the treatment pathway look like for most patients?

The standard approach is probably some type of habit-reversal therapy, of which there have been many variants over the years. It involves doing something different with your hand, identifying the triggers that may set you off, and then doing something in response to those triggers that is not pulling and might neutralize whatever that anxious or stressed feeling is. That could be different with each person.

At this point, there is no drug approved by the U.S. Food and Drug Administration for trichotillomania. Our best approaches have included N-acetylcysteine, a glutamate modulator, which we’ve done research in.

That’s kind of a go-to option for people because its side-effect profile is generally innocuous. The data show that it could be beneficial in many people with very few, if any, side effects. That would be one “medication,” although it’s actually an over-the-counter vitamin. But we’re constantly looking for better and better treatments.

Do you have any final advice for clinicians or researchers?

Given how common it is, I don’t think clinicians should just see it as an innocuous little habit that people should be able to stop on their own. Clinicians should educate themselves about trichotillomania and know where the person should get the appropriate care.

From the research perspective, given the fact that we see this in animals of multiple species – that they overgroom – this seems to be deeply ingrained in us as animals. So when it comes to the underlying neuroscience, people should pay more attention because it probably has a lot to do with our understanding of habit and compulsive behaviors. It arguably can cut across a lot of different behaviors.

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

The first comprehensive guidelines to manage pregnant women with anorexia nervosa (AN) have been released.

Pregnant women with AN are at greater risk of poor outcomes, including stillbirth, underweight infant, or pre-term birth, yet there are no clear guidelines on the management of the condition.

“Anorexia in pregnancy has been an overlooked area of clinical care, as many believed only women in remission become pregnant, and it is clear that is not the case,” lead author Megan Galbally, MBBS, PhD, professor and director, Centre of Women’s and Children’s Mental Health at Monash University School of Clinical Sciences, Melbourne, told this news organization.

“There are great opportunities to support women in their mental health and give them and their babies a healthier start to parenthood and life,” said Dr. Galbally.

“For instance, reducing the likelihood of prematurity or low birth weight at birth that can be associated with anorexia in pregnancy has extraordinary benefits for that child for lifelong health and well-being,” she added.

The guidelines were published online in Lancet Psychiatry.
 

Spike in cases

Dr. Galbally noted that during her 20 years of working in perinatal mental health within tertiary maternity services, she only ever saw an occasional pregnant woman with current AN.

In contrast, over the last 3 to 4 years, there has been a “steep increase in women presenting in pregnancy with very low body mass index (BMI) and current anorexia nervosa requiring treatment in pregnancy,” Dr. Galbally said.

Despite the complexity of managing AN in pregnancy, few studies are available to guide care. In a systematic literature review, the researchers identified only eight studies that addressed the management of AN in pregnancy. These studies were case studies or case reports examining narrow aspects of management.

Digging deeper, the researchers conducted a state-of-the-art research review in relevant disciplines and areas of expertise for managing anorexia nervosa in pregnancy. They synthesized their findings into “recommendations and principles” for multidisciplinary care of pregnant women with AN.

The researchers note that AN in pregnancy is associated with increased risks of pregnancy complications and poorer outcomes for infants, and measures such as BMI are less accurate in pregnancy for assessing severity or change in anorexia nervosa.

Anorexia affects pregnancy and neonatal outcomes through low calorie intake, nutritional and vitamin deficiencies, stress, fasting, low body mass, and poor placentation and uteroplacental function.

The authors note that managing AN in pregnancy requires multidisciplinary care that considers the substantial physiological changes for women and requirements for monitoring fetal growth and development.

At a minimum, they recommend monitoring the following:

• Sodium, potassium, magnesium, phosphate, and chloride concentration
• Iron status, vitamin D and bone mineral density, blood sugar concentration (fasting or random), and A1c
• Liver function (including bilirubin, aspartate transaminase, alanine aminotransferase, and gamma-glutamyl transferase) and bone marrow function (including full blood examination, white cell count, neutrophil count, platelets, and hemoglobin)
• Inflammatory markers (C-reactive protein and erythrocyte sedimentation rate)
• Cardiac function (electrocardiogram and echocardiogram)
• Blood pressure and heart rate (lying and standing) and body temperature

“There are considerable risks for women and their unborn child in managing moderate to severe AN in pregnancy,” said Dr. Galbally.

“While we have provided some recommendations, it still requires considerable adaptation to individual presentations and circumstances, and this is best done with a maternity service that manages other high-risk pregnancies such as through maternal-fetal medicine teams,” she said.

“While this area of clinical care can be new to high-risk pregnancy teams, it is clearly important that high-risk pregnancy services and mental health work together to improve care for women with anorexia in pregnancy,” Dr. Galbally added.
 

A nightmare, a dream come true

Reached for comment, Kamryn T. Eddy, PhD, co-director, Eating Disorders Clinical and Research Program, Massachusetts General Hospital, said, “for many with anorexia nervosa, pregnancy realizes their greatest nightmare and dream come true, both at once.”

“The physical demands of pregnancy can be taxing, and for those with anorexia nervosa, closer clinical management makes sense and may help to support patients who are at risk for return to or worsening of symptoms with the increased nutritional needs and weight gain that occur in pregnancy,” Dr. Eddy, associate professor, department of psychiatry, Harvard Medical School, Boston, told this news organization.

“At the same time, the desire to have a child can be a strong motivator for patients to make the changes needed to recover, and for some, the transition to mother can also help in recovery by broadening the range of things that influence their self-worth,” Dr. Eddy added.

This research had no specific funding. Dr. Galbally and Dr. Eddy report no relevant conflicts of interest.

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

The first comprehensive guidelines to manage pregnant women with anorexia nervosa (AN) have been released.

Pregnant women with AN are at greater risk of poor outcomes, including stillbirth, underweight infant, or pre-term birth, yet there are no clear guidelines on the management of the condition.

“Anorexia in pregnancy has been an overlooked area of clinical care, as many believed only women in remission become pregnant, and it is clear that is not the case,” lead author Megan Galbally, MBBS, PhD, professor and director, Centre of Women’s and Children’s Mental Health at Monash University School of Clinical Sciences, Melbourne, told this news organization.

“There are great opportunities to support women in their mental health and give them and their babies a healthier start to parenthood and life,” said Dr. Galbally.

“For instance, reducing the likelihood of prematurity or low birth weight at birth that can be associated with anorexia in pregnancy has extraordinary benefits for that child for lifelong health and well-being,” she added.

The guidelines were published online in Lancet Psychiatry.
 

Spike in cases

Dr. Galbally noted that during her 20 years of working in perinatal mental health within tertiary maternity services, she only ever saw an occasional pregnant woman with current AN.

In contrast, over the last 3 to 4 years, there has been a “steep increase in women presenting in pregnancy with very low body mass index (BMI) and current anorexia nervosa requiring treatment in pregnancy,” Dr. Galbally said.

Despite the complexity of managing AN in pregnancy, few studies are available to guide care. In a systematic literature review, the researchers identified only eight studies that addressed the management of AN in pregnancy. These studies were case studies or case reports examining narrow aspects of management.

Digging deeper, the researchers conducted a state-of-the-art research review in relevant disciplines and areas of expertise for managing anorexia nervosa in pregnancy. They synthesized their findings into “recommendations and principles” for multidisciplinary care of pregnant women with AN.

The researchers note that AN in pregnancy is associated with increased risks of pregnancy complications and poorer outcomes for infants, and measures such as BMI are less accurate in pregnancy for assessing severity or change in anorexia nervosa.

Anorexia affects pregnancy and neonatal outcomes through low calorie intake, nutritional and vitamin deficiencies, stress, fasting, low body mass, and poor placentation and uteroplacental function.

The authors note that managing AN in pregnancy requires multidisciplinary care that considers the substantial physiological changes for women and requirements for monitoring fetal growth and development.

At a minimum, they recommend monitoring the following:

• Sodium, potassium, magnesium, phosphate, and chloride concentration
• Iron status, vitamin D and bone mineral density, blood sugar concentration (fasting or random), and A1c
• Liver function (including bilirubin, aspartate transaminase, alanine aminotransferase, and gamma-glutamyl transferase) and bone marrow function (including full blood examination, white cell count, neutrophil count, platelets, and hemoglobin)
• Inflammatory markers (C-reactive protein and erythrocyte sedimentation rate)
• Cardiac function (electrocardiogram and echocardiogram)
• Blood pressure and heart rate (lying and standing) and body temperature

“There are considerable risks for women and their unborn child in managing moderate to severe AN in pregnancy,” said Dr. Galbally.

“While we have provided some recommendations, it still requires considerable adaptation to individual presentations and circumstances, and this is best done with a maternity service that manages other high-risk pregnancies such as through maternal-fetal medicine teams,” she said.

“While this area of clinical care can be new to high-risk pregnancy teams, it is clearly important that high-risk pregnancy services and mental health work together to improve care for women with anorexia in pregnancy,” Dr. Galbally added.
 

A nightmare, a dream come true

Reached for comment, Kamryn T. Eddy, PhD, co-director, Eating Disorders Clinical and Research Program, Massachusetts General Hospital, said, “for many with anorexia nervosa, pregnancy realizes their greatest nightmare and dream come true, both at once.”

“The physical demands of pregnancy can be taxing, and for those with anorexia nervosa, closer clinical management makes sense and may help to support patients who are at risk for return to or worsening of symptoms with the increased nutritional needs and weight gain that occur in pregnancy,” Dr. Eddy, associate professor, department of psychiatry, Harvard Medical School, Boston, told this news organization.

“At the same time, the desire to have a child can be a strong motivator for patients to make the changes needed to recover, and for some, the transition to mother can also help in recovery by broadening the range of things that influence their self-worth,” Dr. Eddy added.

This research had no specific funding. Dr. Galbally and Dr. Eddy report no relevant conflicts of interest.

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

The first comprehensive guidelines to manage pregnant women with anorexia nervosa (AN) have been released.

Pregnant women with AN are at greater risk of poor outcomes, including stillbirth, underweight infant, or pre-term birth, yet there are no clear guidelines on the management of the condition.

“Anorexia in pregnancy has been an overlooked area of clinical care, as many believed only women in remission become pregnant, and it is clear that is not the case,” lead author Megan Galbally, MBBS, PhD, professor and director, Centre of Women’s and Children’s Mental Health at Monash University School of Clinical Sciences, Melbourne, told this news organization.

“There are great opportunities to support women in their mental health and give them and their babies a healthier start to parenthood and life,” said Dr. Galbally.

“For instance, reducing the likelihood of prematurity or low birth weight at birth that can be associated with anorexia in pregnancy has extraordinary benefits for that child for lifelong health and well-being,” she added.

The guidelines were published online in Lancet Psychiatry.
 

Spike in cases

Dr. Galbally noted that during her 20 years of working in perinatal mental health within tertiary maternity services, she only ever saw an occasional pregnant woman with current AN.

In contrast, over the last 3 to 4 years, there has been a “steep increase in women presenting in pregnancy with very low body mass index (BMI) and current anorexia nervosa requiring treatment in pregnancy,” Dr. Galbally said.

Despite the complexity of managing AN in pregnancy, few studies are available to guide care. In a systematic literature review, the researchers identified only eight studies that addressed the management of AN in pregnancy. These studies were case studies or case reports examining narrow aspects of management.

Digging deeper, the researchers conducted a state-of-the-art research review in relevant disciplines and areas of expertise for managing anorexia nervosa in pregnancy. They synthesized their findings into “recommendations and principles” for multidisciplinary care of pregnant women with AN.

The researchers note that AN in pregnancy is associated with increased risks of pregnancy complications and poorer outcomes for infants, and measures such as BMI are less accurate in pregnancy for assessing severity or change in anorexia nervosa.

Anorexia affects pregnancy and neonatal outcomes through low calorie intake, nutritional and vitamin deficiencies, stress, fasting, low body mass, and poor placentation and uteroplacental function.

The authors note that managing AN in pregnancy requires multidisciplinary care that considers the substantial physiological changes for women and requirements for monitoring fetal growth and development.

At a minimum, they recommend monitoring the following:

• Sodium, potassium, magnesium, phosphate, and chloride concentration
• Iron status, vitamin D and bone mineral density, blood sugar concentration (fasting or random), and A1c
• Liver function (including bilirubin, aspartate transaminase, alanine aminotransferase, and gamma-glutamyl transferase) and bone marrow function (including full blood examination, white cell count, neutrophil count, platelets, and hemoglobin)
• Inflammatory markers (C-reactive protein and erythrocyte sedimentation rate)
• Cardiac function (electrocardiogram and echocardiogram)
• Blood pressure and heart rate (lying and standing) and body temperature

“There are considerable risks for women and their unborn child in managing moderate to severe AN in pregnancy,” said Dr. Galbally.

“While we have provided some recommendations, it still requires considerable adaptation to individual presentations and circumstances, and this is best done with a maternity service that manages other high-risk pregnancies such as through maternal-fetal medicine teams,” she said.

“While this area of clinical care can be new to high-risk pregnancy teams, it is clearly important that high-risk pregnancy services and mental health work together to improve care for women with anorexia in pregnancy,” Dr. Galbally added.
 

A nightmare, a dream come true

Reached for comment, Kamryn T. Eddy, PhD, co-director, Eating Disorders Clinical and Research Program, Massachusetts General Hospital, said, “for many with anorexia nervosa, pregnancy realizes their greatest nightmare and dream come true, both at once.”

“The physical demands of pregnancy can be taxing, and for those with anorexia nervosa, closer clinical management makes sense and may help to support patients who are at risk for return to or worsening of symptoms with the increased nutritional needs and weight gain that occur in pregnancy,” Dr. Eddy, associate professor, department of psychiatry, Harvard Medical School, Boston, told this news organization.

“At the same time, the desire to have a child can be a strong motivator for patients to make the changes needed to recover, and for some, the transition to mother can also help in recovery by broadening the range of things that influence their self-worth,” Dr. Eddy added.

This research had no specific funding. Dr. Galbally and Dr. Eddy report no relevant conflicts of interest.

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

DENVER – An investigational once-daily oral neuroactive steroid is linked to significant improvement in quality of life (QoL) and well-being in patients with major depressive disorder (MDD), new research shows.

In a phase 3 trial that included more than 500 adult patients with MDD, those who received zuranolone for 14 days showed greater improvement at day 15 across numerous QoL outcomes, compared with their counterparts in the placebo group.

In addition, combined analysis of four zuranolone clinical trials showed “mental well-being and functioning improved to near general population norm levels” for the active-treatment group, reported the researchers, led by Anita H. Clayton, MD, chair and professor of psychiatry, University of Virginia, Charlottesville.

“Based on these integrated analyses, the benefit of treatment with zuranolone may extend beyond reduction in depressive symptoms to include potential improvement in quality of life and overall health, as perceived by patients,” they add.

The findings were presented as part of the Anxiety and Depression Association of America Anxiety & Depression conference.
 

First oral formulation

Zuranolone represents the second entry in the new class of neuroactive steroid drugs, which modulate GABA-A receptor activity – but it would be the first to have an oral formulation. Brexanolone, which was approved by the Food and Drug Administration in 2019 for postpartum depression, is administered through continuous IV infusion over 60 hours.

As previously reported by this news organization, zuranolone improved depressive symptoms as early as day 3, achieving the primary endpoint of significantly greater reduction in scores on the 17-item Hamilton Rating Scale for Depression from baseline to day 15 versus placebo (P = .014).

In the new analysis, patient-reported measures of functional health and well-being were assessed in the WATERFALL trial. It included 266 patients with MDD who were treated with zuranolone 50 mg daily for 2 weeks and 268 patients with MDD who were treated with placebo.

The study used the Short Form–36 (SF-36v2), which covers a wide range of patient-reported measures, including physical function, bodily pain, general health, vitality, social function, and “role-emotional” symptoms.

Results showed that although the treatment and placebo groups had similar baseline SF-36v2 scores, those receiving zuranolone reported significantly greater improvements at day 15 in almost all of the assessment’s domains, including physical function (treatment difference, 0.8), general health (1.0), vitality (3.1), social functioning (1.1), and role-emotional symptoms (1.5; for all comparisons, P < .05). The only exceptions were in role-physical symptoms and bodily pain.

In measures that included physical function, bodily pain, and general health, the patients achieved improvements at day 15 that were consistent with normal levels, with the improvement in vitality considered clinically meaningful versus placebo.

Integrated data

In further analysis of integrated data from four zuranolone clinical trials in the NEST and LANDSCAPE programs for patients with MDD and postpartum depression, results showed similar improvements at day 15 for zuranolone in QoL and overall health across all of the SF-36v2 functioning and well-being domains (P <.05), with the exceptions of physical measure and bodily pain.

By day 42, all of the domains showed significantly greater improvement with zuranolone versus placebo (all, P <.05).

Among the strongest score improvements in the integrated trials were measures in social functioning, which improved from baseline scores of 29.66 to 42.82 on day 15 and to 43.59 on day 42.

Emotional domain scores improved from 24.43 at baseline to 39.13 on day 15 and to 39.82 on day 42. For mental health, the integrated scores for the zuranolone group improved from 27.13 at baseline to 42.40 on day 15 and 42.62 on day 42.

Of note, the baseline scores for mental health represented just 54.3% of those in the normal population; with the increase at day 15, the level was 84.8% of the normal population.

“Across four completed placebo-controlled NEST and LANDSCAPE clinical trials, patient reports of functional health and well-being as assessed by the SF-36v2 indicated substantial impairment at baseline compared to the population norm,” the researchers reported.

The improvements are especially important in light of the fact that in some patients with MDD, functional improvement is a top priority.

“Patients have often prioritized returning to their usual level of functioning over reduction in depressive symptoms, and functional recovery has been associated with better prognosis of depression,” the investigators wrote.

Zuranolone trials have shown that treatment-emergent adverse events (AEs) occur among about 60% of patients, versus about 44% with placebo. The most common AEs are somnolence, dizziness, headache, sedation, and diarrhea, with no increases in suicidal ideation or withdrawal.

The rates of severe AEs are low, and they are observed in about 3% of patients, versus 1.1% with placebo, the researchers noted.

Further, as opposed to serotonergic antidepressants such as SNRIs and SSRIs, zuranolone does not appear to have the undesirable side effects of decreased libido and sexual dysfunction, they added.
 

Clinically meaningful?

Andrew J. Cutler, MD, clinical associate professor of psychiatry at State University of New York, Syracuse, said the data are “very significant” for a number of reasons.

“We need more options to treat depression, especially ones with novel mechanisms of action and faster onset of efficacy, such as zuranolone,” said Dr. Cutler, who was not involved in the current study. He has coauthored other studies on zuranolone.

Regarding the study’s QoL outcomes, “while improvement in depressive symptoms is very important, what really matters to patients is improvement in function and quality of life,” Dr. Cutler noted.

Also commenting on the study, Jonathan E. Alpert, MD, PhD, chair of the department of psychiatry and behavioral sciences and professor of psychiatry, neuroscience, and pediatrics at Albert Einstein College of Medicine, New York, said the investigational drug could represent an important addition to the armamentarium for treating depression.

“Zuranolone has good oral bioavailability and would represent the first neuroactive steroid antidepressant available in oral form and, indeed, the first non–monoamine-based antidepressant available in oral form,” he said in an interview.

Courtesy Dr. Jonathan E. Alpert

Dr. Alpert was not involved in the research and has no relationship with the drug’s development.

He noted that although there are modest differences between the patients who received zuranolone and those who received placebo in the trials, “this may have been related to high placebo response rates, which often complicate antidepressant trials.

“Further research is needed to determine whether differences between zuranolone and placebo are clinically meaningful, though the separation between drug and placebo on the primary endpoint, as well as some other measures, such as quality of life measures, is promising,” Dr. Alpert said.

However, he added that comparisons with other active antidepressants in terms of efficacy and tolerability remain to be seen.

“Given the large number of individuals with major depressive disorder who have incomplete response to or do not tolerate monoaminergic antidepressants, the development of agents that leverage novel nonmonoaminergic mechanisms is important,” Dr. Alpert concluded.

The study was funded by Sage Therapeutics and Biogen. Dr. Cutler has been involved in research of zuranolone for Sage Therapeutics. Dr. Alpert has reported no relevant financial relationships.

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

DENVER – An investigational once-daily oral neuroactive steroid is linked to significant improvement in quality of life (QoL) and well-being in patients with major depressive disorder (MDD), new research shows.

In a phase 3 trial that included more than 500 adult patients with MDD, those who received zuranolone for 14 days showed greater improvement at day 15 across numerous QoL outcomes, compared with their counterparts in the placebo group.

In addition, combined analysis of four zuranolone clinical trials showed “mental well-being and functioning improved to near general population norm levels” for the active-treatment group, reported the researchers, led by Anita H. Clayton, MD, chair and professor of psychiatry, University of Virginia, Charlottesville.

“Based on these integrated analyses, the benefit of treatment with zuranolone may extend beyond reduction in depressive symptoms to include potential improvement in quality of life and overall health, as perceived by patients,” they add.

The findings were presented as part of the Anxiety and Depression Association of America Anxiety & Depression conference.
 

First oral formulation

Zuranolone represents the second entry in the new class of neuroactive steroid drugs, which modulate GABA-A receptor activity – but it would be the first to have an oral formulation. Brexanolone, which was approved by the Food and Drug Administration in 2019 for postpartum depression, is administered through continuous IV infusion over 60 hours.

As previously reported by this news organization, zuranolone improved depressive symptoms as early as day 3, achieving the primary endpoint of significantly greater reduction in scores on the 17-item Hamilton Rating Scale for Depression from baseline to day 15 versus placebo (P = .014).

In the new analysis, patient-reported measures of functional health and well-being were assessed in the WATERFALL trial. It included 266 patients with MDD who were treated with zuranolone 50 mg daily for 2 weeks and 268 patients with MDD who were treated with placebo.

The study used the Short Form–36 (SF-36v2), which covers a wide range of patient-reported measures, including physical function, bodily pain, general health, vitality, social function, and “role-emotional” symptoms.

Results showed that although the treatment and placebo groups had similar baseline SF-36v2 scores, those receiving zuranolone reported significantly greater improvements at day 15 in almost all of the assessment’s domains, including physical function (treatment difference, 0.8), general health (1.0), vitality (3.1), social functioning (1.1), and role-emotional symptoms (1.5; for all comparisons, P < .05). The only exceptions were in role-physical symptoms and bodily pain.

In measures that included physical function, bodily pain, and general health, the patients achieved improvements at day 15 that were consistent with normal levels, with the improvement in vitality considered clinically meaningful versus placebo.

Integrated data

In further analysis of integrated data from four zuranolone clinical trials in the NEST and LANDSCAPE programs for patients with MDD and postpartum depression, results showed similar improvements at day 15 for zuranolone in QoL and overall health across all of the SF-36v2 functioning and well-being domains (P <.05), with the exceptions of physical measure and bodily pain.

By day 42, all of the domains showed significantly greater improvement with zuranolone versus placebo (all, P <.05).

Among the strongest score improvements in the integrated trials were measures in social functioning, which improved from baseline scores of 29.66 to 42.82 on day 15 and to 43.59 on day 42.

Emotional domain scores improved from 24.43 at baseline to 39.13 on day 15 and to 39.82 on day 42. For mental health, the integrated scores for the zuranolone group improved from 27.13 at baseline to 42.40 on day 15 and 42.62 on day 42.

Of note, the baseline scores for mental health represented just 54.3% of those in the normal population; with the increase at day 15, the level was 84.8% of the normal population.

“Across four completed placebo-controlled NEST and LANDSCAPE clinical trials, patient reports of functional health and well-being as assessed by the SF-36v2 indicated substantial impairment at baseline compared to the population norm,” the researchers reported.

The improvements are especially important in light of the fact that in some patients with MDD, functional improvement is a top priority.

“Patients have often prioritized returning to their usual level of functioning over reduction in depressive symptoms, and functional recovery has been associated with better prognosis of depression,” the investigators wrote.

Zuranolone trials have shown that treatment-emergent adverse events (AEs) occur among about 60% of patients, versus about 44% with placebo. The most common AEs are somnolence, dizziness, headache, sedation, and diarrhea, with no increases in suicidal ideation or withdrawal.

The rates of severe AEs are low, and they are observed in about 3% of patients, versus 1.1% with placebo, the researchers noted.

Further, as opposed to serotonergic antidepressants such as SNRIs and SSRIs, zuranolone does not appear to have the undesirable side effects of decreased libido and sexual dysfunction, they added.
 

Clinically meaningful?

Andrew J. Cutler, MD, clinical associate professor of psychiatry at State University of New York, Syracuse, said the data are “very significant” for a number of reasons.

“We need more options to treat depression, especially ones with novel mechanisms of action and faster onset of efficacy, such as zuranolone,” said Dr. Cutler, who was not involved in the current study. He has coauthored other studies on zuranolone.

Regarding the study’s QoL outcomes, “while improvement in depressive symptoms is very important, what really matters to patients is improvement in function and quality of life,” Dr. Cutler noted.

Also commenting on the study, Jonathan E. Alpert, MD, PhD, chair of the department of psychiatry and behavioral sciences and professor of psychiatry, neuroscience, and pediatrics at Albert Einstein College of Medicine, New York, said the investigational drug could represent an important addition to the armamentarium for treating depression.

“Zuranolone has good oral bioavailability and would represent the first neuroactive steroid antidepressant available in oral form and, indeed, the first non–monoamine-based antidepressant available in oral form,” he said in an interview.

Courtesy Dr. Jonathan E. Alpert

Dr. Alpert was not involved in the research and has no relationship with the drug’s development.

He noted that although there are modest differences between the patients who received zuranolone and those who received placebo in the trials, “this may have been related to high placebo response rates, which often complicate antidepressant trials.

“Further research is needed to determine whether differences between zuranolone and placebo are clinically meaningful, though the separation between drug and placebo on the primary endpoint, as well as some other measures, such as quality of life measures, is promising,” Dr. Alpert said.

However, he added that comparisons with other active antidepressants in terms of efficacy and tolerability remain to be seen.

“Given the large number of individuals with major depressive disorder who have incomplete response to or do not tolerate monoaminergic antidepressants, the development of agents that leverage novel nonmonoaminergic mechanisms is important,” Dr. Alpert concluded.

The study was funded by Sage Therapeutics and Biogen. Dr. Cutler has been involved in research of zuranolone for Sage Therapeutics. Dr. Alpert has reported no relevant financial relationships.

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

DENVER – An investigational once-daily oral neuroactive steroid is linked to significant improvement in quality of life (QoL) and well-being in patients with major depressive disorder (MDD), new research shows.

In a phase 3 trial that included more than 500 adult patients with MDD, those who received zuranolone for 14 days showed greater improvement at day 15 across numerous QoL outcomes, compared with their counterparts in the placebo group.

In addition, combined analysis of four zuranolone clinical trials showed “mental well-being and functioning improved to near general population norm levels” for the active-treatment group, reported the researchers, led by Anita H. Clayton, MD, chair and professor of psychiatry, University of Virginia, Charlottesville.

“Based on these integrated analyses, the benefit of treatment with zuranolone may extend beyond reduction in depressive symptoms to include potential improvement in quality of life and overall health, as perceived by patients,” they add.

The findings were presented as part of the Anxiety and Depression Association of America Anxiety & Depression conference.
 

First oral formulation

Zuranolone represents the second entry in the new class of neuroactive steroid drugs, which modulate GABA-A receptor activity – but it would be the first to have an oral formulation. Brexanolone, which was approved by the Food and Drug Administration in 2019 for postpartum depression, is administered through continuous IV infusion over 60 hours.

As previously reported by this news organization, zuranolone improved depressive symptoms as early as day 3, achieving the primary endpoint of significantly greater reduction in scores on the 17-item Hamilton Rating Scale for Depression from baseline to day 15 versus placebo (P = .014).

In the new analysis, patient-reported measures of functional health and well-being were assessed in the WATERFALL trial. It included 266 patients with MDD who were treated with zuranolone 50 mg daily for 2 weeks and 268 patients with MDD who were treated with placebo.

The study used the Short Form–36 (SF-36v2), which covers a wide range of patient-reported measures, including physical function, bodily pain, general health, vitality, social function, and “role-emotional” symptoms.

Results showed that although the treatment and placebo groups had similar baseline SF-36v2 scores, those receiving zuranolone reported significantly greater improvements at day 15 in almost all of the assessment’s domains, including physical function (treatment difference, 0.8), general health (1.0), vitality (3.1), social functioning (1.1), and role-emotional symptoms (1.5; for all comparisons, P < .05). The only exceptions were in role-physical symptoms and bodily pain.

In measures that included physical function, bodily pain, and general health, the patients achieved improvements at day 15 that were consistent with normal levels, with the improvement in vitality considered clinically meaningful versus placebo.

Integrated data

In further analysis of integrated data from four zuranolone clinical trials in the NEST and LANDSCAPE programs for patients with MDD and postpartum depression, results showed similar improvements at day 15 for zuranolone in QoL and overall health across all of the SF-36v2 functioning and well-being domains (P <.05), with the exceptions of physical measure and bodily pain.

By day 42, all of the domains showed significantly greater improvement with zuranolone versus placebo (all, P <.05).

Among the strongest score improvements in the integrated trials were measures in social functioning, which improved from baseline scores of 29.66 to 42.82 on day 15 and to 43.59 on day 42.

Emotional domain scores improved from 24.43 at baseline to 39.13 on day 15 and to 39.82 on day 42. For mental health, the integrated scores for the zuranolone group improved from 27.13 at baseline to 42.40 on day 15 and 42.62 on day 42.

Of note, the baseline scores for mental health represented just 54.3% of those in the normal population; with the increase at day 15, the level was 84.8% of the normal population.

“Across four completed placebo-controlled NEST and LANDSCAPE clinical trials, patient reports of functional health and well-being as assessed by the SF-36v2 indicated substantial impairment at baseline compared to the population norm,” the researchers reported.

The improvements are especially important in light of the fact that in some patients with MDD, functional improvement is a top priority.

“Patients have often prioritized returning to their usual level of functioning over reduction in depressive symptoms, and functional recovery has been associated with better prognosis of depression,” the investigators wrote.

Zuranolone trials have shown that treatment-emergent adverse events (AEs) occur among about 60% of patients, versus about 44% with placebo. The most common AEs are somnolence, dizziness, headache, sedation, and diarrhea, with no increases in suicidal ideation or withdrawal.

The rates of severe AEs are low, and they are observed in about 3% of patients, versus 1.1% with placebo, the researchers noted.

Further, as opposed to serotonergic antidepressants such as SNRIs and SSRIs, zuranolone does not appear to have the undesirable side effects of decreased libido and sexual dysfunction, they added.
 

Clinically meaningful?

Andrew J. Cutler, MD, clinical associate professor of psychiatry at State University of New York, Syracuse, said the data are “very significant” for a number of reasons.

“We need more options to treat depression, especially ones with novel mechanisms of action and faster onset of efficacy, such as zuranolone,” said Dr. Cutler, who was not involved in the current study. He has coauthored other studies on zuranolone.

Regarding the study’s QoL outcomes, “while improvement in depressive symptoms is very important, what really matters to patients is improvement in function and quality of life,” Dr. Cutler noted.

Also commenting on the study, Jonathan E. Alpert, MD, PhD, chair of the department of psychiatry and behavioral sciences and professor of psychiatry, neuroscience, and pediatrics at Albert Einstein College of Medicine, New York, said the investigational drug could represent an important addition to the armamentarium for treating depression.

“Zuranolone has good oral bioavailability and would represent the first neuroactive steroid antidepressant available in oral form and, indeed, the first non–monoamine-based antidepressant available in oral form,” he said in an interview.

Courtesy Dr. Jonathan E. Alpert

Dr. Alpert was not involved in the research and has no relationship with the drug’s development.

He noted that although there are modest differences between the patients who received zuranolone and those who received placebo in the trials, “this may have been related to high placebo response rates, which often complicate antidepressant trials.

“Further research is needed to determine whether differences between zuranolone and placebo are clinically meaningful, though the separation between drug and placebo on the primary endpoint, as well as some other measures, such as quality of life measures, is promising,” Dr. Alpert said.

However, he added that comparisons with other active antidepressants in terms of efficacy and tolerability remain to be seen.

“Given the large number of individuals with major depressive disorder who have incomplete response to or do not tolerate monoaminergic antidepressants, the development of agents that leverage novel nonmonoaminergic mechanisms is important,” Dr. Alpert concluded.

The study was funded by Sage Therapeutics and Biogen. Dr. Cutler has been involved in research of zuranolone for Sage Therapeutics. Dr. Alpert has reported no relevant financial relationships.

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