Anxiety Disorders

CHICAGO – One-third of patients with cancer also experience anxiety or depression, and an estimated 70% of the 18 million patients with cancer and cancer survivors in the US experience emotional symptoms, including fear of recurrence.

Despite many having these symptoms, few patients with cancer have access to psycho-oncologic support.

A digital cognitive-behavioral stress management (CBSM) application may help to ease some of the burden, reported Allison Ramiller, MPH, of Blue Note Therapeutics in San Francisco, which developed the app version of the program.

In the randomized controlled RESTORE study, use of the cell phone–based CBSM app was associated with significantly greater reduction in symptoms of anxiety and depression compared with a digital health education control app.

In addition, patients assigned to the CBSM app were twice as likely as control persons to report that their symptoms were “much” or “very much” improved after using the app for 12 weeks, Ms. Ramiller reported at an oral abstract session at the annual meeting of the American Society of Clinical Oncology (ASCO).

However, the investigators did not report baseline characteristics of patients in each of the study arms, which might have helped to clarify the depth of the effects they saw.

The CBSM program was developed by Michael H. Antoni, PhD, and colleagues in the University of Miami Health System. It is based on cognitive-behavioral therapy but also includes stress management and relaxation techniques to help patients cope with cancer-specific stress.

“”It has been clinically validated and shown to benefit patients with cancer,” Ms. Ramiller said. “However, access is a problem,” she said.

“There aren’t enough qualified, trained providers for the need, and patients with cancer encounter barriers to in-person participation, including things like transportation or financial barriers. So to overcome this, we developed a digitized version of CBSM,” she explained.
 

Impressive and elegant

“Everything about [the study] I thought was very impressive, very elegant, very nicely done,” said invited discussant Raymond U. Osarogiagbon, MBBS, FACP, chief scientist at Baptist Memorial Health Care Corp in Memphis, Tenn.

“They showed efficacy, they showed safety – very nice – user friendliness – very good. Certainly they look like they’re trying to address a highly important, unmet need in a very elegant way. Certainly, they pointed out it needs longer follow-up to see sustainability. We need to see will this work in other settings. Will this be cost-effective? You’ve gotta believe it probably will be,” he said.

CBSM has previously been shown to help patients with cancer reduce stress, improve general and cancer-specific quality of life at various stages of treatment, reduce symptom burden, and improve coping skills, Ms. Ramiller said.

To see whether these benefits could be conveyed digitally rather than in face-to-face encounters, Ms. Ramiller and colleagues worked with Dr. Antoni to develop the CBSM app.

Patients using the app received therapeutic content over 10 sessions with audio, video, and interactive tools that mimicked the sessions they would have received during in-person interventions.

They then compared the app against the control educational app in the randomized, decentralized RESTORE study.
 

High-quality control

Ms. Ramiller said that the control app set “a high bar.”

“The control also offered 10 interactive self-guided sessions. Both treatment apps were professionally designed and visually similar in styling, and they were presented as digital therapeutic-specific for cancer patients. And they were also in a match condition, meaning they received the same attention from study staff and cadence of reminders, but importantly, only the intervention app was based on CBSM,” she explained.

A total of 449 patients with cancers of stage I–III who were undergoing active systemic treatment or were planning to undergo such treatment within 6 months were randomly assigned to the CBSM app or the control app.

The CBSM app was superior to the control app for the primary outcome of anxiety reduction over baseline, as measured at 4, 8 and 12 weeks by the Patient-Reported Outcomes Measurement Information System Anxiety Scale (PROMIS-A) (beta = -.03; P = .019).

CBSM was also significantly better than the control app for the secondary endpoints of reducing symptoms of depression, as measured by the PROMIS-D scale (beta = -.02, P = .042), and also at increasing the percentage of patients who reported improvement in anxiety and depression symptoms on the Patient Global Impression of Change instrument (P < .001)

An extension study of the durability of the effects at 3 and 6 months is underway.

The investigators noted that the incremental cost of management of anxiety or depression is greater than $17,000 per patient per year.

“One of the big promises of a digital therapeutic like this is that it could potentially reduce costs,” Ms. Ramiller told the audience, but she acknowledged, “More work is really needed, however, to directly test the potential savings.”

The RESTORE study is funded by Blue Note Therapeutics. Dr. Osarogiagbon owns stock in Gilead, Lilly, and Pfizer, has received honoraria from Biodesix and Medscape, and has a consulting or advisory role for the American Cancer Society AstraZeneca, Genentech/Roche, LUNGevity, National Cancer Institute, and Triptych Health Partners.
 

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

CHICAGO – One-third of patients with cancer also experience anxiety or depression, and an estimated 70% of the 18 million patients with cancer and cancer survivors in the US experience emotional symptoms, including fear of recurrence.

Despite many having these symptoms, few patients with cancer have access to psycho-oncologic support.

A digital cognitive-behavioral stress management (CBSM) application may help to ease some of the burden, reported Allison Ramiller, MPH, of Blue Note Therapeutics in San Francisco, which developed the app version of the program.

In the randomized controlled RESTORE study, use of the cell phone–based CBSM app was associated with significantly greater reduction in symptoms of anxiety and depression compared with a digital health education control app.

In addition, patients assigned to the CBSM app were twice as likely as control persons to report that their symptoms were “much” or “very much” improved after using the app for 12 weeks, Ms. Ramiller reported at an oral abstract session at the annual meeting of the American Society of Clinical Oncology (ASCO).

However, the investigators did not report baseline characteristics of patients in each of the study arms, which might have helped to clarify the depth of the effects they saw.

The CBSM program was developed by Michael H. Antoni, PhD, and colleagues in the University of Miami Health System. It is based on cognitive-behavioral therapy but also includes stress management and relaxation techniques to help patients cope with cancer-specific stress.

“”It has been clinically validated and shown to benefit patients with cancer,” Ms. Ramiller said. “However, access is a problem,” she said.

“There aren’t enough qualified, trained providers for the need, and patients with cancer encounter barriers to in-person participation, including things like transportation or financial barriers. So to overcome this, we developed a digitized version of CBSM,” she explained.
 

Impressive and elegant

“Everything about [the study] I thought was very impressive, very elegant, very nicely done,” said invited discussant Raymond U. Osarogiagbon, MBBS, FACP, chief scientist at Baptist Memorial Health Care Corp in Memphis, Tenn.

“They showed efficacy, they showed safety – very nice – user friendliness – very good. Certainly they look like they’re trying to address a highly important, unmet need in a very elegant way. Certainly, they pointed out it needs longer follow-up to see sustainability. We need to see will this work in other settings. Will this be cost-effective? You’ve gotta believe it probably will be,” he said.

CBSM has previously been shown to help patients with cancer reduce stress, improve general and cancer-specific quality of life at various stages of treatment, reduce symptom burden, and improve coping skills, Ms. Ramiller said.

To see whether these benefits could be conveyed digitally rather than in face-to-face encounters, Ms. Ramiller and colleagues worked with Dr. Antoni to develop the CBSM app.

Patients using the app received therapeutic content over 10 sessions with audio, video, and interactive tools that mimicked the sessions they would have received during in-person interventions.

They then compared the app against the control educational app in the randomized, decentralized RESTORE study.
 

High-quality control

Ms. Ramiller said that the control app set “a high bar.”

“The control also offered 10 interactive self-guided sessions. Both treatment apps were professionally designed and visually similar in styling, and they were presented as digital therapeutic-specific for cancer patients. And they were also in a match condition, meaning they received the same attention from study staff and cadence of reminders, but importantly, only the intervention app was based on CBSM,” she explained.

A total of 449 patients with cancers of stage I–III who were undergoing active systemic treatment or were planning to undergo such treatment within 6 months were randomly assigned to the CBSM app or the control app.

The CBSM app was superior to the control app for the primary outcome of anxiety reduction over baseline, as measured at 4, 8 and 12 weeks by the Patient-Reported Outcomes Measurement Information System Anxiety Scale (PROMIS-A) (beta = -.03; P = .019).

CBSM was also significantly better than the control app for the secondary endpoints of reducing symptoms of depression, as measured by the PROMIS-D scale (beta = -.02, P = .042), and also at increasing the percentage of patients who reported improvement in anxiety and depression symptoms on the Patient Global Impression of Change instrument (P < .001)

An extension study of the durability of the effects at 3 and 6 months is underway.

The investigators noted that the incremental cost of management of anxiety or depression is greater than $17,000 per patient per year.

“One of the big promises of a digital therapeutic like this is that it could potentially reduce costs,” Ms. Ramiller told the audience, but she acknowledged, “More work is really needed, however, to directly test the potential savings.”

The RESTORE study is funded by Blue Note Therapeutics. Dr. Osarogiagbon owns stock in Gilead, Lilly, and Pfizer, has received honoraria from Biodesix and Medscape, and has a consulting or advisory role for the American Cancer Society AstraZeneca, Genentech/Roche, LUNGevity, National Cancer Institute, and Triptych Health Partners.
 

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

CHICAGO – One-third of patients with cancer also experience anxiety or depression, and an estimated 70% of the 18 million patients with cancer and cancer survivors in the US experience emotional symptoms, including fear of recurrence.

Despite many having these symptoms, few patients with cancer have access to psycho-oncologic support.

A digital cognitive-behavioral stress management (CBSM) application may help to ease some of the burden, reported Allison Ramiller, MPH, of Blue Note Therapeutics in San Francisco, which developed the app version of the program.

In the randomized controlled RESTORE study, use of the cell phone–based CBSM app was associated with significantly greater reduction in symptoms of anxiety and depression compared with a digital health education control app.

In addition, patients assigned to the CBSM app were twice as likely as control persons to report that their symptoms were “much” or “very much” improved after using the app for 12 weeks, Ms. Ramiller reported at an oral abstract session at the annual meeting of the American Society of Clinical Oncology (ASCO).

However, the investigators did not report baseline characteristics of patients in each of the study arms, which might have helped to clarify the depth of the effects they saw.

The CBSM program was developed by Michael H. Antoni, PhD, and colleagues in the University of Miami Health System. It is based on cognitive-behavioral therapy but also includes stress management and relaxation techniques to help patients cope with cancer-specific stress.

“”It has been clinically validated and shown to benefit patients with cancer,” Ms. Ramiller said. “However, access is a problem,” she said.

“There aren’t enough qualified, trained providers for the need, and patients with cancer encounter barriers to in-person participation, including things like transportation or financial barriers. So to overcome this, we developed a digitized version of CBSM,” she explained.
 

Impressive and elegant

“Everything about [the study] I thought was very impressive, very elegant, very nicely done,” said invited discussant Raymond U. Osarogiagbon, MBBS, FACP, chief scientist at Baptist Memorial Health Care Corp in Memphis, Tenn.

“They showed efficacy, they showed safety – very nice – user friendliness – very good. Certainly they look like they’re trying to address a highly important, unmet need in a very elegant way. Certainly, they pointed out it needs longer follow-up to see sustainability. We need to see will this work in other settings. Will this be cost-effective? You’ve gotta believe it probably will be,” he said.

CBSM has previously been shown to help patients with cancer reduce stress, improve general and cancer-specific quality of life at various stages of treatment, reduce symptom burden, and improve coping skills, Ms. Ramiller said.

To see whether these benefits could be conveyed digitally rather than in face-to-face encounters, Ms. Ramiller and colleagues worked with Dr. Antoni to develop the CBSM app.

Patients using the app received therapeutic content over 10 sessions with audio, video, and interactive tools that mimicked the sessions they would have received during in-person interventions.

They then compared the app against the control educational app in the randomized, decentralized RESTORE study.
 

High-quality control

Ms. Ramiller said that the control app set “a high bar.”

“The control also offered 10 interactive self-guided sessions. Both treatment apps were professionally designed and visually similar in styling, and they were presented as digital therapeutic-specific for cancer patients. And they were also in a match condition, meaning they received the same attention from study staff and cadence of reminders, but importantly, only the intervention app was based on CBSM,” she explained.

A total of 449 patients with cancers of stage I–III who were undergoing active systemic treatment or were planning to undergo such treatment within 6 months were randomly assigned to the CBSM app or the control app.

The CBSM app was superior to the control app for the primary outcome of anxiety reduction over baseline, as measured at 4, 8 and 12 weeks by the Patient-Reported Outcomes Measurement Information System Anxiety Scale (PROMIS-A) (beta = -.03; P = .019).

CBSM was also significantly better than the control app for the secondary endpoints of reducing symptoms of depression, as measured by the PROMIS-D scale (beta = -.02, P = .042), and also at increasing the percentage of patients who reported improvement in anxiety and depression symptoms on the Patient Global Impression of Change instrument (P < .001)

An extension study of the durability of the effects at 3 and 6 months is underway.

The investigators noted that the incremental cost of management of anxiety or depression is greater than $17,000 per patient per year.

“One of the big promises of a digital therapeutic like this is that it could potentially reduce costs,” Ms. Ramiller told the audience, but she acknowledged, “More work is really needed, however, to directly test the potential savings.”

The RESTORE study is funded by Blue Note Therapeutics. Dr. Osarogiagbon owns stock in Gilead, Lilly, and Pfizer, has received honoraria from Biodesix and Medscape, and has a consulting or advisory role for the American Cancer Society AstraZeneca, Genentech/Roche, LUNGevity, National Cancer Institute, and Triptych Health Partners.
 

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

The U.S. Preventive Services Task Force (USPSTF) has posted final recommendations on screening for anxiety, depression, and suicide risk in adults.

In line with draft recommendations, the task force for the first time has endorsed screening for anxiety disorders in all adults younger than age 65 without recognized signs or symptoms of anxiety.

This “B” recommendation reflects “moderate certainty” evidence that screening for anxiety in this population has a moderate net benefit. There currently is not enough evidence to recommend for or against screening for anxiety disorders in adults 65 and older, the task force said.

The USPSTF final recommendation statements and corresponding evidence summaries were published online in the Journal of the American Medical Association, as well as on the task force website.
 

Jury out on screening for suicide risk

The task force continues to recommend screening all adults for depression. This “B” recommendation reflects moderate-certainty evidence that screening for major depression in adults has a moderate net benefit.

However, there is not enough evidence to recommend for or against screening for suicide risk in all adults. Therefore, the task issued an “I” statement, indicating that the balance of benefits and harms cannot be determined at present.

“We are urgently calling for more research to determine the effectiveness of screening all adults for suicide risk and screening adults 65 and older for anxiety disorders,” task force member Gbenga Ogedegbe, MD, MPH, founding director of the Institute for Excellence in Health Equity at NYU Langone Health, New York, said in a statement.

The authors of an accompanying editorial noted that a positive screen result for anxiety “should be immediately followed with clinical evaluation for suicidality”.

Murray Stein, MD, MPH, and Linda Hill, MD, MPH, both with University of California, San Diego, also noted that a positive screen for anxiety could be indicative of posttraumatic stress disorder (PTSD) and clinicians should “be prepared to follow up with requisite questions about traumatic experiences that will be needed to home in on a diagnosis of PTSD that may require additional follow-up, referral, or both.

“Anxiety disorders can be distressing and disabling, and appropriate recognition and treatment can be life-altering and, in some cases, lifesaving, for patients,” Dr. Stein and Dr. Hill pointed out.

Effective, evidence-based psychological and pharmacologic treatments for anxiety disorders are available, they added. But the recommendation to routinely screen for anxiety disorder “must be accompanied by the recognition that there are too few mental health specialists available to manage the care of all patients with anxiety disorders, and even fewer who provide services for low-income and non-English-speaking populations,” they wrote.

This research report received no commercial funding. Disclosures for task force members and editorial writers are listed with the original articles.
 

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

The U.S. Preventive Services Task Force (USPSTF) has posted final recommendations on screening for anxiety, depression, and suicide risk in adults.

In line with draft recommendations, the task force for the first time has endorsed screening for anxiety disorders in all adults younger than age 65 without recognized signs or symptoms of anxiety.

This “B” recommendation reflects “moderate certainty” evidence that screening for anxiety in this population has a moderate net benefit. There currently is not enough evidence to recommend for or against screening for anxiety disorders in adults 65 and older, the task force said.

The USPSTF final recommendation statements and corresponding evidence summaries were published online in the Journal of the American Medical Association, as well as on the task force website.
 

Jury out on screening for suicide risk

The task force continues to recommend screening all adults for depression. This “B” recommendation reflects moderate-certainty evidence that screening for major depression in adults has a moderate net benefit.

However, there is not enough evidence to recommend for or against screening for suicide risk in all adults. Therefore, the task issued an “I” statement, indicating that the balance of benefits and harms cannot be determined at present.

“We are urgently calling for more research to determine the effectiveness of screening all adults for suicide risk and screening adults 65 and older for anxiety disorders,” task force member Gbenga Ogedegbe, MD, MPH, founding director of the Institute for Excellence in Health Equity at NYU Langone Health, New York, said in a statement.

The authors of an accompanying editorial noted that a positive screen result for anxiety “should be immediately followed with clinical evaluation for suicidality”.

Murray Stein, MD, MPH, and Linda Hill, MD, MPH, both with University of California, San Diego, also noted that a positive screen for anxiety could be indicative of posttraumatic stress disorder (PTSD) and clinicians should “be prepared to follow up with requisite questions about traumatic experiences that will be needed to home in on a diagnosis of PTSD that may require additional follow-up, referral, or both.

“Anxiety disorders can be distressing and disabling, and appropriate recognition and treatment can be life-altering and, in some cases, lifesaving, for patients,” Dr. Stein and Dr. Hill pointed out.

Effective, evidence-based psychological and pharmacologic treatments for anxiety disorders are available, they added. But the recommendation to routinely screen for anxiety disorder “must be accompanied by the recognition that there are too few mental health specialists available to manage the care of all patients with anxiety disorders, and even fewer who provide services for low-income and non-English-speaking populations,” they wrote.

This research report received no commercial funding. Disclosures for task force members and editorial writers are listed with the original articles.
 

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

The U.S. Preventive Services Task Force (USPSTF) has posted final recommendations on screening for anxiety, depression, and suicide risk in adults.

In line with draft recommendations, the task force for the first time has endorsed screening for anxiety disorders in all adults younger than age 65 without recognized signs or symptoms of anxiety.

This “B” recommendation reflects “moderate certainty” evidence that screening for anxiety in this population has a moderate net benefit. There currently is not enough evidence to recommend for or against screening for anxiety disorders in adults 65 and older, the task force said.

The USPSTF final recommendation statements and corresponding evidence summaries were published online in the Journal of the American Medical Association, as well as on the task force website.
 

Jury out on screening for suicide risk

The task force continues to recommend screening all adults for depression. This “B” recommendation reflects moderate-certainty evidence that screening for major depression in adults has a moderate net benefit.

However, there is not enough evidence to recommend for or against screening for suicide risk in all adults. Therefore, the task issued an “I” statement, indicating that the balance of benefits and harms cannot be determined at present.

“We are urgently calling for more research to determine the effectiveness of screening all adults for suicide risk and screening adults 65 and older for anxiety disorders,” task force member Gbenga Ogedegbe, MD, MPH, founding director of the Institute for Excellence in Health Equity at NYU Langone Health, New York, said in a statement.

The authors of an accompanying editorial noted that a positive screen result for anxiety “should be immediately followed with clinical evaluation for suicidality”.

Murray Stein, MD, MPH, and Linda Hill, MD, MPH, both with University of California, San Diego, also noted that a positive screen for anxiety could be indicative of posttraumatic stress disorder (PTSD) and clinicians should “be prepared to follow up with requisite questions about traumatic experiences that will be needed to home in on a diagnosis of PTSD that may require additional follow-up, referral, or both.

“Anxiety disorders can be distressing and disabling, and appropriate recognition and treatment can be life-altering and, in some cases, lifesaving, for patients,” Dr. Stein and Dr. Hill pointed out.

Effective, evidence-based psychological and pharmacologic treatments for anxiety disorders are available, they added. But the recommendation to routinely screen for anxiety disorder “must be accompanied by the recognition that there are too few mental health specialists available to manage the care of all patients with anxiety disorders, and even fewer who provide services for low-income and non-English-speaking populations,” they wrote.

This research report received no commercial funding. Disclosures for task force members and editorial writers are listed with the original articles.
 

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

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

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

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

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

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

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

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

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

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

Build a network

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

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

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

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

Screen for depression and anxiety

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

To save time, he suggested a cascading approach.

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

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

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

Use other screening tools only as needed

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

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

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

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

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

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

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

Leverage online resources

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

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

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

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

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

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

Consider virtual support

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

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

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

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

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

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

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

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

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

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

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

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

Keep learning

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

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

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

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

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

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

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

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

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

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

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

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

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

The interviewees disclosed no conflicts of interest.

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

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

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

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

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

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

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

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

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

Build a network

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

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

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

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

Screen for depression and anxiety

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

To save time, he suggested a cascading approach.

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

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

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

Use other screening tools only as needed

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

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

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

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

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

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

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

Leverage online resources

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

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

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

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

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

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

Consider virtual support

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

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

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

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

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

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

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

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

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

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

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

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

Keep learning

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

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

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

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

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

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

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

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

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

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

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

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

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

The interviewees disclosed no conflicts of interest.

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

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

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

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

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

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

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

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

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

Build a network

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

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

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

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

Screen for depression and anxiety

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

To save time, he suggested a cascading approach.

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

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

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

Use other screening tools only as needed

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

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

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

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

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

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

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

Leverage online resources

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

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

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

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

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

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

Consider virtual support

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

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

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

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

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

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

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

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

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

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

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

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

Keep learning

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

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

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

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

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

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

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

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

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

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

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

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

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

The interviewees disclosed no conflicts of interest.

When used as an adjunctive treatment, probiotic supplements reduce symptoms in patients with major depression, results of a randomized, placebo-controlled trial suggest.
 

By the end of the 8-week pilot study, participants who had an incomplete response to antidepressants prior to taking probiotics scored better on measures of anxiety and depression versus placebo.

“This was a pilot study, designed as an initial exploration of whether improving gut health with probiotics could act as a new pathway for supporting mood and mental health,” study investigator Viktoriya Nikolova, PhD, Institute of Psychiatry, Psychology and Neuroscience at King’s College London, said in an interview.

“While very promising and exciting, our findings are only the first step, and larger trials are needed,” she noted.

The findings were published online in JAMA Psychiatry.
 

Gut-brain axis

It is estimated that up to 60% of people taking antidepressants for major depressive disorder (MDD) do not achieve full response.

With an eye on the so-called gut-brain axis as a treatment target for depression, the researchers conducted a meta-analysis of seven randomized controlled trials (RCT) in 2021 and found that probiotics appeared effective in reducing depressive symptoms when taken alongside antidepressants. The studies in this meta-analysis either reported poor adherence rates or did not investigate how well study participants tolerated probiotics.

To further investigate, Dr. Nikolova and team launched a pilot RCT by recruiting study participants from primary and secondary health care services, and  through general advertising in London. Data were collected from September 2019 to May 2022.

They included 49 adults diagnosed with MDD with an incomplete antidepressant response, indicated by a score of greater than 13 on the Hamilton Depression Rating Scale-17 (HAMD-17).

Half of the participants were randomly assigned to receive a widely available, proprietary, 14-strain blend probiotic supplement, and half received placebo. Both groups took their study drug four times per day during the 8-week trial.

At baseline, 4 weeks, and 8 weeks, investigators assessed the participants for depression with the HAMD-17, the Inventory of Depressive Symptomatology (IDS) Self-Report, and anxiety with the Hamilton Anxiety Rating Scale (HAMA).

The majority of participants (80%) were female with a mean age of 32 years. Adherence was high, with 97% of the doses taken as required, and no adverse events were reported.

Standardized effect sizes from linear mixed models demonstrated that, when compared with the placebo group, the probiotic group had more improvement in depressive symptoms according to the HAMD-17 (week 4: SES, 0.70; 95% confidence interval, 0.01-0.98) and IDS Self Report (week 8: SES, 0.64; 95% CI, 0.03-0.87).

When compared with the placebo group, the probiotic group also experienced greater improvements in anxiety symptoms according to the HAMA (week 4: SES, 0.67; 95% CI, 0-0.95; week 8: SES, 0.79; 95% CI, 0.06-1.05).

Dr. Nikolova said a large follow-up trial is planned to further confirm the results.

Nutritional psychiatrist Drew Ramsey, MD, author of Eat to Beat Depression and Anxiety and assistant clinical professor of psychiatry at Columbia University, New York, said in an interview: “This randomized clinical trial adds to the considerable evidence that food choices impact depression outcomes.”

He further noted that, “in nutritional psychiatry, we recommend eating fermented foods as they have been shown to improve microbiome diversity and decrease markers of inflammation.”

Dr. Ramsey noted that the RCT used the equivalent colony-forming unit of a “single serving of kombucha.”

“In our clinical group and our nutritional psychiatry course for clinicians, we recommend fermented foods over probiotics as this is the most sustainable, evidence-based way to improve microbiome diversity,” said Dr. Ramsey, citing recent research by Gardner and colleagues at Stanford (Calif.) University.

“This is an industry-funded trial that adds to the evidence base but should be interpreted by patients and clinicians as promoting consumption of more kefir, kimchi, and kombucha, not that patients should take probiotics,” he said.
 

A key place for probiotics in mental health

Commenting on the study, Uma Naidoo, MD, said: “As I shared throughout my first book, This is Your Brain on Food, there is a real place for the use of probiotics in mental health, including the importance of the gut-brain connection.”

Dr. Naidoo is the director of nutritional and metabolic psychiatry at Massachusetts General Hospital and of nutritional psychiatry at the MGH Academy, both in Boston.

She noted that, when a person stops using a probiotic after trying it out, the positive changes in the gut are reversed, so “remaining consistent in taking the probiotic is important if you have found it helpful for your mood.”

Dr. Naidoo added that “each person’s gut microbiome is so unique that it is likely not every human being will have the same reaction to a probiotic.”

“Eating foods with live probiotics may also benefit gut health and, therefore, mood,” she said. The same goes with eating fermented foods with live active cultures.”

The study was funded by a Medical Research Council Industrial CASE PhD Studentship with ADM Protexin (supplier of the probiotics) as the industry partner and additional support from Freya Green. Dr. Nikolova has received grants from the Medical Research Council and ADM Protexin during the conduct of the study as well as personal fees from Janssen outside the submitted work.

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

When used as an adjunctive treatment, probiotic supplements reduce symptoms in patients with major depression, results of a randomized, placebo-controlled trial suggest.
 

By the end of the 8-week pilot study, participants who had an incomplete response to antidepressants prior to taking probiotics scored better on measures of anxiety and depression versus placebo.

“This was a pilot study, designed as an initial exploration of whether improving gut health with probiotics could act as a new pathway for supporting mood and mental health,” study investigator Viktoriya Nikolova, PhD, Institute of Psychiatry, Psychology and Neuroscience at King’s College London, said in an interview.

“While very promising and exciting, our findings are only the first step, and larger trials are needed,” she noted.

The findings were published online in JAMA Psychiatry.
 

Gut-brain axis

It is estimated that up to 60% of people taking antidepressants for major depressive disorder (MDD) do not achieve full response.

With an eye on the so-called gut-brain axis as a treatment target for depression, the researchers conducted a meta-analysis of seven randomized controlled trials (RCT) in 2021 and found that probiotics appeared effective in reducing depressive symptoms when taken alongside antidepressants. The studies in this meta-analysis either reported poor adherence rates or did not investigate how well study participants tolerated probiotics.

To further investigate, Dr. Nikolova and team launched a pilot RCT by recruiting study participants from primary and secondary health care services, and  through general advertising in London. Data were collected from September 2019 to May 2022.

They included 49 adults diagnosed with MDD with an incomplete antidepressant response, indicated by a score of greater than 13 on the Hamilton Depression Rating Scale-17 (HAMD-17).

Half of the participants were randomly assigned to receive a widely available, proprietary, 14-strain blend probiotic supplement, and half received placebo. Both groups took their study drug four times per day during the 8-week trial.

At baseline, 4 weeks, and 8 weeks, investigators assessed the participants for depression with the HAMD-17, the Inventory of Depressive Symptomatology (IDS) Self-Report, and anxiety with the Hamilton Anxiety Rating Scale (HAMA).

The majority of participants (80%) were female with a mean age of 32 years. Adherence was high, with 97% of the doses taken as required, and no adverse events were reported.

Standardized effect sizes from linear mixed models demonstrated that, when compared with the placebo group, the probiotic group had more improvement in depressive symptoms according to the HAMD-17 (week 4: SES, 0.70; 95% confidence interval, 0.01-0.98) and IDS Self Report (week 8: SES, 0.64; 95% CI, 0.03-0.87).

When compared with the placebo group, the probiotic group also experienced greater improvements in anxiety symptoms according to the HAMA (week 4: SES, 0.67; 95% CI, 0-0.95; week 8: SES, 0.79; 95% CI, 0.06-1.05).

Dr. Nikolova said a large follow-up trial is planned to further confirm the results.

Nutritional psychiatrist Drew Ramsey, MD, author of Eat to Beat Depression and Anxiety and assistant clinical professor of psychiatry at Columbia University, New York, said in an interview: “This randomized clinical trial adds to the considerable evidence that food choices impact depression outcomes.”

He further noted that, “in nutritional psychiatry, we recommend eating fermented foods as they have been shown to improve microbiome diversity and decrease markers of inflammation.”

Dr. Ramsey noted that the RCT used the equivalent colony-forming unit of a “single serving of kombucha.”

“In our clinical group and our nutritional psychiatry course for clinicians, we recommend fermented foods over probiotics as this is the most sustainable, evidence-based way to improve microbiome diversity,” said Dr. Ramsey, citing recent research by Gardner and colleagues at Stanford (Calif.) University.

“This is an industry-funded trial that adds to the evidence base but should be interpreted by patients and clinicians as promoting consumption of more kefir, kimchi, and kombucha, not that patients should take probiotics,” he said.
 

A key place for probiotics in mental health

Commenting on the study, Uma Naidoo, MD, said: “As I shared throughout my first book, This is Your Brain on Food, there is a real place for the use of probiotics in mental health, including the importance of the gut-brain connection.”

Dr. Naidoo is the director of nutritional and metabolic psychiatry at Massachusetts General Hospital and of nutritional psychiatry at the MGH Academy, both in Boston.

She noted that, when a person stops using a probiotic after trying it out, the positive changes in the gut are reversed, so “remaining consistent in taking the probiotic is important if you have found it helpful for your mood.”

Dr. Naidoo added that “each person’s gut microbiome is so unique that it is likely not every human being will have the same reaction to a probiotic.”

“Eating foods with live probiotics may also benefit gut health and, therefore, mood,” she said. The same goes with eating fermented foods with live active cultures.”

The study was funded by a Medical Research Council Industrial CASE PhD Studentship with ADM Protexin (supplier of the probiotics) as the industry partner and additional support from Freya Green. Dr. Nikolova has received grants from the Medical Research Council and ADM Protexin during the conduct of the study as well as personal fees from Janssen outside the submitted work.

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

When used as an adjunctive treatment, probiotic supplements reduce symptoms in patients with major depression, results of a randomized, placebo-controlled trial suggest.
 

By the end of the 8-week pilot study, participants who had an incomplete response to antidepressants prior to taking probiotics scored better on measures of anxiety and depression versus placebo.

“This was a pilot study, designed as an initial exploration of whether improving gut health with probiotics could act as a new pathway for supporting mood and mental health,” study investigator Viktoriya Nikolova, PhD, Institute of Psychiatry, Psychology and Neuroscience at King’s College London, said in an interview.

“While very promising and exciting, our findings are only the first step, and larger trials are needed,” she noted.

The findings were published online in JAMA Psychiatry.
 

Gut-brain axis

It is estimated that up to 60% of people taking antidepressants for major depressive disorder (MDD) do not achieve full response.

With an eye on the so-called gut-brain axis as a treatment target for depression, the researchers conducted a meta-analysis of seven randomized controlled trials (RCT) in 2021 and found that probiotics appeared effective in reducing depressive symptoms when taken alongside antidepressants. The studies in this meta-analysis either reported poor adherence rates or did not investigate how well study participants tolerated probiotics.

To further investigate, Dr. Nikolova and team launched a pilot RCT by recruiting study participants from primary and secondary health care services, and  through general advertising in London. Data were collected from September 2019 to May 2022.

They included 49 adults diagnosed with MDD with an incomplete antidepressant response, indicated by a score of greater than 13 on the Hamilton Depression Rating Scale-17 (HAMD-17).

Half of the participants were randomly assigned to receive a widely available, proprietary, 14-strain blend probiotic supplement, and half received placebo. Both groups took their study drug four times per day during the 8-week trial.

At baseline, 4 weeks, and 8 weeks, investigators assessed the participants for depression with the HAMD-17, the Inventory of Depressive Symptomatology (IDS) Self-Report, and anxiety with the Hamilton Anxiety Rating Scale (HAMA).

The majority of participants (80%) were female with a mean age of 32 years. Adherence was high, with 97% of the doses taken as required, and no adverse events were reported.

Standardized effect sizes from linear mixed models demonstrated that, when compared with the placebo group, the probiotic group had more improvement in depressive symptoms according to the HAMD-17 (week 4: SES, 0.70; 95% confidence interval, 0.01-0.98) and IDS Self Report (week 8: SES, 0.64; 95% CI, 0.03-0.87).

When compared with the placebo group, the probiotic group also experienced greater improvements in anxiety symptoms according to the HAMA (week 4: SES, 0.67; 95% CI, 0-0.95; week 8: SES, 0.79; 95% CI, 0.06-1.05).

Dr. Nikolova said a large follow-up trial is planned to further confirm the results.

Nutritional psychiatrist Drew Ramsey, MD, author of Eat to Beat Depression and Anxiety and assistant clinical professor of psychiatry at Columbia University, New York, said in an interview: “This randomized clinical trial adds to the considerable evidence that food choices impact depression outcomes.”

He further noted that, “in nutritional psychiatry, we recommend eating fermented foods as they have been shown to improve microbiome diversity and decrease markers of inflammation.”

Dr. Ramsey noted that the RCT used the equivalent colony-forming unit of a “single serving of kombucha.”

“In our clinical group and our nutritional psychiatry course for clinicians, we recommend fermented foods over probiotics as this is the most sustainable, evidence-based way to improve microbiome diversity,” said Dr. Ramsey, citing recent research by Gardner and colleagues at Stanford (Calif.) University.

“This is an industry-funded trial that adds to the evidence base but should be interpreted by patients and clinicians as promoting consumption of more kefir, kimchi, and kombucha, not that patients should take probiotics,” he said.
 

A key place for probiotics in mental health

Commenting on the study, Uma Naidoo, MD, said: “As I shared throughout my first book, This is Your Brain on Food, there is a real place for the use of probiotics in mental health, including the importance of the gut-brain connection.”

Dr. Naidoo is the director of nutritional and metabolic psychiatry at Massachusetts General Hospital and of nutritional psychiatry at the MGH Academy, both in Boston.

She noted that, when a person stops using a probiotic after trying it out, the positive changes in the gut are reversed, so “remaining consistent in taking the probiotic is important if you have found it helpful for your mood.”

Dr. Naidoo added that “each person’s gut microbiome is so unique that it is likely not every human being will have the same reaction to a probiotic.”

“Eating foods with live probiotics may also benefit gut health and, therefore, mood,” she said. The same goes with eating fermented foods with live active cultures.”

The study was funded by a Medical Research Council Industrial CASE PhD Studentship with ADM Protexin (supplier of the probiotics) as the industry partner and additional support from Freya Green. Dr. Nikolova has received grants from the Medical Research Council and ADM Protexin during the conduct of the study as well as personal fees from Janssen outside the submitted work.

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

Not everyone will suffer an episode of posttraumatic stress disorder, even though everyday American life is characterized by a lot of uncertainty these days, particularly considering the proliferation of gun violence.

Robert T. London

Also, everyone who does experience a traumatic event will not suffer an episode of PTSD – just as not everyone develops a heart attack or cancer, nor will everyone get every illness.

The data suggest that of those exposed to trauma, up to 25% of people will develop PTSD, according to Massachusetts General/McLean Hospital, Belmont, psychiatrist Kerry J. Ressler, MD, PhD, chief of the division of depression and anxiety disorders.

As I wrote in December 2022, our “kids” are not all right and psychiatry can help. I would say that many adolescents, and adults as well, may not be all right as we are terrorized not only by mass school shootings, but shootings happening almost anywhere and everywhere in our country: in supermarkets, hospitals, and shopping malls, at graduation parties, and on the streets.

According to a report published in Clinical Psychiatry News, a poll conducted by the American Psychiatric Association showed that most American adults [70%] reported that they were anxious or extremely anxious about keeping themselves or their families safe. APA President Rebecca W. Brendel, MD, JD, pointed out that there is “a lot of worry out there about economic uncertainty, about violence and how we are going to come out of this time period.”

Meanwhile, PTSD is still defined in the DSM-5 as exposure to actual or threatened death, serious injury, or sexual violence experienced directly, witnessing the traumatic event as it occurs to others, learning that a traumatic event occurred to a close family member or friend, or experiencing of traumatic events plus extreme exposure to aversive details of the event.

Examples of traumatic events can be numerous. They include natural disasters, man-made disasters, various types of assaults, war trauma, and severe illness with ICU experiences. I would add encounters with racism and bigotry – including homophobia when one fears for their very life or physical injury. This list includes only a few triggers that may invoke this disorder.

Interestingly, the DSM-5 excludes aversive exposure through electronic media, television, movies, or pictures. Including these aspects of trauma exposure would indeed increase PTSD diagnoses, and I believe this type of exposure needs to be included, especially considering how different people process information. Some viewers of media remain “outside” the events depicted on television, movies, or electronic media while others fit directly “into” the film or TV show. Even, for example, a news program, as evidenced by those people suffering from PTSD after viewing the Sept. 11, 2001, disaster on TV.

I have interviewed numerous people who witnessed Sept. 11 tragedies on TV, some during and some after the event, and they genuinely had experienced key factors of PTSD, including nightmares and intrusive recollections of the event. It’s important to include the ways in which people process information and events in order to make a correct diagnosis, in that “one [diagnostic] size does not fit all.”
 

PTSD at school

In my December column, I noted the fear of death that my generation and beyond experienced with the endless threat of nuclear war, which by its very nature meant death, and if not, the saying went “the living would envy the dead” – that is, in post–nuclear war.

As I pointed out in the column, that war never came and hopefully never will, yet the intensity of those many decades of threatened terror with regular school exercises of “hide under the desk” and “don’t look at the flash” left some with intrusive fearful thoughts, nightmares, and even visualization of atomic destruction, as well as the many scenes of destruction portrayed in news casts and films of nuclear explosions.

Clearly, most U.S. school children who participate in school lockdown drills will not suffer from PTSD episodes, but some will. If that “some” approaches 20% or even 10% or less, that will amount to a lot of kids.

I decided to interview two of my grandchildren, each living in different communities and attending different school systems, but both experiencing “lockdown drills.”

Jack, who is 13 and going into eighth grade, was quite clear regarding the drills and reported that in his age group, both he and the kids in his class felt scared while in lockdown. He told me some kids looked nervous. He mentioned that they were taught in school that if the “real thing” happened, the message was “hide, run, and fight.” I was curious and asked why not run first. He was quick to answer and said if you run, you might run into danger, so it’s better to hide and wait for help to arrive. I said to myself, if not PTSD, then being scared or nervous may also lead to anxiety or even to an anxiety disorder.

Next, I interviewed almost 11-year-old Charley, who is going into sixth grade. She was very clear about not at all being fearful or nervous during these drills and was confident that her classmates felt the same way. Then she explained that the school did a great job with a security officer and had locked doors all around that only opened from the inside. She was proud of the school and not fearful or worried at all.

The diverse views of these two young people surprised me but confirm that PTSD is not at all a given based on what is occurring in society. However, it should always be considered by clinicians if a child or adolescent begins to show signs consistent with PTSD.

These two interviews were quite short, but after I finished talking with Charley, she reported spontaneously that while she and her classmates were neither worried nor scared, some of their teachers did look nervous and seemed scared.

I was quite impressed with her sharpness and nuanced observation, and as noted, adults as well may be adversely affected by the entire concept of school lockdowns, as the awareness of their purpose rests in the forefront of their minds.
 

The way forward

So how do we prepare kids and adolescents for potential emotional problems like PTSD arising from lockdowns, even though most children or adults will not suffer any of these PTSD issues?

First, I believe that as we develop and teach health education in schools, mental health issues should be included according to grade level without generating fear or worry. Second, it is important that school children be aware that if they feel bad in any way emotionally, they should speak to their parents, guardians, teachers, or school nurses.

Clearly, communicating simple problems without embarrassment or shame can lead to solutions, often quickly. Larger, more complicated issues may need professional intervention. Equally important, many mental health interventions need not be long in duration but client-centered, focused, and short term.

But what needs to be emphasized is that speaking and addressing what’s going on, if your thoughts and emotions are troubling, are in themselves therapeutic. Talk therapy works – especially if you get a new perspective on the old set of problems.

Dr. London is a practicing psychiatrist and has been a newspaper columnist for 35 years, specializing in and writing about short-term therapy, including cognitive-behavioral therapy and guided imagery. He is author of “Find Freedom Fast” (New York: Kettlehole Publishing, 2019). He has no conflicts of interest.

Not everyone will suffer an episode of posttraumatic stress disorder, even though everyday American life is characterized by a lot of uncertainty these days, particularly considering the proliferation of gun violence.

Robert T. London

Also, everyone who does experience a traumatic event will not suffer an episode of PTSD – just as not everyone develops a heart attack or cancer, nor will everyone get every illness.

The data suggest that of those exposed to trauma, up to 25% of people will develop PTSD, according to Massachusetts General/McLean Hospital, Belmont, psychiatrist Kerry J. Ressler, MD, PhD, chief of the division of depression and anxiety disorders.

As I wrote in December 2022, our “kids” are not all right and psychiatry can help. I would say that many adolescents, and adults as well, may not be all right as we are terrorized not only by mass school shootings, but shootings happening almost anywhere and everywhere in our country: in supermarkets, hospitals, and shopping malls, at graduation parties, and on the streets.

According to a report published in Clinical Psychiatry News, a poll conducted by the American Psychiatric Association showed that most American adults [70%] reported that they were anxious or extremely anxious about keeping themselves or their families safe. APA President Rebecca W. Brendel, MD, JD, pointed out that there is “a lot of worry out there about economic uncertainty, about violence and how we are going to come out of this time period.”

Meanwhile, PTSD is still defined in the DSM-5 as exposure to actual or threatened death, serious injury, or sexual violence experienced directly, witnessing the traumatic event as it occurs to others, learning that a traumatic event occurred to a close family member or friend, or experiencing of traumatic events plus extreme exposure to aversive details of the event.

Examples of traumatic events can be numerous. They include natural disasters, man-made disasters, various types of assaults, war trauma, and severe illness with ICU experiences. I would add encounters with racism and bigotry – including homophobia when one fears for their very life or physical injury. This list includes only a few triggers that may invoke this disorder.

Interestingly, the DSM-5 excludes aversive exposure through electronic media, television, movies, or pictures. Including these aspects of trauma exposure would indeed increase PTSD diagnoses, and I believe this type of exposure needs to be included, especially considering how different people process information. Some viewers of media remain “outside” the events depicted on television, movies, or electronic media while others fit directly “into” the film or TV show. Even, for example, a news program, as evidenced by those people suffering from PTSD after viewing the Sept. 11, 2001, disaster on TV.

I have interviewed numerous people who witnessed Sept. 11 tragedies on TV, some during and some after the event, and they genuinely had experienced key factors of PTSD, including nightmares and intrusive recollections of the event. It’s important to include the ways in which people process information and events in order to make a correct diagnosis, in that “one [diagnostic] size does not fit all.”
 

PTSD at school

In my December column, I noted the fear of death that my generation and beyond experienced with the endless threat of nuclear war, which by its very nature meant death, and if not, the saying went “the living would envy the dead” – that is, in post–nuclear war.

As I pointed out in the column, that war never came and hopefully never will, yet the intensity of those many decades of threatened terror with regular school exercises of “hide under the desk” and “don’t look at the flash” left some with intrusive fearful thoughts, nightmares, and even visualization of atomic destruction, as well as the many scenes of destruction portrayed in news casts and films of nuclear explosions.

Clearly, most U.S. school children who participate in school lockdown drills will not suffer from PTSD episodes, but some will. If that “some” approaches 20% or even 10% or less, that will amount to a lot of kids.

I decided to interview two of my grandchildren, each living in different communities and attending different school systems, but both experiencing “lockdown drills.”

Jack, who is 13 and going into eighth grade, was quite clear regarding the drills and reported that in his age group, both he and the kids in his class felt scared while in lockdown. He told me some kids looked nervous. He mentioned that they were taught in school that if the “real thing” happened, the message was “hide, run, and fight.” I was curious and asked why not run first. He was quick to answer and said if you run, you might run into danger, so it’s better to hide and wait for help to arrive. I said to myself, if not PTSD, then being scared or nervous may also lead to anxiety or even to an anxiety disorder.

Next, I interviewed almost 11-year-old Charley, who is going into sixth grade. She was very clear about not at all being fearful or nervous during these drills and was confident that her classmates felt the same way. Then she explained that the school did a great job with a security officer and had locked doors all around that only opened from the inside. She was proud of the school and not fearful or worried at all.

The diverse views of these two young people surprised me but confirm that PTSD is not at all a given based on what is occurring in society. However, it should always be considered by clinicians if a child or adolescent begins to show signs consistent with PTSD.

These two interviews were quite short, but after I finished talking with Charley, she reported spontaneously that while she and her classmates were neither worried nor scared, some of their teachers did look nervous and seemed scared.

I was quite impressed with her sharpness and nuanced observation, and as noted, adults as well may be adversely affected by the entire concept of school lockdowns, as the awareness of their purpose rests in the forefront of their minds.
 

The way forward

So how do we prepare kids and adolescents for potential emotional problems like PTSD arising from lockdowns, even though most children or adults will not suffer any of these PTSD issues?

First, I believe that as we develop and teach health education in schools, mental health issues should be included according to grade level without generating fear or worry. Second, it is important that school children be aware that if they feel bad in any way emotionally, they should speak to their parents, guardians, teachers, or school nurses.

Clearly, communicating simple problems without embarrassment or shame can lead to solutions, often quickly. Larger, more complicated issues may need professional intervention. Equally important, many mental health interventions need not be long in duration but client-centered, focused, and short term.

But what needs to be emphasized is that speaking and addressing what’s going on, if your thoughts and emotions are troubling, are in themselves therapeutic. Talk therapy works – especially if you get a new perspective on the old set of problems.

Dr. London is a practicing psychiatrist and has been a newspaper columnist for 35 years, specializing in and writing about short-term therapy, including cognitive-behavioral therapy and guided imagery. He is author of “Find Freedom Fast” (New York: Kettlehole Publishing, 2019). He has no conflicts of interest.

Not everyone will suffer an episode of posttraumatic stress disorder, even though everyday American life is characterized by a lot of uncertainty these days, particularly considering the proliferation of gun violence.

Robert T. London

Also, everyone who does experience a traumatic event will not suffer an episode of PTSD – just as not everyone develops a heart attack or cancer, nor will everyone get every illness.

The data suggest that of those exposed to trauma, up to 25% of people will develop PTSD, according to Massachusetts General/McLean Hospital, Belmont, psychiatrist Kerry J. Ressler, MD, PhD, chief of the division of depression and anxiety disorders.

As I wrote in December 2022, our “kids” are not all right and psychiatry can help. I would say that many adolescents, and adults as well, may not be all right as we are terrorized not only by mass school shootings, but shootings happening almost anywhere and everywhere in our country: in supermarkets, hospitals, and shopping malls, at graduation parties, and on the streets.

According to a report published in Clinical Psychiatry News, a poll conducted by the American Psychiatric Association showed that most American adults [70%] reported that they were anxious or extremely anxious about keeping themselves or their families safe. APA President Rebecca W. Brendel, MD, JD, pointed out that there is “a lot of worry out there about economic uncertainty, about violence and how we are going to come out of this time period.”

Meanwhile, PTSD is still defined in the DSM-5 as exposure to actual or threatened death, serious injury, or sexual violence experienced directly, witnessing the traumatic event as it occurs to others, learning that a traumatic event occurred to a close family member or friend, or experiencing of traumatic events plus extreme exposure to aversive details of the event.

Examples of traumatic events can be numerous. They include natural disasters, man-made disasters, various types of assaults, war trauma, and severe illness with ICU experiences. I would add encounters with racism and bigotry – including homophobia when one fears for their very life or physical injury. This list includes only a few triggers that may invoke this disorder.

Interestingly, the DSM-5 excludes aversive exposure through electronic media, television, movies, or pictures. Including these aspects of trauma exposure would indeed increase PTSD diagnoses, and I believe this type of exposure needs to be included, especially considering how different people process information. Some viewers of media remain “outside” the events depicted on television, movies, or electronic media while others fit directly “into” the film or TV show. Even, for example, a news program, as evidenced by those people suffering from PTSD after viewing the Sept. 11, 2001, disaster on TV.

I have interviewed numerous people who witnessed Sept. 11 tragedies on TV, some during and some after the event, and they genuinely had experienced key factors of PTSD, including nightmares and intrusive recollections of the event. It’s important to include the ways in which people process information and events in order to make a correct diagnosis, in that “one [diagnostic] size does not fit all.”
 

PTSD at school

In my December column, I noted the fear of death that my generation and beyond experienced with the endless threat of nuclear war, which by its very nature meant death, and if not, the saying went “the living would envy the dead” – that is, in post–nuclear war.

As I pointed out in the column, that war never came and hopefully never will, yet the intensity of those many decades of threatened terror with regular school exercises of “hide under the desk” and “don’t look at the flash” left some with intrusive fearful thoughts, nightmares, and even visualization of atomic destruction, as well as the many scenes of destruction portrayed in news casts and films of nuclear explosions.

Clearly, most U.S. school children who participate in school lockdown drills will not suffer from PTSD episodes, but some will. If that “some” approaches 20% or even 10% or less, that will amount to a lot of kids.

I decided to interview two of my grandchildren, each living in different communities and attending different school systems, but both experiencing “lockdown drills.”

Jack, who is 13 and going into eighth grade, was quite clear regarding the drills and reported that in his age group, both he and the kids in his class felt scared while in lockdown. He told me some kids looked nervous. He mentioned that they were taught in school that if the “real thing” happened, the message was “hide, run, and fight.” I was curious and asked why not run first. He was quick to answer and said if you run, you might run into danger, so it’s better to hide and wait for help to arrive. I said to myself, if not PTSD, then being scared or nervous may also lead to anxiety or even to an anxiety disorder.

Next, I interviewed almost 11-year-old Charley, who is going into sixth grade. She was very clear about not at all being fearful or nervous during these drills and was confident that her classmates felt the same way. Then she explained that the school did a great job with a security officer and had locked doors all around that only opened from the inside. She was proud of the school and not fearful or worried at all.

The diverse views of these two young people surprised me but confirm that PTSD is not at all a given based on what is occurring in society. However, it should always be considered by clinicians if a child or adolescent begins to show signs consistent with PTSD.

These two interviews were quite short, but after I finished talking with Charley, she reported spontaneously that while she and her classmates were neither worried nor scared, some of their teachers did look nervous and seemed scared.

I was quite impressed with her sharpness and nuanced observation, and as noted, adults as well may be adversely affected by the entire concept of school lockdowns, as the awareness of their purpose rests in the forefront of their minds.
 

The way forward

So how do we prepare kids and adolescents for potential emotional problems like PTSD arising from lockdowns, even though most children or adults will not suffer any of these PTSD issues?

First, I believe that as we develop and teach health education in schools, mental health issues should be included according to grade level without generating fear or worry. Second, it is important that school children be aware that if they feel bad in any way emotionally, they should speak to their parents, guardians, teachers, or school nurses.

Clearly, communicating simple problems without embarrassment or shame can lead to solutions, often quickly. Larger, more complicated issues may need professional intervention. Equally important, many mental health interventions need not be long in duration but client-centered, focused, and short term.

But what needs to be emphasized is that speaking and addressing what’s going on, if your thoughts and emotions are troubling, are in themselves therapeutic. Talk therapy works – especially if you get a new perspective on the old set of problems.

Dr. London is a practicing psychiatrist and has been a newspaper columnist for 35 years, specializing in and writing about short-term therapy, including cognitive-behavioral therapy and guided imagery. He is author of “Find Freedom Fast” (New York: Kettlehole Publishing, 2019). He has no conflicts of interest.

Anxiety, depression, and COVID-19 can be a bad combination for your brain – and your long-term health.

Having anxiety and depression before a COVID infection increases the risk of developing long COVID, researchers have found. 

Those with long COVID who develop anxiety and depression after an infection may have brain shrinkage in areas that regulate memory, emotion, and other functions as well as disruption of brain connectivity. 

While many questions remain about these intertwined relationships, the associations aren’t a complete surprise. Experts already know that depression and anxiety are associated with inflammation and immune dysfunction, perhaps helping to explain the link between these mental health conditions, the risk of long COVID, and the changes in the brain.

Brain changes accompanying a COVID infection have concerned researchers since earlier in the pandemic, when U.K. Biobank researchers found brain atrophy, loss of grey matter, and decline in cognition in those infected with COVID, compared with those not infected.
 

Common conditions

The ramifications of the research linking anxiety, depression, and long COVID are far-reaching. According to the Centers for Disease Control and Prevention, 12.5% of U.S. adults have regular feelings of anxiety (as well as nervousness and worry), and the latest Gallup Poll found that nearly 18% of adults currently have or are being treated for depression. 

As of May 8, 10% of infected adults in the United States have long COVID, according to the CDC, and among U.S. adults ever infected, 27% have reported long COVID. Long COVID has been defined by the CDC as symptoms such as fatigue, brain fog, and cough that persist longer than 4 weeks and by the World Health Organization as symptoms persisting for 3 months or more. 

Here’s a roundup of what the research shows about mental health and long COVID risk – along with other research finding that paying attention to health habits may reduce that risk. 
 

Pre-existing depression, anxiety, and long COVID risk

A history of mental health issues – including depression, anxiety, worry, perceived stress, and loneliness – raises the risk of long COVID if infection occurs, Harvard researchers have found.

The researchers evaluated data from three large, ongoing studies including nearly 55,000 participants to determine the effects of high levels of psychological distress before a COVID infection. 

“Our study was purely survey based,” said Siwen Wang, MD, the study’s lead author and a research fellow at Harvard School of Public Health, Boston.

At the start of the survey in April 2020, none of the participants reported a current or previous COVID infection. They answered surveys about psychological distress at the start of the study, at 6 monthly time points, then quarterly until November 2021.

Over the follow up, 3,193 people reported a positive COVID test and 43% of those, or 1,403, developed long COVID. That number may seem high, but 38% of the 55,000 were active health care workers. On the final questionnaire, they reported whether their symptoms persisted for 4 weeks or longer and thus had long COVID by the standard CDC definition.

Dr. Wang’s team then looked at the infected participants’ psychological status. Anxiety raised the risk of long COVID by 42%, depression by 32%, worry about COVID by 37%, perceived stress, 46%, and loneliness, 32%.

COVID patients with a history of depression or anxiety are also more likely than others to report trouble with cognition in the weeks after a COVID infection and to develop brain fog and long COVID, UCLA researchers found. They evaluated 766 people with a confirmed COVID infection; 36% said their thinking was affected within 4 weeks of the infection. Those with anxiety and depression were more likely to report those difficulties.
 

Long COVID, then anxiety, depression, brain changes

Even mild cases of COVID infection can lead to long COVID and brain changes in those who suffer anxiety or depression after the infection, according to Clarissa Yasuda, MD, PhD, assistant professor of neurology at the University of Campinas in Sao Paulo. She has researched long COVID’s effects on the brain, even as she is coping with being a long COVID patient.

In one of her studies, presented at the 2023 annual meeting of the American Academy of Neurology, she found brain changes in people with anxiety, depression, and COVID but not in those infected who did not have either mental health issue. She evaluated 254 people, median age 41, after about 82 days from their positive PCR test for COVID.  Everyone completed a standard questionnaire for depression (the Beck Depression Inventory) and another for anxiety (the Beck Anxiety Inventory). She further divided them into two groups – the 102 with symptoms and the 152 who had no symptoms of either depression or anxiety. 

Brain scans showed those with COVID who also had anxiety and depression had shrinkage in the limbic area of the brain (which helps process emotion and memory), while those infected who didn’t have anxiety or depression did not. The researchers then scanned the brains of 148 healthy people without COVID and found no shrinkage.

The atrophy, Dr. Yasuda said, “is not something you can see with your eyes. It was only detected with computer analysis. Visualization on an MRI is normal.”

The number of people in this study with mental health issues was surprisingly high, Dr. Yasuda said. “It was intriguing for us that we noticed many individuals have both symptoms, anxiety and depression. We were not expecting it at that proportion.”

The researchers found a pattern of change not only in brain structure but in brain communication. They found those changes by using specialized software to analyze brain networks in some of the participants. Those with anxiety and depression had widespread functional changes in each of 12 networks tested. The participants without mental health symptoms showed changes in just five networks. These changes are enough to lead to problems with thinking skills and memory, Dr. Yasuda said.
 

Explaining the links

Several ideas have been proposed to explain the link between psychological distress and long COVID risk, Dr. Wang said. “The first and most mainstream mechanism for long COVID is chronic inflammation and immune dysregulation. Several mental health conditions, such as anxiety and depression, are associated with inflammation and dysfunction and that might be the link between depression, anxiety, and long COVID.”

Another less mainstream hypothesis, she said, is that “those with long COVID have more autoantibodies and they are more likely to have blood clotting issues. These have also been found in people with anxiety, depression, or other psychological distress.”

Other researchers are looking more broadly at how COVID infections affect the brain. When German researchers evaluated the brain and other body parts of 20 patients who died from non-COVID causes but had documented COVID infections, they found that 12 had accumulations of the SARS-CoV-2 spike protein in the brain tissue as well as the skull and meninges, the membranes that line the skull and spinal cord. Healthy controls did not. 

The findings suggest the persistence of the spike protein may contribute to the long-term neurologic symptoms of long COVID and may also lead to understanding of the molecular mechanisms as well as therapies for long COVID, the researchers said in their preprint report, which has not yet been peer reviewed. 

In another recent study, researchers from Germany performed neuroimaging and neuropsychological assessments of 223 people who were not vaccinated and recovered from mild to moderate COVID infections, comparing them with 223 matched healthy controls who had the same testing. In those infected, they found alterations in the cerebral white matter but no worse cognitive function in the first year after recovering. They conclude that the infection triggers a prolonged neuroinflammatory response. 

Can the brain changes reverse? “We don’t have an answer right now, but we are working on that,” Dr. Yasuda said. For now, she speculates about the return of brain volume: “I think for most it will. But I think we need to treat the symptoms. We can’t disregard the symptoms of long COVID. People are suffering a lot, and this suffering is causing some brain damage.”
 

Lifestyle habits and risk of long COVID

Meanwhile, healthy lifestyle habits in those infected can reduce the risk of long COVID, research by Dr. Wang and colleagues found. They followed nearly 2,000 women with a positive COVID test over 19 months. Of these, 44%, or 871, developed long COVID. Compared with women who followed none of the healthy lifestyle habits evaluated, those with five to six of the habits had a 49% lower risk of long COVID.

The habits included: a healthy body mass index (18.5-24.9 kg/m²), never smoking, at least 150 minutes weekly of moderate to vigorous physical activity, moderate alcohol intake (5-15 grams a day), high diet quality, and good sleep (7-9 hours nightly).
 

Long-term solutions 

Dr. Yasuda hopes that mental health care – of those infected and those not – will be taken more seriously. In a commentary on her own long COVID experience, she wrote, in part: “I fear for the numerous survivors of COVID-19 who do not have access to medical attention for their post-COVID symptoms. ... The mental health system needs to become prepared to receive survivors with different neuropsychiatric symptoms, including anxiety and depression.” 

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

Anxiety, depression, and COVID-19 can be a bad combination for your brain – and your long-term health.

Having anxiety and depression before a COVID infection increases the risk of developing long COVID, researchers have found. 

Those with long COVID who develop anxiety and depression after an infection may have brain shrinkage in areas that regulate memory, emotion, and other functions as well as disruption of brain connectivity. 

While many questions remain about these intertwined relationships, the associations aren’t a complete surprise. Experts already know that depression and anxiety are associated with inflammation and immune dysfunction, perhaps helping to explain the link between these mental health conditions, the risk of long COVID, and the changes in the brain.

Brain changes accompanying a COVID infection have concerned researchers since earlier in the pandemic, when U.K. Biobank researchers found brain atrophy, loss of grey matter, and decline in cognition in those infected with COVID, compared with those not infected.
 

Common conditions

The ramifications of the research linking anxiety, depression, and long COVID are far-reaching. According to the Centers for Disease Control and Prevention, 12.5% of U.S. adults have regular feelings of anxiety (as well as nervousness and worry), and the latest Gallup Poll found that nearly 18% of adults currently have or are being treated for depression. 

As of May 8, 10% of infected adults in the United States have long COVID, according to the CDC, and among U.S. adults ever infected, 27% have reported long COVID. Long COVID has been defined by the CDC as symptoms such as fatigue, brain fog, and cough that persist longer than 4 weeks and by the World Health Organization as symptoms persisting for 3 months or more. 

Here’s a roundup of what the research shows about mental health and long COVID risk – along with other research finding that paying attention to health habits may reduce that risk. 
 

Pre-existing depression, anxiety, and long COVID risk

A history of mental health issues – including depression, anxiety, worry, perceived stress, and loneliness – raises the risk of long COVID if infection occurs, Harvard researchers have found.

The researchers evaluated data from three large, ongoing studies including nearly 55,000 participants to determine the effects of high levels of psychological distress before a COVID infection. 

“Our study was purely survey based,” said Siwen Wang, MD, the study’s lead author and a research fellow at Harvard School of Public Health, Boston.

At the start of the survey in April 2020, none of the participants reported a current or previous COVID infection. They answered surveys about psychological distress at the start of the study, at 6 monthly time points, then quarterly until November 2021.

Over the follow up, 3,193 people reported a positive COVID test and 43% of those, or 1,403, developed long COVID. That number may seem high, but 38% of the 55,000 were active health care workers. On the final questionnaire, they reported whether their symptoms persisted for 4 weeks or longer and thus had long COVID by the standard CDC definition.

Dr. Wang’s team then looked at the infected participants’ psychological status. Anxiety raised the risk of long COVID by 42%, depression by 32%, worry about COVID by 37%, perceived stress, 46%, and loneliness, 32%.

COVID patients with a history of depression or anxiety are also more likely than others to report trouble with cognition in the weeks after a COVID infection and to develop brain fog and long COVID, UCLA researchers found. They evaluated 766 people with a confirmed COVID infection; 36% said their thinking was affected within 4 weeks of the infection. Those with anxiety and depression were more likely to report those difficulties.
 

Long COVID, then anxiety, depression, brain changes

Even mild cases of COVID infection can lead to long COVID and brain changes in those who suffer anxiety or depression after the infection, according to Clarissa Yasuda, MD, PhD, assistant professor of neurology at the University of Campinas in Sao Paulo. She has researched long COVID’s effects on the brain, even as she is coping with being a long COVID patient.

In one of her studies, presented at the 2023 annual meeting of the American Academy of Neurology, she found brain changes in people with anxiety, depression, and COVID but not in those infected who did not have either mental health issue. She evaluated 254 people, median age 41, after about 82 days from their positive PCR test for COVID.  Everyone completed a standard questionnaire for depression (the Beck Depression Inventory) and another for anxiety (the Beck Anxiety Inventory). She further divided them into two groups – the 102 with symptoms and the 152 who had no symptoms of either depression or anxiety. 

Brain scans showed those with COVID who also had anxiety and depression had shrinkage in the limbic area of the brain (which helps process emotion and memory), while those infected who didn’t have anxiety or depression did not. The researchers then scanned the brains of 148 healthy people without COVID and found no shrinkage.

The atrophy, Dr. Yasuda said, “is not something you can see with your eyes. It was only detected with computer analysis. Visualization on an MRI is normal.”

The number of people in this study with mental health issues was surprisingly high, Dr. Yasuda said. “It was intriguing for us that we noticed many individuals have both symptoms, anxiety and depression. We were not expecting it at that proportion.”

The researchers found a pattern of change not only in brain structure but in brain communication. They found those changes by using specialized software to analyze brain networks in some of the participants. Those with anxiety and depression had widespread functional changes in each of 12 networks tested. The participants without mental health symptoms showed changes in just five networks. These changes are enough to lead to problems with thinking skills and memory, Dr. Yasuda said.
 

Explaining the links

Several ideas have been proposed to explain the link between psychological distress and long COVID risk, Dr. Wang said. “The first and most mainstream mechanism for long COVID is chronic inflammation and immune dysregulation. Several mental health conditions, such as anxiety and depression, are associated with inflammation and dysfunction and that might be the link between depression, anxiety, and long COVID.”

Another less mainstream hypothesis, she said, is that “those with long COVID have more autoantibodies and they are more likely to have blood clotting issues. These have also been found in people with anxiety, depression, or other psychological distress.”

Other researchers are looking more broadly at how COVID infections affect the brain. When German researchers evaluated the brain and other body parts of 20 patients who died from non-COVID causes but had documented COVID infections, they found that 12 had accumulations of the SARS-CoV-2 spike protein in the brain tissue as well as the skull and meninges, the membranes that line the skull and spinal cord. Healthy controls did not. 

The findings suggest the persistence of the spike protein may contribute to the long-term neurologic symptoms of long COVID and may also lead to understanding of the molecular mechanisms as well as therapies for long COVID, the researchers said in their preprint report, which has not yet been peer reviewed. 

In another recent study, researchers from Germany performed neuroimaging and neuropsychological assessments of 223 people who were not vaccinated and recovered from mild to moderate COVID infections, comparing them with 223 matched healthy controls who had the same testing. In those infected, they found alterations in the cerebral white matter but no worse cognitive function in the first year after recovering. They conclude that the infection triggers a prolonged neuroinflammatory response. 

Can the brain changes reverse? “We don’t have an answer right now, but we are working on that,” Dr. Yasuda said. For now, she speculates about the return of brain volume: “I think for most it will. But I think we need to treat the symptoms. We can’t disregard the symptoms of long COVID. People are suffering a lot, and this suffering is causing some brain damage.”
 

Lifestyle habits and risk of long COVID

Meanwhile, healthy lifestyle habits in those infected can reduce the risk of long COVID, research by Dr. Wang and colleagues found. They followed nearly 2,000 women with a positive COVID test over 19 months. Of these, 44%, or 871, developed long COVID. Compared with women who followed none of the healthy lifestyle habits evaluated, those with five to six of the habits had a 49% lower risk of long COVID.

The habits included: a healthy body mass index (18.5-24.9 kg/m²), never smoking, at least 150 minutes weekly of moderate to vigorous physical activity, moderate alcohol intake (5-15 grams a day), high diet quality, and good sleep (7-9 hours nightly).
 

Long-term solutions 

Dr. Yasuda hopes that mental health care – of those infected and those not – will be taken more seriously. In a commentary on her own long COVID experience, she wrote, in part: “I fear for the numerous survivors of COVID-19 who do not have access to medical attention for their post-COVID symptoms. ... The mental health system needs to become prepared to receive survivors with different neuropsychiatric symptoms, including anxiety and depression.” 

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

Anxiety, depression, and COVID-19 can be a bad combination for your brain – and your long-term health.

Having anxiety and depression before a COVID infection increases the risk of developing long COVID, researchers have found. 

Those with long COVID who develop anxiety and depression after an infection may have brain shrinkage in areas that regulate memory, emotion, and other functions as well as disruption of brain connectivity. 

While many questions remain about these intertwined relationships, the associations aren’t a complete surprise. Experts already know that depression and anxiety are associated with inflammation and immune dysfunction, perhaps helping to explain the link between these mental health conditions, the risk of long COVID, and the changes in the brain.

Brain changes accompanying a COVID infection have concerned researchers since earlier in the pandemic, when U.K. Biobank researchers found brain atrophy, loss of grey matter, and decline in cognition in those infected with COVID, compared with those not infected.
 

Common conditions

The ramifications of the research linking anxiety, depression, and long COVID are far-reaching. According to the Centers for Disease Control and Prevention, 12.5% of U.S. adults have regular feelings of anxiety (as well as nervousness and worry), and the latest Gallup Poll found that nearly 18% of adults currently have or are being treated for depression. 

As of May 8, 10% of infected adults in the United States have long COVID, according to the CDC, and among U.S. adults ever infected, 27% have reported long COVID. Long COVID has been defined by the CDC as symptoms such as fatigue, brain fog, and cough that persist longer than 4 weeks and by the World Health Organization as symptoms persisting for 3 months or more. 

Here’s a roundup of what the research shows about mental health and long COVID risk – along with other research finding that paying attention to health habits may reduce that risk. 
 

Pre-existing depression, anxiety, and long COVID risk

A history of mental health issues – including depression, anxiety, worry, perceived stress, and loneliness – raises the risk of long COVID if infection occurs, Harvard researchers have found.

The researchers evaluated data from three large, ongoing studies including nearly 55,000 participants to determine the effects of high levels of psychological distress before a COVID infection. 

“Our study was purely survey based,” said Siwen Wang, MD, the study’s lead author and a research fellow at Harvard School of Public Health, Boston.

At the start of the survey in April 2020, none of the participants reported a current or previous COVID infection. They answered surveys about psychological distress at the start of the study, at 6 monthly time points, then quarterly until November 2021.

Over the follow up, 3,193 people reported a positive COVID test and 43% of those, or 1,403, developed long COVID. That number may seem high, but 38% of the 55,000 were active health care workers. On the final questionnaire, they reported whether their symptoms persisted for 4 weeks or longer and thus had long COVID by the standard CDC definition.

Dr. Wang’s team then looked at the infected participants’ psychological status. Anxiety raised the risk of long COVID by 42%, depression by 32%, worry about COVID by 37%, perceived stress, 46%, and loneliness, 32%.

COVID patients with a history of depression or anxiety are also more likely than others to report trouble with cognition in the weeks after a COVID infection and to develop brain fog and long COVID, UCLA researchers found. They evaluated 766 people with a confirmed COVID infection; 36% said their thinking was affected within 4 weeks of the infection. Those with anxiety and depression were more likely to report those difficulties.
 

Long COVID, then anxiety, depression, brain changes

Even mild cases of COVID infection can lead to long COVID and brain changes in those who suffer anxiety or depression after the infection, according to Clarissa Yasuda, MD, PhD, assistant professor of neurology at the University of Campinas in Sao Paulo. She has researched long COVID’s effects on the brain, even as she is coping with being a long COVID patient.

In one of her studies, presented at the 2023 annual meeting of the American Academy of Neurology, she found brain changes in people with anxiety, depression, and COVID but not in those infected who did not have either mental health issue. She evaluated 254 people, median age 41, after about 82 days from their positive PCR test for COVID.  Everyone completed a standard questionnaire for depression (the Beck Depression Inventory) and another for anxiety (the Beck Anxiety Inventory). She further divided them into two groups – the 102 with symptoms and the 152 who had no symptoms of either depression or anxiety. 

Brain scans showed those with COVID who also had anxiety and depression had shrinkage in the limbic area of the brain (which helps process emotion and memory), while those infected who didn’t have anxiety or depression did not. The researchers then scanned the brains of 148 healthy people without COVID and found no shrinkage.

The atrophy, Dr. Yasuda said, “is not something you can see with your eyes. It was only detected with computer analysis. Visualization on an MRI is normal.”

The number of people in this study with mental health issues was surprisingly high, Dr. Yasuda said. “It was intriguing for us that we noticed many individuals have both symptoms, anxiety and depression. We were not expecting it at that proportion.”

The researchers found a pattern of change not only in brain structure but in brain communication. They found those changes by using specialized software to analyze brain networks in some of the participants. Those with anxiety and depression had widespread functional changes in each of 12 networks tested. The participants without mental health symptoms showed changes in just five networks. These changes are enough to lead to problems with thinking skills and memory, Dr. Yasuda said.
 

Explaining the links

Several ideas have been proposed to explain the link between psychological distress and long COVID risk, Dr. Wang said. “The first and most mainstream mechanism for long COVID is chronic inflammation and immune dysregulation. Several mental health conditions, such as anxiety and depression, are associated with inflammation and dysfunction and that might be the link between depression, anxiety, and long COVID.”

Another less mainstream hypothesis, she said, is that “those with long COVID have more autoantibodies and they are more likely to have blood clotting issues. These have also been found in people with anxiety, depression, or other psychological distress.”

Other researchers are looking more broadly at how COVID infections affect the brain. When German researchers evaluated the brain and other body parts of 20 patients who died from non-COVID causes but had documented COVID infections, they found that 12 had accumulations of the SARS-CoV-2 spike protein in the brain tissue as well as the skull and meninges, the membranes that line the skull and spinal cord. Healthy controls did not. 

The findings suggest the persistence of the spike protein may contribute to the long-term neurologic symptoms of long COVID and may also lead to understanding of the molecular mechanisms as well as therapies for long COVID, the researchers said in their preprint report, which has not yet been peer reviewed. 

In another recent study, researchers from Germany performed neuroimaging and neuropsychological assessments of 223 people who were not vaccinated and recovered from mild to moderate COVID infections, comparing them with 223 matched healthy controls who had the same testing. In those infected, they found alterations in the cerebral white matter but no worse cognitive function in the first year after recovering. They conclude that the infection triggers a prolonged neuroinflammatory response. 

Can the brain changes reverse? “We don’t have an answer right now, but we are working on that,” Dr. Yasuda said. For now, she speculates about the return of brain volume: “I think for most it will. But I think we need to treat the symptoms. We can’t disregard the symptoms of long COVID. People are suffering a lot, and this suffering is causing some brain damage.”
 

Lifestyle habits and risk of long COVID

Meanwhile, healthy lifestyle habits in those infected can reduce the risk of long COVID, research by Dr. Wang and colleagues found. They followed nearly 2,000 women with a positive COVID test over 19 months. Of these, 44%, or 871, developed long COVID. Compared with women who followed none of the healthy lifestyle habits evaluated, those with five to six of the habits had a 49% lower risk of long COVID.

The habits included: a healthy body mass index (18.5-24.9 kg/m²), never smoking, at least 150 minutes weekly of moderate to vigorous physical activity, moderate alcohol intake (5-15 grams a day), high diet quality, and good sleep (7-9 hours nightly).
 

Long-term solutions 

Dr. Yasuda hopes that mental health care – of those infected and those not – will be taken more seriously. In a commentary on her own long COVID experience, she wrote, in part: “I fear for the numerous survivors of COVID-19 who do not have access to medical attention for their post-COVID symptoms. ... The mental health system needs to become prepared to receive survivors with different neuropsychiatric symptoms, including anxiety and depression.” 

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

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

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

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

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

Benzodiazepine pharmacodynamics

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

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

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

Continue to: Pharmacology and clinical effects

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

Absorption

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

CNS penetration

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

Lipophilicity and duration of effect

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

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

Continue to: Metabolism

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

Drug-drug interactions

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

Hepatic disease

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

Aging and benzodiazepine metabolism/clearance

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

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

Continue to: Obesity

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

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

How quickly do benzodiazepines work?

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

What is the ‘best’ dose?

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

Which benzodiazepine should I prescribe?

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

Continue to: Another aspect of the superiority...

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

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

Practical considerations

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

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

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

Continue to: The properties of individual benzodiazepines...

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

Bottom Line

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

Related Resources

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

Drug Brand Names

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

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

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

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

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

Benzodiazepine pharmacodynamics

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

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

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

Continue to: Pharmacology and clinical effects

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

Absorption

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

CNS penetration

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

Lipophilicity and duration of effect

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

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

Continue to: Metabolism

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

Drug-drug interactions

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

Hepatic disease

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

Aging and benzodiazepine metabolism/clearance

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

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

Continue to: Obesity

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

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

How quickly do benzodiazepines work?

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

What is the ‘best’ dose?

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

Which benzodiazepine should I prescribe?

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

Continue to: Another aspect of the superiority...

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

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

Practical considerations

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

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

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

Continue to: The properties of individual benzodiazepines...

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

Bottom Line

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

Related Resources

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

Drug Brand Names

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

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

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

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

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

Benzodiazepine pharmacodynamics

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

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

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

Continue to: Pharmacology and clinical effects

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

Absorption

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

CNS penetration

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

Lipophilicity and duration of effect

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

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

Continue to: Metabolism

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

Drug-drug interactions

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

Hepatic disease

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

Aging and benzodiazepine metabolism/clearance

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

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

Continue to: Obesity

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

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

How quickly do benzodiazepines work?

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

What is the ‘best’ dose?

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

Which benzodiazepine should I prescribe?

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

Continue to: Another aspect of the superiority...

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

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

Practical considerations

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

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

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

Continue to: The properties of individual benzodiazepines...

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

Bottom Line

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

Related Resources

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

Drug Brand Names

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

Stress-related disorders and anxiety are associated with a higher risk of out-of-hospital cardiac arrest (OHCA), a new case-control study suggests.

Investigators compared more than 35,000 OHCA case patients with a similar number of matched control persons and found an almost 1.5 times higher hazard of long-term stress conditions among OHCA case patients, compared with control persons, with a similar hazard for anxiety. Posttraumatic stress disorder was associated with an almost twofold higher risk of OHCA.

The findings applied equally to men and women and were independent of the presence of cardiovascular disease (CVD).

“This study raises awareness of the higher risks of OHCA and early risk monitoring to prevent OHCA in patients with stress-related disorders and anxiety,” write Talip Eroglu, of the department of cardiology, Copenhagen University Hospital, and colleagues.

The study was published online  in BMJ Open Heart.
 

Stress disorders and anxiety overrepresented

OHCA “predominantly arises from lethal cardiac arrhythmias ... that occur most frequently in the setting of coronary heart disease,” the authors write. However, increasing evidence suggests that rates of OHCA may also be increased in association with noncardiac diseases.

Individuals with stress-related disorders and anxiety are “overrepresented” among victims of cardiac arrest as well as those with multiple CVDs. But previous studies of OHCA have been limited by small numbers of cardiac arrests. In addition, those studies involved only data from selected populations or used in-hospital diagnosis to identify cardiac arrest, thereby potentially omitting OHCA patients who died prior to hospital admission.

The researchers therefore turned to data from Danish health registries that include a large, unselected cohort of patients with OHCA to investigate whether long-term stress conditions (that is, PTSD and adjustment disorder) or anxiety disorder were associated with OHCA.

They stratified the cohort according to sex, age, and CVD to identify which risk factor confers the highest risk of OHCA in patients with long-term stress conditions or anxiety, and they conducted sensitivity analyses of potential confounders, such as depression.

The design was a nested-case control model in which records at an individual patient level across registries were cross-linked to data from other national registries and were compared to matched control persons from the general population (35,195 OHCAs and 351,950 matched control persons; median IQR age, 72 [62-81] years; 66.82% men).

The prevalence of comorbidities and use of cardiovascular drugs were higher among OHCA case patients than among non-OHCA control persons.
 

Keep aware of stress and anxiety as risk factors

Among OHCA and non-OHCA participants, long-term stress conditions were diagnosed in 0.92% and 0.45%, respectively. Anxiety was diagnosed in 0.85% of OHCA case patients and in 0.37% of non-OHCA control persons.

These conditions were associated with a higher rate of OHCA after adjustment for common OHCA risk factors.

Detrimental to the heart, not just the psyche

Glenn Levine, MD, master clinician and professor of medicine, Baylor College of Medicine, Houston, called it an “important study in that it is a large, nationwide cohort study and thus provides important information to complement much smaller, focused studies.”

Like those other studies, “it finds that negative psychological health, specifically, long-term stress (as well as anxiety), is associated with a significantly increased risk of out-of-hospital cardiac arrest,” continued Dr. Levine, who is the chief of the cardiology section at Michael E. DeBakey VA Medical Center, Houston, and was not involved with the study.

Dr. Levine thinks the study “does a good job, as best one can for such a study, in trying to control for other factors, and zeroing in specifically on stress (and anxiety), trying to assess their independent contributions to the risk of developing cardiac arrest.”

The take-home message for clinicians and patients “is that negative psychological stress factors, such as stress and anxiety, are not only detrimental to one’s psychological health but likely increase one’s risk for adverse cardiac events, such as cardiac arrest,” he stated.

No specific funding for the study was disclosed. Mr. Eroglu has disclosed no relevant financial relationships. The other authors’ disclosures are listed in the original article. Dr. Levine reports no relevant financial relationships.

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

Stress-related disorders and anxiety are associated with a higher risk of out-of-hospital cardiac arrest (OHCA), a new case-control study suggests.

Investigators compared more than 35,000 OHCA case patients with a similar number of matched control persons and found an almost 1.5 times higher hazard of long-term stress conditions among OHCA case patients, compared with control persons, with a similar hazard for anxiety. Posttraumatic stress disorder was associated with an almost twofold higher risk of OHCA.

The findings applied equally to men and women and were independent of the presence of cardiovascular disease (CVD).

“This study raises awareness of the higher risks of OHCA and early risk monitoring to prevent OHCA in patients with stress-related disorders and anxiety,” write Talip Eroglu, of the department of cardiology, Copenhagen University Hospital, and colleagues.

The study was published online  in BMJ Open Heart.
 

Stress disorders and anxiety overrepresented

OHCA “predominantly arises from lethal cardiac arrhythmias ... that occur most frequently in the setting of coronary heart disease,” the authors write. However, increasing evidence suggests that rates of OHCA may also be increased in association with noncardiac diseases.

Individuals with stress-related disorders and anxiety are “overrepresented” among victims of cardiac arrest as well as those with multiple CVDs. But previous studies of OHCA have been limited by small numbers of cardiac arrests. In addition, those studies involved only data from selected populations or used in-hospital diagnosis to identify cardiac arrest, thereby potentially omitting OHCA patients who died prior to hospital admission.

The researchers therefore turned to data from Danish health registries that include a large, unselected cohort of patients with OHCA to investigate whether long-term stress conditions (that is, PTSD and adjustment disorder) or anxiety disorder were associated with OHCA.

They stratified the cohort according to sex, age, and CVD to identify which risk factor confers the highest risk of OHCA in patients with long-term stress conditions or anxiety, and they conducted sensitivity analyses of potential confounders, such as depression.

The design was a nested-case control model in which records at an individual patient level across registries were cross-linked to data from other national registries and were compared to matched control persons from the general population (35,195 OHCAs and 351,950 matched control persons; median IQR age, 72 [62-81] years; 66.82% men).

The prevalence of comorbidities and use of cardiovascular drugs were higher among OHCA case patients than among non-OHCA control persons.
 

Keep aware of stress and anxiety as risk factors

Among OHCA and non-OHCA participants, long-term stress conditions were diagnosed in 0.92% and 0.45%, respectively. Anxiety was diagnosed in 0.85% of OHCA case patients and in 0.37% of non-OHCA control persons.

These conditions were associated with a higher rate of OHCA after adjustment for common OHCA risk factors.

Detrimental to the heart, not just the psyche

Glenn Levine, MD, master clinician and professor of medicine, Baylor College of Medicine, Houston, called it an “important study in that it is a large, nationwide cohort study and thus provides important information to complement much smaller, focused studies.”

Like those other studies, “it finds that negative psychological health, specifically, long-term stress (as well as anxiety), is associated with a significantly increased risk of out-of-hospital cardiac arrest,” continued Dr. Levine, who is the chief of the cardiology section at Michael E. DeBakey VA Medical Center, Houston, and was not involved with the study.

Dr. Levine thinks the study “does a good job, as best one can for such a study, in trying to control for other factors, and zeroing in specifically on stress (and anxiety), trying to assess their independent contributions to the risk of developing cardiac arrest.”

The take-home message for clinicians and patients “is that negative psychological stress factors, such as stress and anxiety, are not only detrimental to one’s psychological health but likely increase one’s risk for adverse cardiac events, such as cardiac arrest,” he stated.

No specific funding for the study was disclosed. Mr. Eroglu has disclosed no relevant financial relationships. The other authors’ disclosures are listed in the original article. Dr. Levine reports no relevant financial relationships.

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

Stress-related disorders and anxiety are associated with a higher risk of out-of-hospital cardiac arrest (OHCA), a new case-control study suggests.

Investigators compared more than 35,000 OHCA case patients with a similar number of matched control persons and found an almost 1.5 times higher hazard of long-term stress conditions among OHCA case patients, compared with control persons, with a similar hazard for anxiety. Posttraumatic stress disorder was associated with an almost twofold higher risk of OHCA.

The findings applied equally to men and women and were independent of the presence of cardiovascular disease (CVD).

“This study raises awareness of the higher risks of OHCA and early risk monitoring to prevent OHCA in patients with stress-related disorders and anxiety,” write Talip Eroglu, of the department of cardiology, Copenhagen University Hospital, and colleagues.

The study was published online  in BMJ Open Heart.
 

Stress disorders and anxiety overrepresented

OHCA “predominantly arises from lethal cardiac arrhythmias ... that occur most frequently in the setting of coronary heart disease,” the authors write. However, increasing evidence suggests that rates of OHCA may also be increased in association with noncardiac diseases.

Individuals with stress-related disorders and anxiety are “overrepresented” among victims of cardiac arrest as well as those with multiple CVDs. But previous studies of OHCA have been limited by small numbers of cardiac arrests. In addition, those studies involved only data from selected populations or used in-hospital diagnosis to identify cardiac arrest, thereby potentially omitting OHCA patients who died prior to hospital admission.

The researchers therefore turned to data from Danish health registries that include a large, unselected cohort of patients with OHCA to investigate whether long-term stress conditions (that is, PTSD and adjustment disorder) or anxiety disorder were associated with OHCA.

They stratified the cohort according to sex, age, and CVD to identify which risk factor confers the highest risk of OHCA in patients with long-term stress conditions or anxiety, and they conducted sensitivity analyses of potential confounders, such as depression.

The design was a nested-case control model in which records at an individual patient level across registries were cross-linked to data from other national registries and were compared to matched control persons from the general population (35,195 OHCAs and 351,950 matched control persons; median IQR age, 72 [62-81] years; 66.82% men).

The prevalence of comorbidities and use of cardiovascular drugs were higher among OHCA case patients than among non-OHCA control persons.
 

Keep aware of stress and anxiety as risk factors

Among OHCA and non-OHCA participants, long-term stress conditions were diagnosed in 0.92% and 0.45%, respectively. Anxiety was diagnosed in 0.85% of OHCA case patients and in 0.37% of non-OHCA control persons.

These conditions were associated with a higher rate of OHCA after adjustment for common OHCA risk factors.

Detrimental to the heart, not just the psyche

Glenn Levine, MD, master clinician and professor of medicine, Baylor College of Medicine, Houston, called it an “important study in that it is a large, nationwide cohort study and thus provides important information to complement much smaller, focused studies.”

Like those other studies, “it finds that negative psychological health, specifically, long-term stress (as well as anxiety), is associated with a significantly increased risk of out-of-hospital cardiac arrest,” continued Dr. Levine, who is the chief of the cardiology section at Michael E. DeBakey VA Medical Center, Houston, and was not involved with the study.

Dr. Levine thinks the study “does a good job, as best one can for such a study, in trying to control for other factors, and zeroing in specifically on stress (and anxiety), trying to assess their independent contributions to the risk of developing cardiac arrest.”

The take-home message for clinicians and patients “is that negative psychological stress factors, such as stress and anxiety, are not only detrimental to one’s psychological health but likely increase one’s risk for adverse cardiac events, such as cardiac arrest,” he stated.

No specific funding for the study was disclosed. Mr. Eroglu has disclosed no relevant financial relationships. The other authors’ disclosures are listed in the original article. Dr. Levine reports no relevant financial relationships.

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

Mass shootings, often on school campuses, have become a regular and sad reality in the United States.
 

The statistics are grim. Every day 12 children die from gun violence in America and another 32 are shot and injured. Since the Columbine High School shooting in 1999, more than 338,000 students in the United States have experienced school gun violence, according to the nonprofit organization Sandy Hook Promise.

A new analysis from the Columbia Mass Murder Database (CMMD) sheds fresh light on the debate over whether mental illness or easy access to guns is the key driver of mass shootings.

The findings, which are published in the Journal of Forensic Sciences, show that most perpetrators of mass school shootings are young, White men without serious mental illness.
 

A ‘straw man’

Mental health is often used as a “straw man” in debates about mass shootings, lead investigator Ragy Girgis, MD, told this news organization.

“There are many factors that contribute to the mass shooting epidemic, including gun access, criminality, substance use and misuse, and many others. Mental illness is incidental in the vast majority of cases,” said Dr. Girgis, with Columbia University Irving Medical Center, New York, and the New York State Psychiatric Institute.

“People with serious mental illness constitute only a small portion of the perpetrators of gun violence in this country,” coinvestigator Paul Appelbaum, MD, professor of psychiatry, medicine, and law at Columbia University, New York, told this news organization.

Using the CMMD, the researchers examined 82 incidents of mass murder perpetrated in academic settings including schools, colleges, and universities. The average number of victims of these incidents was eight. More than half (60%) of mass school shootings involved at least one semi- or fully automatic firearm.

All 82 incidents were initiated by men (mean age, 28), and 67% were White. About two-thirds (63%) involved guns.

More than three-quarters (77%) of all perpetrators of mass murders in academic settings had no recorded history of psychotic symptoms.

Despite the absence of serious mental illness, almost half (46%) of the mass school shooters took their own lives at the scene, suggesting that they viewed themselves as engaging in some form of “final act,” the researchers note.

“The major difference between mass shooters in school settings and elsewhere is the higher rate of suicide by the perpetrators in school settings. That suggests that the shootings are often part of a preexisting intent to die on the part of the shooter,” said Dr. Appelbaum.
 

Epidemic of emptiness

He noted that the typical profile of a mass school shooter is that of “a young male with anger problems, often as a result of bullying or abuse, frequently described as a loner, who has signaled a desire to kill other people.”

“If we only focus on mental illness, we will miss the warning signs in the majority of cases associated with victimization (such as bullying) and consequent anger,” Dr. Appelbaum said.

Dr. Girgis said there is a need to deal with the “epidemic of emptiness, narcissism, anger, and societal rejection felt by many young men/boys who, when combined with a desire to take their own lives and a great need for notoriety, feel that perpetrating a mass school shooting is their only option.”

“We also need to understand why it is so easy for so many mass school shooters to obtain firearms that are not theirs – either illegally or from someone else who themselves may have obtained the firearm legally,” Dr. Girgis said.

“All countries have people with mental illness,” Dr. Appelbaum said, “but among developed countries the U.S. is unique in the easy availability of weapons and in our disproportionate rate of murders.”

He also noted that school shootings are not a problem that clinicians are going to solve.

“Although they can be alert to signals from their patients of an intent to harm people in a school (or other) setting, the vast majority of shooters are not receiving treatment for a mental disorder,” Dr. Appelbaum said.

“This is a problem that can only be substantially diminished by reducing access to firearms, which includes requirements for safe storage, universal background checks, waiting periods to purchase firearms, and similar means-oriented interventions,” he added.
 

Need for regular mental health checks

Thea Gallagher, PsyD, who was not involved in the study, noted that mass school shooters may not have a psychotic illness, but with mental health there is a “spectrum, and obviously, that individual is struggling to some extent, most likely, mentally, if they are at a place where they are willing to take the lives of others and themselves.”

“We need to understand more about how people get to this place and the issues people are struggling with. We need to push for yearly mental health checks just like the yearly physical,” Dr. Gallagher, with the department of psychiatry at NYU Langone Health, New York, told this news organization.

“The more that we create conversation and moments to talk about how people are feeling internally, the better chance we have to give people who are struggling healthy coping strategies and the opportunity to process their emotions and not bury them,” Dr. Gallagher said.

Support for the study was provided in part by the New York State Office of Mental Hygiene, and the Elizabeth K. Dollard Charitable Trust. Dr. Girgis has received royalties and/or advances from books on mental health published by Wipf and Stock, and Routledge/Taylor and Francis. He has consulted for Noble Insights, IMS Expert Services, and Fowler White Burnett. Dr. Appelbaum and Dr. Gallagher report no relevant financial relationships.

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

Mass shootings, often on school campuses, have become a regular and sad reality in the United States.
 

The statistics are grim. Every day 12 children die from gun violence in America and another 32 are shot and injured. Since the Columbine High School shooting in 1999, more than 338,000 students in the United States have experienced school gun violence, according to the nonprofit organization Sandy Hook Promise.

A new analysis from the Columbia Mass Murder Database (CMMD) sheds fresh light on the debate over whether mental illness or easy access to guns is the key driver of mass shootings.

The findings, which are published in the Journal of Forensic Sciences, show that most perpetrators of mass school shootings are young, White men without serious mental illness.
 

A ‘straw man’

Mental health is often used as a “straw man” in debates about mass shootings, lead investigator Ragy Girgis, MD, told this news organization.

“There are many factors that contribute to the mass shooting epidemic, including gun access, criminality, substance use and misuse, and many others. Mental illness is incidental in the vast majority of cases,” said Dr. Girgis, with Columbia University Irving Medical Center, New York, and the New York State Psychiatric Institute.

“People with serious mental illness constitute only a small portion of the perpetrators of gun violence in this country,” coinvestigator Paul Appelbaum, MD, professor of psychiatry, medicine, and law at Columbia University, New York, told this news organization.

Using the CMMD, the researchers examined 82 incidents of mass murder perpetrated in academic settings including schools, colleges, and universities. The average number of victims of these incidents was eight. More than half (60%) of mass school shootings involved at least one semi- or fully automatic firearm.

All 82 incidents were initiated by men (mean age, 28), and 67% were White. About two-thirds (63%) involved guns.

More than three-quarters (77%) of all perpetrators of mass murders in academic settings had no recorded history of psychotic symptoms.

Despite the absence of serious mental illness, almost half (46%) of the mass school shooters took their own lives at the scene, suggesting that they viewed themselves as engaging in some form of “final act,” the researchers note.

“The major difference between mass shooters in school settings and elsewhere is the higher rate of suicide by the perpetrators in school settings. That suggests that the shootings are often part of a preexisting intent to die on the part of the shooter,” said Dr. Appelbaum.
 

Epidemic of emptiness

He noted that the typical profile of a mass school shooter is that of “a young male with anger problems, often as a result of bullying or abuse, frequently described as a loner, who has signaled a desire to kill other people.”

“If we only focus on mental illness, we will miss the warning signs in the majority of cases associated with victimization (such as bullying) and consequent anger,” Dr. Appelbaum said.

Dr. Girgis said there is a need to deal with the “epidemic of emptiness, narcissism, anger, and societal rejection felt by many young men/boys who, when combined with a desire to take their own lives and a great need for notoriety, feel that perpetrating a mass school shooting is their only option.”

“We also need to understand why it is so easy for so many mass school shooters to obtain firearms that are not theirs – either illegally or from someone else who themselves may have obtained the firearm legally,” Dr. Girgis said.

“All countries have people with mental illness,” Dr. Appelbaum said, “but among developed countries the U.S. is unique in the easy availability of weapons and in our disproportionate rate of murders.”

He also noted that school shootings are not a problem that clinicians are going to solve.

“Although they can be alert to signals from their patients of an intent to harm people in a school (or other) setting, the vast majority of shooters are not receiving treatment for a mental disorder,” Dr. Appelbaum said.

“This is a problem that can only be substantially diminished by reducing access to firearms, which includes requirements for safe storage, universal background checks, waiting periods to purchase firearms, and similar means-oriented interventions,” he added.
 

Need for regular mental health checks

Thea Gallagher, PsyD, who was not involved in the study, noted that mass school shooters may not have a psychotic illness, but with mental health there is a “spectrum, and obviously, that individual is struggling to some extent, most likely, mentally, if they are at a place where they are willing to take the lives of others and themselves.”

“We need to understand more about how people get to this place and the issues people are struggling with. We need to push for yearly mental health checks just like the yearly physical,” Dr. Gallagher, with the department of psychiatry at NYU Langone Health, New York, told this news organization.

“The more that we create conversation and moments to talk about how people are feeling internally, the better chance we have to give people who are struggling healthy coping strategies and the opportunity to process their emotions and not bury them,” Dr. Gallagher said.

Support for the study was provided in part by the New York State Office of Mental Hygiene, and the Elizabeth K. Dollard Charitable Trust. Dr. Girgis has received royalties and/or advances from books on mental health published by Wipf and Stock, and Routledge/Taylor and Francis. He has consulted for Noble Insights, IMS Expert Services, and Fowler White Burnett. Dr. Appelbaum and Dr. Gallagher report no relevant financial relationships.

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

Mass shootings, often on school campuses, have become a regular and sad reality in the United States.
 

The statistics are grim. Every day 12 children die from gun violence in America and another 32 are shot and injured. Since the Columbine High School shooting in 1999, more than 338,000 students in the United States have experienced school gun violence, according to the nonprofit organization Sandy Hook Promise.

A new analysis from the Columbia Mass Murder Database (CMMD) sheds fresh light on the debate over whether mental illness or easy access to guns is the key driver of mass shootings.

The findings, which are published in the Journal of Forensic Sciences, show that most perpetrators of mass school shootings are young, White men without serious mental illness.
 

A ‘straw man’

Mental health is often used as a “straw man” in debates about mass shootings, lead investigator Ragy Girgis, MD, told this news organization.

“There are many factors that contribute to the mass shooting epidemic, including gun access, criminality, substance use and misuse, and many others. Mental illness is incidental in the vast majority of cases,” said Dr. Girgis, with Columbia University Irving Medical Center, New York, and the New York State Psychiatric Institute.

“People with serious mental illness constitute only a small portion of the perpetrators of gun violence in this country,” coinvestigator Paul Appelbaum, MD, professor of psychiatry, medicine, and law at Columbia University, New York, told this news organization.

Using the CMMD, the researchers examined 82 incidents of mass murder perpetrated in academic settings including schools, colleges, and universities. The average number of victims of these incidents was eight. More than half (60%) of mass school shootings involved at least one semi- or fully automatic firearm.

All 82 incidents were initiated by men (mean age, 28), and 67% were White. About two-thirds (63%) involved guns.

More than three-quarters (77%) of all perpetrators of mass murders in academic settings had no recorded history of psychotic symptoms.

Despite the absence of serious mental illness, almost half (46%) of the mass school shooters took their own lives at the scene, suggesting that they viewed themselves as engaging in some form of “final act,” the researchers note.

“The major difference between mass shooters in school settings and elsewhere is the higher rate of suicide by the perpetrators in school settings. That suggests that the shootings are often part of a preexisting intent to die on the part of the shooter,” said Dr. Appelbaum.
 

Epidemic of emptiness

He noted that the typical profile of a mass school shooter is that of “a young male with anger problems, often as a result of bullying or abuse, frequently described as a loner, who has signaled a desire to kill other people.”

“If we only focus on mental illness, we will miss the warning signs in the majority of cases associated with victimization (such as bullying) and consequent anger,” Dr. Appelbaum said.

Dr. Girgis said there is a need to deal with the “epidemic of emptiness, narcissism, anger, and societal rejection felt by many young men/boys who, when combined with a desire to take their own lives and a great need for notoriety, feel that perpetrating a mass school shooting is their only option.”

“We also need to understand why it is so easy for so many mass school shooters to obtain firearms that are not theirs – either illegally or from someone else who themselves may have obtained the firearm legally,” Dr. Girgis said.

“All countries have people with mental illness,” Dr. Appelbaum said, “but among developed countries the U.S. is unique in the easy availability of weapons and in our disproportionate rate of murders.”

He also noted that school shootings are not a problem that clinicians are going to solve.

“Although they can be alert to signals from their patients of an intent to harm people in a school (or other) setting, the vast majority of shooters are not receiving treatment for a mental disorder,” Dr. Appelbaum said.

“This is a problem that can only be substantially diminished by reducing access to firearms, which includes requirements for safe storage, universal background checks, waiting periods to purchase firearms, and similar means-oriented interventions,” he added.
 

Need for regular mental health checks

Thea Gallagher, PsyD, who was not involved in the study, noted that mass school shooters may not have a psychotic illness, but with mental health there is a “spectrum, and obviously, that individual is struggling to some extent, most likely, mentally, if they are at a place where they are willing to take the lives of others and themselves.”

“We need to understand more about how people get to this place and the issues people are struggling with. We need to push for yearly mental health checks just like the yearly physical,” Dr. Gallagher, with the department of psychiatry at NYU Langone Health, New York, told this news organization.

“The more that we create conversation and moments to talk about how people are feeling internally, the better chance we have to give people who are struggling healthy coping strategies and the opportunity to process their emotions and not bury them,” Dr. Gallagher said.

Support for the study was provided in part by the New York State Office of Mental Hygiene, and the Elizabeth K. Dollard Charitable Trust. Dr. Girgis has received royalties and/or advances from books on mental health published by Wipf and Stock, and Routledge/Taylor and Francis. He has consulted for Noble Insights, IMS Expert Services, and Fowler White Burnett. Dr. Appelbaum and Dr. Gallagher report no relevant financial relationships.

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

Disappointment – “I failed this exam, my life is ruined” or regret – “I am getting a divorce, I wasted so much of my life.” Patients present with a wide variety of complaints that can be understood as a form of death anxiety.

Fundamentally, patients come to see us to understand and explain their lives. One can reinterpret this as a patient asking, “If I died today, would my life have been good enough?” or “When I die, how will I look back at this moment in time and judge the choices I made?”

Other patients come to us attempting to use the same maladaptive defenses that did not serve them well in the past in the hopes of achieving a new outcome that will validate their lives. While it may be understandable that a child dissociates when facing abuse, hoping that this defense mechanism – as an adult – will work, it is unlikely to be fruitful and will certainly not validate or repair the past. This hope to repair one’s past can be interpreted as a fear of death – “I cannot die without correcting this.” This psychic conflict can intensify if one does not adopt a more adaptive understanding of his or her life.

Courtesy Dr. Neha Akkoor

Death anxiety is the feeling associated with the finality of life. Not only is life final, but a constant reminder of that fact is the idea that any one moment is final. Other than in science fiction, one cannot return to a prior moment and repair the past in the hope of a better future. Time goes only in one direction and death is the natural outcome of all life.

Death may have some evolutionary purpose that encourages the promotion of newer and more fitter genes, but one doesn’t have to consider its origin and reason to admit death’s constancy throughout humanity. People die and that is an anxiety-provoking fact of life. Death anxiety can feel especially tangible in our connected world. In a world of constant news, it can feel – for many people – that if your house wasn’t displaced because of global warming or that you are not a war refugee, you don’t deserve to be seen and heard.

This can be a particularly strong feeling for and among physicians, who don’t think that the mental health challenges generated by their own tough circumstances deserve to be labeled a mental disorder, so they designate themselves as having “burnout”¹ – as they don’t deserve the sympathy of having the clinically significant impairments of “depression.” Our traumas don’t seem important enough to deserve notice, and thus we may feel like we could die without ever having truly mattered.

This can also be applied in the reverse fashion. Certain individuals, like celebrities, live such extravagant lives that our simpler achievements can feel futile in comparison. While the neighbor’s grass has always felt greener, we are now constantly exposed to perfectly manicured lawns on social media. When compounded, the idea that our successes and our pains are both simultaneously irrelevant can lead one to have very palpable death anxiety – my life will never matter if none of the things I do matter, or my life will never matter because I will never achieve the requisite number of “likes” or “views” on social media required to believe that one’s life was worth living.

A way of alleviating death anxiety can be through the concept of legacy, or what we leave behind. How will people remember me? Will people remember me, or will I disappear like a shadow into the distant memory of my near and dear ones? The idea of being forgotten or lost to memory is intolerable to some and can be a strong driving force to “make a name” for oneself. For those who crave fame, whether a celebrity or a generous alumnus, part of this is likely related to remaining well known after death. After all, one can argue that you are not truly dead as long as you continue to live in the memory and/or genes of others.

Legacy thus serves as a form of posthumous transitional object; a way of calming our fears about how we will be remembered. For many, reconciling their feelings towards their legacy is an avenue to tame death anxiety.
 

A case study

The case of Mr. B illustrates this. As a 72-year-old male with a long history of generalized anxiety, he once had a nightmare as a child, similar to the plot of Sleeping Beauty. In his dream, he walks up a spiral staircase in a castle and touches the spindle on a spinning wheel, thus ending his life. The dream was vivid and marked him.

His fear of death has subsequently reared its head throughout his life. In more recent years, he has suffered from cardiovascular disease. Although he is now quite stable on his current cardiac medications, he is constantly fearful that he will experience a cardiac event while asleep and suddenly die. He is so anxious about not waking up in the morning that falling asleep is nearly impossible.

Mr. B is single, with no close family besides a sister who lives in another state. He has a dog and few friends. He worries about what will happen to his dog if he doesn’t wake up in the morning, but perhaps most distressing to him is “there’s so much left for me to do, I have so much to write!” As an accomplished author, he continues to write, and hopes to publish many more novels in his lifetime. It is unsurprising that someone without a strong social network may fear death and feel pressured to somehow make a mark on the world before the curtain falls. It is scary to think that even without us, life goes on.

By bringing to Mr. B’s attention that his ever-present anxiety is rooted in fear of death, he was able to gain more insight into his own defensive behaviors. By confronting his death anxiety and processing his definition of a life well lived together in therapy, he’s acknowledged his lack of social connection as demoralizing, and has made significant strides to remedy this. He’s been able to focus on a more fulfilling life day to day, with less emphasis on his to-do list and aspirations. Instead, he’s connected more with his faith and members of his church. He’s gotten close to several neighbors and enjoys long dinners with them on his back patio.

At a recent meeting, he confessed that he feels “lighter” and not as fearful about sudden cardiac death, and thus has noticed that his overall anxiety has diminished greatly. He concluded that experiencing meaningful relationships in the present moment would give him greater joy than spending his remaining time engaged in preserving a future identity for himself. It seems elementary, but if we look within, we may find that we all suffer similarly: How much of our daily actions, thoughts, and fears are tied to the looming threat of death?
 

Conclusion

While modern psychiatry continues to advance with better understandings of our neurobiology, improved knowledge of pathophysiological processes of mental illness, and expanding discovery of novel pharmacotherapeutics, the modern psychiatrist should not forget fundamental truths of behavior and humanity that were once the staple of psychiatry.

Death anxiety is one of those truths; it is the ultimate stressor that we will all face and should be regular study and practice for psychiatrists. In this article, we explored some of those facets most meaningful to us but recommend you expand your study to the many more available.

Death anxiety is a constant reminder that life is final, and it is natural to feel anxious when thinking about it. Patients often come to physicians seeking validation of their lives or trying to use the same maladaptive defense mechanisms that did not serve them well in the past to achieve a better outcome.

In today’s world, death anxiety can feel palpable due to the constant exposure to global news and social media that can make us feel irrelevant. However, legacy, or what we leave behind, can serve as a way to alleviate death anxiety. For many, reconciling their feelings toward their legacy is an avenue to tame death anxiety. Therapy can help individuals gain insight into their defensive behaviors and process their definition of a life well lived. By focusing on a life worth living, individuals can alleviate their death anxiety and gain a sense of fulfillment.

Dr. Akkoor is a psychiatry resident at the University of California, San Diego. She is interested in immigrant mental health, ethics, consultation-liaison psychiatry, and medical education. Dr. Badre is a clinical and forensic psychiatrist in San Diego. He holds teaching positions at the University of California, San Diego, and the University of San Diego. He teaches medical education, psychopharmacology, ethics in psychiatry, and correctional care. Dr. Badre can be reached at his website, BadreMD.com. Dr. Badre and Dr. Akkoor have no conflicts of interest.

Reference

1. Badre N. Burnout: A concept that rebrands mental illness for professionals. Clinical Psychiatry News. 2020 Mar 5.

Disappointment – “I failed this exam, my life is ruined” or regret – “I am getting a divorce, I wasted so much of my life.” Patients present with a wide variety of complaints that can be understood as a form of death anxiety.

Fundamentally, patients come to see us to understand and explain their lives. One can reinterpret this as a patient asking, “If I died today, would my life have been good enough?” or “When I die, how will I look back at this moment in time and judge the choices I made?”

Other patients come to us attempting to use the same maladaptive defenses that did not serve them well in the past in the hopes of achieving a new outcome that will validate their lives. While it may be understandable that a child dissociates when facing abuse, hoping that this defense mechanism – as an adult – will work, it is unlikely to be fruitful and will certainly not validate or repair the past. This hope to repair one’s past can be interpreted as a fear of death – “I cannot die without correcting this.” This psychic conflict can intensify if one does not adopt a more adaptive understanding of his or her life.

Courtesy Dr. Neha Akkoor

Death anxiety is the feeling associated with the finality of life. Not only is life final, but a constant reminder of that fact is the idea that any one moment is final. Other than in science fiction, one cannot return to a prior moment and repair the past in the hope of a better future. Time goes only in one direction and death is the natural outcome of all life.

Death may have some evolutionary purpose that encourages the promotion of newer and more fitter genes, but one doesn’t have to consider its origin and reason to admit death’s constancy throughout humanity. People die and that is an anxiety-provoking fact of life. Death anxiety can feel especially tangible in our connected world. In a world of constant news, it can feel – for many people – that if your house wasn’t displaced because of global warming or that you are not a war refugee, you don’t deserve to be seen and heard.

This can be a particularly strong feeling for and among physicians, who don’t think that the mental health challenges generated by their own tough circumstances deserve to be labeled a mental disorder, so they designate themselves as having “burnout”¹ – as they don’t deserve the sympathy of having the clinically significant impairments of “depression.” Our traumas don’t seem important enough to deserve notice, and thus we may feel like we could die without ever having truly mattered.

This can also be applied in the reverse fashion. Certain individuals, like celebrities, live such extravagant lives that our simpler achievements can feel futile in comparison. While the neighbor’s grass has always felt greener, we are now constantly exposed to perfectly manicured lawns on social media. When compounded, the idea that our successes and our pains are both simultaneously irrelevant can lead one to have very palpable death anxiety – my life will never matter if none of the things I do matter, or my life will never matter because I will never achieve the requisite number of “likes” or “views” on social media required to believe that one’s life was worth living.

A way of alleviating death anxiety can be through the concept of legacy, or what we leave behind. How will people remember me? Will people remember me, or will I disappear like a shadow into the distant memory of my near and dear ones? The idea of being forgotten or lost to memory is intolerable to some and can be a strong driving force to “make a name” for oneself. For those who crave fame, whether a celebrity or a generous alumnus, part of this is likely related to remaining well known after death. After all, one can argue that you are not truly dead as long as you continue to live in the memory and/or genes of others.

Legacy thus serves as a form of posthumous transitional object; a way of calming our fears about how we will be remembered. For many, reconciling their feelings towards their legacy is an avenue to tame death anxiety.
 

A case study

The case of Mr. B illustrates this. As a 72-year-old male with a long history of generalized anxiety, he once had a nightmare as a child, similar to the plot of Sleeping Beauty. In his dream, he walks up a spiral staircase in a castle and touches the spindle on a spinning wheel, thus ending his life. The dream was vivid and marked him.

His fear of death has subsequently reared its head throughout his life. In more recent years, he has suffered from cardiovascular disease. Although he is now quite stable on his current cardiac medications, he is constantly fearful that he will experience a cardiac event while asleep and suddenly die. He is so anxious about not waking up in the morning that falling asleep is nearly impossible.

Mr. B is single, with no close family besides a sister who lives in another state. He has a dog and few friends. He worries about what will happen to his dog if he doesn’t wake up in the morning, but perhaps most distressing to him is “there’s so much left for me to do, I have so much to write!” As an accomplished author, he continues to write, and hopes to publish many more novels in his lifetime. It is unsurprising that someone without a strong social network may fear death and feel pressured to somehow make a mark on the world before the curtain falls. It is scary to think that even without us, life goes on.

By bringing to Mr. B’s attention that his ever-present anxiety is rooted in fear of death, he was able to gain more insight into his own defensive behaviors. By confronting his death anxiety and processing his definition of a life well lived together in therapy, he’s acknowledged his lack of social connection as demoralizing, and has made significant strides to remedy this. He’s been able to focus on a more fulfilling life day to day, with less emphasis on his to-do list and aspirations. Instead, he’s connected more with his faith and members of his church. He’s gotten close to several neighbors and enjoys long dinners with them on his back patio.

At a recent meeting, he confessed that he feels “lighter” and not as fearful about sudden cardiac death, and thus has noticed that his overall anxiety has diminished greatly. He concluded that experiencing meaningful relationships in the present moment would give him greater joy than spending his remaining time engaged in preserving a future identity for himself. It seems elementary, but if we look within, we may find that we all suffer similarly: How much of our daily actions, thoughts, and fears are tied to the looming threat of death?
 

Conclusion

While modern psychiatry continues to advance with better understandings of our neurobiology, improved knowledge of pathophysiological processes of mental illness, and expanding discovery of novel pharmacotherapeutics, the modern psychiatrist should not forget fundamental truths of behavior and humanity that were once the staple of psychiatry.

Death anxiety is one of those truths; it is the ultimate stressor that we will all face and should be regular study and practice for psychiatrists. In this article, we explored some of those facets most meaningful to us but recommend you expand your study to the many more available.

Death anxiety is a constant reminder that life is final, and it is natural to feel anxious when thinking about it. Patients often come to physicians seeking validation of their lives or trying to use the same maladaptive defense mechanisms that did not serve them well in the past to achieve a better outcome.

In today’s world, death anxiety can feel palpable due to the constant exposure to global news and social media that can make us feel irrelevant. However, legacy, or what we leave behind, can serve as a way to alleviate death anxiety. For many, reconciling their feelings toward their legacy is an avenue to tame death anxiety. Therapy can help individuals gain insight into their defensive behaviors and process their definition of a life well lived. By focusing on a life worth living, individuals can alleviate their death anxiety and gain a sense of fulfillment.

Dr. Akkoor is a psychiatry resident at the University of California, San Diego. She is interested in immigrant mental health, ethics, consultation-liaison psychiatry, and medical education. Dr. Badre is a clinical and forensic psychiatrist in San Diego. He holds teaching positions at the University of California, San Diego, and the University of San Diego. He teaches medical education, psychopharmacology, ethics in psychiatry, and correctional care. Dr. Badre can be reached at his website, BadreMD.com. Dr. Badre and Dr. Akkoor have no conflicts of interest.

Reference

1. Badre N. Burnout: A concept that rebrands mental illness for professionals. Clinical Psychiatry News. 2020 Mar 5.

Disappointment – “I failed this exam, my life is ruined” or regret – “I am getting a divorce, I wasted so much of my life.” Patients present with a wide variety of complaints that can be understood as a form of death anxiety.

Fundamentally, patients come to see us to understand and explain their lives. One can reinterpret this as a patient asking, “If I died today, would my life have been good enough?” or “When I die, how will I look back at this moment in time and judge the choices I made?”

Other patients come to us attempting to use the same maladaptive defenses that did not serve them well in the past in the hopes of achieving a new outcome that will validate their lives. While it may be understandable that a child dissociates when facing abuse, hoping that this defense mechanism – as an adult – will work, it is unlikely to be fruitful and will certainly not validate or repair the past. This hope to repair one’s past can be interpreted as a fear of death – “I cannot die without correcting this.” This psychic conflict can intensify if one does not adopt a more adaptive understanding of his or her life.

Courtesy Dr. Neha Akkoor

Death anxiety is the feeling associated with the finality of life. Not only is life final, but a constant reminder of that fact is the idea that any one moment is final. Other than in science fiction, one cannot return to a prior moment and repair the past in the hope of a better future. Time goes only in one direction and death is the natural outcome of all life.

Death may have some evolutionary purpose that encourages the promotion of newer and more fitter genes, but one doesn’t have to consider its origin and reason to admit death’s constancy throughout humanity. People die and that is an anxiety-provoking fact of life. Death anxiety can feel especially tangible in our connected world. In a world of constant news, it can feel – for many people – that if your house wasn’t displaced because of global warming or that you are not a war refugee, you don’t deserve to be seen and heard.

This can be a particularly strong feeling for and among physicians, who don’t think that the mental health challenges generated by their own tough circumstances deserve to be labeled a mental disorder, so they designate themselves as having “burnout”¹ – as they don’t deserve the sympathy of having the clinically significant impairments of “depression.” Our traumas don’t seem important enough to deserve notice, and thus we may feel like we could die without ever having truly mattered.

This can also be applied in the reverse fashion. Certain individuals, like celebrities, live such extravagant lives that our simpler achievements can feel futile in comparison. While the neighbor’s grass has always felt greener, we are now constantly exposed to perfectly manicured lawns on social media. When compounded, the idea that our successes and our pains are both simultaneously irrelevant can lead one to have very palpable death anxiety – my life will never matter if none of the things I do matter, or my life will never matter because I will never achieve the requisite number of “likes” or “views” on social media required to believe that one’s life was worth living.

A way of alleviating death anxiety can be through the concept of legacy, or what we leave behind. How will people remember me? Will people remember me, or will I disappear like a shadow into the distant memory of my near and dear ones? The idea of being forgotten or lost to memory is intolerable to some and can be a strong driving force to “make a name” for oneself. For those who crave fame, whether a celebrity or a generous alumnus, part of this is likely related to remaining well known after death. After all, one can argue that you are not truly dead as long as you continue to live in the memory and/or genes of others.

Legacy thus serves as a form of posthumous transitional object; a way of calming our fears about how we will be remembered. For many, reconciling their feelings towards their legacy is an avenue to tame death anxiety.
 

A case study

The case of Mr. B illustrates this. As a 72-year-old male with a long history of generalized anxiety, he once had a nightmare as a child, similar to the plot of Sleeping Beauty. In his dream, he walks up a spiral staircase in a castle and touches the spindle on a spinning wheel, thus ending his life. The dream was vivid and marked him.

His fear of death has subsequently reared its head throughout his life. In more recent years, he has suffered from cardiovascular disease. Although he is now quite stable on his current cardiac medications, he is constantly fearful that he will experience a cardiac event while asleep and suddenly die. He is so anxious about not waking up in the morning that falling asleep is nearly impossible.

Mr. B is single, with no close family besides a sister who lives in another state. He has a dog and few friends. He worries about what will happen to his dog if he doesn’t wake up in the morning, but perhaps most distressing to him is “there’s so much left for me to do, I have so much to write!” As an accomplished author, he continues to write, and hopes to publish many more novels in his lifetime. It is unsurprising that someone without a strong social network may fear death and feel pressured to somehow make a mark on the world before the curtain falls. It is scary to think that even without us, life goes on.

By bringing to Mr. B’s attention that his ever-present anxiety is rooted in fear of death, he was able to gain more insight into his own defensive behaviors. By confronting his death anxiety and processing his definition of a life well lived together in therapy, he’s acknowledged his lack of social connection as demoralizing, and has made significant strides to remedy this. He’s been able to focus on a more fulfilling life day to day, with less emphasis on his to-do list and aspirations. Instead, he’s connected more with his faith and members of his church. He’s gotten close to several neighbors and enjoys long dinners with them on his back patio.

At a recent meeting, he confessed that he feels “lighter” and not as fearful about sudden cardiac death, and thus has noticed that his overall anxiety has diminished greatly. He concluded that experiencing meaningful relationships in the present moment would give him greater joy than spending his remaining time engaged in preserving a future identity for himself. It seems elementary, but if we look within, we may find that we all suffer similarly: How much of our daily actions, thoughts, and fears are tied to the looming threat of death?
 

Conclusion

While modern psychiatry continues to advance with better understandings of our neurobiology, improved knowledge of pathophysiological processes of mental illness, and expanding discovery of novel pharmacotherapeutics, the modern psychiatrist should not forget fundamental truths of behavior and humanity that were once the staple of psychiatry.

Death anxiety is one of those truths; it is the ultimate stressor that we will all face and should be regular study and practice for psychiatrists. In this article, we explored some of those facets most meaningful to us but recommend you expand your study to the many more available.

Death anxiety is a constant reminder that life is final, and it is natural to feel anxious when thinking about it. Patients often come to physicians seeking validation of their lives or trying to use the same maladaptive defense mechanisms that did not serve them well in the past to achieve a better outcome.

In today’s world, death anxiety can feel palpable due to the constant exposure to global news and social media that can make us feel irrelevant. However, legacy, or what we leave behind, can serve as a way to alleviate death anxiety. For many, reconciling their feelings toward their legacy is an avenue to tame death anxiety. Therapy can help individuals gain insight into their defensive behaviors and process their definition of a life well lived. By focusing on a life worth living, individuals can alleviate their death anxiety and gain a sense of fulfillment.

Dr. Akkoor is a psychiatry resident at the University of California, San Diego. She is interested in immigrant mental health, ethics, consultation-liaison psychiatry, and medical education. Dr. Badre is a clinical and forensic psychiatrist in San Diego. He holds teaching positions at the University of California, San Diego, and the University of San Diego. He teaches medical education, psychopharmacology, ethics in psychiatry, and correctional care. Dr. Badre can be reached at his website, BadreMD.com. Dr. Badre and Dr. Akkoor have no conflicts of interest.

Reference

1. Badre N. Burnout: A concept that rebrands mental illness for professionals. Clinical Psychiatry News. 2020 Mar 5.