Quetiapine, Clozapine, and Olanzapine Associated With Increased Pneumonia Risk

Individuals with schizophrenia who take high-dose olanzapine, quetiapine, or clozapine may face an increased risk of pneumonia, according to an analysis in JAMA Psychiatry. Broadly speaking, the findings of this population study also showed that the anticholinergic burden of an antipsychotic —not how strongly it blocks dopamine receptors—may drive pneumonia risk.

“[P]neumonia constitutes the fourth leading cause of death in [patients with] schizophrenia,” wrote Jurjen J. Luykx, M.D., Ph.D., of Amsterdam University Medical Center and colleagues. They pointed out that many schizophrenia practice guidelines provide no guidance on how to manage pneumonia or mitigate pneumonia risk. “Identification of antipsychotic drugs that are associated with pneumonia risk may better inform prevention programs [like vaccinations],” they wrote.

The researchers examined the incidence of pneumonia in 61,889 individuals aged 16 or older in Finland who received inpatient care due to schizophrenia or schizoaffective disorder between 1972 and 2014. The patients were followed for an average of 22 years, and their antipsychotic medications and doses during this time were carefully tracked.

Overall, Luykx and colleagues found a modest 15% increase in pneumonia risk among individuals taking one antipsychotic medication (monotherapy) compared with individuals taking no antipsychotics; interestingly, there was no increased pneumonia risk among individuals taking multiple antipsychotics. The pneumonia risk associated with antipsychotic monotherapy was mainly limited to individuals taking high doses of medication (at least 1.1 times the World Health Organization’s defined daily dose for a particular medication).

Specifically, high-dose quetiapine was associated with a 78% increased risk of pneumonia compared with no antipsychotic use, while high-dose olanzapine was associated with a 29% increased risk. Clozapine was associated with pneumonia risk at both high doses (44% increased risk) and standard doses (43% increased risk).

All three of these antipsychotics are anticholinergic, which means they can inhibit receptors that control involuntary functions like swallowing and saliva production (saliva has antimicrobial properties).

Luykx and colleagues said these findings highlight the value of promoting healthy eating habits in schizophrenia patients taking high-dose antipsychotics, especially older individuals. “Other prevention strategies targeting at-risk groups of patients with schizophrenia include pneumococcal pneumonia, influenza, or SARS-CoV-2 vaccination programs,” they said.

For related information, see the Psychiatric News article “Study Finds Higher-Dose Antipsychotic Polypharmacy Does Not Increase Hospitalization.”

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Surgeon General Lays Out Approach to Stem Growing Crisis of Gun Violence

The U.S. Surgeon General issued a landmark advisory Tuesday spelling out the crisis of firearm violence and calling for a commitment from the nation—from firearm owners to clinicians to community leaders—to tackle the growing and urgent threat using a public health approach.

The report calls for implementing community violence prevention programs and firearm risk reduction strategies; expanding research funding; and improving access to mental health care and support for those exposed to or at risk for firearm violence including trauma-informed care.

More than half of adults (54%) report that they or a family member have experienced a firearm-related incident, leading to ripples of harm across society, Vice Adm. Vivek Murthy, M.D., M.B.A., said in a video briefing. “The collective trauma and fear that Americans are experiencing is contributing to the mental health challenges that we are facing today. Nearly 6 in 10 U.S. adults say they worry about a loved one being a victim of firearm violence.

“Our children should not have to live in fear that they are going to get shot if they go to school. None of us should have to worry that going to the mall or a concert or a house of worship means putting our lives at risk, or that we'll get a call that a loved one in a moment of crisis has taken their own life with a firearm,” Murthy said.

The report noted that the rate of firearm deaths has reached a nearly three-decade high. More than 48,000 people died from firearm-related injuries in 2022, an increase of more than 16,000 lives since 2010. The majority of such deaths were from suicide (56%), and 40% were from homicide. Firearm injuries became the leading cause of death of U.S. children and adolescents starting in 2020, surpassing motor vehicle crashes, cancer, and drug overdose and poisoning.

The report also calls for building a strong foundation of gun violence prevention research, as well as launching community risk reduction strategies to support populations at increased risk of firearm violence involvement. Organizations can help address the issue with early intervention strategies like behavioral threat assessment and management teams (BTAM) in schools or having health systems educate patients on safe and secure firearm storage.

In addition, the report discusses the importance of “building distance in terms of time and space” between firearms and people who are at risk of harming themselves and others. To that end, it recommends various gun control measures and temporary firearm removal policies such as Extreme Risk Protection Orders and Domestic Violence Protection Orders, the latter of which have been implemented in some capacity in all 50 states.

“The members of the American Psychiatric Association have become all too familiar with suicides and homicides involving gun violence and the additional impacts on people’s mental and physical health,” said Marketa Wills, M.D., M.B.A., APA CEO and medical director in response to the report. “The Surgeon General’s Advisory on Firearm Violence elevates this crisis in our national attention and emphasizes the damage gun violence has caused to families across the United States. It affirms that people with mental illness are especially vulnerable and includes prevention strategies that could help save lives.”

For more information, see the Psychiatric News article “Psychiatrists Have Tools to Prevent Gun Violence.”

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Editorial Challenges the Concept of ‘Treatment Resistance’

When patients undergoing treatment for psychiatric disorders do not improve, clinicians should consider such patients as experiencing a distinct treatment failure, rather than having a treatment-resistant disorder, said H. Paul Putnam III, M.D., in an editorial in The Journal of Psychiatric Research and Clinical Practice.

“Our responsibility to our therapeutic alliances demands that we avoid applying the term treatment resistance in practice and never quit searching for the true and possibly multiple causes of treatment failure,” Putnam wrote. “When we label an individual's diagnosis as treatment resistance, we are essentially objectifying our patient, distancing ourselves from our failure, and effectively abandoning the patient, along with the sense of hope we should be sharing.”

Epidemiological studies have indicated that between 20-60% of psychiatric patient cases eventually get classified as treatment-resistant, depending on the disorder. Yet Putnam asserted that there is no consensus definition or criteria for treatment resistance and that very often when a case is labelled “treatment resistant,” there are effective treatments that need to be identified and tried. Clinicians should consider the diverse reasons that may account for every case in which clinical improvement is not seen—including genetic, biological, psychological, and lifestyle causes.

He outlined some steps that psychiatrists can take with patients who experience a treatment failure, including:

• Ensure patient evaluations and monitoring efforts are thorough.
• Consider all possible comorbidities, including those outside psychiatry
• Confirm the therapeutic guidance has been provided with clarity.
• Re-examine the clinical reasoning of a diagnosis; self-assess and self-correct if needed.
• Assess the quality of the therapeutic alliance with the patient.

“There is still abundant reason for hope when early treatment attempts are disappointing,” he wrote. “Our attitude must embody this optimism, and we must share it generously with our patients as we continue to work with them and our colleagues until answers are found. Not only is this sharing the truth; it is an essential factor in their recovery.”

For more information, see Putnam’s Psychiatric News Special Report, “Rethinking Treatment Resistance as Impasse Rather Than Endpoint.”

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Depressive Symptoms During Intern Year Found To Persist Through Residency and Beyond

Physicians who screen positive for depressive symptoms as interns are more likely to screen positive up to 10 years later than their peers who did not, a study in JAMA Network Open has found.

“This research suggests that there may be lasting consequences of depressive symptoms well beyond the years spent in medical training, emphasizing the need to support training doctors to safeguard the long-term health of those entrusted to ensure the health of others,” wrote Erin Kim, B.S., of the University of Michigan Medical School and colleagues.

The researchers examined data from physicians who participated in the Intern Health Study, an annual study begun in 2007 that assesses the mental health of incoming U.S.-based resident physicians. Enrolled participants had baseline assessments of depressive symptoms before starting residency and were followed up quarterly during their first year of training (their intern year). Participants were then invited to continue in the study and undergo annual assessments. The researchers used the Patient Health Questionnaire-9 (PHQ-9) to assess depressive symptoms and defined an elevated score as a score of 10 or higher, which suggests moderate to severe depression.

The final analysis included 2,867 follow-up assessments among 858 participants with complete PHQ-9 data and no elevated symptoms at baseline. Participants were followed for up to 10 years, and the mean follow-up was five years.

Overall, 35.2% of participants had elevated PHQ-9 scores on at least one quarterly survey during their intern year. A greater proportion of participants in this group had elevated scores at their annual follow-ups than those who did not have elevated scores as interns, as follows:

• 21.9% vs 6.6% at year 1
• 8.8% vs 2.4% at year 5
• 8.9% vs 3.7% at year 8

In addition, at the 10-year follow-up, participants who screened positive for depressive symptoms as interns had a higher prevalence of screening positive than the general adult population, 12.6% vs 7.7%. Across the 10-year study period, the participants who had elevated PHQ-9 scores as interns also had higher mean scores than those who did not have elevated scores as interns.

“Our research also highlights the need to better support mental health among physicians as they progress through training and to destigmatize mental health care within our professional culture,” The researchers wrote. “Universal well-being needs assessments for counseling services, opt-out counseling programs, and autoenrollment of interns in mental health resources to decrease barriers to access and overcome stigma should be further considered as potential solutions.”

For related information, see the Psychiatric News article “Positive Psychology: Not a ‘Just Be Happy’ Approach to Physician Wellness in 2020.”

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Mental Health Plummets Among Transgender, Gender-Diverse Adults

The prevalence of mental distress and depression more than doubled among transgender and gender-diverse adults in the U.S. between 2014 and 2022, a research letter in JAMA Internal Medicine has reported.

Michael Liu, M.Phil., of Harvard Medical School and colleagues examined data from the 2014 to 2022 Behavioral Risk Factor Surveillance System (BRFSS), an annual state-based telephone survey of adults run by the CDC in which participants report on their health behaviors and whether health care professionals had ever diagnosed them with a health condition; different participants are surveyed each year. The BRFSS introduced an optional gender identity module in 2014, with more states adopting the module over the study period.

The researchers classified respondents as transgender or gender-diverse if the respondents identified as transgender, male to female; transgender, female to male; or transgender, gender nonconforming. The researchers then assessed three self-reported health outcomes: poor or fair health status, frequent mental distress, and diagnosed depression. Frequent mental distress was defined as reporting 14 or more poor mental health days during the past month.

Overall, 8,884 respondents (out of 1.92 million total across the nine surveys) were transgender or gender-diverse. Between 2014 and 2022, the prevalence of frequent mental distress increased from 18.8% to 38.9% among transgender or gender-diverse adults, while the prevalence of depression rose from 19.7% to 51.3%. Cisgender adults experienced significantly smaller increases in the prevalence of frequent mental distress (11.2% to 15.5%) and depression (18.6% to 21.1%) during this period. The prevalence of poor or fair general health also increased among transgender or gender-diverse adults between 2014 and 2022.

“Further research is required to identify factors contributing to the widening health inequities in this population, especially amid recent proliferation of anti-[transgender or gender-diverse] legislation,” Liu and colleagues wrote. “Our findings highlight the need for the health sector to follow established standards of care and advocate for policies that protect [this population].”

In an accompanying commentary, Carl Streed Jr., M.D., M.P.H., of Boston University and colleagues noted that in 2023, there were 574 bill proposals explicitly targeting transgender and nonbinary populations, of which 83 were signed into law. They added that in 2024 there have been 544 such bills, of which 23 had been passed as of April.

“These efforts to exclude transgender and nonbinary people from civic life threaten the well-being of the more than 1.6 million transgender and nonbinary people in the U.S.,” they wrote. “Given the sociopolitical trajectory of the U.S. regarding increasing discrimination and political attacks on transgender and nonbinary people, we can expect to see worsening mental health in these populations for the foreseeable future.

“To reverse this, we need high-quality health care as well as legal and economic protections for this population,” they concluded.

For related information, see the Psychiatric News Special Report “What You Should Know to Care for LGBTQ Patients.”

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Diabetes Medication Shows Promise at Reducing Sleep Apnea Severity

The antidiabetic tirzepatide reduces the frequency of breathing interruptions and other sleep-related symptoms in adults with obstructive sleep apnea (OSA), according to findings from two placebo-controlled clinical trials published today in the New England Journal of Medicine. Adults who took tirzepatide also exhibited reductions in risk factors associated with sleep apnea like body weight and blood pressure compared with those who took placebo.

“Historically, treating OSA meant using devices during sleep, like a CPAP [continuous positive airway pressure] machine, to alleviate breathing difficulties and symptoms,” said lead investigator Atul Malhotra, M.D., of the University of California, San Diego, in a press release. “However, its effectiveness relies on consistent use. This new drug treatment offers a more accessible alternative for individuals who cannot tolerate or adhere to existing therapies.”

Malhotra and colleagues enrolled 469 adults diagnosed with clinical obesity and moderate-to-severe OSA; the participants were equally divided into two groups: Group one consisted of those who were not using CPAP devices to manage their sleep apnea and group two consisted of those who were.

In each CPAP group, the participants were randomly assigned to a subcutaneous injection of 10-15 mg of tirzepatide or a placebo weekly for 52 weeks. At the end of one year, the investigators assessed the change in participants’ apnea–hypopnea index (AHI, the number of breathing pauses per hour of sleep) relative to baseline. Other symptoms assessed included hypoxic burden (percentage decrease in blood oxygen levels), patient-reported sleep impairment, body weight, and systolic blood pressure.

At baseline, the participants had an average AHI of around 50 events an hour. After 52 weeks, the AHI among adults in group one who took tirzepatide dropped by 25.3 events an hour versus 5.3 events an hour in the placebo group. Among adults in group two, AHI dropped by 29.3 events an hour versus 5.5 events an hour in the placebo group. In addition, the participants taking tirzepatide lost around 18% (group one) and 20% (group two) of their baseline body weight and had greater improvements than the placebo group for all other sleep and metabolic symptoms assessed.

The most common tirzepatide-associated side effects were gastrointestinal issues such as diarrhea, nausea, or vomiting; 7.5% of the participants reported serious adverse events, with similar rates in the tirzepatide and placebo groups.

In an accompanying NEJM editorial, Sanjay R. Patel, M.D., of the University of Pittsburgh said these study findings were promising but noted that whether “tirzepatide improves patient-centered outcomes in obstructive sleep apnea remains unclear because a change in the AHI has not been validated as a surrogate marker of clinically relevant end points.” Though patient-reported sleep impairment also improved with tirzepatide, Patel said important outcomes like daytime sleepiness and overall functioning need to be assessed.

These trials were funded by Eli Lilly, manufacturer of tirzepatide; Malhotra is a consultant for Eli Lilly.

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Education, Resources, and Support Needed for Physicians Who Experience Patient Suicide

Patient suicide has a profound effect on health care professionals, and institutions that train or employ them should develop best practices for suicide education, prevention, and post-suicide intervention, according to a report in Psychiatric Services in Advance.

A literature review revealed that more than half of all health care professionals and nearly three-quarters of all psychiatrists have experienced the suicide of a patient; just under half of all psychiatric trainees have experienced the suicide of a patient.

“Patient suicide is common and occurs across the spectrum of health care professionals at all career stages, including training,” wrote lead author Madison Jupina, D.O., of MetroHealth Hospital, Cleveland, and colleagues. “The impacts of patient suicide can be serious, and it appears that certain groups of professionals may be more vulnerable to adverse outcomes, including individuals in training and those who are more isolated within systems of care.”

The authors conducted a systematic literature review in October 2021 and August 2022 using keywords related to patient suicide to capture articles on the prevalence of patient suicide and its impact on health care professionals. In total, 66 articles met the inclusion criteria. Of these, 41 studies from 15 countries reported the prevalence of patient suicide experienced by health care professionals; the sample sizes of health care professionals in these studies ranged from 5 to 1,391.

The following are significant findings from the review:

• An average of 51% of health care professionals across the studies experienced a patient suicide, and an average of 73% of psychiatrists across the studies experienced a suicide; among psychiatric trainees, the average was 48%.
• Eleven articles reported that health care professionals developed increased self-doubt or decreased self-confidence after a patient suicide. Eight articles reported that they considered a career change, and two reported that they made a career change. Six articles examined the practice of taking time off after a patient suicide and found that only 0% to 10% of health care professionals did so.
• Fifty articles reported on the professional impact of patient suicide on health care professionals, and 33 articles noted a change in practice. Changes in practice included an increased tendency to hospitalize suicidal patients; they also become more cautious, used more consultations, avoided or no longer treated suicidal patients, and recorded more details in patient charts.

The literature review highlighted the usefulness of informal institutional supports after a patient suicide. “Time off should be actively encouraged to allow health care professionals to grieve and to utilize informal supports, such as family and friends,” Jupina and colleagues wrote. “Because informal support offered by colleagues was rated as very helpful and highly desirable, it would be beneficial to consider providing allotted time during the workday for peer-led grief or process groups, and facilitator training could be provided for these groups.”

For related information, see the Psychiatric News article “Preventing Suicide Begins With Regular Assessments.”

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Financial Incentives May Boost USPSTF-Recommended Interventions for Childhood Obesity

Today in JAMA, the U.S. Preventive Services Task Force (USPSTF) recommended that clinicians either provide or refer children aged 6 and older who are overweight or obese to intensive behavioral therapies. Based on an updated systematic review of the evidence, the USPSTF affirmed its 2017 stance that such multidisciplinary interventions focusing on physical activity, healthy eating, and behavioral modifications are more beneficial than medications like semaglutide (Ozempic).

In fact, a study published in JAMA Pediatrics yesterday demonstrated that an intervention that combines prepared healthy meals with financial incentives can lead to significant weight loss in adolescents with severe obesity after one year.

Amy C. Gross, Ph.D., of the University of Minnesota Center for Pediatric Obesity Medicine and colleagues enrolled 126 adolescents (aged 13-17) who had a body mass index (BMI) of at least 35 or 120% above the 95th percentile for their age and sex. Half the adolescents received standard meal replacement therapy, in which they were provided healthy, well-balanced meals free of charge to their homes, along with monthly meetings with research staff. The other half received the meal-replacement therapy along with a $20 gift card for every 0.5% reduction of baseline body weight, paid out every two months.

After 52 weeks, the adolescents who could earn financial incentives lost an average of 6.1 kg (13.4 pounds), compared with 1.3 kg (2.9 pounds) in the meal replacement-only group. The weight loss in the financial incentive group equated to about a 6.6% reduction in BMI and an average payout of $330 per participant.

In an accompanying editorial, Aaron Carroll, M.D., M.S., of AcademyHealth in Washington, D.C., said the weight loss achieved in this study was encouraging, but questioned whether paying teens to lose weight on top of providing free meals (averaging around $700 a month) was a sustainable strategy at scale. He noted that even with these favorable parameters, 30% of the participants still did not complete the study.

“Behavioral interventions keep getting more and more complicated because they don’t work well, except in extreme circumstances and often in ways that defy implementation,” he wrote. “Maybe it’s time to stop focusing on them.”

The USPSTF recommendations acknowledged that behavioral interventions for obesity provide small benefits unless they offer regular clinician contact and physical activity sessions (as opposed to encouraging physical activity); and that such “comprehensive, intensive behavioral interventions remain inaccessible for the vast majority of U.S. children and adolescents with obesity.”

Carroll suggested that more research should be dedicated to enabling the safe use of medications like semaglutide in children, which have shown robust weight loss results as of now and will become more available once the price comes down. (Carroll disclosed that he has successfully lost weight with these drugs.)

The USPSTF did not offer any recommendations of weight loss medications for children, noting that while “several medications demonstrated greater weight loss than placebo, the totality of the evidence was found to be inadequate. An important limitation of the pharmacotherapy studies was that there was only a single trial for each effective medication (i.e., phentermine/topiramate, semaglutide, and liraglutide) that lasted longer than 2 months.”

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NIH Study Shows That Tackling Opioid Overdose Deaths in Communities Requires Time

Large-scale community-wide interventions to address opioid overdose deaths can be difficult to implement and require sustained effort before positive results are seen.

That’s one of the lessons from a large National Institutes of Health (NIH) study that found no statistically significant difference in overdose death rates between communities that implemented system-wide evidence-based practices aimed at opioid overdose and communities that did not. But those results, published yesterday in the New England Journal of Medicine, may have been compromised by the COVID-19 pandemic, the growing fentanyl epidemic, and the time required for large-scale strategies to take effect.

“This study brought researchers, providers, and communities together to break down barriers and promote the use of evidence-based strategies that we know are effective, including medications for opioid use disorder and naloxone,” said National Institute on Drug Abuse director, Nora D. Volkow, M.D., in a press release. “Yet, particularly in the era of fentanyl and its increased mixture with psychostimulant drugs, it’s clear we need to continue developing new tools and approaches for addressing the overdose crisis. Ongoing analyses of the rich data from this study will be critical to guiding our efforts in the future.”

As part of the NIH HEALing (Helping to End Addiction Long-term) Communities Study, 67 rural and urban communities in Kentucky, Massachusetts, New York, and Ohio were randomly divided to the Communities That Heal (CTH) intervention or a wait-list control. All communities had a baseline opioid-related overdose death rate of at least 25 per 100,000 adults.

The CTH intervention used a phased-planning process wherein researchers worked with community coalitions to identify and implement evidence-based strategies to improve existing gaps in three areas of opioid management: overdose education and naloxone distribution, the use of medications for opioid use disorder, and prescription opioid safety. The CTH intervention began on January 2020, and overdose outcomes between the CTH and wait-list communities were compared between July 2021 and June 2022.

The rates of opioid-related overdose deaths were similar in the intervention group and the control group during the comparison year (47.2 deaths per 100,000 population vs. 51.7 per 100,000 population, respectively). The effect of the intervention on the rate of opioid-related overdose deaths did not differ appreciably according to state, urban or rural category, age, sex, or race or ethnic group.

Overall, 615 evidence-based practices were implemented by the 34 CTH communities, but only 235 (38%) had been initiated by July 2021. “After the strategy selection process, only 10 months preceded the comparison period to establish agency partnerships and implement evidence-based practices,” wrote Jeffrey H. Samet, M.D., M.P.H., at Boston University School of Medicine and colleagues. “The time frame was insufficient to initiate many strategies for evidence-based practices, which often required recruiting new staff from an increasingly scarce health care workforce, changing clinical practice workflows, or developing new interagency collaborations.”

Moreover, the onset of COVID-19 shutdowns just two months after the CTH intervention started severely disrupted the systems targeted by these new practices CTH intervention, the authors noted.

For related information see the Psychiatric News article “AMA Identifies Six State Strategies for Ending Opioid Epidemic.”

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Significant Brain Changes Found in Adults With Phobias, but Not Youth

Adults—but not youth—with phobia show significant and phobia-specific differences in brain structure compared with adults without any psychiatric illness, according to a report published in AJP in Advance. The brain imaging data also revealed that the neurological changes in adults with phobias were more profound than those observed in people with general anxiety or social anxiety.

Kevin Hilbert, Ph.D., of the Humboldt University of Berlin and colleagues with the ENIGMA (Enhancing Neuroimaging Genetics Through Meta-Analysis) consortium noted that a phobia is the most common anxiety disorder, with a prevalence of up to 12.5%. Yet “few studies have examined differences in brain structure associated with specific phobia, and those were generally conducted in small samples and targeted isolated regions of interest,” they wrote.

To address this gap, the ENIGMA team examined MRI scans from 1,452 children and adults with a specific phobia as well as 2,991 healthy participants. The most common phobia subtypes in the sample were animal phobias (739 participants) and blood/injury/injection phobias (182 participants).

The researchers found that individuals with phobia displayed increased thickness in some parts of the frontal cortex, as well as reduced subcortical volumes in the caudate nucleus, putamen, and hippocampus. The altered regions are involved in fear-related processes like movement, aversion, and emotional processing; notably, the size of the amygdala—a central regulator of fear and aggression—was not significantly altered in people with phobia.

Most of the differences in structure relative to healthy controls were seen in people with animal phobias. However, individuals with blood/injury/injection phobias showed increased thickness in the medial orbitofrontal cortex relative to both controls and people with animal phobias, which supports the idea that impairments in people with blood/injury/injection phobias involve higher cognitive processes such as evaluating external stimuli (which is why this phobia type can elicit both fear and disgust).

Interestingly, Hilbert and colleagues found no differences in brain structure between people with phobias and healthy controls when they compared only people under the age of 21—these differences seem to manifest during adulthood. [I]t was a surprising finding given that [phobia] onset early in childhood is so common and given that neurofunctional and structural correlates are observed in individuals with other anxiety disorders, and even in youths at risk for anxiety disorders,” they wrote.

Since many childhood phobias remit in adulthood, the large structural changes seen in the MRI scans of adults may reflect a more persistent form of the disorder, they added.

For related information, see the AJP article “Subcortical Brain Volume, Regional Cortical Thickness, and Cortical Surface Area Across Disorders: Findings From the ENIGMA ADHD, ASD, and OCD Working Groups.”

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About 1 in 20 Risk Protection Orders To Remove a Firearm Prevent a Suicide, Researchers Find

For every 22 extreme risk protection orders (ERPOs) issued in Connecticut, one suicide is prevented, according to a report in JAMA Network Open. ERPOs, also known as red flag gun laws, allow firearms to be removed from people at high risk of self-injury or injury to others.

The suicides prevented are “only one of many considerations pertinent to evaluating the potential risks and benefits of ERPO laws,” wrote Matthew Miller, M.D., Sc.D., of the Bouvé College of Health Sciences at Northeastern University in Boston, and colleagues. “Other potential benefits, such as averting homicides and mass shootings and alleviating stress among family and friends of an individual in crisis, need to be weighed against possible harms, such as intrusions into liberty interests and the likelihood that ERPOs would precipitate harms when law enforcement officers attempt to remove firearms.”

Miller and colleagues first used 11 years of data (October 2004 through December 2015) from a California database linking handgun ownership and mortality records to identify the number and distribution of suicide deaths among handgun owners and nonowners in the state; the 11-year period preceded California’s first ERPO law in 2016.

The researchers then examined data on suicide deaths of people who were subject to an ERPO in Connecticut over a 14-year span (1999-2013) and used the California data to estimate the number of suicide deaths if no ERPOs had been issued.

In all, about 1,200 California handgun owners died by suicide between 2004 and 2015, as did about 15,000 nonowners. Among handgun owners, 25% of suicidal acts (fatal suicides plus attempts) involved firearms while 57% involved drugs and 6% involved cutting, researchers noted. By contrast, among nonowners, just 2% of suicidal acts involved firearms.

In Connecticut, 762 people were subject to an ERPO during the 14-year study, 21 of whom died by suicide. Those deaths resulted from 187 suicidal acts, the researchers estimated. Had no ERPOs been issued, 52 of those acts would likely have involved firearms, resulting in an estimated 47 deaths, while the remaining 135 nonfirearm suicide acts would have resulted in eight deaths. In all, researchers estimated that the ERPOs prevented 34 suicides, or 1 suicide for every 22 ERPOs issued.

“As policymakers attempt to learn how to use ERPOs most effectively and equitably, the heterogeneous U.S. landscape presents an opportunity for future studies to identify and learn more about the effect of different ERPO implementation approaches, which, in turn, could help guide policy and legislative decisions,” researchers concluded.

For more information, see the Psychiatric News article “Multiple Barriers Inhibit Civilian Use of Red Flag Laws, Study Shows.”

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Naltrexone-Bupropion Combination Found To Reduce Methamphetamine Use Over 12 Weeks.

Individuals with methamphetamine use disorder treated with a combination of injectable naltrexone and extended-release bupropion gradually declined their use of methamphetamine over 12 weeks at a rate that was significantly greater than patients receiving placebo, according to a report in Addiction.

The report is a follow-up analysis of the Accelerated Development of Additive Pharmacotherapy Treatment for Methamphetamine Use Disorder (ADAPT-2) trial; the primary results reported the effectiveness of the combination treatment over six weeks.

Lead author Michael Li, M.D., of the Center for Behavioral and Addiction Medicine at the University of California, Los Angeles, and colleagues noted that methamphetamine and other amphetamine-type stimulants account for the second largest class of substances used by people globally. Over the past decade, overdose deaths due to methamphetamine have increased about fivefold in the United States, and there is currently no approved medication to treat methamphetamine use disorder, they wrote.

In ADAPT-2, 403 individuals with methamphetamine use disorder were randomized to receive either 380 mg injectable naltrexone every three weeks plus 150 mg extended-release bupropion weekly or placebo for 12 weeks; after six weeks, some placebo participants were randomly switched to the combination treatment. The primary outcome was decrease in methamphetamine use as defined by negative urine tests. Urine samples were obtained twice weekly during treatment, then once on week 13 and 16 post treatment. The study was carried out at multiple U.S. centers that are part of the National Institute on Drug Abuse Clinical Trials Network.

Participants receiving the combination treatment over 12 weeks had about an 18% increase in negative urine tests after the first six weeks, and a further 9% increase in negative urine tests during the second six weeks for a total increase of 27% over the 12-week period. In comparison the number of negative urine tests increased by about 11% for those receiving placebo in that same period.

Urine tests at week 13 and 16, after treatment had ended, showed no significant difference between the two groups, suggesting that the decrease in methamphetamine use during the 12 weeks was due to treatment.

“Prior stimulant use disorder treatment trials suggest that change in use is gradual (consistent with our findings), unlikely to result in sustained abstinence in a typical 12-week trial, and dependent on treatment duration,” wrote Li and colleagues. “This warrants future clinical trials to quantify changes in [methamphetamine] use beyond 12 weeks and to identify the optimal duration of treatment with this medication.”

For related information, see the Psychiatric News article “Naltrexone-Bupropion Combination May Reduce Methamphetamine Use.”

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Brief, Culturally Sensitive Screener Helps Primary Care Providers Diagnose Dementia

Older, socioeconomically disadvantaged patients with cognitive concerns were nearly three and a half times more likely to receive improved dementia care when a brief, culturally sensitive screening test was deployed at their primary care clinic, according to a study in Nature Medicine.

“Despite the availability of many cognitive assessment tools, dementia is often undiagnosed; over half of dementia cases are missed in primary care. This problem is more prevalent among older Black and Hispanic people than older white people in the United States,” wrote Joe Verghese, M.D., M.S., at the Albert Einstein College of Medicine in Bronx, N.Y., and colleagues.

Verghese and colleagues enrolled 1,200 older adults with cognitive concerns (average age 73; predominantly Black or Hispanic) who resided in economically disadvantaged neighborhoods in Bronx County. Participants’ cognition was evaluated at their primary care clinic, with half receiving a frailty/grip strength test and a health literacy assessment and half receiving the 5-Cog, a non-language-based assessment that incorporates photographic recall, symbol matching, and a gait test. Both evaluations were administered by research assistants and were paired with a set of recommendations in the electronic medical records to assist doctors when making dementia care choices.

Patients screened with 5-Cog were 3.43 times more likely to receive improved dementia care within 90 days compared with the control group; improved care included receiving a new diagnosis of mild cognitive impairment (MCI) or dementia or the ordering of lab tests, imaging, medication prescriptions, or specialist referrals for cognitive indications. The majority of the 242 participants in the 5-Cog group who received a diagnosis were given the diagnosis on the same day as their assessment (89%). New prescriptions were rare in both groups (1.0% versus 0.3%).

The researchers acknowledged that MCI and dementia classifications were not based on a neuropsychological evaluation, but such an evaluation “takes over an hour and is neither routine nor practical for detecting cognitive impairment in primary care. This approach is reflective of the real world.” The researchers also noted that their results do not apply to asymptomatic patients, calling for a study on the utility of the 5-Cog in a general primary care population.

For more information, see the Psychiatric News article “Common Dementia Screening Tests Often Misclassify Patients.”

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Service Dogs Prove Their Worth in PTSD Clinical Trial

Service dogs with specialized skills may help reduce symptoms of posttraumatic stress disorder (PTSD) in veterans in as little as three months, a study in JAMA Network Open has found.

“These results are notable given the relatively short follow-up period [of 3 months] compared with the typical service dog partnership length [of 8 years or more],” wrote Sarah C. Leighton, M.S., of the University of Arizona and colleagues.

The researchers enrolled 81 veterans with a diagnosis of PTSD who received a trained service dog as well as 75 veterans on a waiting list for a service dog. The service dogs were trained in specialized PTSD-related skills such as calming veterans when they feel distressed, positioning themselves to create personal space for veterans or guard their back, and offering a paw to greet people. All participants received unrestricted access to usual care.

The researchers analyzed the results of the participants’ self-reported PTSD Checklist for DSM-5 (PCL-5) to measure symptom severity at baseline and at three months. They also used the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) to assess PTSD diagnosis at baseline and at three months. Clinician raters were blinded to the study topic, design, timing, and how participants were grouped.

At three months, participants who received service dogs had a mean score of 41.9 on the PCL-5 (down from a baseline of 57), compared with 51.7 among participants on the waiting list (down from 55.7). Those who received service dogs also had a lower mean score of 30.2 on the CAPS-5 (down from 42), compared with 36.9 among participants on the waiting list (down from 40). Measures of depression, anxiety, and social isolation were lower in those who received dogs, as well.

“Based on standardized self-reported and clinician assessed symptom severity, service dog partnership may serve as an effective complementary intervention for military service–related PTSD,” the researchers wrote. “Including both subjective (self-report) and objective (blinded clinician assessment) measures of PTSD symptoms strengthens the reliability of these findings and reflects clinical practice to help inform evidence-based practices.”

For related information, see the Psychiatric News special report “How Companion Animals Can Participate in Treatment of Mental Illness.”

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Emotion-Focused Therapy Comparable to CBT at Preventing Relapse Among Bipolar Patients

Skills-focused cognitive-behavioral therapy and emotion-focused psychotherapy were equally effective at preventing relapse in patients with bipolar disorder when added to standard treatment, reports a study in JAMA Psychiatry. What affected the relapse rate more than the therapy delivered was whether the patients attended all their psychotherapy sessions and whether they had bipolar I versus bipolar II disorder.

Martin Hautzinger, Ph.D., of Eberhard Karls University in Tuebingen, Germany, and colleagues enrolled 305 adults with stabilized bipolar disorder (68% with bipolar I and 32% with bipolar II) for this comparative study. The participants were assigned to one of two group psychotherapy programs as an add-on to their usual care, which included lithium and/or other medications and routine clinical visits. The psychotherapies were as follows:

• SEKT, a skill-oriented version of cognitive-behavioral therapy that integrates elements of mindfulness and interpersonal social rhythm therapy (building healthy sleep and social routines).
• FEST, an unstructured, emotion-focused therapy that teaches participants to understand their feelings and emotional processes during personal problems to help prevent depression or mania recurrence.

Both programs involved 24 hours of therapy in a small group setting, split into four full-day sessions over five months. Participants were assessed for any depressive or manic symptoms 2 to 4 weeks after their last therapy session, and again 6 and 12 months later.

At the 12-month follow-up, 49% of participants in the SEKT group and 46% in the FEST group experienced symptom relapse, after making statistical adjustments to match the groups (the SEKT group had a higher percentage of bipolar II patients). Regardless of therapy type, individuals with bipolar II were more likely to experience relapse than those with bipolar I (61% versus 42%, respectively); individuals with bipolar II receiving SEKT had the highest relapse rate at 70%. Other factors that increased the risk of relapse included the presence of a psychiatric comorbidity and missing two or more therapy sessions.

Hautzinger and colleagues wrote that a large majority of the study participants had previous psychotherapy experience. “For them, another structured, educational, and exercise-oriented treatment (SEKT) did not provide any new information, skills, or preventive strategies, whereas the open, supportive FEST treatment allowed for personal input, mutual support, and the activation of personal resources. This might explain why FEST was well received and successful.

For related information, see the American Journal of Psychotherapy article “Psychosocial Interventions for Bipolar II Disorder.”

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1 in 6 Who Stop Antidepressants Experience Discontinuation Symptoms, Analysis Finds

About 1 in 6 individuals who stop taking their antidepressant experience at least one withdrawal symptom such as dizziness, headache, insomnia, or irritability, according to the results of a study published yesterday in Lancet Psychiatry. About 1 in 33 individuals experience severe withdrawal symptoms such that they would drop out of a clinical trial or restart their antidepressant.

“Today, the existence of symptoms emerging after antidepressant discontinuation or dose reduction is no longer questioned: Recent national and transnational clinical practice guidelines recommend informing patients on the risks of abrupt antidepressant discontinuation and suggest tapering of antidepressive agents,” wrote Jonathan Henssler, M.D., of the University of Cologne in Germany and colleagues.

“What remains controversial is the incidence and severity of symptoms,” they continued.

To address this, Henssler and colleagues collected data from 79 studies that assessed adverse symptoms following antidepressant discontinuation whether patients did so intentionally or unintentionally as part of a clinical trial. Medication “discontinuation” included both abrupt stopping and dose tapering (typically over one to four weeks). The researchers included patients taking antidepressants for any psychiatric illness except for pain due to an organic disease such as cancer.

Their final sample encompassed 44 randomized clinical trials and 35 observational studies, encompassing 16,532 patients who discontinued an antidepressant, and 4,470 patients who discontinued a placebo.

After factoring in potential placebo effects, the researchers calculated that a little over 15% of people stopping their antidepressant experienced at least one discontinuation symptom, while around 3% experienced severe symptoms.

Some findings related to specific medications were as follows:

• Desvenlafaxine, venlafaxine, imipramine, and escitalopram were associated with a higher frequency of symptoms.
• Desvenlafaxine, venlafaxine, imipramine, and paroxetine were associated with a higher severity of symptoms.

The incidence of discontinuation symptoms was similar in people who stopped abruptly and those who tapered, though Henssler and colleagues cautioned that since tapering protocols were varied, no firm conclusions should be drawn. Residual or reemerging psychiatric illness also should be considered when interpreting the results, they wrote, “but our findings can inform clinicians and patients about the probable extent of antidepressant discontinuation symptoms without causing undue alarm.”

For related information, see the Psychiatric News article “To Minimize Medication Withdrawal, Taper Slowly.”

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FDA Expert Panel Votes Against Approval of Psychedelic Drug MDMA for PTSD

Federal approval of psychedelic drugs for the treatment of intractable mental illnesses hit a snag yesterday as a Food and Drug Administration panel voted overwhelmingly against the approval of midomafetamine (MDMA) to assist with the treatment of posttraumatic stress disorder (PTSD).

By a vote of 10-1, FDA’s Psychopharmacologic Drugs Advisory Committee, composed of independent experts including psychiatrists, found that the benefits of MDMA did not outweigh its risks. The panel also voted 9-2 that the available data did not show the effectiveness of MDMA for the treatment of PTSD.

While the committee’s vote is not binding, the agency often follows its recommendations. The FDA expects to render a final decision on the application by Lykos Therapeutics for its MDMA-assisted psychotherapy (MDMA-AP) by August 11.

"We remain committed to working with the FDA to address outstanding questions so that we may find a path forward to ensure the responsible and careful introduction of MDMA-assisted therapy into the health care system, if approved,” said Amy Emerson, chief executive officer of sponsor Lykos Therapeutics, in a media release following the decision.

MDMA, also known as ecstasy, is a psychedelic that can elicit feelings of empathy or social connectedness in users, potentially enhancing the benefit obtained from psychotherapy by reducing sensations of fear or threat.

Prior to the meeting, an FDA analysis pointed out that while the sponsor’s two clinical trials showed significant improvement in PTSD symptoms among participants who took MDMA, they also raised major concerns. The issues included lack of blinding that could inject biases; significant increases in blood pressure and pulse; limited clinical laboratory data and incomplete QT-interval assessments; and lack of long-term outcome data. During yesterday’s meeting, the advisory committee also raised concerns about sexual abuse that occurred during the clinical trial.

APA submitted comments to the FDA advisory committee last month expressing support for research into use of psychedelic agents in general, but stressed such endeavors must be conducted with the same scientific integrity and regulatory standards afforded to other emerging therapies. APA also urged a cautious approach: “[A]ny FDA approval of MDMA must be accompanied by rigorous regulations, strict prescribing and dispensing controls, comprehensive patient education, and ongoing monitoring and surveillance systems,” according to the letter.

The Institute for Clinical and Economic Review (ICER) also issued a research report last month rating the evidence presented by Lykos as “insufficient” and expressing substantial concerns about the clinical trial results’ validity. In the report, ICER pointed out that the trials were essentially unblinded as nearly all patients who received MDMA correctly identified that they were in the MDMA group.

“This would always raise concerns about bias, but these concerns are particularly heightened as we heard from multiple experts about the very strong prior beliefs of those involved in the trials (as investigators, therapists, and patients) about the benefits of MDMA-AP,” the ICER report stated. Furthermore, some therapists involved in the trial allegedly encouraged participants to give the drug favorable reviews and discouraged participants from reporting substantial harms.

For related information, see APA’s “Position Statement on the Use of Psychedelic and Empathogenic Agents for Mental Health Conditions.”

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PTSD is More Heritable in Females Than Males, Study Finds

Females appear to be genetically more prone to posttraumatic stress disorder (PTSD) than males, according to a report published today in AJP in Advance. This analysis of twins and siblings confirms that PTSD is moderately heritable, with environmental effects unique to the individual who experiences trauma also contributing to the disorder.

“There are well-established sex differences in the prevalence of PTSD, whereby females are approximately twice as likely as males to develop PTSD, a disparity that is robust against trauma type, diagnostic criteria, and methodology,” wrote Ananda Amstadter, Ph.D., of Virginia Commonwealth University and colleagues. This disparity underscores the need to examine genetic differences in PTSD risk across the sexes, they continued.

The researchers made use of data from Swedish national registries to investigate the genetic and environmental factors influencing PTSD among 16,242 twin pairs and 376,093 sibling pairs who were within two years of age of each other; all subjects were born between 1955 and 1980. A total of 148,823 unique individuals were diagnosed with PTSD; the lifetime prevalence of the disorder was higher among females than males (27.8% vs. 11.8%).

The study revealed a modest influence of genetics on the development of PTSD, with that influence being greater among females (35.42%) than among males (28.60%). Unique environmental effects—that is, influences that were not necessarily shared by twins or siblings—accounted for the remaining variance.

Amstadter and colleagues found that the genes that influence PTSD in women and men are not entirely the same, suggesting one line of future research should investigate the genetic influences of sex hormones—estrogen and testosterone—which may play a role in the disorder.

They noted, as well, that one recent meta-analysis of trauma-focused PTSD treatments found a higher rate of treatment response for women versus men. “Although the source of these differential psychosocial treatment effects is not yet known, they constitute a growing area of research,” Amstadter and colleagues wrote. “One such future direction includes the exploration of genetic influences on treatment response.”

For related information, see the Psychiatric News article “Genetic Makeup May Affect PTSD Risk.”

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Study Highlights Tobacco Industry’s Research on Using Menthol To Manipulate Smokers

A study in Drug and Alcohol Dependence has found that beginning in the 1970s, tobacco companies added menthol to regular, nonflavored cigarettes imperceptibly, or subliminally, to alter perceived harshness, strength, mouthfeel, and after-taste. The study also found that tobacco companies began looking into using menthol as a subliminal additive as early as the mid-1950s, when filtered cigarettes, which generally have a milder tobacco taste than unfiltered cigarettes, shot up in popularity among smokers.

“The companies studied which concentrations of menthol (including levels detectable and subliminal … to smokers) increase experimentation, promote initiation and progression to regular smoking, and attract specific demographic groups,” wrote Andre Luiz Oliveira da Silva, Ph.D., of the Brazilian Health Regulatory Agency in Rio de Janeiro, and colleagues.

Studies going back to 2009 have suggested that smoking menthol cigarettes makes it harder for people to quit smoking. More than 50 countries have now placed some restrictions on the use of menthol in tobacco products, though in most instances menthol is not banned outright but rather prohibited from being used as a primary flavor.

The researchers examined reports and other materials obtained from the Truth Tobacco Industry Documents archive, a web-based repository of millions of previously secret, internal documents in the tobacco industry dated from 1955 to 2012. These documents were revealed during litigation between U.S. states and the major tobacco companies and other sources.

As early as 1957, a “motivation survey” market research report showed that research was already being conducted about the importance of converting people who smoke nonmenthol cigarettes to menthol cigarettes.

The researchers found that the tobacco companies studied menthol’s sensory effects to determine how many parts per million of menthol they could add to their tobacco without smokers detecting it. The tobacco companies also considered which menthol concentrations to use with the goal of converting people who smoked nonmenthol cigarettes to menthol cigarettes. The reports showed the companies did not identify a precise menthol concentration to convert a nonmentholated smoker, and as a result they used a continuum of menthol levels across their brands.

“There is no scientific or health justification for allowing menthol, its derivatives, and/or synthetic cooling chemicals as tobacco/nicotine product additives or flavor add-ons at any concentration,” the researchers wrote. “The industry research and product development activities described here indicate that just prohibiting menthol as a characterizing flavor is at best an incomplete regulatory approach.”

For related information, see the Psychiatric News article “FDA Bans Some Flavored E-Cigarettes but Advocates Say Policy Falls Short.”

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Psychiatric News Seeks Contributions From Members

New Editor in Chief Adrian Preda, M.D., invites APA members to become involved in Psychiatric News by writing news or opinion articles on the topic of their choice or by applying for leadership positions to invite and curate articles from other members in new sections that include the areas of technology, sex and gender issues, advocacy, psychotherapy, integrated psychiatry and primary care, and consultation-liaison psychiatry. Interested? For more information, send an email to editor@psych.org.