Continuous Clozapine Use Linked to Lower All-Cause Mortality, Meta-Analysis Shows

Patients who took clozapine on a long-term basis had a longer life expectancy than those taking other antipsychotics, according to a meta-analysis in Schizophrenia Bulletin.

The results should reassure clinicians concerned about the safety of long-term use of clozapine, especially with regard to cardiovascular-related adverse effects, wrote Jentien M. Vermeulen, M.D., of the University of Amsterdam and colleagues. “Combined with the known superior efficacy of clozapine for treatment-resistant schizophrenia, [this finding] is clinically highly relevant and may lead to alleviation of earlier concerns about the mortality risk when switching patients to clozapine.”

Vermeulen and colleagues systematically searched the medical literature for studies that followed patients at least 52 weeks and reported on mortality in adults diagnosed with schizophrenia-spectrum disorders who had received clozapine treatment continuously or at any time during the follow-up.

A total of 1,327 deaths from any causes were reported for patients with schizophrenia-spectrum disorders across 24 studies, eight of which compared patients exposed to clozapine with patients exposed to other antipsychotics. The studies including patients treated with clozapine continuously during follow-up had a median length of 7.2 years, and the studies including patients who ever used clozapine during follow-up had a median length of 5.9 years.

The long-term risk of death from any cause was significantly lower for patients continuously exposed to clozapine compared with patients continuously exposed to other antipsychotics. There was no significant difference in long-term mortality rates between patients who ever took clozapine but did not take it continuously throughout follow-up and those who took other antipsychotics.

The researchers said the findings suggest that the continuous effects of clozapine are most beneficial for prolonging life expectancy and that this effect seems to be diminished or lost when clozapine is discontinued.

For related information, see the Psychiatric News article “Clozapine, LAI Antipsychotics Found Best at Preventing Relapse.”

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Lamotrigine May Cause Serious Immune System Reaction, FDA Warns

The Food and Drug Administration (FDA) this week issued a safety announcement warning that the anticonvulsant medication lamotrigine (sold under the brand name Lamictal) can cause a rare but serious immune reaction. Lamotrigine is approved for the treatment of patients with epilepsy and maintenance treatment of bipolar I disorder to delay the time to occurrence of mood episodes in adults 18 and older.

According to the agency, there have been several reports of hemophagocytic lymphohistiocytosis (HLH) in patients taking lamotrigine. HLH, which triggers an uncontrolled immune system response, typically presents as a persistent fever (usually greater than 101°F). HLH can lead to severe problems with blood cells and organs throughout the body such as the liver, kidneys, and lungs.

“Health care professionals should be aware that prompt recognition and early treatment are important for improving HLH outcomes and decreasing mortality,” the notice stated. “Evaluate patients who develop fever or rash promptly, and discontinue lamotrigine if HLH or another serious immune-related adverse reaction is suspected and an alternative etiology for the signs and symptoms cannot be established.”

The FDA noted that since lamotrigine’s approval in 1994, the agency has identified eight cases worldwide of confirmed or suspected HLH associated with the medicine in children and adults. “This number includes only reports submitted to FDA and found in the medical literature, so there are likely additional cases about which we are unaware,” the safety notice stated.

In the eight cases examined, symptoms of HLH were reported to have occurred within 8 to 24 days following treatment initiation. “We determined there was reasonable evidence that lamotrigine was the cause of HLH in these eight cases based on the timing of events and the order in which they occurred. The patients in these cases required hospitalization and received drug and other medical treatments, with one dying.”

The agency is now requiring that the prescribing information in the lamotrigine label contain a warning about the risk of HLH. Other serious adverse reactions already included in the drug label include serious rashes, suicidal thoughts and actions, and aseptic meningitis.

Health care providers are encouraged to report adverse events involving lamotrigine to the FDA MedWatch program.

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Regular Exercise Lowers Odds of Developing Depression, Meta-Analysis Finds

Physical activity can protect against the development of depression, regardless of age and geographical region, according to a meta-analysis published yesterday in AJP in Advance.

Depressive disorders are the second leading cause of global burden of illness and account for more than 44 million years lived with disability, according to Felipe B. Schuch, Ph.D., of LaSalle University in Canoas, Brazil, and colleagues.

While previous reviews have suggested that physical activity can protect against the development of depression, this study is believed to be “the first pooled meta-analysis investigating this relationship, which allows a clearer understanding of a true association between an exposure and outcome, rather than when studies are considered separately,” Schuch and colleagues wrote.

The meta-analysis included 49 studies involving nearly 267,000 participants from across four geographic regions (Asia, Europe, North America, and Oceania), who were followed for an average of 7.4 years. Participants were free of depression or depressive symptoms at the outset of the studies.

The study found overall that people with higher levels of physical activity were significantly less likely to develop depression, compared with people with low levels of physical activity (adjusted odds ratio=0.83). Physical activity had a protective effect against the emergence of depression in young people (adjusted odds ratio=0.90), adults (adjusted odds ratio=0.78), and in elderly people (adjusted odds ratio=0.79). Protective effects against depression were found across geographical regions, with adjusted odds ratios ranging from 0.65 to 0.84 in Asia, Europe, North America, and Oceania, and against major depression diagnosis (adjusted odds ratio=0.86).

“Our meta-analysis suggests that physical activity is associated with a decrease in the risk of developing depression, which raises an inevitable question: How might physical activity offer protection against depression onset?” the authors wrote. “It is likely that no single mechanism can explain this relationship. A range of biochemical and psychosocial factors are likely responsible, including biological mechanisms through which exercise increases neurogenesis and reduces inflammatory and oxidant markers and activates the endocannabinoid system.”

“Our data further emphasize the importance of policies targeting increased physical activity levels,” they concluded. However, randomized, controlled trials are needed to discern whether physical activity can prevent the development of depression in those at highest risk of the disorder.

For related information, see the Psychiatric News article “Minimal Exercise May Help Prevent Future Depression.”

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Substance Use Associated With Conversion From Schizotypal Disorder to Schizophrenia

An estimated 25% to 50% of patients diagnosed with schizotypal disorder develop schizophrenia within five years. A study published today in JAMA Psychiatry suggests that substance use by these patients may be associated with conversion to schizophrenia.

The findings highlight the need to educate this population about the risks associated with substance use and closely monitor patients’ substance use.

Substance use disorders are known to be common in patients with schizotypal disorder, but whether these disorders might be associated with conversion to schizophrenia was previously unclear, according to lead author Carsten Hjorthøj, Ph.D., M.Sc., of Copenhagen University Hospital and colleagues.

Hjorthøj and colleagues relied on data contained in Danish registries to identify a cohort of 2,539 people born in Denmark who had been diagnosed with schizotypal disorder. The researchers then tracked the patients from schizotypal diagnosis until diagnosis of schizophrenia, death, migration, or August 10, 2014.

According to the researchers, 16.3% of those with schizotypal disorder had experienced conversion to schizophrenia after two years. After 20 years, 30.6% of individuals without any substance use disorder had experienced conversion to schizophrenia. For those with cannabis use disorder, the 20-year conversion rate was 58.2%.

Further analysis revealed that cannabis use disorders, amphetamine use disorders, and opioid use disorders were associated with conversion to schizophrenia. “These associations were not explained by concurrent use of antipsychotics, functional level before incident schizotypal disorder, or parental history of mental disorders,” Hjorthøj and colleagues wrote.

Though the findings suggest substance use disorders—in particular cannabis, amphetamines, and opioids—may be associated with conversion from schizotypal disorder to schizophrenia, the authors noted that “conversion rates are high even in those without substance use disorders, indicating a need for universal and substance-targeted prevention in individuals with schizotypal disorder.”

For related information, see the Psychiatric News article “Early End to Substance Use Linked to Better Outcome in First-Episode Psychosis.”

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Antidepressants May Be Less Effective in Patients With Mild General Anxiety Disorder, Panic Disorder

Patients with mild general anxiety disorder (GAD) or panic disorder (PD) may be less likely to benefit from antidepressants than patients with severe cases of these disorders, suggests a meta-analysis in Depression and Anxiety.

While previous studies have suggested that the benefits of antidepressants are smaller in patients with mild versus severe symptoms of depression, few have examined how symptom severity might influence other conditions for which antidepressants are prescribed.

Ymkje Anna de Vries, Ph.D., and colleagues of the University of Groningen, The Netherlands, combined patient data from randomized, controlled trials of selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors in 3,430 patients with GAD; 1,195 with social anxiety disorder (SAD); 1,132 with obsessive-compulsive disorder (OCD); 1,071 with posttraumatic stress disorder (PTSD); and 2,151 with panic disorder (PD). All of the trials involved patients who were treated with either duloxetine, fluoxetine, paroxetine, or placebo.

The authors found that symptom severity moderated antidepressant efficacy in patients with GAD and PD. For GAD, the symptom improvements in patients taking an antidepressant relative to those taking placebo were 1.4 points on the Hamilton Anxiety Rating Scale (HAM-A) for participants with mild anxiety (baseline HAM-A score=10), 2.7 points for patients with moderate anxiety (baseline HAM-A score=20), and 4.0 points for severe anxiety (baseline HAM-A score=30). Compared with patients taking placebo, patients with mild PD (10 panic attacks every two weeks at baseline) experienced 0.4 fewer panic attacks every two weeks, patients with moderate PD (20 panic attacks/two weeks at baseline) experienced 0.9 fewer panic attacks every two weeks, and patients with severe PD (40 panic attacks/two weeks at baseline) experienced 4.7 fewer panic attacks every two weeks.

Regardless of initial symptom severity, patients with SAD, OCD, and PTSD responded similarly to antidepressants.

“To understand the implications of these findings, it should be noted that the clinical relevance of a treatment effect is context-specific, depending on such factors as the expected sequelae of the disease, the costs and drawbacks of the treatment, and the efficacy of alternative treatments,” de Vries and colleagues wrote.

“[I]t is clear that the risk-benefit ratio for GAD and PD becomes less favorable as initial severity decreases. It is therefore imperative that clinicians transparently discuss the expected benefits of antidepressants with patients with mild to moderate symptoms,” they concluded.

For related information, see the Psychiatric News article “Percentage of Americans Taking Antidepressants Climbs.”

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Handgrip Strength May Offer Clues About Cognitive Function in People With Mood Disorders

Handgrip strength may provide a useful indicator of cognitive impairment in people with major depression and bipolar disorder, according to a study in JAMA Psychiatry. 

Joseph Firth, Ph.D., of the University of Western Sydney and colleagues found that greater grip strength in individuals with major depression and bipolar disorder was associated with better performance on measures of reasoning, reaction time, and memory.

Firth and colleagues analyzed data from the UK Biobank—a nationwide, health-oriented, cohort study conducted across the United Kingdom. The final analysis included 110,067 people who had their handgrip strength evaluated (each participant received a single, maximum score indicating the greatest strength for each hand). The participants also performed a variety of cognitive functioning tasks on a computer (these tasks evaluated visuospatial memory, reaction time, reasoning, prospective memory, and numeric memory).

Of the group, 85,893 participants had no indication of any mood disorders, 22,699 reported recurrent major depression, and 1,475 reported bipolar disorder (type I or type II). The mean age of the healthy control, bipolar disorder, and major depression samples was 53.7 years, 54.4 years, and 55.5 years, respectively.

In participants with major depression and no indication of any mood disorders, greater handgrip strength was a significant predictor of better cognitive performance in all five domains: visual memory, reaction time, reasoning, number memory, and prospective memory. In people with bipolar disorder, greater handgrip strength was significantly associated with visual memory, reaction time, reasoning, and prospective memory. 

“To our knowledge, this study is the first to identify handgrip strength as a marker of cognitive function in mood disorders,” Firth and colleagues wrote. “However, the cross-sectional design of this investigation means that further longitudinal and mechanistic research must be conducted to determine the causative nature of the association between handgrip strength and cognition in psychiatric populations.”

Noting that strength training exercise interventions have been shown to improve cognitive functioning in aging populations, the authors suggested that improving muscular fitness may be a “therapeutic target” for individuals with mood disorders. 

“Future research should investigate causality, assess the functional implications of handgrip strength in psychiatric populations, and examine how interventions to improve muscular fitness affect neurocognitive status and socio-occupational functioning,” they concluded.   

For related information, see the Psychiatric News article “Minimal Exercise May Help Prevent Future Depression.”

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Identifying, Treating Mothers’ Depression Could Positively Impact Children’s Neurodevelopment, Study Suggests

Children whose mothers experienced depression during and after pregnancy may be slower to hit early childhood developmental milestones than children whose mothers did not experience depression, suggests a study published this week in Depression & Anxiety. The findings demonstrate the benefit that early recognition and treatment of maternal depression symptoms can have on both mothers and children.

While previous studies have suggested symptoms of depression during and after pregnancy are associated with poorer neurodevelopmental outcomes in offspring, questions remain about whether such symptoms during pregnancy and postpartum as well as early childhood periods exert different, independent, or additive effects on child neurodevelopment.

For the current study, Soile Tuovinen, Ph.D., of the University of Helsinki in Finland and colleagues examined maternal depression and child development data collected from women in Finland as part of the Prediction and Prevention of Pre-eclampsia and Intrauterine Growth Restriction (PREDO) study. A total of 2,231 mothers in the PREDO study completed the Center for Epidemiological Studies Depression Scale biweekly up to 14 times during pregnancy and twice up to 12 months after pregnancy. When the children were between 1.9 and 5.7 years old, the mothers completed the Beck Depression Inventory-II and filled out the Ages and Stages Questionnaire (ASQ), which asks caregivers to assess children’s fine and gross motor, problem solving, communication, and personal/social skills.

The researchers found that higher depression symptoms during and after pregnancy predicted lower ASQ total scores and subscale scores in fine and gross motor, communication, problem solving, and personal/social skills in children.

“The after-pregnancy effects were additive to those during pregnancy: children whose mothers had chronically elevated depressive symptoms during and after pregnancy had the poorest developmental milestones scores,” Tuovinen and colleagues wrote. “Compared with children whose mothers never had clinically significant depressive symptoms, neurodevelopmental scores were significantly worse for children whose mothers had clinically relevant depressive symptoms either only during pregnancy, both during and up to 12 months after pregnancy, or across all three developmental stages.”

The authors concluded, “[I]ntervention in early pregnancy may benefit both mothers and children: early treatment may prevent the accumulative cascade of depressive symptoms from pregnancy onwards, which may all possibly reflect positively on child neurodevelopment.”

For related information on efforts to recognize and treat pregnant and postpartum women with depression, see the Psychiatric News article “UMass Researcher Turns Idea Into a Nationally Recognized Program.”

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Naltrexone May Reduce Stimulant-Related Euphoria

Stimulants are a preferred option for treating attention-deficit/hyperactivity disorder (ADHD), but concerns remain about their potential for misuse. A small study in the Journal of Clinical Psychiatry now suggests that treating patients with ADHD with a combination of the opioid blocker naltrexone and methylphenidate could reduce the feelings of euphoria some patients experience when taking stimulants.

For the study, Thomas Spencer, M.D., the assistant chief of the Pediatric Psychopharmacology Research Program at Massachusetts General Hospital, and colleagues enrolled 37 young adults (aged 18 to 30) with ADHD who reported a feeling of euphoria when taking stimulants. The participants were randomly assigned to take either placebo or 50 mg naltrexone in the morning along with an extended-release methylphenidate formulation taken in the morning and afternoon (up to 80 mg/day). 

At baseline and three and six weeks later, the participants were asked to take a drug likeability test, where they answered questions about how good they felt after taking their medications. On the days they were given the drug likeability test, the participants took either an immediate-release methylphenidate pill in the morning or afternoon instead of their regular extended-release medication.

Spencer and colleagues observed that naltrexone significantly diminished the euphoric effect of immediate-release methylphenidate during the first three weeks of the study (the titration phase) but not during weeks 4 to 6 (the maintenance phase) of the study. Research has shown that stimulants pose the most risk for abuse when introduced abruptly and unevenly, such as the first few weeks of treatment when the optimal dose is being determined. “It is possible that the experience of euphoria attenuated because the study subjects only had mild euphoria at outset. Our nonsignificant effect for euphoria at week 6 should be viewed with caution due to the possibility of a floor effect, which would have reduced statistical power,” they wrote.

“[T]his double-blind, randomized clinical trial showed that treatment with naltrexone diminished the euphoric effect of immediate-release methylphenidate during the initial methylphenidate titration period of heightened vulnerability,” Spencer and colleagues continued. “If confirmed, these findings could lead to the development of a nonaddictive form of stimulant treatment for ADHD, which could facilitate access to an effective ADHD treatment.”

For related information, see the Psychiatric News article “Six-Question Screen for ADHD Developed for Adults.”

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Timing of First, Second Deployments May Influence Soldiers’ Risk of Suicide, Study Suggests

Soldiers who deployed overseas within their first year of service in the Army are twice as likely as their peers to attempt suicide after a subsequent deployment, reports a study published today in JAMA Psychiatry. Soldiers who have less than six months between their first two deployments are also at greater risk of attempting suicide.

“These time-related deployment variables are potentially modifiable risk factors for SA [suicide attempt],” wrote Robert J. Ursano, M.D., of the Uniformed Services University of the Health Sciences in Bethesda, Md., and colleagues. “Further consideration should be given to how well the timing of first deployment corresponds with the U.S. Army’s training and preparedness goals for new soldiers.”

While a previous study found that soldiers who were deployed in their first year of service were at an elevated risk of death by suicide in the short term, it was unknown what long-term impact deployment within the first year may have on suicidal behavior during or after subsequent deployments.

Ursano and colleagues analyzed data from Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS), which includes health information on more than 1.5 million soldiers who were on active duty between January 1, 2004, and December 31, 2009. They identified 593 soldiers with a medically documented suicide attempt during or after their second deployment, as well as 19,034 matched controls with two deployments.

After adjusting for sociodemographic factors, service-related characteristics (such as age at entry into U.S. Army) and mental health history, Ursano and colleagues found that the odds of a suicide attempt during or after the second deployment were twice as high among soldiers whose first deployment occurred within the first 12 months of service compared with those who deployed after 12 months.

Although the duration of the first deployment was not associated with a higher risk for suicide attempt, the researchers found that the length of time between the first and second deployments (dwell time) was a factor in suicide attempts during or following the second deployment. Soldiers with a dwell time of six months or less had 1.6 higher odds of suicide attempt compared with those with dwell times of more than six months.

Further analysis suggested that suicide attempts might be reduced by about 14% if all soldiers served in the U.S. Army for more than 12 months before their first deployment. Additionally, dwell time of longer than six months for all soldiers could result in a 4% reduction in suicide attempts among those who have deployed twice, the authors noted.

“Future research that examines factors associated with DT [dwell time], including type and extent of social support at home, training and reset opportunities, parenting and household responsibilities and challenges, and family and financial stressors, would provide a better understanding of the association between this period and SA [suicide attempt] risk,” Ursano and colleagues concluded.

To read more on this topic, see the Psychiatric News article “Suicide Attempts Linked to Previous Attempts in Soldiers’ Unit, Says Army Study.”

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Peer Mentoring Found to Be Effective for People With Serious Mental Illness

Being paired with a person who is willing to share stories of their recovery from serious mental illness and provide coaching and encouragement may lead patients with serious mental illness to experience greater improvements in psychiatric symptoms and functioning than those who receive standard care only, according to a study published yesterday in Psychiatric Services in Advance.

“This study provides evidence in support of theories and emerging research that peers may play uniquely beneficial roles in connecting with individuals who may be difficult to engage or less responsive to traditional outpatient care,” wrote Maria O'Connell, Ph.D., of Yale University School of Medicine and colleagues.

O'Connell and colleagues enrolled 76 patients who were diagnosed with a major psychotic or mood disorder and had at least two psychiatric hospitalizations or more than three emergency department visits within the past 18 months. The study participants were randomly assigned to either standard inpatient and post-discharge community care or standard care plus a peer mentor. Peer mentors were individuals who self-identified as being in recovery from serious mental illness and who agreed to share their experiences to assist others. The mentors were trained in principles of recovery psychiatry by the study supervisors, but were also instructed to work independently and use their own experiences as the basis from which to provide support.

Nine months after hospital discharge, participants assigned to mentors had greater reductions in substance use as well as greater improvement in several components of the Brief Psychiatric Rating Scale (BPRS), including physical health, hygiene/self-care, and unusual behavior compared with those who received standard care only. Individuals with mentors also had a significantly longer average time to rehospitalization than those receiving standard care—270 days compared with 135 days.

“The suggestive findings from this randomized but small-scale study warrant further testing with larger and more representative samples,” the authors concluded. “To the degree that they are useful, though, they suggest that peer support services that build explicitly and directly on a peer’s lived experiences of mental illness and recovery may offer more than simply adjunctive, nonspecific support.”

To read more on this topic, see the Psychiatric News article “Orientation Program Shows Value of Recovery-Oriented Care.”

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Intranasal Esketamine Found Effective in Rapid Reduction of Depression, Suicidal Thoughts

Intranasal esketamine—a derivative of ketamine—appears to rapidly reduce symptoms of depression, including suicidal thoughts, in depressed patients determined to be at imminent risk of suicide, according to a report published today in AJP in Advance.

“This is a significant and important study because it provides early evidence demonstrating that esketamine produces antidepressant effects greater than that found with intensive standard of care approaches over the first hours and days of treatment in patients believed to be at imminent risk of suicide requiring hospitalization,” study co-author Gerard Sanacora, M.D., Ph.D. (pictured at left), told Psychiatric News. “If confirmed, this type of rapid onset antidepressant effect could potentially shorten hospital stays or possibly even allow patients to avoid hospitalization altogether and more rapidly return to their normal lives.”

In the study, sponsored by Janssen Research and Development LLC, 68 patients with a diagnosis of major depressive disorder were randomly assigned to receive esketamine (84 mg) or placebo twice weekly for four weeks. Candidates were screened shortly after presenting to an emergency department or an inpatient psychiatric unit in the previous 24 hours and found to be in clinical need of acute psychiatric hospitalization due to imminent risk for suicide.

The study participants were asked about depressive symptom severity (using Montgomery-Åsberg Depression Rating Scale, or MADRS) before receiving their initial dose of ketamine or placebo as well as four and 24 hours later. Depressive symptoms were reassessed at each follow-up visit during the study. Clinicians were also asked to evaluate the suicide risk of the study participants throughout the trial (using the Suicide Ideation and Behavior Assessment Tool).

Throughout the trial, patients in both groups received optimized standard-of-care antidepressant medication.

A significantly greater improvement in MADRS score was observed in the esketamine group compared with the placebo group at 4 hours and at 24 hours. Significantly greater improvement was also observed in the esketamine group on the MADRS suicidal thoughts item score at 4 hours. Additionally, a significantly greater proportion of patients in the esketamine group achieved resolution of suicide risk 24 hours after the first dose, as defined by a clinical global judgment of suicide risk score of 0 to 1. This finding is consistent with results of a recently published meta-analysis of intravenous ketamine, which reported similar differences in ketamine compared with control agent in the proportion of patients without suicidal ideation one day after dosing.

At one month, patients in both the treatment and placebo arms had met remission criteria, defined as a MADRS score of 12 or less, but the statistically significant advantage over placebo disappeared for esketamine on measures both of depressive symptoms and suicidality at Day 25.

“If positive, longer-duration results emerge for intranasal esketamine, it is possible that this treatment will help a significant number of patients who do not respond adequately to existing antidepressant therapies,” AJP Editor Robert Freedman, M.D., and members of the AJP Editorial Board wrote in an accompanying editorial.

Ketamine has been used recreationally as a “party” drug, and the authors added that safeguards need to be established against the risk of abuse. “The FDA and the pharmaceutical companies marketing ketamine have the primary ability to control how the drug is distributed and in what circumstances it can be used, but input from psychiatrists and other interested professional groups as well as the Centers for Disease Control and Prevention and the National Institute on Drug Abuse, should inform the development of effective controls.”

For more information, see the Psychiatric News article “Cautious Optimism' Marks Outlook for Ketamine, Mood Disorders.”

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TBI Found to Increase Long-Term Risk of Dementia

A study of nearly 2.8 million adults spanning 36 years suggests that people with traumatic brain injury (TBI) are more likely to develop dementia than those with no history of TBI. The findings, which were published this week in Lancet Psychiatry, demonstrate the heightened risk of dementia years following a TBI.

TBI affects 47 million people globally and is a major cause of mortality and disability, yet large-scale studies with long follow-up have been sparse, wrote lead author Jesse Fann, M.D., M.P.H., a professor of psychiatry and behavioral sciences at the University of Washington School of Medicine, and colleagues. The researchers used the Danish Civil Registration System to track a cohort of 2,794,852 people aged 50 and older. Of this group, 132,093 individuals (4.7%) had at least one TBI diagnosis between 1977 and 2013, and 126,734 (4.5%) developed dementia between 1999 and 2013. 

Fann and colleagues found that the risk of dementia in people with a history of TBI was higher than in those without a history of TBI (hazard ratio[HR]=1.24), as was the specific risk of Alzheimer's disease (HR=1.16). The risk of dementia was highest during the first 6 months after TBI (HR=4.06), after which it gradually decreased (HR=1.17 at more than 14 years since TBI). The risk of dementia also increased consistently with increasing number of TBIs. 

“The risk was highest among people with multiple TBIs and those who sustained a severe TBI, but the risk was significant even after a single mild TBI and remained high for many years after injury,” the authors concluded. “Considering the increasing burden of dementia and the high prevalence of TBI globally, heightened efforts are needed to prevent TBI, particularly among younger individuals, and strategies to ameliorate the risk and impact of subsequent dementia must be identified.”

For related information on assessing TBI, see the Psychiatric News article “Computer-Based Tool Can Offer Rapid Screening After TBI.”

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Register Now to Vote for Leaders of APA’s Minority and Underrepresented Caucuses

APA members have formed seven Minority and Underrepresented (M/UR) Caucuses, which provide networking opportunities, advance treatment of minority patient populations, advocate for minority mental health issues, provide representation in APA governance, and foster communication among members who share interests. To vote in the upcoming elections of the leaders of these caucuses, APA members must join their desired caucus and select their voting caucus by April 30, 2018.

These caucuses are free and open to all APA members who are interested in topics concerning psychiatrists or patients belonging to the following seven groups: American Indian/Alaska Native/Native Hawaiians, Asian Americans, Blacks, Hispanics, LBGTQ members, International Medical Graduates, and Women.

While APA members may join more than one caucus, APA members can vote for the leadership of only one caucus. If you are an APA member who is already a registered caucus member, you must still select the caucus in which you wish to vote. To join a caucus or update your caucus membership, please log in to your member profile. Details on the nominations and election processes will be provided to caucus members who register by April 30, 2018.

For more information on the caucus leadership positions that will be open for election, check out the Minority and Underrepresented (M/UR) Caucus Elections webpage or contact Omar Davis of the APA Division of Diversity and Health Equity at odavis@psych.org.

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Disordered Eating Behavior in Youth May Increase Future Risk of Depression

Youth who display behavior commonly associated with eating disorders may be at a greater risk of future depressive symptoms and bullying by peers, reports a study published today in JAMA Psychiatry. Disordered eating behavior includes such actions as eating in secret or purposefully vomiting after a meal.

The findings suggest that “interventions to treat disordered eating behavior could prove to be beneficial for reductions in depressive symptoms and problematic peer relations,” wrote study authors Kirsty S. Lee, Ph.D., and Tracy Vaillancourt, Ph.D., of the University of Ottawa. “Interventions for disordered eating behavior should ideally target negative attitudes, promote healthy weight control behavior, and contain an element of self-compassion, which can reduce symptoms of disordered eating and other psychopathologic symptoms.”

To examine the concurrent and long-term relationship between bullying by peers, disordered eating behavior, and symptoms of depression, Lee and Vaillancourt analyzed data from the McMaster Teen Study—an ongoing longitudinal study that has been collecting information about bullying and mental health in youth annually since 2008 (when the participants were in 5th grade, or about 10 years old). The current analysis focused on data collected from students in grades 7 through 11 (aged 13 to 17).

A total of 612 students completed annual online or paper questionnaires, which asked them to gauge how often they experienced bullying at school, engaged in disordered eating behavior, and felt depressed.

A statistical model used by the authors revealed that “bullying by peers was concurrently associated with disordered eating behavior and depressive symptoms at every time point during the five-year period,” they reported. The model also revealed that disordered eating behavior was associated with increases in depressive symptoms in the following year.

“Notably, the pathway was always from disordered eating behavior to depression and not depression to disordered eating behavior,” Vaillancourt told Psychiatric News by email. “Thus, a focus on disordered eating behavior could help prevent mood problems in teens, particularly girls (the link between disordered eating behavior and depression was stronger in girls compared with boys).”

For related information on eating disorders, see the book Handbook of Assessment and Treatment of Eating Disorders, by APA Publishing.

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Be Aware of Drug Interactions With Lithium to Avoid Toxicity

Medications that interact adversely with lithium appear to be a major driver of lithium toxicity, according to a report in Psychiatric Services in Advance.

“Collectively, our findings emphasize potentially interacting medications as an important target for population-based strategies to mitigate risk of ACS [acute care services] utilization for lithium toxicity,” wrote Lauren Heath, Pharm.D., and colleagues with Kaiser Permanente Colorado.

The researchers compared the characteristics of 50 patients exposed to lithium who presented with lithium toxicity for ACS with those exposed to lithium who did not experience lithium toxicity or utilize ACS. Cases were drawn from all Kaiser Permanent Colorado (KPCO) patients who filled at least one prescription for lithium between January 1, 2010, and December 31, 2014, and who had been a KPCO member for at least 365 days prior to the initial date of the ACS encounter for lithium toxicity.

Of 3,115 individuals who took lithium, 70 experienced unintentional lithium toxicity, with or without ACS utilization, for a prevalence of 2.2%. Among the 50 patients with lithium toxicity who sought ACS, 25 were hospitalized, 21 presented to the emergency department and were not hospitalized, and four presented to an urgent care facility. Five patients had been dispensed a potentially interacting medication with lithium within 28 days of developing toxicity (lisinopril, n=2; losartan, n=1; indomethacin, n=1; and furosemide, n=1).

The researchers found that utilization of ACS for lithium toxicity was associated with 30-fold higher odds of initiation of a possibly interacting medication. Patients who were older and being treated for a higher number of chronic diseases were also slightly more likely to seek acute services for lithium toxicity.

“Because we considered only potentially interacting medications that had been introduced in the past 28 days, the results reinforce the importance of efforts to immediately identify and adjust for interacting medications,” the authors wrote. “Elderly patients with a new prescription for a medication with the potential to interact dangerously with lithium are especially vulnerable to lithium toxicity.”

For related information, see the Psychiatric News article “Lithium Intoxication Manageable, Say Experts.”

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Lamotrigine Not Effective Option for Borderline Personality Disorder, Study Finds

While no medications are approved for the treatment of borderline personality disorder (BPD)—which is characterized by sudden changes in mood—several small, short-term studies have suggested mood stabilizers such as lamotrigine may be able to reduce core symptoms of the disorder. A study that compared mental health outcomes in patients with BPD who were prescribed lamotrigine with those prescribed placebo for 12 months found no differences between the two groups. The results were published Friday in AJP in Advance.

“[W]e found no evidence that prescribing lamotrigine for people with borderline personality disorder led to improvements in their mental health,” wrote Mike Crawford, M.D., of Imperial College London and colleagues.

To examine the long-term effects of lamotrigine on patients with BPD, Crawford and colleagues randomly assigned 276 adults with BPD to take either lamotrigine (up to 400 mg daily) or placebo for one year. All study participants continued to receive standard care, which included contact with primary and secondary health services, including access to psychological treatment services and inpatient admission if required. A total of 195 patients remained in the trial at 52 weeks.

The researchers found that there were no differences in patient symptom scores between the groups, which were measured with the Zanarini Rating Scale for Borderline Personality Disorder (ZAN-BPD) 3, 6, and 12 months after the study began. The average ZAN-BPD score was 11.3 in the lamotrigine group and 11.5 in the placebo group. There were no significant differences between the two groups in secondary outcomes (also assessed a 3, 6, and 12 months), including depressive symptoms, rates of self-harm, social functioning, and health-related quality of life.

The researchers also found that the use of lamotrigine did not reduce direct health care costs (such as hospital care or medication fees). At baseline, costs during the preceding six months were about $8,160 for patients in the lamotrigine group and $5,163 for those in the placebo group. The average total costs over the next year were $17,785 for the lamotrigine group and $12,340 for the placebo group, which resulted in no significant cost savings relative to placebo (The difference in cost was not statistically significant, according to the study authors).

“Clinicians may feel under considerable pressure to prescribe medication for people with borderline personality disorder, especially at times of crisis,” Crawford said. “In the absence of clear evidence suggesting benefits associated with any type of medication, nonpharmacological approaches should be offered.”

To read more on this topic, see the Psychiatric News article “Psychotherapy Found Generally Effective for Borderline Personality Disorder.”

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Study Challenges Halting Antipsychotics in Stabilized Patients With Schizophrenia After Several Years

Many guidelines for treating patients with schizophrenia with antipsychotics recommend that after stabilization, antipsychotics should be continued for one to five years, and, if possible, longer exposure should be avoided. A study published today in AJP in Advance by Jari Tiihonen, M.D., Ph.D., of the Karolinska Institutet in Stockholm and colleagues suggests that the risk of treatment failure or relapse after discontinuation of antipsychotic medication does not decrease the longer a patient is stable on antipsychotics and that long-term antipsychotic treatment is associated with increased survival.

“We expected to observe that relapse risk decreases as [a] function of time, and if the decrease reached a plateau at a certain time point, that might help in estimating an optimal duration of antipsychotic treatment among stabilized patients,” Tiihonen and colleagues wrote. “To our surprise, however, the risk of relapse and treatment failure related to antipsychotic discontinuation increased at least through the first eight years, and no hint of any safe timing for discontinuation of treatment could be observed.”

The authors gathered nationwide data of all patients hospitalized for schizophrenia in Finland from 1972 to 2014. The researchers focused their analysis on data from patients with a first hospitalization for schizophrenia to study the risk of treatment failure (defined as psychiatric rehospitalization or death) after discontinuation of antipsychotics.

The lowest risk of rehospitalization or death was observed for patients who received antipsychotic treatment continuously (adjusted hazard ratio=1.00), followed by patients who discontinued antipsychotic use immediately after discharge from their first hospitalization (hazard ratio=1.63), within 1 year (hazard ratio=1.88), within 1 to 2 years (hazard ratio=2.12), within 2 to 5 years (hazard ratio=3.26), and after 5 years (a median of 7.9 years) (hazard ratio=7.28). (Tiihonen told Psychiatric News by email that while some patients stopped taking antipsychotics after more than eight years, there were too few to draw conclusions about this population’s risk of treatment failure.)

The risk of death was 174% to 214% higher among patients who never started taking antipsychotics or stopped using them within one year of their first hospitalization in comparison with patients who consistently took medications for up to 16.4 years.

While the authors noted the potential value of identifying a subgroup of patients with schizophrenia who could discontinue antipsychotics without relapsing, they pointed out that compared with patients who took antipsychotics, those who did not take the medications or discontinued them early were at a greater risk of death. “This suggests that, in general, there is no valid argument for stopping antipsychotic treatment in patients with a first episode of schizophrenia on the basis of concerns about their long-term physical well-being,” they wrote.

For related information, see the Psychiatric News article “Benefits of Maintenance Antipsychotics Outweigh Risks, International Panel Concludes.”

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Early Intervention Service Improves Long-Term Survival in Patients With First-Episode Psychosis

Patients experiencing a first episode of schizophrenia-spectrum disorder who participate in an early intervention program may be less likely to die by suicide over the long term, suggests a study published Wednesday in JAMA Psychiatry.

Patients aged 15 to 25 with first-episode schizophrenia-spectrum (FES) disorders who received two years of early intervention services in Hong Kong were less likely to die by suicide (4.4%) than those who received standard care (7.5%) over the 12 years they were followed, according to Sherry Kit Wa Chan, M.R.C.Psych., of the University of Hong Kong and colleagues.

To evaluate the effect of early intervention on suicide risk, the study authors compared the suicide rates of 617 patients with FES who received the early intervention service with 617 patients with FES who received standard general psychiatric care over a 12-year period. Hong Kong’s early intervention service, deployed region-wide in 2001, is a phase-specific, assertive intervention based on the protocol of the Psychological Intervention Program in Early Psychosis.

The researchers found that patients receiving the early intervention service had significantly better survival, with the main difference observed during the first three years.

Patients with a high number of suicide attempts prior to being treated successfully were more likely to die by suicide during the first three years of the study. Meanwhile, patients with impaired occupational functioning prior to illness, poor treatment adherence, and higher relapse rates were more likely to die by suicide during years 4 to 12 of the study. “This finding highlights the importance of the further improvement of the early intervention model to effectively reduce the relapse rate,” the authors noted.

The significance of suicide attempts during the period of untreated psychosis highlights the importance of developing successful treatments faster for patients, the researchers wrote. In addition, “[s]uicide at different stages of schizophrenia was associated with unique risk factors, highlighting the importance of a phase-specific service,” the authors wrote.

For related information, see the Psychiatric News article “High Mortality Rate Found in Youth Newly Diagnosed With Psychosis.”

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Heavy Drinking in Adolescence Appears to Change Developing Brain

Initiating heavy drinking of alcohol during adolescence appears to alter normal brain development, suggests a study in the April issue of the American Journal of Psychiatry.

It is well known that during adolescence the brain undergoes significant changes—marked by decreases in gray matter (neuronal cell bodies, dendrites, unmyelinated axons, and synapses) and increases in white matter (myelinated axons that coordinate signals between neurons). To examine the effects of alcohol consumption on neurodevelopment, Adolf Pfefferbaum, M.D., of SRI International and colleagues compared structural MRI data from 483 youth aged 12 to 21 before the initiation of drinking and at follow-up one and two years later. Youth were also asked about their alcohol and marijuana use at each follow-up.

“At baseline, all participants met the study-entry criteria for no or low drinking and drug use,” Pfefferbaum and colleagues wrote. (No/low drinkers reported drinking less than one time per month, less than two drinks on average, and less than four drinks maximum). “As anticipated, however, a proportion of these youths (n=127) initiated drinking to levels that exceeded, to varying degrees, the study entry criteria, thereby enabling pursuit of a naturalistic study on the effects of drinking on the adolescent brain.”

At the two-year follow-up, 356 youth continued to meet the study’s no/low drinking criteria and 127 youth transitioned from the no/low drinking group to one of two drinking groups: 65 moderate drinkers and 62 heavy drinkers (see online data supplement for descriptions of alcohol consumption in heavy and moderate drinkers).

The authors found that while no/low drinkers experienced reductions in gray matter and increases in white matter over time, “[v]olumes of frontal, cingulate, and total gray matter declined more rapidly and central white matter expanded more slowly in the heavy drinkers than in the no/low drinking group.”

In an accompanying editorial, Jennifer L. Stewart, Ph.D., of Queens College, City University of New York, pointed out: “It is important to note that baseline gray and white matter volume alone did not differentiate the alcohol use groups, which suggests that the differences in brain structure were not present before onset of heavy alcohol use. On the contrary, increases in alcohol consumption paralleled aberrant structural brain changes over the two-year period, providing evidence supporting the idea that gray and white matter derailment is indeed present at early stages of problem alcohol use.”

“What we’re seeing here is an alteration in normal development,” Pfefferbaum said in the April AJP audio podcast. “When we did this study, we saw that children as young as 12 sometimes start drinking.” Clinicians should be sure to ask youth about alcohol and other drug use, just as they do adults, he said.

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Risk of Victimization Is High in Patients With Psychosis, Meta-Analysis Finds

A meta-analysis in Schizophrenia Bulletin found that rates of victimization were between 4 and 6 times higher among individuals with psychosis than in the general community.

“Every year approximately 1 in 5 individuals with a psychotic disorder becomes victimized,” wrote Bertine de Vries, Ph.D., and colleagues at the University of Groningen, the Netherlands. “Clinical factors such as hallucinations, delusions, manic symptoms, and a personality disorder may increase target attractiveness.”

The researchers searched the literature for studies reporting victimization rates among individuals with a diagnosis in the psychosis spectrum according to DSM-5, DSM-IV, DSM-III-R, or ICD criteria. Four categories of victimization were distinguished: violent victimization, sexual victimization, nonviolent victimization, and victimization not otherwise specified (studies that did not differentiate between victimization types or gave total score based on more than one type).

A total of 27 studies were included in the meta-analysis. When victimization was examined over a short period (less than 3 years) approximately 1 in 5 patients reported violent, nonviolent, sexual, or victimization not otherwise specified. When victimization was examined during their entire adulthood, 2 out of 3 people were found to have been a victim of violent victimization, and 39% reported nonviolent victimization. The median prevalence rate of sexual victimization among individuals with psychosis over their entire adulthood was 27%.

Clinical risk factors for victimization included delusions and hallucinations, the presence of a personality disorder, and/or manic symptoms. The meta-analysis also revealed that both drug and alcohol misuse and abuse are associated with victimization.

“The offender may see someone with many symptoms as an easy target, or they may provoke anger or aggression more easily in potential offenders,” de Vries and colleagues wrote. “People whose social functioning is impaired face additional risks because they may not be able to develop a social network that protects them and because they may have difficulty [detecting] social threats in time.”

The authors concluded, “More prospective research is needed to capture the causal trajectories of victimization and investigate mediating or moderating factors that protect or increase the victimization risk.”

For more information, see the Psychiatric News article “Schizophrenia and Violence Risk: Media Distort the Picture” and the Psychiatric Services article “Violence to Others, Violent Self-Victimization, and Violent Victimization by Others Among Persons With a Mental Illness.”

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Gender-Affirming Hormone Therapy Poses No Significant Health Risks in Youth, Study Finds

Many transgender youth undergo hormonal therapy so their physical gender more closely aligns with their gender identity. However, little is known about the safety and impact of gender-affirming hormones in youth, and some caregivers are cautious about using hormone therapy in transgender adolescents.

A study in the April issue of the Journal of Adolescent Health reports that hormonal therapy significantly alters many lab values in transgender youth, such as levels of potassium and hemoglobin. However, during the roughly two-year period of this study, almost none of these changes led to any clinical safety concerns.

“To our knowledge, this is the first prospective study examining the physiologic changes that occur among minors and young adults undergoing treatment with gender-affirming hormones, for the purpose of … gender transition,” wrote Johanna Olson-Kennedy, M.D., of Children’s Hospital Los Angeles and colleagues. 

Olson-Kennedy and colleagues enrolled 101 youth aged 12 to 23 who were planning to undergo gender transition at Children’s Hospital’s Center for Transyouth Health and Development and followed them for 21 to 31 months. At the end of the follow-up period, data were available for analysis on 59 participants (25 transfeminine and 34 transmasculine).

The transfeminine youth showed statistically significant changes in the levels of high-density lipoprotein (HDL), aspartate aminotransferase, potassium, prolactin, and hemoglobin at follow-up. Transmasculine youth experienced statistically significant changes in blood pressure, HDL, triglycerides, aspartate aminotransferase, alanine aminotransferase, potassium, and hemoglobin levels. None of these changes required any clinical intervention, with the exception of blood pressure elevation in some of the transmasculine youth that warranted hypertensive drugs.

“As the demand for care continues to exponentially increase across the United States, much more data are needed about the impact of hormonal therapy on both physical and mental health in transgender adolescents,” the authors concluded.

To read more on this topic, see the Psychiatric News article “Resident Helps Young People in Gender Transition Find Their Way.”

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