Prazosin May Reduce Heavy Drinking in Patients With Alcohol Use Disorder

Prazosin—an α-1 adrenergic receptor antagonist—may be able to help people with alcohol use disorder reduce heavy drinking over time, according to a study published this week in the AJP in Advance.

“This study supports the growing body of work suggesting that α-1 noradrenergic antagonists that cross the blood-brain barrier may help people limit unsafe heavy drinking,” wrote Tracy L. Simpson, Ph.D., of the VA Puget Sound Health Care System and colleagues.

Simpson and colleagues previously conducted a pilot study of 24 adults with alcohol dependence treated with prazosin for six weeks; the study found that those treated with prazosin reported fewer drinking days toward the end of the six-week trial than those treated with placebo. For the current study, the researchers assigned 92 participants with alcohol use disorder to receive prazosin or placebo in a 12-week double-blind study.

The study participants attended twice-weekly study visits during weeks 1 and 2—as prazosin was titrated (target dosing of 4 mg in the morning, 4 mg in the afternoon, and 8 mg at bedtime)—and then weekly study visits weeks 3 through 12. During the study visits, the researchers collected urine (to measure medication adherence), checked patient vitals such as blood pressure, and assessed the medication’s effects. Additionally, participants were asked to complete 4- to 5-minute interactive voice response calls daily to report the previous day’s drinking, cravings, and study medication doses consumed.

Analysis of data from the 80 participants who completed the two-week titration phase revealed that days of heavy drinking (≥4 drinks for women, ≥5 drinks for men) decreased more rapidly from week 3 to week 12 in the prazosin group than in the placebo group. Similarly, from week 3 to week 12, the prazosin group reduced the number of drinks per week by 8.0, compared with 1.5 for the placebo group. In contrast, at week 12 there was no difference between the two groups in the total number of drinking days or in craving changes over time, the authors noted. Participants in the prazosin condition were more likely to report drowsiness and edema than participants in the placebo condition.

“These results indicate that prazosin has the potential to reduce the likelihood of heavy drinking and number of drinks per week over time but not the number of drinking days per week,” Simpson and colleagues wrote. “[P]razosin may be most useful in reducing heavy drinking associated with negative consequences, which is consistent with a harm reduction approach characterized by safer consumption rather than full abstinence.”

For related information, see the Psychiatric News article “Varenicline May Lower Heavy Drinking, Smoking In Men With AUD.”

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Soldiers Who Attempt Suicide Often Have No Prior Mental Health Diagnosis

More than one-third of enlisted U.S. soldiers who attempted suicide (36%) had no previous mental health diagnosis, according to an study published yesterday in JAMA Psychiatry.

“It is likely such soldiers had undetected mental disorders,” wrote Robert J. Ursano, M.D., director of the Center for the Study of Traumatic Stress at the Uniformed Services University of the Health Sciences, and colleagues. Many factors may contribute to mental health problems going undiagnosed, including soldiers not perceiving a need for treatment or seeking help, they wrote.

Ursano and colleagues studied administrative data from the Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS), including records of 9,650 enlisted Army soldiers who had attempted suicide to pinpoint risk factors among those without a previous mental health diagnosis. The authors examined event report records, as well as army personnel, medical, legal, and family services records for soldiers who attempted suicide and compared them with soldiers with no history of suicidality or death.

More than 3,500 soldiers with a documented suicide attempt did not have a previous mental health diagnosis. Among these soldiers, those in the first year of service were most likely to attempt suicide (odds ratio [OR]=6). Among the other variables examined, suicide risk was also highest among soldiers with physical health care issues: inpatient hospitalizations (OR=3.8), eight or more outpatient visits in the past two months (OR=3.3), or past-month injury related outpatient care (OR=3.0). Soldiers with family violence, too, were 2.9 times more likely to attempt suicide.

Other significant risk factors for suicide attempt among soldiers with no prior mental health diagnosis included female sex (OR=2.6), previous deployment (OR=2.4), major violent crime perpetration (OR=2.0), or less than high school education (OR=1.9).

Most of these risk factors were also associated with suicide attempts among soldiers with a previous mental health diagnosis, although the strength of the associations differed. In both groups—soldiers with and without a history of mental health diagnosis—the odds of suicide attempt were higher among soldiers who were female, younger, non-Hispanic white, less educated, in their first four years of service, not currently deployed, with a delayed promotion or demotion, or an occupation of combat medic or combat arms.

“Interactions with medical, legal, and family services systems create assessment and prevention opportunities for soldiers with previously undetected suicide attempt risk,” the authors wrote. “Ensuring routine assessment of psychological distress and suicide risk during all encounters can help identify at-risk soldiers who are unknown to the mental health care system.”

For related information, see the Psychiatric News article “STARRS Findings Shed More Light on Army Suicides.”

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Ketamine's Antidepressant Effects Appear to Depend on Opioid System, Study Shows

The antidepressant effects of ketamine appear to depend on activation of the brain’s opioid receptors, underscoring the drug’s addictive potential, according to a report published today in AJP in Advance.

The study, by Alan Schatzberg, M.D. (pictured left), the Kenneth T. Norris Jr. Professor of Psychiatry and Behavioral Sciences at Stanford University School of Medicine, and colleagues, found that when patients with treatment-resistant depression were treated with the opioid antagonist naltrexone before receiving an infusion of ketamine, the antidepressant effects of ketamine were dramatically diminished.

“While opioids have a history of use as antidepressants, they pose a significant risk if used chronically,” Schatzberg and colleagues wrote. “Thus, the abuse and dependence potential of frequent ketamine treatment in major depression needs further study, and our results provide strong justification for further caution against widespread and repeated use of ketamine before further mechanistic testing has been performed.”

The researchers originally planned a crossover trial of 30 adults with treatment-resistant depression comparing a 0.5 mg/kg intravenous infusion of ketamine preceded by either oral placebo or oral naltrexone (50 mg). All participants were required to have a score of at least 20 on the 17-item Hamilton Depression Rating Scale (HAM-D). Each participant was also required not to have benefited sufficiently from trials of at least four antidepressant medications or other somatic treatments (such as electroconvulsive therapy, vagus nerve stimulation, or deep brain stimulation).

An initial 12 patients completed both arms of the crossover trial. In the ketamine plus placebo condition, seven of the 12 patients met the criterion for response (defined as a reduction of 50 percent from baseline to post-infusion day 1 in 17-item HAM-D score); five of the seven responders met criteria for remission (defined as a score of 7 or less on HAM-D). In contrast, none of the patients who responded to ketamine plus placebo met the criteria for response the day after receiving ketamine plus naltrexone.

Patients receiving ketamine plus placebo experienced a dramatic reduction in mean 17-item HAM-D, with an average reduction of 22.3. There was also a statistically significant reduction from baseline in the ketamine plus naltrexone condition, but that improvement was significantly lower, with an average reduction of 5.6. Because patients who took naltrexone before ketamine continued to experience the dissociative effects of ketamine without the robust antidepressant response seen in the placebo group, the investigators halted the trial without recruiting more patients.

“With these new findings, we should be cautious about widespread and repeated use of ketamine before further mechanistic testing has been performed to determine whether ketamine is merely another opioid in a novel form,” Mark George, M.D., a professor of psychiatry, radiology, and neuroscience and director of the Brain Stimulation Laboratory at the Medical University of South Carolina, wrote in an accompanying editorial. “[W]e need to better understand ketamine’s mode of action and how it should best be used and administered.”

A detailed report of this study will appear in a future issue of Psychiatric News and its enewsletter PsychoPharm. For related information, see the Psychiatric News article “ ‘Cautious Optimism’ Marks Outlook for Ketamine, Mood Disorders.”

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Engagement in Family Psychoeducation for FEP May Vary by Race, Ethnicity

While connecting individuals with first-episode psychosis (FEP) to coordinated specialty care is known to benefit patients, a report published today in Psychiatric Services in Advance suggests that patients who are members of racial/ethnic minority groups may be less likely to receive a key component of this care.

Oladunni Oluwoye, Ph.D., of Washington State University and colleagues conducted a secondary data analysis of the Recovery After an Initial Schizophrenia Episode, Early Treatment Program (RAISE-ETP) data set. The study included 181 patients with schizophrenia and related disorders who received usual community care and 223 who received coordinated specialty care called NAVIGATE. NAVIGATE includes four core interventions: personalized medication management, family psychoeducation, resilience-focused individual therapy, and supported employment and education.

As part of the RAISE-ETP study, patients were assessed at baseline and at months 6, 12, 18, and 24 using the Positive and Negative Syndrome Scale (PANSS) total score and scores on five PANSS subscales (negative symptoms, positive symptoms, uncontrolled hostility, disorganized thoughts, and anxiety and depression). Also, the participants were asked to assess their use of services, such as medication management, family psychoeducation, and individual therapy monthly over the 24-month treatment period.

Among those in the community care group, “non-Hispanic blacks scored significantly higher throughout treatment on measures of positive symptoms, disorganized thoughts, and uncontrolled hostility compared with non-Hispanic whites, and non-Hispanic blacks were less likely than non-Hispanic whites to receive individual therapy,” Oluwoye and colleauges wrote. “Families of Hispanic participants in usual community care were less likely than non-Hispanic white families to receive family psychoeducation.”

Race and ethnicity were not associated with differences in psychiatric symptoms over time in the NAVIGATE group; however, “among NAVIGATE participants, non-Hispanic blacks and those in the group categorized as other were less likely than non-Hispanic whites to engage in family psychoeducation during the 24-month treatment period,” the authors reported. “These findings suggest that family psychoeducation may not appeal, may not be consistently offered, or may not be appropriately tailored [to] non-Hispanic blacks and other racial and ethnic minority groups.”

Oluwoye and colleagues concluded, “[O]ur secondary data analyses highlight the effectiveness of NAVIGATE, compared with usual community care, as a coordinated specialty care program for improving functioning and symptoms for individuals from racial-ethnic minority groups experiencing FEP. However, the findings also highlight racial-ethnic disparities in the NAVIGATE condition in participation in family psychoeducation, resulting in lower rates of family engagement among non-Hispanic blacks and individuals from other racial and ethnic minority groups.”

For related information, see the Psychiatric News article “Social Therapy Improves Engagement in Early Psychosis Treatment.”

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Prenatal Maternal Depression, Anxiety May Alter Early Brain Development

Depression and anxiety during the third trimester of pregnancy may affect early brain development, reports a study published today in JAMA Pediatrics. The study suggests that the intensity of maternal depressive and/or anxious symptoms influences the density of the infants’ white matter—bundles of nerve fibers that connect various brain regions.

“Maternal depression and anxiety are known to adversely affect child behavioral and emotional outcomes,” wrote Douglas Dean III, Ph.D., of the University of Wisconsin-Madison and colleagues. “[O]ur findings show that neural pathways may differ in these children as well.”

Dean and colleagues enrolled 149 mother-infant pairs for this neuroimaging study. The pairs were part of an ongoing clinical study examining the association between early-life experience and infant brain development. As part of this study, the mothers completed depression and anxiety questionnaires at weeks 28 and 35 of pregnancy. The investigators later took MRI scans of sleeping infants at age one month. Not all infants slept through the entire scan, so the final analysis included 101 infants (53 male, 48 female).

The investigators found a sex-specific connection between the mother’s depression and anxiety scores and infants’ white matter composition. In female infants, higher maternal depression/anxiety scores were associated with lower white matter density (which reflects fewer, less tightly packed nerve fibers) in frontal brain regions. In boys, however, higher symptom scores were associated with higher white matter density in these regions.

“Such associations may be linked to differing time courses of white matter development, with white matter in females developing earlier than in males,” Dean and colleagues wrote. “These findings do not imply that white matter in males is resilient to prenatal maternal symptoms; instead, they suggest the possibility that such microstructural alterations in males may be detected at a different time during development.”

They added, “Because of the rapid postnatal maturation of white matter and the likelihood that prenatal and postnatal influences within the first month contribute to shaping brain connectivity, it is likely that any developmental outcome that we study is the joint product of prenatal and postnatal influences.”

For related information, see the Psychiatric News article “Maternal Mental Health: Moving Mental Health Care Upstream,” by Amritha Bhat, M.D., M.P.H.

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Lower White Matter Density at Age 14 May Signal Future Depression

Adolescents with a lower density of white matter—the nerve fibers that connect different brain regions—are at higher risk of developing depression, according to a report in AJP in Advance.

Previous research has shown that adolescents with depression have reduced white matter density. This new study shows that these structural changes predate the onset of depression, suggesting they may represent a biomarker of depression vulnerability.

Researchers with Europe’s IMAGEN Consortium took brain scans of 96 14-year-olds with subthreshold depression and 336 age-matched healthy controls. The participants were categorized as having subthreshold depression if they had experienced at least three depressive symptoms, including at least one core symptom (abnormally depressed, irritable mood, or loss of interest) in the past four weeks, without fulfilling criteria for a DSM-IV major depressive episode. The adolescents then had a follow-up assessment at age 16 to screen for depression and other psychiatric disorders (no brain scans were taken during follow-up).

The investigators used a technique called fractional anisotropy to measure the density of nerve fibers in the brains of the adolescents. They found that on average those with subthreshold depression at age 14 had lower fiber density, particularly in two regions: the corpus callosum (the band of nerves that joins the two hemispheres of the brain) and the nerve fibers that connect the corpus callosum to the anterior cingulate cortex (a brain region that mediates behaviors such as attention and reward anticipation).

This reduced nerve fiber density was more pronounced in the adolescents who developed depression by 16. The researchers developed an algorithm that identified adolescents who developed depression with about 75% accuracy.

Previous studies have suggested that white matter changes may be associated with other psychiatric disorders in adolescents, including generalized anxiety disorder and attention-deficit/hyperactivity disorder, the authors wrote. According to their analysis, reduced nerve fiber density “did not predict higher risk for any diagnosis other than depression at follow-up,” the authors noted.

They confirmed the association between reduced nerve fiber density and depression risk in an independent set of 686 adolescent brain scans (all from adolescents without psychiatric disorders at baseline) that were part of the IMAGEN database. “[O]ur imaging findings appear to be specific to increased risk for depression,” they wrote.

For more information on depression in adolescents, see the Psychiatric News article “Brains of Teen Girls Resilient to Depression Differ From Brains of Others.”

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Adjunctive Aripiprazole May Reduce Prolactin-Related Side Effects of Antipsychotics in Women

Adjunctive aripiprazole appears to effectively treat prolactin-related side effects of antipsychotic treatment in women, according to a report in the August issue of the Journal of Clinical Psychopharmacology.

Antipsychotic treatment in women can result in hyperprolactinemia—a condition of elevated prolactin in the bloodstream that may cause irregular menstrual periods or no menstrual periods (amenorrhea), milky discharge from the breasts (galactorrhea) when not pregnant or breast-feeding, and/or painful intercourse due to vaginal dryness.

Deanna Kelly, Pharm.D., director of the Treatment Research Program at Maryland Psychiatric Research Center, and colleagues randomized 46 premenopausal women with a diagnosis of schizophrenia, schizoaffective disorder, or bipolar disorder who were stable on antipsychotics to 16 weeks of placebo or adjunctive aripiprazole (starting with 5 mg/day for the first two weeks and escalating doses to 15 mg/day if symptoms didn’t resolve). All women in the trial had elevated prolactin levels of greater than 24 ng/mL and reported menstrual dysfunction, galactorrhea, and/or sexual dysfunction related to use of an antipsychotic. At baseline, 70% of the women had at least two of these side effects.

The study participants were evaluated every two weeks for measurement of morning prolactin levels, breast exams, menstrual diary review, and a review of side effects, including sexual function.

Improvements were seen on all prolactin-related side effects for women taking adjunctive aripiprazole compared with women taking placebo. Aripiprazole was particularly effective at improving galactorrhea, with almost 80% of women having resolution of this side effect at the end of the 16 weeks compared with 33% in the placebo group.

Women also responded favorably to questions related to resumption of their menstrual periods and improvements in sexual function and libido. Women in the study indicated at exit interview that the resolution of prolactin-related symptoms would make them more inclined to continue taking their antipsychotic medication.

Psychiatric News first reported on the results of the Dopamine Partial Agonist Aripiprazole for the Management of Symptomatic Elevated Prolactin (DAAMSEL) trial after a presentation by Kelly at the 2017 meeting of the International Congress on Schizophrenia Research.

At the time, Kelly said the addition of aripiprazole to an antipsychotic regimen should be regarded as an example of “rational polypharmacy” that can help treatment adherence. “These are improvements that do really matter to women and may help with recovery-oriented treatment,” she said.

For related information, see Managing the Side Effects of Psychotropic Medications, Second Edition, from APA Publishing.

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Maternal Depression Impairs Immune System, Stress Response of Children, Study Suggests

Numerous studies have shown that maternal depression can create significant challenges for children, including social and behavior problems as they age. A study published Tuesday in Depression and Anxiety suggests maternal depression may also impair a child’s immune system and stress response.

“[W]hile most research has focused on the negative effects of maternal depression during pregnancy or the first months of life on children's physiology and behavior, our findings show that exposure to maternal depression at any timepoint in childhood bears negative consequences for children's immunity and emotional well-being,” wrote senior author Ruth Feldman, Ph.D., of the Interdisciplinary Center Herzliya in Israel and Yale University and colleagues.

The researchers followed 125 children from birth to 10 years. At the beginning of the study, the mothers received screening for depression and anxiety; depression assessments were repeated at six and nine months, and again six years later. At 10 years, the researchers collected cortisol and secretory immunoglobulin (s-IgA)—markers of stress and the immune system—from the mother-children pairs and observed interactions between the mothers and children; the mothers and children were also evaluated for psychiatric disorders, and mothers were asked to assess their child’s behavior using the Child Behavior Checklist 4-16 years. The maternal depression group was defined as mothers receiving a diagnosis of major depressive disorder at 6 years, 10 years, or both (42.8%).

Depressed mothers had higher cortisol and s-IgA levels and displayed greater negativity, intrusion, and hostility toward their children compared with mothers without depression, the researchers found. Children of depressed mothers had higher s-IgA levels, exhibited greater social withdrawal during interaction with their mothers, and displayed more externalizing and internalizing symptoms compared with children of mothers without depression.

“Using structural equation modeling, we found that stress and immune biomarkers jointly mediated the effects of maternal depression on child symptoms via four independent paths: by augmenting maternal and child's CT [cortisol] production, by increasing s-IgA levels, by impairing maternal and child relational behavior, and via a mixed hormonal-immune pathway by which maternal s-IgA impacts child CT levels,” the researchers wrote.

“Our findings show the complex effects of maternal depression on children's physiology, health, and psychopathology and advocate the need for early interventions that specifically target maternal stress and enhance parenting behavior,” Feldman stated in a press release.

For related information, see the American Journal of Psychiatry article “Perinatal Maternal Depressive Symptoms as an Issue for Population Health,” by Michael Meany, Ph.D.

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Nondaily Cigarette Smoking Increases Among People With Mental Illness, Substance Use Disorders

Nondaily cigarette smoking by U.S. adults with common mental health and substance use problems increased significantly between 2005 and 2014, while simultaneously declining among those without these disorders, according to a report in the Journal of Clinical Psychiatry. The report also found daily smoking declined among those with and without these disorders.

“While the decrease in daily cigarette smoking among persons with MHSUP [mental health or substance use problem] is promising, the prevalence of cigarette smoking among persons with MHSUP remained very high,” wrote Andrea H. Weinberger, Ph.D., of Yeshiva University in New York and colleagues. The authors found the prevalence of cigarette smoking among people with mental health and substance use problems in 2014 was more than twice that of those without these problems.

Weinberger and colleagues analyzed data from the National Survey on Drug Use and Health from 2005 and 2014, comparing current, daily, and nondaily cigarette smoking among adults with and without any MHSUP. Individuals who reported experiencing past-year major depressive episode, serious psychological stress, substance use disorders, alcohol use disorders, heavy alcohol use, or daily cannabis use were classified as having a MHSUP. People with a history of smoking who smoked cigarettes 1 to 29 days of the previous 30 days were classified as nondaily smokers, while those who smoked 30 of the previous 30 days were classified as daily smokers.

The prevalence of nondaily cigarette smoking increased from 29.54% in 2005 to 33.73% in 2014 among people with MHSUP. In contrast, nondaily smoking declined among people without these disorders from 29.13% in 2005 to 27.43% in 2014. The prevalence of daily smoking declined significantly over the same period among individuals in both groups (from 29.42% to 24.21% among people with MHSUP; from 13.48% to 10.21% among people without MHSUP).

“When patients enter treatment for MHSUP, it provides an opportunity to identify smokers (nondaily and daily) and provide cessation treatment options,” Weinberger and colleagues wrote.

For related information, see the Psychiatric News article “Could FDA’s Proposed Plan Help Smokers With Mental Disorders Quit For Good?”

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Researchers Develop Calculator to Predict Risk of Bipolar Disorder in Youth

Youth with subthreshold manic symptoms are at greater risk of developing bipolar disorder. Researchers have developed a risk calculator that can predict which of these at-risk youth are most likely to convert to bipolar disorder within five years. In a study published in the Journal of the American Academy of Child & Adolescent Psychiatry, the researchers showed this bipolar risk calculator could identify bipolar conversion with about 71% accuracy.

“The quantification of an individual’s risk could inform treatment decisions, such as the use and specific choice of antidepressant medications for a depressed BP-NOS [bipolar disorder–not otherwise specified] youth at high risk for conversion vs. a depressed BP-NOS youth at low risk for conversion,” wrote Boris Birmaher, M.D., of the University of Pittsburgh School of Medicine and colleagues. “Moreover, quantification of an individual’s risk will enable the youth (and the family) to more accurately understand his/her own level of risk, which may in turn have a positive effect on treatment engagement and adherence.”

Birmaher and colleagues selected predictor variables for the risk calculator based on the results of a recent meta-analysis that identified common prodromal symptoms in individuals who later developed bipolar disorder. The final calculator included mood-related scores on the K-SADS Kiddie Mania Rating Scale and Kiddie Depression Rating Scale, as well as scores on the Screen for Child Anxiety Related Emotional Disorders, Behavior Control Scale, and Children’s Global Assessment Scale. Family history of mania, duration of subthreshold symptoms, and demographic factors including age, sex, and race were also incorporated.

The researchers tested this calculator on 140 youth aged 6 to 17 who were part of a long-term bipolar disorder study. All the youth had subthreshold bipolar symptoms (known as bipolar disorder–not otherwise specified [BP-NOS] in DSM-IV). These youth were assessed every seven months for about 11.5 years; 75 of the youth converted to either bipolar I or bipolar II disorder, 57 of whom converted within five years. The risk calculator could discriminate those youth who did or did not convert with around 71% accuracy overall (74% accuracy for bipolar I and 70% for bipolar II). This prediction rate is comparable to the performance of recently developed risk calculators for psychosis.

The researchers then validated the calculator in a second, independent cohort of 58 BP-NOS youth, and the calculator predicted five-year bipolar conversion with 75% accuracy, suggesting the calculator is generalizable to other samples of patients.

“If replicated, the risk calculator provided in this study offers a useful tool for clinicians to predict an individual’s child’s risk of converting from subsyndromal mania to BP-I/II, and thus inform personalized treatment decisions,” the authors wrote. 

To read more about risk calculators, see the Psychiatric News article “Multimodal Approach May Improve Ability to Predict Transition to Psychosis.”

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Quetiapine Use During First Trimester Does Not Increase Risk of Major Birth Defects, Study Suggests

Use of the antipsychotic quetiapine during the first trimester of pregnancy does not appear to increase the risk for major malformations in offspring, according to a report published yesterday in AJP in Advance.

“Given the considerable use of quetiapine among women of reproductive age across multiple indications, it is critical to have better information regarding the potential risks of fetal exposure to this medication so that women can make informed treatment decisions consistent with their personal wishes and the severity of their underlying psychiatric disorder,” wrote Lee Cohen, M.D., of Harvard Medical School and colleagues. “The study results suggest that quetiapine is not a major teratogen.”

To quantify the relative risk of major malformations associated with first-trimester exposure to quetiapine compared with women with psychiatric disorders not taking second-generation antipsychotics, Cohen and colleagues analyzed data from the National Pregnancy Registry for Atypical Antipsychotics. As part of participation in the registry, pregnant women aged 18 to 45 with a history of psychiatric illness were interviewed across pregnancy and the early postpartum period by telephone. Obstetric, labor, and delivery medical records and pediatric medical records from the first six months of life were screened for evidence of major malformations.

For the analysis, 155 infants (including three sets of twins) exposed to quetiapine during the first trimester were compared with 210 infants born in the unexposed group (including five sets of twins). Two major malformations (1.2%) were confirmed among infants exposed to quetiapine compared with three (1.4%) major malformations among infants who were not exposed to second-generation antipsychotics. 

“These findings represent preliminary yet important data with profound clinical implications for pregnant women and women of reproductive potential,” Cohen and colleagues wrote. “It is imperative that research efforts continue to focus on the reproductive safety of psychiatric medications that are commonly used by women during their childbearing years.”

For related information, see the Psychiatric News article “Taking Some Antipsychotics During Pregnancy Raises Risk of Gestational Diabetes.”

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Autism Linked to Maternal Exposure to DDT, Study Finds

Though the organic pollutants DDT (dichlorodiphenyltrichloroethane) and PCBs (polychlorinated biphenyls) were banned in the U.S. and many other countries more than 30 years ago, these toxic compounds can persist in the environment for decades. According to a study published today in AJP in Advance, maternal exposure to DDT is associated with an increased risk of autism in children, particularly autism with significant intellectual disability. There was no association between maternal exposure to PCBs and autism.

While several studies have established a connection between environmental pollutants and autism, “few studies have examined an association between prenatal exposure to toxins and autism, and among these, most have been based on ecologically, rather than serologically, documented exposures,” Alan Brown, M.D., M.P.H., of Columbia University Medical Center and colleagues wrote. The researchers used blood samples from mothers to assess DDT and PCB exposure, providing the first biomarker-based evidence for this connection.

The researchers obtained their data from the Finnish Maternity Cohort, which has archived serum samples from more than 1 million pregnant women since 1983. Using national health registries, they next identified 778 diagnoses of autism among children born to these mothers between 1987 and 2005. These 778 mother-child pairs were matched 1:1 with pairs that included a child without autism, and blood samples from all 1,556 mothers were analyzed for PCBs and the DDT metabolite p,p′-DDE.

The average level of p,p′-DDE in the mothers of children with autism was 1,032 pg/mL and 811 pg/mL in corresponding control subjects. The average level of PCBs was 1,022 pg/mL in mothers of children with autism and 999 pg/mL in controls.

Mothers with the highest concentrations of p,p′-DDE (top 25% of p,p′-DDE levels) were 32% more likely than those with lower p,p′-DDE levels to have a child with autism, and the odds of having a child diagnosed with autism with intellectual disability was more than double. There was no association between total levels of maternal PCBs and autism.

The authors proposed two reasons for why DDT appeared to be linked with autism while maternal exposure to PCB did not. First, DDT exposure is also known to increase the risk of both premature birth and small birthweight—two known autism risk factors. Second, DDT can reduce the production of androgen receptors, another autism risk factor.

To read more about environmental risk factors for mental illness, see Chapter 9: Poisons and Toxins in the Textbook of Neuropsychiatry and Clinical Neurosciences.

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FDA Approves Bedtime ADHD Medication

The Food and Drug Administration has approved Jornay PM (extended-release methylphenidate capsules) for the treatment of attention-deficit/hyperactivity disorder (ADHD) in patients aged 6 years and older. The oral medication is a novel formulation of methylphenidate, which is taken in the evening in order to reduce the severity of early-morning ADHD symptoms the following day.

The approval of Jornay PM was based in part on the results of two clinical trials, involving 278 children aged 6 to 12 who met DSM-5 criteria for ADHD inattentive, hyperactive-impulsive, or combined inattentive/hyperactive-impulsive subtypes. Children who took Jornay PM at night were found to have lower ADHD symptoms in the early morning and throughout the day than those taking placebo. The most common adverse reactions (incidence of ≥ 5% and at a rate at least twice placebo) reported during the trial included insomnia, decreased appetite, headache, vomiting, nausea, psychomotor hyperactivity, and exaggerated mood swings.

Jornay PM is available in 20 mg, 40 mg, 60 mg, 80 mg, and 100 mg doses. It is recommended that patients 6 years and above start at 20 mg daily.

“The FDA approval of this agent would appear to add to the armamentarium of medications available for clinicians to treat ADHD,” Robert M. Bilder, Ph.D., the Michael E. Tennenbaum Family Professor of Psychiatry & Biobehavioral Sciences at UCLA David Geffen School of Medicine, told Psychiatric News by email. “The formulation, which involves use of a proprietary coating to delay release, appears to have been associated with benefits especially with early morning dysfunction associated with ADHD, which is a significant clinical problem.”

Bilder added, “The pivotal trials used placebo rather than another active treatment, so it remains unclear if Jornay PM has any benefits relative to other agents with demonstrated efficacy.”

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Risk of Suicide Increases After TBI, Study Finds

Individuals who have experienced a traumatic brain injury (TBI) appear to be at a higher risk of suicide than those who have not experienced such an injury, according to a study appearing today in JAMA. The report suggests that suicide risk is particularly elevated during the first six months after medical contact for the injury. Further, individuals who were diagnosed with a psychiatric disorder and/or engaged in deliberate self-harm after experiencing a TBI had a higher risk of suicide than those with TBI only.

Trine Madsen, Ph.D., of the Danish Institute of Suicide Prevention and colleagues conducted a retrospective cohort study using nationwide registers that included more than 7.4 million people aged 10 years and older living in Denmark in 1980. These individuals were followed up until their dates of death or emigration from Denmark or December 31, 2014, whichever came first.

Of the total population included in the analysis, 423,502 individuals (5.7%) were diagnosed with a mild TBI, 24,221 (0.3%) with skull fracture, and 120,100 (1.6%) with severe TBI. Among the 34,529 people who died by suicide, 3,536 (10.2%) had previously been diagnosed with TBI (2,578 men; 958 women), Madsen and colleagues reported.

“The absolute suicide rate in Denmark was 21 per 100,000 person-years in the 1980-2014 period, but it was almost twice as high among individuals with TBI, 41 per 100,000 person-years,” the authors wrote. Additional analysis revealed that the risk of suicide was higher for individuals with severe TBI, numerous medical contacts for TBI, and longer hospital stays.

“Suicide is preventable, but only with recognition of risk and prompt intervention,” Lee Goldstein, M.D., Ph.D., of Boston University School of Medicine and Ramon Diaz-Arrastia, M.D., Ph.D., of the University of Pennsylvania Perelman School of Medicine wrote in an accompanying editorial. “The results reported by Madsen et al. point to an important clinical triad—TBI history, recent injury (especially long hospital stays), and more numerous postinjury medical contacts for TBI—that serves as ‘red flags’ for increased suicide risk. Notably, the results of this study indicate that increased suicide risk is relevant across all TBI severity levels, including the far more common mild injuries.”

For related information, see Management of Adults With Traumatic Brain Injury from APA Publishing.

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SAMHSA Is Taking ‘New Directions,’ Says Agency’s Leader

The Substance Abuse and Mental Health Services Administration (SAMHSA) is taking a new approach to helping people with serious mental illness (SMI), Elinore F. McCance-Katz, M.D., Ph.D., assistant secretary of mental health and substance use at the Department of Health and Human Services and head of SAMHSA, wrote in an article published today in Psychiatric Services in Advance. These efforts include a renewed focus on evidence-based, collaborative care and greater reliance on community resource providers, including peer support.

SAMHSA is also prioritizing the training of health care practitioners, working toward providing free national technical assistance to modernize the care and delivery of services, and funding innovative programs to address major mental health issues, in particular the opioid epidemic, wrote McCance-Katz, the first psychiatrist to head SAMHSA.

Mental health and substance use disorders affect more than 64 million Americans every year. “Never in the history of this country has there been a time of greater need for attention to these issues,” McCance-Katz wrote. “We are in the grip of an opioids crisis characterized by addiction and death such as we have never seen. Too often affecting our young people, the consequences of untreated mental illness and addiction have been tragic, frequently associated with violence and death.”

The agency’s new approach to SMI will be supported by the Interdepartmental Serious Mental Illness Coordinating Committee, a public-federal partnership aimed at improving services for adults and youth living with SMI. The agency will continue to focus on mental health court programs, assisted outpatient treatment, assertive community treatment, and the expansion of its successful Certified Community Behavioral Health Clinics—now established in eight states—that provide integrated services as well as crisis care. The agency is also helping to expand suicide prevention programs. In 2016, more than 45,000 Americans died by suicide, a 30% increase in the past 15 years.

SAMHSA is prioritizing its training of health care practitioners and transforming its approach to one of evidence-based programs and practices. The agency is now working to build a national system of free or low-cost practical training available to any organization or provider. As part of that effort, SAMHSA had announced in July that APA is the grantee for its newly created national Clinical Support System for Serious Mental Illness. It will provide online training, webinars, and classroom-style training on evidence-based approaches to serious mental illness. A component of the system will focus on pharmacotherapy, including the use of clozapine, long-acting antipsychotics, and ways to address metabolic syndrome.

“SAMHSA will play a key role in establishing these new care approaches and in preparing the behavioral health workforce,” summed up McCance-Katz. “I look forward to both the challenges and the metamorphosis of our health care system for those living with mental and substance use disorders in the United States.”

For related information, see the Psychiatric News article “McCance-Katz Leads Effort to Focus SAMHSA on Serious Mental Illness.”

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Opioid Prescribing Found to Drop After Physicians Notified of Patient Death From Overdose

Physicians who were notified by letter from a medical examiner that a former patient had died of an opioid overdose reduced their subsequent opioid prescribing by around 10%, according to a study published yesterday in Science.

“Clinicians may prescribe with greater care when they perceive they are being watched,” wrote lead author Jason Doctor. Ph.D., of the University of Southern California and colleagues. “A message communicating a patient’s overdose death from the medical examiner may have particular weight."

Doctor and colleagues identified 170 individuals who had died of an opioid overdose in San Diego County between July 1, 2015, and June 30, 2016, and had received a legitimate opioid prescription. The individuals were randomly assigned to two groups. For one group of decedents, the 404 physicians who had prescribed opioids to them received a letter from the medical examiner. The letter was intended to be supportive and included safe opioid-prescribing strategies developed by the Centers for Disease Control and Prevention as well as information on how to access the California state prescription drug monitoring program. The control group consisted of the 457 physicians who prescribed to the other half of the decedents.

Four months after the letters were mailed, opioid prescribing among the 404 physicians in the intervention group dropped from 72.5 MMEs (milligram morphine equivalents) per physician a day to 65.7 MMEs per physician a day. Rates held steady in the control group (71.6 and 71.7 MMEs before and after the notification, respectively). The authors also found that physicians in the intervention group were about 7% less likely than controls to start new patients on opioids.

“Judicious prescribing represents only one of the components necessary to correct the missteps caused by overly enthusiastic use of opioids to relieve pain,” Doctor and colleagues wrote. “Access to medication-assisted therapies, counseling, and naloxone for resuscitation after overdose and efforts to address social determinants responsible for increased opioid use all play equally important roles in ending the crisis.”

To read more about opioid prescribing practices, see the Psychiatric News article “Opioid Prescribing Falls But but Still Remains High” and the Psychiatric Services article “Prescriptions Filled Following an Opioid-Related Hospitalization.”

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Risk of Agranulocytosis for Patients on Clozapine May Be Overstated, Study Shows

Neutropenia appears to be common both in patients with schizophrenia who are taking clozapine as well as those who have never used clozapine. Moreover, progression from mild neutropenia (1500-1900/mm3) to agranulocytosis appears to be rare, according to a report in BMC Psychiatry.

The results suggest that the risk of agranulocytosis associated with clozapine may be overstated. They also appear to lend support to the 2015 decision by the Food and Drug Administration to lower the neutrophil count cutoff at which patients are required to discontinue Clozaril from 1500/mm3 to 1000/mm3.

Clozapine has been shown to be the drug of choice for treatment-resistant schizophrenia. Yet since its introduction, the drug has been linked to a risk for agranulocytosis, requiring regular blood monitoring, a disincentive to both clinicians and patients. Guidelines originally called for discontinuation of the medication when neutrophil counts dropped below 1500/mm. That was lowered to 1000/mm3 in 2015; in Europe and the U.K., the lower limit is still 1500/mm3.

Engilbert Sigurdsson, M.D., and colleagues at the University of Iceland and Landspitali University, Reykjavik, sought to analyze the risk of neutropenia and the progression to agranulocytosis in a sample of patients with schizophrenia in Iceland. In that country, providing blood samples at certain intervals is not required for dispensing clozapine. The patient sample included those who were taking clozapine and those who had never used the drug.

Searching the electronic health records of Landspitali, the National University Hospital of Iceland, they identified 201 patients with schizophrenia treated with clozapine and 410 patients with schizophrenia who had never taken clozapine. They identified patients who developed neutropenia/agranulocytosis through neutrophil counts in the databases. They also examined the frequency of neutrophil measurements.

Despite being monitored much less frequently, the rate of neutropenia overall was not significantly greater for patients on clozapine than for patients who had never used the medication. Only mild neutropenia (between 1500-1900/mm3) was more common in clozapine users, and none of those patients (n=24, or 12.8%) progressed to agranulocytosis. For moderate (1000-1400/mm3) and severe neutropenia (500-1000/mm3), the rate was actually higher among patients who had never been prescribed clozapine.

Sigurdsson and colleagues stated that the results support the safety of lowering the neutrophil-count cutoff for discontinuation of clozapine from 1500 to the U.S. standard of 1000/mm3. “This change would result in a much lower rate of clozapine discontinuation, and our findings suggest that the progression to agranulocytosis would remain a rare event,” they wrote.

For related information see the article, "Addressing Barriers to Clozapine Underutilization: A National Effort."

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Reminder: APA Joins With Research!America to Offer Scientists Grants to Engage Candidates During Midterm Elections

Calling all student science policy groups: APA is supporting an initiative by Research!America and the National Science Policy Network to offer grants to young scientists who can increase engagement between scientists and candidates in the upcoming midterm elections. Learn more and apply.

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Study Identifies Factors Linked to Adverse Events, Errors During Psychiatric Hospitalization

Older patients and those with a longer length of stay are more likely to experience an adverse event or medical error during psychiatric hospitalization, according to a report in Psychiatric Services.

Jentien Vermeulen, M.D., of the University of Amsterdam and colleagues in the United States analyzed a random sample of 4,371 charts from 14 inpatient psychiatric units at acute care general hospitals in urban and rural Pennsylvania. Rates of adverse events and medical errors were calculated overall, then stratified by patient and hospital factors.

The following were categorized as adverse events: self-harm or injury, adverse drug event, assault, sexual contact, patient fall, and “other.” Medical errors included any mention in the chart of medication errors, elopement (when a patient leaves the facility without authorization), possession of contraband, and other nonmedication errors.

Adverse events were identified in 14.5% of hospitalizations, and medical errors were identified in 9.0%. Factors associated with a lower risk of an adverse events or medical errors were being aged 31 to 42, having private insurance, and being treated at high-volume hospitals (defined as between 1,061 and 1,280 admissions annually).

Factors associated with a higher risk of adverse events or medical errors were being aged 54 or older, admitted during the weekend, admitted to a rural hospital, and treated at very-high-volume hospitals (more than 1,280 admissions a year). Patients over 54, who accounted for 23.9% of all adverse events, were more than twice as likely to experience an adverse event compared with patients aged 18 to 30 (11.5%).

Regarding the higher risk for very high-volume hospitals, Vermeulen and colleagues noted that “operating at overcapacity and with higher patient-to-nurse ratios are factors known to be associated with an increase in rates of patient safety events.” In contrast, “smaller hospitals may be under-resourced. ... The optimal equilibrium of staffing and resources to provide safe care may be present in high-volume hospitals.”

They noted that in general medicine, research has established a framework to lower rates of preventable harm in five steps: measurement of events and errors, development of evidence-based care practices, investment in implementing safety plans, local hospital ownership and peer learning, and alignment of efforts around common goals and measures.

“The field of mental health care would do well to adopt a similar framework,” they continued. “From our findings, we can then move to the next step and develop evidence-based practices that address the specific vulnerabilities to patient safety in inpatient psychiatry. … These interventions should be targeted to patient groups with the highest risk of experiencing a patient safety event.”

For related information on patient safety, see the Psychiatric News article “Ensuring Patient, Staff Safety Begins With Supportive Management, Staff Training.”

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Chronic Pain Associated With PTSD, Study Finds

People with a history of chronic pain (pain persisting six months or longer) may be more likely to report symptoms of posttraumatic stress disorder (PTSD) than those in the general population, according to a report in Psychosomatics: The Journal of Consultation-Liaison Psychiatry.

The findings “emphasize the importance of identifying and screening for PTSD in chronic pain populations, especially in those with severe and refractory pain,” Eeman Akhtar, M.D., of the University of Kansas Medical Center and colleagues wrote.

Individuals with comorbid pain and PTSD often report health problems with greater frequency, higher pain ratings, and increased functional impairment, according to the authors. To estimate the prevalence of PTSD symptoms in a population of patients with chronic pain, they invited patients aged 18 or older at a multidisciplinary pain clinic at the University of Kansas Medical Center to complete the Brief Trauma Questionnaire. Patients who reported they had experienced a traumatic event (defined as a direct or indirect exposure to a life threat or serious injury) or trauma (with no life threat or serious injury) were then assessed using the PTSD Symptom-Scale Self-Report.

Of the 265 patients with a self-reported history of chronic pain who were included in the analysis, 74 (28%) screened positive for PTSD symptoms—a value the authors noted is higher than the lifetime prevalence of PTSD in the general population (6.8%). Those who screened positive for PTSD symptoms were significantly younger and reported higher levels of pain intensity compared with those who screened negative for PTSD symptoms.

“Future longitudinal studies will be important to explore the exact time course of PTSD and chronic pain onset to determine any causal relationship, as well as to test treatment regimens in reducing symptoms of both chronic pain and PTSD,” the authors wrote.

For related information, see the Psychiatric News article “Psychiatrists Need to Be Prepared to Support Patients in Pain.”

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