REMS Program for Fentanyl Formulation Found to Be Inadequate But Slated for Change

Prescriptions for transmucosal immediate-release fentanyl (TIRF) medications decreased in the first year after the Food and Drug Administration (FDA) implemented a Risk Evaluation and Mitigation Strategy (REMS) program to restrict distribution of the potent opioids, but then prescriptions rose to near pre-REMS levels, a study published today in JAMA Network Open has found.

The results suggest that the REMS program, begun in 2011, did not have as strong and lasting an impact as intended. Furthermore, although TIRF medications are approved for treating breakthrough pain in cancer patients who are tolerant to other, around-the-clock opioid analgesics, 72% of the prescriptions in the study period were for patients who did not have cancer. However, overall, prescriptions for TIRF products represented only 0.03% of all opioid prescriptions.

William Fleischman, M.D., M.H.S., an employee of the Centers for Medicare & Medicaid Services at the time of the study, and colleagues assessed TIRF prescribing by analyzing prescription claims data submitted to Medicare Part D for 2010 through 2014. The main outcome measures were TIRF prescription fills per 100,000 Medicare Part D beneficiaries. They also assessed prescribing for patients with no known opioid tolerance.

From the beginning of the study in 2010 through 2012, the first full year of the REMS implementation, TIRF prescribing had decreased by 1% per month. In the year after the REMS program took effect, TIRF prescribing dropped by 26.7%, then rose 2% each month through the study’s end.

“One explanation for the observed attenuation of the decrease in prescribing associated with the program could be that it may have taken a year for patients, prescribers, and pharmacists to familiarize themselves with REMS requirements and to register and complete the educational program,” the researchers wrote. “However, the subsequent return to baseline prescribing levels occurred despite a persistent decrease in the number of prescribers. This points to other possible contributing factors to the subsequent return of increased TIRF prescribing.”

From the beginning of the study in 2010 through 2012, a mean of 30% of initial TIRF prescriptions were for patients without known opioid tolerance. After the REMS was implemented, the number of prescriptions filled by patients without known opioid tolerance dropped 22.5%, followed by 1.98% monthly decreases for the remainder of the study. This outcome suggests that for this population, at least, the REMS program had a lasting impact.

Earlier this week, the FDA announced steps to strengthen the TIRF REMS. “Despite the decline in the use of these medicines, the historical data on the prescribing of TIRF products indicates that prescribing behavior is not consistent with the strict labeling. To the extent that some of these prescribing practices still persist, even as prescriptions declined sharply, that causes the FDA concern,” said FDA Commissioner Scott Gottlieb, M.D., in a statement.

Changes to the TIRF REMS include the following:

• Requiring that prescribers document a patient’s opioid tolerance concurrently with each prescription of a TIRF medication for outpatient use.
• Requiring inpatient pharmacies to develop internal policies and procedures to verify opioid tolerance in patients who require TIRF medications while hospitalized.
• Requiring that a TIRF medication be dispensed for outpatient use with evidence or other documentation of safe use conditions, including concurrent documentation of opioid tolerance.
• Requiring the development of a new patient registry to monitor for serious adverse events including overdose (both fatal and nonfatal).

For related information, see the Psychiatric News article “Tackling Opioid Overdose Epidemic Demands Multiple Approaches.”

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Bullying Found to Raise Risk for Adolescent Suicide Attempts Worldwide

Bullying is a major risk factor for adolescent suicide attempts globally; thus, there is an urgent need for mental health professionals to screen adolescents for bullying as a suicide-prevention measure throughout the world, according to a study in the Journal of the American Academy of Child & Adolescent Psychiatry.

Self-harm is the third-leading cause of death among adolescents worldwide, resulting in about 67,000 deaths a year, wrote Ai Koyanagi, M.D., Ph.D., of the Research and Development Unit at the Universitat de Barcelona in Barcelona, Spain, and the Centro de Investigación Biomédica en Red de Salud Mental in Madrid, Spain, and colleagues.

Researchers examined data from 134,000 adolescents aged 12 to 15 years from 48 mostly lower- to middle-income countries who took the Global School-based Student Health Survey, collecting information on past 30-day bullying victimization and past 12-month suicide attempts and analyzing the association between them.

About 30% of students reported being victims of bullying, and nearly 11% of students reported attempting suicide. There was a wide variation by country in the percentage of students who attempted suicide, ranging from 4% in Indonesia to 61% in Samoa. Countries with higher prevalence of bullying victimization also tended to have higher prevalence of suicide attempts, the researchers wrote. The country with the highest prevalence of bullying, Samoa (74%), also had the most adolescent suicide attempts (61%).

Being bullied for at least one day in the past 30 days was associated with a more than threefold higher risk for suicide attempts overall, and the more days that an individual was bullied was associated with a correspondingly increased risk for suicide attempt. The past-year prevalence of suicide attempts ranged from nearly 6% who were in the “no bullying” group up to 33% of students who were being bullied for “20 to 30 days a month.”

“Efforts to reduce bullying especially at school may be fundamental to prevent or reduce adolescent suicides,” the researchers wrote. “With respect to victims of bullying, it has been suggested that interventions to enhance coping and problem-solving skills for psychological distress associated with bullying, increase social connectedness, improve conditions within the home, and cultivate inclusive and safe environments/spaces in schools may be effective. Mental health practitioners should consider bullying as an important potential risk factor for suicide attempts.”

For more information, see the Psychiatric News article, “Irritability in Childhood May Point to Teens at High Risk for Suicide.”

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APA Criticizes Trump Administration’s Latest Move to Overturn ACA

The Trump Administration’s recent decision not to protect any part of the Affordable Care Act (ACA) in a federal case challenging the constitutionality of the ACA places the health care of millions of Americans at risk, say APA and five of its medical coalition partners in a statement released today.

The statement was in response to a legal filing Monday by the Department of Justice (DOJ) in the case Texas v. United States, in which the DOJ supports a December 2018 court ruling that the ACA is unconstitutional and argues that the entire law should be invalidated.

“The DOJ’s new position, if accepted by the courts, would endanger not only essential protections for persons with preexisting conditions but other programs that millions of Americans depend on to ensure their access to affordable health care,” APA and the other medical groups said. “These include federal funding for Medicaid expansion, premium subsidies to make coverage affordable in the individual market, and the ban on annual and lifetime limits on coverage. In addition, insurers would no longer be required to cover essential health care such as maternity care, pediatric services, cancer screenings, prescription drugs, and mental health and substance use disorder treatments.”

The five other organizations that signed onto the statement are the American Academy of Family Physicians, American Academy of Pediatrics, American College of Obstetricians and Gynecologists, American College of Physicians, and American Osteopathic Association. Together, the organizations represent a membership of more than 560,000 physicians and medical students.

The DOJ ruling surprised many, with a more definitive repudiation of the ACA than the administration had previously ventured in the case.

The ACA ensures access to affordable health care for more than 130 million Americans, including the more than 31 million individuals between the ages of 55 and 64 who have at least one preexisting condition. Legal experts anticipate that the ruling of the United States Court of Appeals for the Fifth Circuit in the Texas lawsuit will be appealed to the Supreme Court.

“We strongly urge the administration to reverse its position in Texas v. United States, and even if it does not do so, we hope and expect that the appellate courts consider the impact on patients and rule against overturning the law,” the medical groups said.

For related information see the Psychiatric News article, “Ruling ACA Unconstitutional Could Have Devastating Effects on Patients, APA Warns.”

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Amphetamine Found to Have Higher Risk of Psychosis Than Methylphenidate for ADHD

The risk of psychosis associated with use of amphetamine for attention-deficit/hyperactivity disorder (ADHD) is twice as high as that of methylphenidate, according to a report in the New England Journal of Medicine.

Both types of medication are commonly prescribed for ADHD. In 2007, the Food and Drug Administration mandated changes to the drug labels of stimulants because of the risk of psychosis associated with their use.

“The risk of new-onset psychosis was approximately 1 in 660 patients who received a prescription for stimulants for ADHD, but the risk was about twice as high among patients who started amphetamine,” wrote Lauren V. Moran, M.D., of the Division of Psychotic Disorders at McLean Hospital and colleagues.

The researchers used two large health care databases, Optum Clinformatics and IBM MarketScan, to analyze claims for 110,923 patients aged 13 to 25 who were prescribed amphetamine for ADHD, and the same number of patients who were prescribe methylphenidate. The primary outcome was a new diagnosis of psychosis for which an antipsychotic medication was prescribed during the first 60 days after the date of the onset of psychosis.

There were 343 episodes of psychosis: 106 episodes (0.10%) in the methylphenidate group and 237 episodes (0.21%) in the amphetamine group.

Moran and colleagues wrote that the absolute rate of psychosis and the difference in the rates of psychosis between the two treatment groups was low, but this difference may be clinically significant in the context of the very large number of people who are prescribed stimulants for ADHD.

“In the databases used for this study, 2 million patients received a prescription for amphetamine,” they wrote. “A difference of 1 per 1000 person-years potentially confers additional risk of psychosis with amphetamine in thousands of patients.”

For related information, see "Helping Parents and Teachers Understand Medications for Behavioral and Emotional Problems: A Resource Book of Medication Information Handouts, Fourth Edition," published by APA Publishing.

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‘Smart Glasses’ May Help Improve Social Behavior in Children With ASD

Wearing glasses embedded with facial recognition technology can help children with autism spectrum disorder identify emotions and facial expressions, reports a study published today in JAMA Pediatrics.

“Autism behavioral therapy is effective but expensive and difficult to access,” wrote Catalin Voss, M.S., and colleagues at Stanford University. “Learning aids based on novel ubiquitous technologies using machine learning can begin to address these problems by creating opportunities for therapy that are accessible outside of the clinician’s office.”

The intervention used in this study, known as Superpower Glass (SG), was deployed via Google Glass. When the device’s camera detects a face, a visual representation of the person’s facial expression is shown on the glasses’ monitor using emojis (audio voice cues can also be enabled). The technology recognizes eight emotions: happy, sad, angry, scared, surprised, disgust, “meh,” and neutral.

The glasses are also linked with a mobile app programmed with three social engagement activities to encourage the children to use the devices. The activities include a game that prompts children to find certain emotions, such as telling a joke to elicit a happy face; a “guess the emotion” activity; and a “free play” mode in which the child receives cues for everyone they interact.

Voss and colleagues enrolled 71 children with ASD aged 6 to 12 years to test the SG system; 41 of the children were given the wearable intervention, and 30 were in the control group. Both groups received standard behavioral therapy at home during the six-week study; the children in the SG group were also tasked to use the device at home for 20 minutes four times a week: three times with family members and once with their behavioral therapist.

After six weeks, the children in the SG group showed significant improvements in their social behavior scores (measured with the Vineland Adaptive Behaviors Scale socialization subscale) compared with the control group. The children using SG also showed greater improvements with other assessments such as the Social Responsiveness Scale, second edition (SRS-II), but these did not reach statistical significance.

“This is the first randomized clinical trial to demonstrate efficacy of a wearable behavioral intervention for children with ASD, to our knowledge,” Voss and colleagues wrote. “Results of this study underscore the potential of digital home therapy to augment the current standard of care.”

To read more about smart glass interventions, see the Psychiatric News article “Smart Glasses May Improve More Than Eyesight in Children With ASD.”

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Study Sheds More Light on Risk of Death After MH Hospitalization

Previous studies have shown that people who are hospitalized for treatment of mental illness have an elevated risk of suicide in the first few months after their discharge. A study in Psychiatric Services in Advance now reports that this immediate postdischarge period carries a higher risk not only of suicide, but also of death from other causes such as overdoses, accidents, and injuries. In addition, the findings suggest important opportunities for prevention.

Ira R. Katz, M.D., Ph.D., of the Office of Mental Health and Suicide Prevention at the U.S. Department of Veterans Affairs (VA) and colleagues analyzed the records of 3,829 VA patients who died within a year of being discharged from inpatient mental health units in 2013 and 2014. They classified the deaths as either suicide, other external causes (accidental or undetermined), or natural causes. Natural causes included circulatory and lung diseases, cancer, infectious disease, and dementia.

The researchers found that suicide rates were higher in the first 30 and 90 days after discharge compared with the remaining nine months of the first year after discharge: 19.4% of deaths attributed to suicide occurred within 30 days of discharge, and 39.8% occurred within 90 days of discharge. They also found a disproportionate number of deaths from other external causes in the initial months after discharge, with 13% occurring within 30 days and 27.3% occurring within 90 days. A significant number of the early deaths due to external causes were classified as accidental or undetermined overdoses.

“The observation of increased mortality from nonsuicide external causes in the period closest to discharge, compared with the remainder of the year, may be related to the stresses of hospitalization and discharge, to residual symptoms of conditions that led to hospitalization, or to adverse effects of medications started in the hospital,” the researchers wrote. “Observations regarding the frequency of overdoses suggest that opportunities for prevention include ensuring that substance use disorders are addressed during hospitalization, including cases in which the admission is related to another condition.”

The researchers also noted the importance of recognizing the potential side effects of the medications patients take when they return home and counseling patients and their families accordingly.

For related information, see the Psychiatric News article “Psychiatric Patients at Highest Suicide Risk Following Hospital Discharge.”

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Low-Cost VR Intervention Found to Benefit Patients With Acrophobia

A rudimentary virtual reality (VR) intervention that uses cardboard goggles, a smartphone, and self-guided cognitive-behavioral therapy (CBT) via a mobile app can reduce acrophobia (fear of heights) symptoms, according to a study published yesterday in JAMA Psychiatry.

“[O]ur findings support the hypothesis that a fully self-guided app-based VR-CBT, which can be done at home at a fraction of the cost of existing evidence-based treatment options, strongly reduces acrophobia symptoms,” wrote Tara Donker, Ph.D., and colleagues at Vrije Universiteit in Amsterdam. “The current study adds to the development of innovative and scalable delivery methods of evidence-based treatments and underlines that new technologies have the potential to transform mental health care worldwide.”

Donker and colleagues enrolled 193 adults with acrophobia (scoring at least 45.45 on the Acrophobia Questionnaire [AQ]-Anxiety) to receive either the active VR treatment or be placed on a wait list. The smartphone-based VR program, known as ZeroPhobia, provides six animated game-like modules that incorporate CBT principles and techniques. ZeroPhobia was downloaded on the participants’ existing smartphones, and VR was simulated with $10 cardboard goggles. Participants could use the program at home or in another natural environment, but they had to complete all six modules within three weeks.

After three weeks, AQ-Anxiety scores dropped from an average of 68.62 to 39.55 in the ZeroPhobia group, compared with a drop from 67.91 to 60.41 in the wait-list group. The strong symptom improvements were maintained at a follow-up assessment three months later. Aside from some transient cases of cyber sickness (headaches and dizziness), the participants found the VR intervention to be tolerable and user friendly.

“One of the key strengths of the present study was its ecological validity because the intervention was conducted in the participants’ natural environments instead of a research laboratory,” Donker and colleagues wrote. “Furthermore, participants received no guidance when using the VR-CBT app or filling in assessments, thereby ruling out any influence of human contact.”

To read more about VR-based phobia therapies, see the Psychiatric News article, “Avatar-Guided VR Therapy for Fear of Heights Shows Promise.”

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FDA Approves First Medication Specifically for Postpartum Depression

Yesterday the U.S. Food and Drug Administration (FDA) approved Zulresso (brexanolone) for the treatment of postpartum depression (PPD). It is the first drug approved by the FDA specifically for PPD. PPD is believed to be caused by the rapid change in hormones immediately after giving birth and is estimated to affect 400,000 women annually.

“Postpartum depression is a serious condition that, when severe, can be life threatening. Women may experience thoughts about harming themselves or harming their child. Postpartum depression can also interfere with the maternal-infant bond,” said Tiffany Farchione, M.D., acting director of the Division of Psychiatry Products in the FDA's Center for Drug Evaluation and Research, in a press announcement.

Zulresso will be available only through a restricted program called the Zulresso REMS Program. Patients must be enrolled in the program prior to treatment with the medication. Only health care professionals in a certified health care facility may administer Zulresso.

Zulresso is given as a continuous intravenous infusion over a total of 60 hours (2.5 days). Patients must be monitored for potential side effects including excessive sedation or sudden loss of consciousness. They also must be accompanied by a caregiver or family member to assist them with child care during the infusion. Patients should not drive, operate machinery, or do other dangerous activities until feelings of sleepiness from the treatment have completely gone away. These requirements are addressed in a black-box warning about which patients must be counseled prior to treatment.

Zulresso, which modulates the GABA neurotransmitter, was evaluated by the FDA under Priority Review and designated as a Breakthrough Therapy in 2016. Efficacy was demonstrated in two phase 3 clinical studies in which participants were followed for four weeks after a 60-hour continuous infusion for changes in depressive symptoms. Greater symptom improvements compared with placebo were noted within 24 hours of the infusion and persisted through the end of the follow-up period.

Zulpresso is expected to be available in late June, and a single course of treatment will cost $34,000. Sage is also developing a similar PPD medication that can be taken daily in pill form.

For more information on PPD, see the Psychiatric News article, “APA Releases New Statement on Perinatal Disorders” and the Psychiatric Services article “Use of Text Messaging for Postpartum Depression Screening and Information Provision.”

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Attention Training Using Computers May Lessen Anxiety in Youth

Computer modules that help young people practice focusing their attention may improve symptoms in youth with treatment-resistant anxiety, according to a report in the Journal of the Academy of Child and Adolescent Psychiatry.

Adolescents who had previously been treated with cognitive-behavioral therapy (CBT) but still experienced anxiety showed significant reductions in symptom severity after they received treatment with either one of two training modules—Attention Bias Modification Treatment (ABMT) and Attention Control Training (ACT).

“These findings suggest that both attention-training protocols may increase attention control and thereby reduce anxiety,” wrote Jeremy W. Pettit, Ph.D., of the Florida International University, and colleagues.

Both modules involve showing simultaneous images of neutral and angry faces, followed by a symbol or probe (“<” or “>”) appearing in the location of one of the faces. Participants are instructed to indicate the orientation of the probe by clicking the left or right mouse button (left for “<”, right for “>”) using their dominant hand. The task tests the subjects' bias toward paying attention to a threatening or nonthreatening stimulus and requires them to repeatedly practice focusing their attention.

Sixty-four youths (34 boys, 30 girls) with an average age of 17 who continued to have anxiety after completing CBT were randomized to four weeks of twice weekly ABMT or ACT. The primary outcome was the score on the six-item version of the Pediatric Anxiety Rating Scale (PARS). The secondary outcome was the score on the Screen for Child Anxiety Related Emotional Disorders–Child and Parent versions (SCARED-C/P). The latter consists of 41 items on which youth and parents rate youth anxiety symptoms.

Scores on both measures were significantly better at four weeks and at two-month follow-up, with no significant differences between the two groups. At two-month follow-up, the primary anxiety disorder diagnostic recovery rate was 50% for ABMT and 65% for ACT.

“We found that both forms of attention training led to improvements in attention control,” said Pettit in comments to Psychiatric News. “Increases in attention control were associated with decreases in anxiety severity. We interpret these findings as indicating that attention training influences later-stage, strategic attentional processing, and improvements in strategic attentional processing are associated with reductions in anxiety.”

For related information, see the Psychiatric News article “ Peer Program Helps High Schoolers Handle Depression, Anxiety.”

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Study Suggests Factors Linked to Teens’ Suicide Attempts

About 12% of adolescents who had suicidal thoughts or engaged in self-harm at age 16 went on to attempt suicide by age 21, but the risk factors for transition differed from established thinking on the subject, according to a large, longitudinal study of adolescents in Lancet Psychiatry.

“Existing research suggests that many well-established risk factors for suicide (such as depression, hopelessness, and impulsivity) do not predict suicide attempts among adolescents who have suicidal thoughts or engage in nonsuicidal self-harm,” wrote Becky Mars, Ph.D., a research fellow in epidemiology in the Department of Population Health Sciences at the University of Bristol and an American Foundation for Suicide Prevention postdoctoral fellow, and colleagues. “Longitudinal studies investigating predictors of future suicide attempts in these high-risk groups are extremely scarce.”

Researchers examined the Avon Longitudinal Study of Parents and Children, a population-based birth cohort study in the United Kingdom, for participants’ answers on two self-report questionnaires on suicidal thoughts and self-harm completed at 16 and 21 years of age. At baseline, 456 adolescents reported suicidal thoughts, and 569 adolescents reported nonsuicidal self-harm. Researchers explored the associations between risk factors at baseline and future first-time suicide attempts through age 21. (Participants who reported attempting suicide at baseline were excluded to focus on predictors of first-time suicide attempts.)

Among participants with suicidal thoughts at age 16, the following factors strongly predicted a suicide attempt by age 21, all of which were associated with two to three times higher risk of suicide attempt:

• Nonsuicidal self-harm
• Cannabis use
• Other illicit drug use
• Higher levels of the personality type intellect/openness

Among participants with nonsuicidal self-harm at age 16, the following factors strongly predicted a suicide attempt by age 21, all of which were associated with twice the risk of a suicide attempt:

• Cannabis use
• Other illicit drug use
• Insufficient sleep

“It might appear surprising that we did not find evidence of an association for several well-established suicide risk factors, including depression symptoms, psychiatric disorder, suicidal plans, and impulsivity. However, our results are consistent with previous research that has suggested that these factors appear to be associated with suicide attempts … but are not involved in the transition,” the researchers wrote.

For related information, see the Psychiatric News article “Irritability in Childhood May Point to Teens at High Risk for Suicide” and the Psychiatric Services article “ ‘13 Reasons Why’: Viewing Patterns and Perceived Impact Among Youths at Risk of Suicide.”

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Trigeminal Nerve Stimulation May Be Effective for Children With ADHD

Trigeminal nerve stimulation (TNS) may be as effective in treating symptoms of attention deficit/hyperactivity disorder (ADHD) in children as nonstimulant medications, according to a study in the Journal of the American Academy of Child & Adolescent Psychiatry. During treatment with TNS, a small stimulator powered by a 9-volt battery delivers a low current to patients through adhesive patches on their foreheads while they sleep. The current stimulates parts of the brain that are involved in concentration and impulse control.

James J. McGough, M.D., of the Semal Institute for Neuroscience and Human Behavior and the David Geffen School of Medicine at UCLA, and colleagues compared active treatment with TNS to sham (fake) treatment in 56 children aged 8 to 12 years. The sham devices were identical in appearance to real ones but did not deliver active treatment. The children received 8 hours of active of sham TNS every night for four weeks.

The researchers used the ADHD Rating Scale (ADHD-RS) and the Clinical Global Impression-Improvement Scale (CGI-I), two common assessments for symptoms of ADHD, to track the children’s response to their assigned devices. They also measured activity in the children’s brains with electroencephalography (EEG) before the study began and at study’s end.

Children in both groups showed improvement during the first week. Improvement leveled off in the sham treatment group after that, but continued in the active TNS group through the fourth week, although at a slower pace.

“ADHD-RS response patterns suggest that the greatest degree of TNS-related improvement occurred during the first week, with additional improvement accruing with ongoing use. The week 4 medium-sized treatment effect is within the same range typically evidenced with nonstimulant ADHD medications,” the researchers wrote. “Weekly CGI-I ratings further indicate that response rates increase with sustained treatment, at least over four weeks.”

The researchers also saw positive changes in brain activity in the active treatment group’s EEG readings, a finding that the researchers said supports that TNS was responsible for the children’s improvement.

“The virtual lack of significant side effects should make [TNS]  a popular treatment choice for many patients with ADHD, particularly for parents who prefer to avoid psychotropic medication,” the researchers concluded.

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Response to PHQ Item May Predict Suicide Risk Among Patients With Psychosis

Answers to a specific questionnaire item about thoughts of self-harm strongly predicted which patients with a psychotic disorder would attempt suicide in the next 90 days, according to a study in the March Psychiatric Services.

Suicidal behavior is especially common among individuals with psychotic disorders: 1 in 20 die by suicide and more than 1 in 4 attempt suicide at some point, wrote Gregory E. Simon, M.D., M.P.H., of the Kaiser Permanente Washington Health Research Institute, and colleagues. “Our findings indicate that individuals with psychotic disorders provide clinically useful responses to simple self-report questions about thoughts of death or self-harm.”

Researchers studied electronic health records over more than six years from seven large integrated health systems in nine states to identify adults with a diagnosis of schizophrenia spectrum psychosis, schizoaffective disorder, or unspecified psychosis. They identified all outpatient visits during which these patients completed the nine-item Patient Health Questionnaire (PHQ-9) and tracked their suicide attempts or completed suicides for 30 days and 90 day after their visits. Altogether, the study sample included 33,000 visits by nearly 6,000 patients.

More than 1 in 10 outpatients with a psychotic disorder reported frequent thoughts of death or self-harm on PHQ-9 item 9, which asks “Over the past 2 weeks, how often have you been bothered by thoughts that you would be better off dead or of hurting yourself in some way?” Researchers found that responses to Item 9 was a strong predictor of a suicide attempt over the ensuing 90 days: nearly half of suicide attempts occurred among those who reported recent thoughts of death or self-harm at the sampled visit. Also, 59% of suicide attempts occurred among those reporting thoughts of death or self-harm at the index visit or any visit in the prior year.

The risk of suicide attempt within 90 days of an outpatient visit was 0.8% among the patients reporting no thoughts of death or self-harm and 3.5% among those reporting such thoughts “nearly every day.” A similar pattern was seen for suicide attempts within 30 days of the visits. Considering patients’ prior-year responses to item 9—not just the current response—improved detection of risk, researchers said.

Researchers said identification of suicide risk should not be limited to self-report questionnaires and information typically recorded in electronic health records. “Providers should also consider important social risk factors for suicidal behavior, such as job loss, bereavement, or relationship disruption.”

Researchers noted the gap between assessment and subsequent treatment of suicidal patients: “Endorsement of frequent thoughts of death or self-harm certainly indicates an increased risk of self-harm and a need for more detailed assessment and appropriate care planning. Of patients reporting thoughts of death or self-harm nearly every day, approximately 1 in 30 received care for self-harm or probable suicide attempt during the following 90 days.”

For more information, see the Psychiatric Services study: “Predicting Suicide Attempts and Suicide Deaths Following Outpatient Visits Using Electronic Health Records.”

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Exposure to Infection in Pregnancy May Increase Risk of Autism, Depression

Autism spectrum disorder and depression were more common in Swedish children and adults born to mothers who had experienced infections during pregnancy while hospitalized, according to a study published in JAMA Psychiatry. The study is one of the first to evaluate a generalized effect of infection and inflammation during pregnancy on a broad spectrum of psychiatric disorders, wrote the authors.

“The developmental origins of mental illness are incompletely understood,” wrote Benjamin al-Haddad, M.D., M.Sc., Ph.D., of the Seattle Children’s Hospital and University of Washington, Seattle, and colleagues. “Maternal and fetal inflammatory responses to infection may alter fetal neurodevelopment, as suggested in some children with autism.”

The researchers used population-based registries to observe approximately one million children born between 1973 and 2014 in Sweden for up to 41 years. Infection and psychiatric diagnoses were derived using codes from hospitalizations. Hospitalization categories for pregnant women included any infection, severe infections, and urinary tract infections (UTIs) to further investigate whether the magnitude of risk to children differed by the type and severity of infection.

The risks of autism and depression increased 79% and 24%, respectively, among children and adults exposed to any maternal infection during pregnancy. Similar results were obtained for exposure to severe infections and UTIs, suggesting that type and severity of infection have no effect on risk of developing these conditions. No evidence was found for increased risk of bipolar disorder or psychosis.

“Our findings amplify the urgency to better understand the role of maternal infection during pregnancy on fetal brain development and suggest that prevention of infection (e.g., influenza vaccination) or anti-inflammatory therapies may be important strategies for the primary prevention of some portion of autism and depression,” the researchers wrote.

For related information, see the American Journal of Psychiatry article “Association of Maternal Insecticide Levels With Autism in Offspring From a National Birth Cohort.”

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Drug Combination Mitigates Weight Gain in Patients With Schizophrenia, Study Shows

The combination of the antipsychotic olanzapine and samidorphan, an experimental agent that acts on opioid receptors in the brain, results in significantly lower weight gain than olanzapine plus placebo in patients with schizophrenia, according to a report in AJP in Advance.

At the same time, olanzapine plus samidorphan demonstrated equal antipsychotic efficacy as olanzapine plus placebo. Olanzapine is highly effective for treating psychotic symptoms in people with schizophrenia but can cause significant weight gain resulting in metabolic disease.

“Antipsychotic-induced weight gain generally has a rapid onset and can occur in the first few weeks of treatment—an effect that was seen in all treatment groups during the first two weeks of this study,” wrote lead author William Martin, M.D., senior director of clinical development at Alkermes, manufacturer of samidorphan. “Thus, the addition of samidorphan mitigates olanzapine-associated weight gain but does not completely prevent it. Rather, treatment with olanzapine plus samidorphan changed the trajectory of weight gain over the remainder of the study period.”

In the study, 309 patients with schizophrenia had a one-week open-label treatment with olanzapine, followed by a 12-week double-blind treatment phase in which patients were randomly assigned to receive olanzapine plus placebo (n=75) or olanzapine plus samidorphan in these doses:5 mg (n=80), 10 mg (n=86), and 20 mg (n=68).

Patients in the olanzapine-plus-samidorphan groups experienced 37 percent lower weight gain than those in the olanzapine plus placebo group. Positive and Negative Symptom Scale (PANSS) scores were equivalent at follow-up for all groups. In addition, olanzapine plus samidorphan was generally well tolerated, with a safety profile similar to olanzapine plus placebo.

Olanzapine plus samidorphan at 10 mg/day was seen to be an effective dosage and superior to the 5 mg/day dosage. The 10 mg/day dosage was associated with a weight gain pattern similar to the 20 mg/day dosage, but overall adverse events were higher at 20 mg/day.

“The findings from this study identified 10 mg of samidorphan as the daily dose to further assess the mitigation of olanzapine-induced weight gain, and they support the continued development of olanzapine plus samidorphan in a phase 3 program,” the researchers concluded.

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

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Many Preteens Who Come to ED Are at Risk of Suicide

About 30 percent of preteens aged 10 to 12 who come to the emergency department (ED) screened positive for suicide risk, according to a study published today in Hospital Pediatrics. Further, 7 percent of those who screened positive were admitted for a nonpsychiatric medical emergency.

These findings highlight “the importance of screening all preteen patients in the ED for suicide risk regardless of their presenting complaint,” wrote Lisa Horowitz, Ph.D., M.P.H., of the National Institute of Mental Health and colleagues.

The researchers assessed data from a large suicide-screening study of youth aged 10 to 21 who came to the ED at one of three urban pediatric hospitals (Children’s National in Washington D.C., Boston Children’s Hospital, and Nationwide Children’s Hospital in Columbus, Ohio) between 2008 and 2011. Participants were screened with two suicidal-behavior questionnaires: the four-item Ask Suicide-Screening Questions (ASQ) and the 15-item Suicidal Ideation Questionnaire-Junior (SIQ-Jr).

Of the 524 patients in the study, 79 were between the ages of 10 and 12. Forty-two of the 79 preteens were admitted to the ED for a medical emergency such as a back injury or chest pain, and 37 were admitted for a psychiatric emergency such as depression or violent behavior.

In total, 23 of the 79 preteens (29.1%) screened positive for suicide risk on the ASQ and/or SIQ-Jr. This included 20 of the 37 patients (54.1%) who had a psychiatric emergency and three of the 42 patients (7.1%) with a medical emergency. Fourteen of the 79 preteens (17.7%)—including several 10-year-olds—reported a previous suicide attempt.

“This study shows that children as young as 10 who show up in the emergency department may be thinking about suicide, and that screening all preteens—regardless of their presenting symptoms—may save lives,” said Maryland Pao, M.D., an author on the paper, in a press statement. “Otherwise, they may pass through our medical systems undetected.”

For related information, see “Emergency Department Intervention May Reduce Suicide Attempts in At-Risk Patients.”

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Adults With Autism Twice as Likely to Be Hospitalized for Self-Harm

Adults with autism spectrum disorder (ASD) were nearly twice as likely as other adults to be hospitalized for self-injurious behavior and ideation, according to a study published yesterday in Psychiatric Services in Advance. In addition, these patients stayed in the hospital two days longer and incurred more costs even after the longer hospitalizations were taken into account.

“Adults with ASD might lack access to appropriate health care services, have difficulty communicating their symptoms to their health care providers, be more sensitive to stimuli and stressors, and lack a healthy support network,” wrote Morgan C. Shields, M.Sc., M.A., of the Lurie Institute for Disability Policy at the Heller School for Social Policy and Management at Brandeis University, and colleagues.

About 28% of U.S. children with ASD experience self-injurious behavior compared with about 8% of U.S. children without ASD, but less is known about U.S. adults with ASD.

Shields and colleagues used the Healthcare Cost and Utilization Project 2014 National Inpatient Sample to compare rates of hospitalization for adults with and without ASD for self-injurious behavior and ideation. They used ICD-9-CM codes to identify more than 5,000 hospital admissions for adults with ASD and more than 16,000 admissions for adults without ASD, matching them on age and gender. The study compared admissions, average length of stay, and costs of hospital stays for both groups.

Nearly 13% of the hospitalizations of adults with ASD were related to self-injurious behavior and ideation compared with 6% for adults without ASD. Adults with ASD were more likely to be non-Hispanic white, more likely to be on Medicare or Medicaid, and less likely to be uninsured or living in a low-income area.

Adults with ASD were hospitalized more than two days longer for self-injurious behavior or ideation (7.6 days versus 5.4 days) and had 37% higher costs ($6,800 versus $5,000). Even when the analysis was adjusted for comorbidity, number of procedures, and length of stay, adults with ASD still had more than 7% higher costs.

In the general population, age generally has a moderating effect on self-injurious behavior and ideation,with younger adults (aged 18 to 24) at substantially increased risk than older adults, according to the researchers. This held true in the study for adults without ASD. But adults with ASD aged 25 to 35 were no less likely than those aged 18 to 24 to have a hospitalization for self-injurious behavior and ideation.

The researchers further found that adults aged 50 and older with ASD were more likely to be hospitalized for self-injurious behavior and ideation compared with adults in this age range without ASD. “This suggests that self-injurious behavior and ideation, or at least those cases requiring hospitalization, remains a constant phenomenon well into adulthood for those with ASD,” the researchers wrote.

For related information, see the Psychiatric News article “Having a Sibling With ADHD or ASD Increases Risk for Both Disorders.”

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UBH Found to Have Wrongfully Denied Care Using Flawed Medical Necessity Criteria

The United States District Court for the Northern District of California this week found that United Behavioral Health (UBH/Optum), the country’s largest managed behavioral health care organization, illegally denied mental health and substance use coverage based on flawed medical necessity criteria.

In the case, David Witt, et. al. v. United Behavioral Health, Chief Magistrate Judge Joseph C. Spero said that UBH used internally developed medical necessity guidelines that comprehensively fell short of accepted standards of care to deny outpatient, intensive outpatient, and residential treatment to UBH beneficiaries. Plaintiffs were individuals insured by UBH.

The court looked to clinical guidelines from APA, the American Society of Addiction Medicine, other professional associations, and the Centers for Medicare and Medicaid Services to establish the applicable standards of care. Judge Spero outlined specific aspects of coverage that the accepted standards call for but that UBH did not meet. They include the following:

• Effective treatment requires treatment of the individual’s underlying condition and is not limited to alleviation of the individual’s current symptoms.
• Effective treatment requires treatment of co-occurring behavioral health disorders and/or medical conditions in a coordinated manner that considers the interactions of the disorders and conditions and their implications for determining the appropriate level of care.
• Patients should receive treatment for mental health and substance use disorders at the least intensive and restrictive level of care that is safe and effective – the fact that a lower level of care is less restrictive or intensive does not justify selecting that level if it is also expected to be less effective. Placement in a less restrictive environment is appropriate only if it is likely to be safe and just as effective as treatment at a higher level of care in addressing a patient’s overall condition, including underlying and co-occurring conditions.
• When there is ambiguity as to the appropriate level of care, the practitioner should err on the side of caution by placing the patient in a higher level of care.
• Effective treatment of mental health and substance use disorders includes services needed to maintain functioning or prevent deterioration.
• Appropriate duration of treatment for behavioral health disorders is based on the individual needs of the patient; there is no specific limit on the duration of such treatment.
• The unique needs of children and adolescents must be taken into account when making level of care decisions involving their treatment for mental health or substance use disorders.
• The determination of the appropriate level of care for patients with mental health and/or substance use disorders should be made on the basis of a multidimensional assessment that takes into account a wide variety of information about the patient.

“Having reviewed all of the versions of the Guidelines that Plaintiffs challenge in this case and considered the testimony of the witnesses addressing the meaning of the Guidelines, the Court finds, by a preponderance of the evidence, that in every version of the Guidelines in the class period, and at every level of care that is at issue in this case, there is an excessive emphasis on addressing acute symptoms and stabilizing crises while ignoring the effective treatment of members’ underlying conditions,” Spero wrote. “[I]n each version of the Guidelines at issue in this case the defect is pervasive and results in a significantly narrower scope of coverage than is consistent with generally accepted standards of care.”

This case is significant for patients and health care professionals who have long advocated for the use of medical necessity guidelines developed by professional organizations rather than those created by the insurance industry. While the case did not directly involve the federal parity law, the court recognized that mental and substance use disorders are chronic illnesses and rejected the insurer's practice of treating patients only for acute symptoms. This establishes a precedent for plans covered by the parity law requiring that they pay for continued treatment for mental and substance use disorders as they would for any other chronic illness.

For related information, see the Psychiatric News article “Assembly Seeks Help forMembers Appealing Insurance Denials.”

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FDA Approves Fast-Acting Esketamine for Treatment-Resistant Depression

Yesterday the Food and Drug Administration (FDA) approved Spravato (esketamine) nasal spray to be used in conjunction with an oral antidepressant for treatment-resistant depression in adults. Spravato is the first medication for depression with a new mechanism of action since Prozac (fluoxetine hydrochloride) was approved in the late 1980s.

“There has been a long-standing need for additional effective treatments for treatment-resistant depression, a serious and life-threatening condition," said Tiffany Farchione, M.D., acting director of the Division of Psychiatry Products in the FDA’s Center for Drug Evaluation and Research, in the agency’s press release. “Controlled clinical trials that studied the safety and efficacy of this drug, along with careful review through the FDA’s drug approval process including a robust discussion with our external advisory committees, were important to our decision to approve this treatment.”

Because of the risks of sedation, dissociation, and misuse, Spravato is subject to a comprehensive Risk Evaluation and Mitigation Strategy (REMS) program and carries a black-box warning. Patients can take Spravato only under the supervision of a health care professional in the office of a certified physician and must be monitored by a health care professional for at least two hours after the administration of the drug. The patient must remain on site until the health care professional determines it is safe for the patient to leave. In addition to the medication’s serious side effects, the black-box warning notes the risk of abuse and misuse.

In a Phase 3 clinical trial of adults with treatment-resistant depression, 223 patients were randomized to receive twice weekly doses of Spravato or placebo. All participants also took an oral antidepressant. Those who took the active nasal spray experienced greater improvement in their depression symptoms at four weeks compared with those who took placebo nasal spray. In a longer study, those who continued taking Spravato along with an oral antidepressant were 51% less likely to relapse than those who took a placebo and an oral antidepressant. Two other short-term trials did not meet prespecified statistical tests for demonstrating effectiveness.

Janssen, maker of Spravato, said in a statement that the company is “working quickly to educate and certify treatment centers in accordance with the REMS.” The company plans to post information about certified treatment centers later this month at https://www.spravato.com.

For related information, see the American Journal of Psychiatry study “Efficacy and Safety of Intranasal Esketamine for the Rapid Reduction of Symptoms of Depression and Suicidality in Patients at Imminent Risk for Suicide: Results of a Double-Blind, Randomized, Placebo-Controlled Study.”

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Specialized Therapy, Micronutrient Supplements Fail to Prevent MDD in Overweight Patients

Nutritional supplements and/or a special kind of therapy focused on improving dietary behaviors do not appear to prevent overweight adults with mild symptoms of depression from episodes of major depressive disorder (MDD) within a year, according to a study published today in JAMA. While some studies have found that improving diet reduces depressive symptoms in adults with depression, this study examined its effects on prevention for overweight adults with mild symptoms of depression.

The type of therapy used in this study was food-related behavioral activation. Behavioral activation is a treatment whose goal is to teach people that their behavior is linked to their mood and that by changing their behavior, they can change their mood.

“This study showed that multinutrient supplements containing omega-3 PUFAs [polyunsaturated fatty acids], vitamin D, folic acid, and selenium neither reduced depressive symptoms [and] anxiety symptoms, nor improved health utility measures,” wrote Mariska Bot, Ph.D., of the Amsterdam Public Health research institute and colleagues. “In fact, they appeared to result in slightly poorer depressive and anxiety symptoms scores compared with placebo.”

The trial included 1,025 overweight adults, aged 18 to 75 years, in four western European countries (Germany, the Netherlands, Spain, and the United Kingdom) with mild depressive symptoms (Patient Health Questionnaire-9, or PHQ-9 scores ≥5). The study participants were randomly assigned to one of four groups: multinutrient supplements with food-related behavioral activation therapy; multinutrient supplements without therapy; placebo supplements with food-related behavioral activation therapy; or placebo supplements without therapy. Participants receiving supplements were assigned to take omega-3 polyunsaturated fatty acids, selenium, folic acid, vitamin D3, and calcium for one year. Those assigned to food-related behavioral activation were invited to participate in a maximum of 21 sessions (15 individual, six group) focused on improving dietary habits for one year.

Bot and colleagues followed the participants in the trial for 12 months to evaluate symptoms of depression, anxiety, and more.

In total, 105 participants (10%) developed an MDD episode during the 12-month follow-up: 25 participants (9.7%) had received placebo alone; 26 (10.2%), placebo with therapy; 32 (12.5%), supplements alone; and 22 (8.6%), supplements combined with therapy. Neither of the interventions nor the combination of the two had an effect on decreasing the participants’ likelihood of developing an MDD episode in the following 12 months.

“Despite the large sample size and selection of people with elevated depressive symptoms, the onset of MDD was lower than expected, which reduced the statistical power to detect a statistically significant effect,” Bot and colleagues wrote. Nonetheless, the authors concluded, “These findings do not support the use of these interventions for prevention of major depressive disorder in this population.”

For additional information, see the American Journal of Psychiatry article “Adjunctive Nutraceuticals for Depression: A Systematic Review andMeta-Analyses.”

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