Wednesday, March 20, 2019

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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Tuesday, March 19, 2019

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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Monday, March 18, 2019

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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Friday, March 15, 2019

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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Thursday, March 14, 2019

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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Wednesday, March 13, 2019

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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Tuesday, March 12, 2019

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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Monday, March 11, 2019

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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Friday, March 8, 2019

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.”

Thursday, March 7, 2019

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.”

Wednesday, March 6, 2019

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.”

Tuesday, March 5, 2019

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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Monday, March 4, 2019

Study Identifies Medications Effective for Treating, Preventing Delirium


Delirium—an acute brain state characterized by confused thoughts and emotions—is a common problem among elderly inpatients and patients in intensive care. A meta-analysis published in JAMA Psychiatry suggests that a combination of haloperidol and lorazepam may be the best option to treat patients with delirium, while ramelteon may be the best medication to prevent delirium.

Yi-Cheng Wu, M.D., of Linkou Chang Gung Memorial Hospital in Taoyuan, Taiwan, and colleagues compiled data from 58 clinical trials for delirium; these included 20 trials assessing therapeutic interventions for delirium and 38 assessing preventive interventions. The trials involved more than 9,600 individuals who had delirium due to a variety of possible causes such as being in critical care, undergoing major surgery, having a chronic illness like cancer, or being of advanced age.

Among the studies testing medications to treat delirium, only patients given haloperidol (currently the most commonly used medication for delirium) or haloperidol plus lorazepam had better response rates (fewer delirium-related symptoms) than those given placebo. The haloperidol-lorazepam combination was superior, according to the analysis; patients prescribed haloperidol plus lorazepam were 28 times more likely to respond than those prescribed placebo, while patients prescribed haloperidol were about 2.4 times as likely to achieve a response than those prescribed placebo.

Among the 38 preventive studies, four treatments were found superior to placebo at reducing the risk of delirium: dexmedetomidine hydrochloride, olanzapine, ramelteon, and risperidone. Of these, ramelteon had the strongest preventive effect, reducing the risk of delirium by 93% relative to placebo.

The study authors cautioned, however, that haloperidol-lorazepam and ramelteon were studied in only one trial each. “Future large-scale RCTs investigating the treatment effect of haloperidol plus lorazepam and the preventive effect of ramelteon are warranted to corroborate the findings,” they concluded.

To read more about the management of delirium, see the Psychiatric News article “Common Delirium Medications Found Not Effective in Critically Ill Patients” and the Journal of Neuropsychiatry and Clinical Neurosciences article “Responding to Ten Common Delirium Misconceptions With Best Evidence: An Educational Review for Clinicians.”

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Friday, March 1, 2019

Age of Parents at Child’s Birth May Raise Risk of Autism, ADHD, Other Conditions


How old mothers and fathers are when their children are born may affect their children’s risk of developing several neuropsychiatric disorders, according to a study published this week in the Journal of the American Academy of Child & Adolescent Psychiatry.

Magdalena Janecka, Ph.D., of the Icahn School of Medicine at Mount Sinai, N.Y., and colleagues analyzed data from the medical and psychiatric records of nearly 1.5 million people in Denmark who were born between 1980 and 2007. They looked at rates of autism spectrum disorders (ASD), attention-deficit/hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), and Tourette’s syndrome/chronic tic disorder (TS/CT). They then looked at the age of the parents at the time people with these disorders were born. Parents who were younger than 27.5 years were considered “younger,” and parents older than 37.5 years were considered “older.”

The researchers found that children born to older mothers had a 34% increased risk of developing ASD, and children born to older fathers had a 26% increased risk of developing ASD. Children born to older mothers had a 23% increased risk of developing OCD, whereas a father’s age did not appear to significantly affect risk.

“Many epidemiological studies have indicated that advancing parental age, and, in particular, advancing paternal age, contribute to offspring risk for ASD and other neuropsychiatric disorders,” Janecka and colleagues wrote. “Our study provides robust evidence for distinct patterns of disorder risk associated with early vs. late parenthood, separately in mothers and fathers.”

The researchers also found that children born to younger mothers had a 70% increased risk of developing ADHD, and children born to younger fathers had a 63% increased risk of developing ADHD. Children born to younger mothers had a 12% increased risk of developing TS/CT, and children born to younger fathers had a 9% increased risk of developing TS/CT.

“Compared to children of older parents, those born to young parents are more often exposed to disadvantageous home environments and parenting behavior,” the researchers noted. “These environmental factors have been associated with higher risk for ADHD and TS/TC, and with regard to ADHD, could account for the shared parental contribution we observed.”

The researchers added that their results could provide insight on other disorders.

“In the light of the heterogeneity of these disorders, it is … plausible that parental age exerts its effects on any given disorder via a number of different routes—for example, the association between paternal age and ASD could be due to considerably different mechanisms in sporadic and familial cases,” they wrote.

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Thursday, February 28, 2019

Prevalence of Mental Disorders Higher in Patients With Head, Neck Cancers After Cancer Diagnosis


Patients with cancers of the head and neck are more likely to have an increased prevalence of mental health disorders after their cancer is diagnosed compared with the general population, according to a report published today in JAMA Otolaryngology-Head and Neck Surgery.

There appears to be an especially strong association between mental health disorders and cancers of the trachea. Additionally, patients who received multimodal therapy—radiotherapy, chemotherapy, and/or surgery—have a higher risk of developing mental health disorders compared with those who receive only surgery, according to the report.

“High mortality and morbidity associated with HNCs [head and neck cancers] may predispose these patients to MHDs [mental health disorders],” wrote Neerav Goyal, M.D., M.P.H., of Pennsylvania State University and colleagues. “In addition, morbidity is associated with the treatment.”

Goyal and colleagues analyzed data from the Truven Health Market Scan Commercial Claims and Encounters database from January 1, 2005, through December 31, 2014. They tracked diagnostic codes from ICD-9-CM associated with head and neck cancers and mental health disorders. Head and neck cancers included cancer of the lip, tongue, oral cavity, oropharynx, nasopharynx, hypopharynx, nasal cavity and sinus, larynx, trachea, mandible, Kaposi sarcoma of the palate, and malignant neoplasm of the head and neck. Mental health disorders included episodic mood disorders, including depression, anxiety, nonalcohol drug dependence, adjustment reaction, and depressive disorder not otherwise specified.

The researchers measured the prevalence of mental health disorders and compared points before and after the diagnosis of head and neck cancers. In this cohort study of 52,641 patients with a diagnosis of head and neck cancer, the proportion with mental health disorders at baseline was 20.6% compared with the national average of 17.9%, as estimated by the National Survey on Drug Use and Health. After diagnosis, the prevalence rose to 29.9%. Patients with tracheal cancers had twice the odds of developing mental health disorders compared with patients with oral cavity cancer.

A total of 15.2% of the cohort received radiotherapy, chemotherapy, and surgery; 12.9%, radiotherapy and surgery; and 2.9%, chemotherapy and surgery. Patients who received all three treatments were more likely to develop mental health disorders than those who had only surgery.

Patients with head and neck cancer should be monitored for mental health issues, Goyal and colleagues wrote. “Our results further support the importance of addressing psychosocial needs in routine treatment discussions.”

For related information, see the Psychiatric News article “Researchers Look at Improving Well-Being of Families Affected by Cancer.”

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Wednesday, February 27, 2019

Children Separated From Families at Border Could Suffer Long-Term MH Consequences, Says APA President


Children separated from their families at the border suffer from “toxic stress,” and some of these children will be significantly impaired for the rest of their lives, APA President Altha J. Stewart, M.D., testified on behalf of APA at a House Appropriations subcommittee today. Some of the factors that she said influence the children’s outcomes are dependent on their age, previous adversity, and the duration of the separation.

APA was among the first organizations to speak out last spring when it became clear that the administration’s “zero tolerance” policy of referring those crossing the border for federal criminal prosecution would result in the widespread separation of children and families.

“As the physician experts in mental health, we will continue to oppose such family separation policies,” Stewart said. “Children depend on their parents or other trusted adults for their comfort, safety, and support. Any forced separation is highly stressful for children and can cause lifelong trauma, as well as increased risk of mental illness, such as depression, anxiety, substance use, and posttraumatic stress disorder.”

Stewart’s goal in testifying was to give lawmakers an overview of the trauma caused by the forced separation of children and warn of the potential for lasting negative outcomes, she said at the hearing held by the Subcommittee on Labor, Health and Human Services, Education, and Related Agencies. She pointed out the need for providing the children with trauma-informed care and access to services and supports for their clinical care after reunification with their families. Trauma-informed care, she said, shifts the dialogue from asking “what’s wrong with you” to “what has happened to you.”

Stewart also explained the concept of Adverse Childhood Experiences (ACEs) and the longstanding body of research about their impact on future health status. Examples of ACEs are physical, sexual, or emotional abuse or neglect; household exposure to mental illness or substance use disorder in parents and caregivers; as well as incarceration itself. “When a child is exposed to such chronic stress and trauma, their underdeveloped brain remains in a very elevated state, and ultimately this consistent exposure to this heightened stress and trauma changes their emotional, behavioral, and cognitive functioning.”

The Flores agreement and subsequent court rulings require the federal government to quickly place immigrant children detained at the border in safe, supportive homes with family members, said Subcommittee Chair Rep. Rosa DeLauro (D-Conn.). “Executing this lawful mission has not been this administration’s approach, however,” she said. “Instead, it has attempted to turn Health and Human Services into an immigration enforcement agency.” In fact, she noted, tens of thousands of children have been held for many months, and the average length of child detentions has nearly tripled.

A full report of the hearing and the testimony of other witnesses will appear in a future issue of Psychiatric News.

For related information, see the Psychiatric News article “APA Maintains Pressure on Administration Regarding Welfare of Migrant Children.

(Image: David Hathcox)

Tuesday, February 26, 2019

Adolescent Opioid Misuse Linked to Parental Misuse


Parental and adolescent misuse of prescription opioids are significantly associated with each other, according to a study published yesterday in Pediatrics.

Pamela C. Griesler, Ph.D., of the New York State Psychiatric Institute and colleagues analyzed data from the National Survey on Drug Use and Health from 2004 to 2012 involving 35,000 parents (nearly two-thirds of whom were mothers) who had an adolescent aged 12 to 17 living in their household. As part of the survey, parents and adolescents were asked if they had ever used one of 21 prescription opioids without a doctor’s prescription or if they took the drug “only for the experience or feeling it caused.” They were also asked questions about lifetime depressive episodes and their use of cigarettes, alcohol, or other drugs.

About 14% of parents had ever misused a prescription opioid; white parents reported higher rates of use (16%) than African American parents (10%) and Hispanic parents (9%). About 9% of adolescents reported opioid misuse, with boys and girls as well as children from various races and ethnic backgrounds all reporting similar rates of use. Misuse increased with age—from 4% among 12-year-olds to 15% among 17-year-olds.

Adolescents were nearly twice as likely to misuse opioids when at least one of their parents had done so: nearly 14% of adolescents had misused opioids in their lifetime when a parent had also done so, compared with 8% when a parent had not. However, the associations differed with the sex of the parent: only mothers’ opioid misuse was significantly associated with that of their adolescents.

The researchers identified several parental factors that were associated with adolescents’ misuse of prescription opioids, including lifetime smoking and high levels of parent-adolescent conflict. Adolescents were more likely to misuse opioids if they smoked cigarettes, used marijuana, were depressed, or perceived that most of their classmates used drugs.

“Similar to other types of parental substance use, parental NMPO [nonmedical prescription opioid] use is associated with offspring use and should be considered in efforts to reduce adolescent NMPO use,” the researchers concluded. “Smoking should also be the target of interventions; there are significant links between parental and adolescent smoking and adolescent NMPO use. Parent-based interventions targeted at NMPO use among youth should not only address parental NMPO use but should also promote positive parenting practices...”

For related information, see the American Journal of Psychiatry article “Improving Our Understanding of Substance Use Disorders.”

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Monday, February 25, 2019

Patients Not Fully Responsive to Antidepressants, CBT Alone Found to Improve With Combined Therapies


A study published in AJP in Advance shows that the success of combined cognitive-behavioral therapy (CBT) and antidepressant therapy is just as likely regardless of which treatment—medication or CBT—is initiated first.

“The sequential combination of CBT or antidepressant medication for patients who do not achieve remission with monotherapy is an effective approach for outpatients with major depression, and the sequence in which the treatments are applied does not appear to affect end-of-treatment outcomes,” wrote lead author Boadie Dunlop, M.D., of Emory University and colleagues.

The findings were based on the second phase of the Predictors of Remission in Depression to Individual and Combined Treatments (PReDICT) study. In the first phase of PReDICT, Dunlop and colleagues randomly assigned 344 adults with depression to 12 weeks of treatment with escitalopram, duloxetine, or 16 one-hour individual sessions of CBT. Patients who did not achieve remission of their depression after 12 weeks (defined as a score of 7 or lower on the Hamilton Depression Rating Scale, or HAM-D) were invited to continue in the second phase of the study—a 12-week treatment period in which they received a combination of medication and CBT. In this second phase, patients who initially received escitalopram or duloxetine (n=75) continued their medication and received 16 sessions of CBT. Patients who initially received CBT (n=37) continued receiving monthly CBT sessions and began taking escitalopram daily.

By the end of second phase of the study, 64.9% (24/37) of the patients initially assigned to CBT and 60% (45/75) of those initially assigned to an antidepressant achieved remission. The rate of remission following combination therapy was significantly higher among patients who showed some response to monotherapy in phase 1 of the study (61%) than among patients who did not respond at all to monotherapy during phase 1 (41%).

Dunlop and colleagues also found that, as in previous research, more severe depression at baseline was associated with a lower chance of achieving remission. However, after controlling for severity of depression, the researchers found that higher levels of anxiety, both prior to monotherapy and prior to beginning combination treatment, predicted poorer outcomes for both treatment groups.

“These results suggest that previous studies that identified depression severity as a negative predictor of outcome should be reanalyzed to examine whether the results persist after controlling for anxiety,” they wrote.

To read more about the PReDICT study, see the Psychiatric News article “CBT, Antidepressants Are Equally Effective in Treatment-Naïve Patients” and the American Journal of Psychiatry article “Effects of Patient Preferences on Outcomes in the Predictors of Remission in Depression to Individual and Combined Treatments (PReDICT) Study.”

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Friday, February 22, 2019

Percentage of Older Adults Taking Insomnia Medications Exceeds Those Diagnosed With Disorder


Far more Medicare patients take insomnia medications than are actually diagnosed with insomnia by a physician, suggesting that insomnia is significantly underdiagnosed in this population despite treatment, according to a study in the American Journal of Geriatric Psychiatry.

Jennifer S. Albrecht, Ph.D., of the University of Maryland School of Medicine and colleagues analyzed data from a random sample of 5% of patients who had at least 10 months of continuous Medicare coverage between 2006 and 2013. They found that over the eight years studied, insomnia diagnoses in this population increased from 3.9% to 6.2%. They also found that insomnia medication use (defined as at least one prescription fill) increased from 21% to 29.6%.

“Annual prevalence of insomnia medication use was up to four times higher than insomnia diagnoses and remained steady over time,” Albrecht and colleagues wrote. “Our data suggest that insomnia is commonly treated but infrequently diagnosed. Future research should seek to understand the consequences and causes of this discrepancy.”

The most common insomnia prescriptions filled were sedating antidepressants, nonbenzodiazepine sedating hypnotics, hydroxyzine, and benzodiazepines. Among these medications, benzodiazepines had the greatest increase in usage between 2012 and 2013; the number of filled prescriptions jumped from 1.1% to 17.6%.

“The increase in prevalence of benzodiazepine use from 2012−2013 came at a time when nursing homes were mandated to reduce antipsychotic use and may reflect substitution of benzodiazepines for antipsychotics to control behavioral symptoms in that population,” Albrecht and colleagues wrote. They added that benzodiazepines are on the Beers list of medications to be avoided in older adults and stated that their use should be monitored closely in this population.

In their conclusion, the researchers noted that they were not able to learn why these medications were prescribed for the patients.

“Because some medications used for the treatment of insomnia (e.g., sedating antidepressants, benzodiazepines) have other indications, it is possible that our results overestimate insomnia medication use,” they wrote. Nonetheless, the study “raises important questions about insomnia diagnosis, prescribing practices, and medication interactions.”

For related information, see the Psychiatric News article “Self-Reports of Poor Sleep Not Always Accurate.”

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Thursday, February 21, 2019

Antipsychotic Polypharmacy May Reduce Long-Term Rehospitalization Risk, Study Finds


A combination of clozapine plus aripiprazole was associated with the lowest risk of psychiatric rehospitalization among patients with schizophrenia who were followed for up to 20 years in Finland, according to a study published Wednesday in JAMA Psychiatry.

As many as 30% of patients with schizophrenia are treated with a combination of antipsychotics, although the practice is controversial because of its lack of evidence of tolerability, safety, and efficacy, wrote Jari Tiihonen, M.D., Ph.D., of the Karolinska Institutet in Sweden and colleagues.

In this study on the long-term use of antipsychotic polypharmacy in schizophrenia, researchers examined seven monotherapies and 22 antipsychotic combinations, excluding polypharmacy periods shorter than 90 days.

Researchers analyzed data on all Finnish patients with schizophrenia treated in an inpatient setting from 1972 to 2014, and the 62,250 patients were followed for a median of 14 years, with researchers pulling data on their dispensation of antipsychotic medication. The primary outcomes studied were the number of psychiatric rehospitalizations, with hospitalizations due to physical illnesses and deaths serving as secondary outcomes.

During that time 58% of participants were readmitted for psychiatric inpatient care.

The study findings include the following:

  • Nearly 60% of participants used antipsychotic polypharmacy for at least 90 days. This practice was associated with a 13% lower risk of psychiatric rehospitalization compared with monotherapy.
  • The treatment associated with the best outcome in terms of psychiatric or all-cause hospitalization was clozapine plus aripiprazole. Patients taking this combination had a 14% lower risk of psychiatric rehospitalization than those taking clozapine alone, which was the monotherapy associated with the best outcome.
  • The advantage of the clozapine plus aripiprazole combination was greater for patients with first-episode schizophrenia, who were 23% less likely to be rehospitalized than other patients with first-episode schizophrenia.
  • Among the 29 therapies examined, patients taking quetiapine monotherapy had highest risk of psychiatric rehospitalization, but adding on any another antipsychotic resulted in a better outcome.

The researchers concluded that certain types of polypharmacy may be beneficial in the treatment of schizophrenia. “Although the results do not indicate that all types of polypharmacy are beneficial, the current treatment guidelines should modify their categorical recommendations discouraging all antipsychotic polypharmacy in the maintenance treatment of schizophrenia,” they wrote.

For more information, see the Psychiatric Services article “Addressing Barriers to Clozapine Underutilization: A National Effort” and the Psychiatric News article “Clozapine, LAI Antipsychotics Found Best at Preventing Relapse.”

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