AJP Editors Highlight Favorite Articles of 2018

Improving outcomes in patients with depression and posttraumatic stress disorder, drug development, and psychotherapy were among the topics of the seven articles selected as favorites of 2018 by the editors of the American Journal of Psychiatry. The articles are listed below in the order they appeared in the print issue of the Journal:

Adjunctive Bright Light Therapy for Bipolar Depression: A Randomized Double-blind Placebo-controlled Trial: Dorothy Sit, M.D., and colleagues randomly assigned adults with bipolar I or II disorder with symptoms of major depression who were on stable concomitant medications to either a 7,000-lux bright white light or 50-lux dim red light (placebo) for six weeks. Compared with the dim light group, the group treated with bright white light experienced a significantly higher remission rate (68.2% compared with 22.2%) after four weeks and significantly lower depression scores by the end of the study. No mood polarity switches were observed.

Role of Complex Epigenetic Switching in Tumor Necrosis Factor-α Upregulation in the Prefrontal Cortex of Suicide Subjects: Qingzhong Wang, Ph.D., and colleagues examined the expression of the pro-inflammatory cytokine gene tumor necrosis factor–alpha (TNF-α) in the postmortem brains of people with and without major depressive disorder who died by suicide and of people with major depressive disorder who died of causes other than suicide. They found TNF-α expression was significantly higher in the dorsolateral prefrontal cortex of people in both groups. However, among the microRNAs that regulate TNF-α levels, only miR-19a-3p was upregulated in the prefrontal cortexes of those who died by suicide and was unaltered in individuals with major depressive disorder who died by other means.

Association Between Insight and Outcome of Psychotherapy: Systematic Review and Meta-analysis: Simone Jennissen, M.Sc., and colleagues conducted a meta-analysis to examine the association between patient insight and psychotherapy outcome across a range of treatment modalities. They found that across studies, more insight is moderately associated with better psychotherapy outcome.

Reduction of PTSD Symptoms With Pre-reactivation Propranolol Therapy: A Randomized Controlled Trial: Alain Brunet, Ph.D., and colleagues randomly assigned patients who had experienced PTSD for at least six months to receive propranolol (a noradrenergic beta-receptor blocker) or placebo 90 minutes before sessions where they actively recalled their traumatic event. Those who participated in the sessions under the influence of propranolol once a week for up to six weeks showed a substantial decrease in symptom ratings compared with those in the placebo group.

Revisiting Antipsychotic Drug Actions Through Gene Networks Associated With Schizophrenia: Karolina Kauppi, Ph.D., and colleagues merged genetic data on schizophrenia risk genes with a database of the known gene targets of 64 antipsychotics to look for interactions between these genes. They found that most of the genes were connected in different biological networks. However, there were also several schizophrenia risk genes that had no genetic links to current antipsychotic drugs, representing potentially novel drug targets.

Epigenetic Aging in Major Depressive Disorder: DNA methylation—a process by which cells regulate gene expression—is considered a good biological clock since methylation normally occurs at a regular rate. Laura K.M. Han, M.Sc., and colleagues found that people with major depression have accelerated methylation activity, especially those who experienced childhood trauma.

Improving Depression Outcome by Patient-Centered Medical Management: As part of an article series that celebrated the 175th year of the Journal, John Rush, M.D., and Michael Thase, M.D., explored the fundamental issue of how doctors work collaboratively with their patients. They noted that while adjunct psychotherapy can boost the effectiveness of pharmacotherapy/neuromodulation for patients with mood disorders, the two treatments are often not well-coordinated. To overcome this challenge, Rush and Thase proposed a new system in which patient care is divided into four clinical tasks: 1) engaging and retaining the patient in treatment; 2) optimizing symptom control; 3) restoring daily functioning and quality of life; and 4) mitigating the long-term risk of relapse. Psychiatrists then work with patients to systematically address each task, tailoring the treatment strategies to the strengths and needs of each patient.

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FDA Downgrades Risk Category for Certain Uses of ECT

The Food and Drug Administration (FDA) issued a final order on Wednesday to downgrade the risk category for certain uses of electroconvulsive therapy (ECT).This was a change for which APA had strongly advocated, saying it could greatly expand access to safe, effective treatment for individuals with serious and persistent psychiatric disorders.

First, the FDA’s final order reclassified ECT devices from Class III (higher risk) to Class II (moderate risk) for the treatment of catatonia or a severe major depressive episode associated with major depressive or bipolar disorder. The order applies to ECT use in patients who are treatment-resistant or who require a rapid response due to the severity of their condition.

In addition, the FDA lowered the minimum age for whom these ECT devices are considered Class II products to 13 years, from its originally proposed 18 years of age.

Finally, the order requires ECT manufacturers to file FDA’s most rigorous application for marketing known as a premarket approval (PMA) application for all other uses of ECT devices, such as for schizoaffective disorder and bipolar manic states. The agency notes that this is because the FDA is unable to identify sufficient information to ensure the safety and effectiveness of ECT for such indications.

“This will give physicians more information on the safe and effective use of these devices and ultimately better protect patients,” said Carlos Peña, Ph.D., director of the Division of Neurological and Physical Medicine Devices in the FDA’s Center for Devices and Radiological Health, in a statement. FDA regulates medical devices and categorizes them into one of three classes (I, II, or III) based on their level of risk and the regulatory controls necessary to provide a reasonable assurance of safety and effectiveness.

For years, APA has strongly supported the reclassification of ECT devices as Class II. APA submitted formal comments to the FDA after the FDA proposed an administrative order for the reclassification in late 2015. APA cited numerous studies demonstrating evidence to support the safety and effectiveness of ECT for patients with treatment-resistant major depressive episodes. APA also encouraged members to submit comments to the Federal Register explaining the potential benefit of ECT reclassification. A similar effort was initiated years earlier when the FDA invited public comments on how ECT devices should be reclassified.

APA had also recommended the FDA designate ECT as Class II for use in mania in bipolar disorder, schizophrenia, and schizoaffective disorder, as well as for use in children and adolescents who meet the criteria for treatment resistance and who are in need of a potentially lifesaving intervention.

The reclassification of ECT devices is part of FDA’s 515 Program Initiative, which it began in 2009 to address some 26 devices that were issued “temporary” Class III designations some 40 years ago. ECT devices were one of the last two medical devices awaiting reclassification.

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Daughters of Men With Postnatal Depression May Be at Higher Risk for Depression in Adolescence

Girls whose dads experienced depression shortly after their birth are more likely to develop depression by age 18, according to a study published Wednesday in JAMA Psychiatry.

This cohort study of 3,176 father-offspring pairs in Southwest England explored the association of depression symptoms in fathers eight weeks after the birth of their infant and depression symptoms in the offspring 18 years later. The researchers also examined potential environmental pathways for depression risk. After adjusting for the age and education level of the father, they found that maternal depression had the greatest influence on depression risk, which explained 21% of the association, followed by conduct problems in the offspring at age 3.5 years, which explained 8% of the association.

“Our findings suggest that paternal depression during the postnatal period appears to exert its influence on late emotional problems in girls at least in part through maternal depression,” wrote Leticia Gutierrez-Galve, Ph.D., of the Centre for Psychiatry at Imperial College in London. “Maternal depression has been previously associated with impaired parenting, particularly sensitive parenting. Mothers with depression may show less maternal responsiveness or sensitivity, less verbal and visual interaction, and more intrusiveness during interactions with their infants.”

Parent participants, who were part of an ongoing population-based cohort study called ALSPAC, took the Edinburgh Postnatal Depression Scale, a 10-item self-report questionnaire at eight weeks after the birth of their infants and again eight months later. Also at eight months, mothers were interviewed about their relationships with their partners using a nine-item scale, asking questions such as “Do you get angry with your partner?” and “Does your partner listen when you want to talk about your feelings?”.

When the offspring were about 3.5 years old, the mothers completed the Rutter Revised Preschool Scales, which assess problem behaviors (emotional problems, conduct problems, and hyperactivity) and prosocial behaviors. The offspring were evaluated for depression at age 18, using the computerized version of the Clinical Interview Schedule-Revised.

Ultimately, just over 7% of the 3,165 adolescents studied had a primary diagnosis of depression at age 18 years. Researchers found that the teens whose dads had depression eight weeks after their birth were 1.5 times more likely to go on to develop depression themselves. Couple conflict and paternal involvement did not appear play a role in the risk of offspring depression, the researchers wrote, noting they did not have enough data to explore the quality of parent-child interactions.

“Early conduct disorder in children appears to be a mechanism of risk transmission between depression in fathers and subsequent depression at age 18 years,” the researchers concluded. “Overall, these findings highlight the importance of recognizing and treating depression in fathers during the postnatal period and considering both parents when one parent presents with depression.”

For related information, see the Psychiatric News article “New Primary Care Guidelines Recommend Routine Screening for Depression in Adolescents.”

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Relatives of People With Depression Perform Worse on Cognitive Tests

First-degree relatives of people with major depressive disorder (MDD) perform slightly worse on cognitive tests compared with individuals with no family history of major mental illness, reports a meta-analysis published today in JAMA Psychiatry. According to the study authors, the findings support the idea that cognitive difficulties may be a risk factor for MDD.

Such information could help guide early intervention in individuals considered to be at high familial risk for developing MDD, Lynn MacKenzie, M.A., of Dalhousie University in Halifax, Nova Scotia, and colleagues wrote.

MacKenzie and colleagues compiled data from 54 individual studies that assessed cognition; the studies included 3,246 first-degree relatives of people with MDD (such as children or siblings) and 5,222 people without a first-degree relative diagnosed with MDD, bipolar disorder, or schizophrenia.

The researchers found that compared with the control group, first-degree relatives of individuals with MDD performed worse on several cognitive tests—including assessments of verbal intelligence, perception, memory, and language. First-degree relatives of people with MDD also had slightly lower academic performance on average compared with controls. There were no statistical differences in tests for attention, processing speed, executive function, hot cognition (cognitive ability during an emotionally aroused state), and psychomotor skills such as coordination.

“There are several possible explanations for impaired cognitive performance in first-degree relatives of individuals with MDD. The lower cognitive ability seen in relatives of individuals with MDD may reflect genetic and social factors associated with the risk of MDD,” Mackenzie and colleagues wrote. “Cognition in relatives may also be affected by environmental factors, such as poverty and low socioeconomic status, that may run in families alongside depression and affect even those who do not develop depressive disorders.”

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Older Adults at Increased Risk of Depression, Anxiety After Rehab Ends

Older adults who receive rehabilitation services are at higher risk for depressive and anxiety symptoms up to a year after rehabilitative services are discontinued compared with those who do not receive rehabilitative services, according to a study in the American Journal of Geriatric Psychiatry.

“As mental illness is associated with considerable morbidity and may affect rehabilitation outcomes, additional efforts to identify and treat depression and anxiety in these older adults may be warranted,” wrote Adam Simning, M.D., Ph.D., of the University of Rochester School of Medicine and Dentistry and colleagues.

The researchers evaluated data from 5,979 adults in the 2016 National Health and Aging Trends Study (NHATS), a nationwide study of Medicare beneficiaries aged 65 years and older. As part of the NHATS, participants are interviewed annually. For this study, the researchers specifically focused on patient responses to the two-item Patient Health Questionaire (PHQ-2); the two-item Generalized Anxiety Disorder (GAD-2) scale; and a question regarding whether they had received rehabilitative services and, if so, where they received these services.

In the study sample, 16.5% reported receiving rehabilitation services in nursing home, inpatient, outpatient, or in-home settings in the prior year. A higher proportion of Medicare beneficiaries who received these rehabilitation services had clinically significant depressive and anxiety symptoms at follow-up than those who did not receive these services (depression: 18.4% vs. 10.4%; anxiety: 11.8% vs. 8.8%), Simning and colleagues reported.

The researchers found that the presence of depressive and anxiety symptoms varied according to where participants had received their rehabilitative services. The majority of participants with depressive symptoms had received their rehabilitative services in either a nursing home or inpatient facility (38.8%) or in their homes (35.3%), compared with those who received services as outpatients (8.6%) or at a combination of rehabilitative sites (20.3%). The rates of anxiety were higher for participants who had received rehabilitative services in a nursing home, inpatient facility, or their homes compared with the other sites, as well.

Compared with participants who did not have depressive or anxiety symptoms, those who had symptoms were more likely to be older, nonwhite, and living alone; have less formal education; have dementia and self-reported decreased functioning in self-care and household activities; and to have had depressive and anxiety symptoms at baseline.

The researchers noted a need for psychiatric interventions for older adults who receive rehabilitation services. “As depressive and anxiety symptoms are common in these patients, associated with considerable morbidity, and/or may interfere with rehabilitation treatment and recovery, devising interventions that target these symptoms in rehabilitation settings could have a significant public health impact,” Simning and colleagues wrote

For related information, see the Psychiatric News article “Older Adults Are More Likely to Receive Prescriptions for Depression, Anxiety.”

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Rising U.S. Youth Firearm, Motor Vehicle Crash Deaths Called ‘Shameful’

There was a 28% increase in the rate of firearm deaths among U.S. children between 2013 and 2016, according to a report published today in the New England Journal of Medicine.

In all, there were more than 20,000 deaths among children and adolescents in the United States in 2016, and the majority—60%—resulted from injury-related causes. Motor vehicle crashes were the leading cause of death for children and adolescents, representing 20% of all deaths, followed by firearm-related injuries (15%), and malignant neoplasm, or cancer (9%).

Declines in deaths from infectious disease or cancer have been eclipsed by increases in deaths from injury-related causes, including motor vehicle crashes, firearm injuries, and the emerging problem of opioid overdoses, wrote Rebecca M. Cunningham, M.D., a professor of emergency medicine and director of the Injury Prevention Center at the University of Michigan Medical School, and colleagues. “Although viewed as ‘accidents,’ injury prevention science increasingly shows that such deaths are preventable with evidence-based approaches,” the authors noted.

Between 2013 and 2016, the firearm homicide rate and suicide rate jumped 32% and 26%, respectively. The U.S. rate of death from firearms among youth was more than 36 times as high as that in 12 other high-income countries in 2016, authors noted. Meanwhile, the rate of suicide by other means increased 15%.

Among youth firearm deaths, 59% were homicides and 35% were suicides. The researchers also found drug overdoses or poisoning made up nearly 5 percent of youth deaths in 2016, and the vast majority (78%) were unintentional.

When viewed by racial or ethnic group, youth mortality was highest among blacks (38 per 100,000) and American Indian or Alaska natives (28 per 100,000) than among whites (24 per 100,000). The disparities were most pronounced for firearm-related deaths, which were the leading cause of death among black youth and occurred at a rate nearly four times higher than the rate among white youth.

An accompanying editorial by Edward W. Campion, M.D., pointed out a child or adolescent in the United States is 57% more likely to die by the age of 19 years than those in other wealthy nations. “Children in America are dying or being killed at rates that are shameful,” Campion wrote. “Both individuals and the larger society need to understand that there is much that can be done to reduce the rate of fatal trauma. Strong leadership by the medical and public health communities is needed. Education, awareness, and very feasible interventions can help protect children and adolescents.”

Over the past decade, the rate of youth death from motor vehicle crashes showed the most notable improvement, dropping 38%, in part to widespread adoption of seat belts and car safety seats, the authors noted. However, since 2013 there has been a reversal of this trend with the rate of youth motor vehicle crash deaths on the rise due to unknown causes, possibly increases in distracted driving by teens because of peer passengers or cell-phone use, the authors wrote.

The report summarizes the leading causes of death for children and adolescents aged 1 to 19 years using ICD-10 codes and causes of death on U.S. death certificates. Data were obtained from the Wide-ranging Online Data for Epidemiologic Research system of the Centers for Disease Control and Prevention (CDC WONDER) in 2016, the most recent year with national data available.

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Peer Troubles Partially Explain Link Between Maternal Depression and Adolescent Problems

A study published in the December issue of the Journal of the American Academy of Child & Adolescent Psychiatry supports the finding that early depression exposure increases the risk of depression and anxiety in teens. This study also demonstrated that teens who are teased, harassed, and/or bullied in middle childhood are especially vulnerable.

”[T]he well-being of adolescents exposed to early maternal depression was associated more with their experience of victimization than with poor quality of parent-child relationships or to poor quality of relationships with friends in middle childhood,” wrote Sylvana Côté, Ph.D., of the University of Montreal and colleagues.

Côté and colleagues analyzed a subset of data from the Quebec Longitudinal Study of Child Development, which tracked and periodically assessed 2,120 families with newborn infants through the children’s adolescence.

The researchers found that children exposed to elevated symptoms of maternal depression during the first five years of life had higher rates of depression, generalized anxiety disorder, and social phobia in adolescence than children with no early depression exposure. They next assessed the influence of three types of relationship difficulties during middle childhood (ages 6 to 12)—negative parenting behaviors, poor friendship quality, and peer victimization. Of these, only victimization by peers was a mediating factor in the association between maternal depression in young childhood and depression, anxiety, and social phobia.

The authors calculated that peer victimization contributes to around 36% of the risk of future depression and 22% of the risk of future anxiety or social phobia.

“The findings highlight the importance of considering … bullying prevention programs as a potentially promising target of intervention for children exposed to maternal depression,” Côté and colleagues concluded.

To read more about the adverse effects of bullying, see the Psychiatric News article “Bullying Linked to Depression in Youth With Autism.”

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Benzodiazepine Use May Be Higher Among U.S. Adults Than Previously Estimated

Over 30 million U.S. adults took benzodiazepines in the past year, including 5.3 million who misused the medication, suggests a study published Monday in Psychiatric Services in Advance.

The findings, which were based on an analysis of data collected as part of a national survey in 2015 and 2016, suggest that annual benzodiazepine use among U.S. adults may be more than double estimates based on data collected in 2013 and 2014, but the differences may be due partly by different survey methodologies, the authors wrote. The findings also point to those most likely to take the medication without a prescription or in greater amounts or over longer periods of time than prescribed.

For the study, Donovan Maust, M.D., M.S., of the University of Michigan and colleagues analyzed data from the National Survey on Drug Use and Health (NSDUH). The NSDUH, which is an annual survey directed by the Substance Abuse and Mental Health Services Administration, asks participants aged 12 and older from across the country about substance use, mental health, and more. Maust and colleagues focused specifically on respondents aged 18 and over in the 2015 and 2016 survey years, who reported benzodiazepine use in response to queries about medications used for anxiety, insomnia, and more. Misuse was defined as “in any way doctor did not direct,” including without a prescription, in greater amounts or more often than prescribed, and longer than prescribed.

Based on their analysis, the researchers estimated that a total of 30.6 million adults (12.6%) reported past-year benzodiazepine use, including 25.3 million (10.4%) who took the medication as prescribed. Prior analyses of 2013-2014 surveys had previously estimated benzodiazepine use in adults to be between 4% and 6%, the authors noted. Adults aged 50 to 64 had the highest overall rate of prevalence of benzodiazepine use as prescribed, and adults 18 to 25 had the highest prevalence of misuse. 

Among those who reported benzodiazepine misuse, most adults indicated that they did so to help them to relax and/or sleep, the study found.

“The presence of past-year mental illness was associated with increased odds of any use, as was worse self-rated health. In almost every instance, past-year use, misuse, or abuse of or dependence on tobacco, alcohol, marijuana, heroin, prescription opioids, or prescription stimulants was associated with any benzodiazepine use,” Maust and colleagues wrote. “Prescription drug monitoring programs are an important tool for clinicians to understand which of their patients may be misusing other medications and would thus be at high risk of benzodiazepine misuse.”

The authors also noted that “a significant proportion of NSDUH-defined ‘misuse’ could reflect use for untreated symptoms among those with poor access to care—specifically, for behavioral treatments for insomnia or anxiety disorders.” Increasing access to insurance coverage and treatment for mental illness and substance use disorder may help to reduce benzodiazepine use and misuse, they wrote.

For related information, see the Psychiatric News article “Benzodiazepine Prescriptions Found to Increase Substantially With Age.”

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Ruling ACA Unconstitutional Could Have Devastating Effects on Patients, APA Warns

APA is calling for vigorous appeal of Friday’s decision by a Texas court that the entire Affordable Care Act (ACA) is unconstitutional.

“This ruling has an unconscionable result,” APA President Altha Stewart, M.D., said in a press statement. “Should this ruling stand, millions of our patients will lose their health care. We cannot afford to go back to the days when Americans were denied coverage due to pre-existing conditions or when insurance companies would not cover mental health and substance use disorders.”

U.S. District Court Judge Reed O’Connor in Texas ruled that since Congress repealed the tax penalty associated with the individual mandate requiring people to have insurance, the mandate “can no longer be sustained as an exercise of Congress’ tax power” and is therefore unconstitutional. O'Connor argued that the individual mandate cannot be separated from the rest of the law, and therefore the remaining provisions of the ACA are invalid.

Through private insurance reforms and Medicaid expansion, the law has provided coverage to roughly 2.8 million Americans with substance use disorders and 1.3 million Americans living with serious mental illness. An estimated 20 million Americans have coverage under the ACA.

O’Connor’s ruling was over a lawsuit filed this year by a group of Republican governors and state attorneys general. The ruling has no immediate effect, and multiple states have vowed to appeal the decision. The case is expected to eventually be heard by the U.S. Supreme Court.

If upheld, the ruling would wreak havoc on the insurance market, and millions of Americans could lose insurance coverage they currently have through the ACA’s expansion of Medicaid, the prohibition on discriminating against people with pre-existing conditions, and the provision allowing children under 26 to be covered by their parents’ health plans.

“This harmful ruling must be appealed and overturned,” said APA CEO and Medical Director Saul Levin, M.D., M.P.A. “The court’s decision to invalidate the ACA, including pre-existing conditions protections and the Medicaid expansion, will hurt our patients with mental illness and all illnesses. This decision must be appealed and reversed.”

For related information, see the Psychiatric News article “APA Calls on Administration to Defend Patient Protections in ACA.”

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Abnormal Childhood BMI May Point to Increased Risk of Eating Disorder

Young children whose BMIs are significantly lower or higher than average may be at increased risk of developing an eating disorder in adolescence, suggests a study published in the Journal of the American Academy of Child & Adolescent Psychiatry.

“Observing children whose BMI trajectories persistently and significantly deviate from age norms for signs and symptoms of ED [eating disorder] could assist in identification of high-risk individuals,” wrote Zeynep Yilmaz, Ph.D., of the University of North Carolina at Chapel Hill and colleagues.

The researchers analyzed a subset of data from the Avon Longitudinal Study of Parents and Children (ALSPAC), which included 1,502 children who had at least one BMI measurement between birth and age 12.5 years. The ALSPAC determined BMI by collecting information about the participants’ height and weight via questionnaires sent to mothers on average every year and via face-to-face assessments with the participants every two years. The participants were assessed for eating disorders at ages 14, 16, and 18 years. The researchers then compared the average BMI over time of participants who had not developed an eating disorder with that of participants who had developed anorexia nervosa, bulimia nervosa, binge-eating disorder, or purge disorder.

Boys who later developed anorexia nervosa had significantly lower BMIs than those with no eating disorder by age 7. Girls who later developed anorexia nervosa had significantly lower BMIs than their peers with no eating disorders by age 3. Boys who later developed binge-eating disorder or purge disorder had higher BMIs than their peers with no eating disorders starting at age 9.5. (The occurrence of bulimia nervosa in boys was too low for the researchers to make a solid comparison between groups.) Girls who later developed binge-eating disorder had higher BMIs than their peers with no eating disorders starting at age 7, and girls who later developed bulimia nervosa or purge disorder began to have higher BMIs than their peers with no eating disorders at age 9.

The researchers emphasized the potential link between low BMI and anorexia nervosa.

“In [anorexia nervosa], premorbid low weight may represent a key biological risk factor or early manifestation of an emerging disease process,” they wrote.

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

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Study Identifies Some Predictors of Bipolar Disorder in At-Risk Youth

Among offspring of individuals with bipolar disorder, 25% were diagnosed with the disorder, according to a study published in AJP in Advance. The study found that childhood sleep and anxiety disorders may be important predictors of the illness.

Participants with childhood anxiety disorders or sleep disorders were nearly twice as likely to develop mood disorder, according to Anne Duffy, M.D., a professor in the Department of Psychiatry at Queen’s University in Canada, and colleagues. Children with depressive or manic symptoms were 2.7 times more likely and 2.3 times more likely, respectively, to develop mood disorder.

The study findings “underscore the importance of taking into account both the family history and the developmental trajectory of emerging psychopathology to improve earlier diagnostic precision in young people manifesting clinically significant symptoms and syndromes,” Duffy and colleagues wrote.

The prospective study included 279 “high-risk” participants (aged 5 to 25 years) who had one parent diagnosed with bipolar disorder I or II, and 87 comparison participants with similar socioeconomic backgrounds from Ottawa schools. Participants were followed for an average of about seven years. All participants completed research assessments administered by a psychiatrist at baseline and about every year thereafter, including a semistructured interview following the Kiddie Schedule for Affective Disorders and Schizophrenia-Present and Lifetime Version (K-SADS-L) or the similar SADS-L.

The researchers observed bipolar spectrum disorders and psychotic spectrum disorders only in the high-risk offspring (25% and 11%, respectively) and not in the comparison group. There was no difference in the rate of bipolar disorder among participants based on whether their parent responded to lithium; however, psychotic disorders manifested almost exclusively among the offspring of lithium-nonresponsive parents (20% compared with 1%).

The researchers diagnosed major depressive disorder exclusively among the high-risk offspring (33% of high-risk group versus 5% of comparison group). A similar pattern emerged for sleep disorders (23% of high-risk group versus 1% of comparison group). Depressive episodes predominated during the early bipolar course.

The findings indicate the major role that anxiety and sleep disorders and major depression—especially with psychotic symptoms—may play in the development of bipolar disorder in young people with a familial risk. “Early clinical intervention and prevention efforts,” the researchers wrote, “should emphasize low-risk interventions addressing mood symptoms, anxiety and sleep disorders, and prevention of substance misuse.”

For related information, see the Psychiatric News article “Researchers Sum Up Current Knowledge of Bipolar Disorder, Call for More Study.”

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Youth Prescribed High Doses of Antipsychotics Off Label May Be at Heightened Risk of Death, Study Finds

Medicaid-enrolled youth aged 5 to 24 years who begin taking high doses of antipsychotics for psychiatric disorders other than psychosis appear to be at an increased risk of death compared with those taking other psychiatric medications, reports a study published today in JAMA Psychiatry. The findings serve as a reminder of the importance of careful prescribing and monitoring of young patients on antipsychotics, according to the study authors.

Wayne R. Ray, Ph.D., of Vanderbilt University School of Medicine and colleagues conducted a retrospective cohort study of youth aged 5 to 24 years who were enrolled in Medicaid in Tennessee between 1999 and 2014. The researchers specifically focused on deaths of patients who began taking oral antipsychotics and/or other medications commonly prescribed for the same indications as antipsychotics (such as mood stabilizers or antidepressants) for recently diagnosed psychiatric disorders. Patients who had a diagnosis of severe somatic illness, schizophrenia or related psychoses, or Tourette syndrome or chronic tic disorder were excluded from the analysis.

Of the 247,858 patients included in the cohort, 70.6% had a diagnosis of behavioral symptoms (ADHD, conduct disorder, or impulsivity). A total of 28,377 began taking a low dose of antipsychotics (defined as 50-mg or less chlorpromazine equivalents); 30,120 began taking a high dose of antipsychotics (higher than 50-mg chlorpromazine equivalents); 81,310 began taking ADHD medications (most frequently psychostimulants); 93,864 began taking antidepressants (most frequently selective serotonin reuptake inhibitors); and 14,187 began taking mood stabilizers (most frequently anticonvulsants). The patients were tracked from the filling of the first prescription for an antipsychotic or other medication until the end of 2014, five years after entering the cohort, loss of Medicaid enrollment, they reached age 25, or death—whichever came first.

The researchers found that “those receiving doses higher than 50-mg chlorpromazine equivalents during follow-up had an 80% increased risk of death that was attributable to a 3.5-fold increased risk of unexpected deaths,” Ray and colleagues wrote. “In contrast, the risk of deaths from injuries or suicides was not increased. The elevated risk persisted for unexpected deaths not due to overdose, with a 4.3-fold increased risk of death from cardiovascular or metabolic causes.”

“These results demonstrate a significant increase in the incidence of unexplained deaths in young people treated with higher doses of antipsychotics,” David Fassler, M.D., a clinical professor of psychiatry at the University of Vermont College of Medicine, told Psychiatric News. Although additional studies are needed to begin to understand how family history, undiagnosed cardiovascular abnormalities, or specific drug interactions as the result of polypharmacy may contribute to this increased risk of death in those taking higher doses of antipsychotics, Fassler said that “the findings represent an important contribution to the field.”

In an accompanying editorial, Barbara Geller, M.D., a professor emerita of child psychiatry at Washington University School of Medicine in St. Louis, added: The “[r]esults in the study by Ray et al heighten the already increased caution about prescribing antipsychotics to children and adolescents…. Concerns about excess deaths are likely to increase because the prevalence of some disorders for which antipsychotics are prescribed off-label (e.g., attention-deficit/hyperactivity disorder) and the number of prescriptions for indicated and off-label use are rising.”

For related information, see the Psychiatric Services article “The Impact of a State Medicaid Peer-Review Authorization Program on Pediatric Use of Antipsychotic Medications.”

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FDA Clears App to Help Retain Patients in Treatment for Opioid Use Disorder

The Food and Drug Administration (FDA) yesterday cleared for marketing a prescription smartphone application to help individuals being treated for opioid use disorder stay in treatment and maintain their motivation to recover.

Modeled on a similar app cleared by the FDA last year for patients with alcohol, cocaine, marijuana, and stimulant substance use disorders, reSET-O is specifically tailored for patients with opioid use disorder. The reSET-O app is intended for use in combination with outpatient psychosocial treatment that also includes treatment with buprenorphine. The app is downloaded directly to a patient’s smartphone after the patient receives a prescription to do so from his or her physician.

According to a statement by Pear Therapeutics, developer of reSET, the app is modeled on the Community Reinforcement Approach (CRA)—a psychosocial intervention for individuals with alcohol and other drug use disorders. The focus of CRA is to help individuals find healthier, more adaptive ways to meet their social and emotional needs than using substances by offering rewards for certain kinds of behavior.

The reSET-O app delivers therapy as a series of interactive therapy lessons, each of which is composed of a cognitive behavioral-therapy component and skill-building exercises. The FDA said that the app can serve as a training, monitoring, and reminder tool for health care professionals and patients in maintaining treatment and includes a reward system whereby patients can earn special icons on a prize wheel within the app.

The FDA reviewed data from a multisite, unblinded, controlled 12-week clinical trial of 170 patients who received supervised buprenorphine treatment paired with a behavior therapy program, either with or without the addition of a desktop-based version of reSET-O. The data showed a statistically significant increase in retention in a treatment program for 12 weeks for the patients who used the desktop computer version of the reSET-O program compared with those who did not.

John Torous, M.D. (pictured above), director of the Division of Digital Psychiatry at Beth Israel Deaconess Medical Center in Boston, told Psychiatric News that he is excited to see technology innovations proposed to help patients with opioid use disorder. Torous is also a member of APA’s Committee on Mental Health Information Technology and chair of the Smartphone App Evaluation Work Group.

“As with any new technology, we want to see how well it really works outside of a structured research environment, in the complicated world of real life,” he continued. “Will people actually use it? Will insurance companies pay for it? And will it be any better than what we have today?”

For related information, see the Psychiatric News article “FDA Clears First Prescription-Based ‘Digital Therapeutic’.”

(Image: John Torous, M.D., Beth Israel Deaconess Medical Center)

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Younger Siblings of Children With ASD Have Greater Risk of ADHD and Vice Versa

Children who have an older sibling who has been diagnosed with autism spectrum disorder (ASD) are not only at an increased risk of ASD, but also at an increased risk of attention-deficit/hyperactivity disorder (ADHD), according to a study published today in JAMA Pediatrics. Similarly, children who have an older sibling diagnosed with ADHD are not only at increased risk of being diagnosed with ADHD, but also ASD.

“Clinically, later-born siblings of children with ASD and ADHD appear to be at elevated risk within and across diagnostic categories and thus should be monitored for both disorders,” wrote Meghan Miller, Ph.D., of the University of California, Davis, and colleagues. “Practitioners may wish to share such information with families given the potential relevance of monitoring social communication, attention, and behavior regulation skills in later-born siblings of children with ASD or ADHD.”

Miller and colleagues analyzed patient data from two large U.S. health care systems: Marshfield Clinic, a large regional health care system in the upper Midwest, and Kaiser Pacific Northwest, an integrated health plan in Oregon and Washington. They assessed the outcomes of 15,175 children with older siblings, of whom 730 had an older sibling diagnosed with ADHD and 158 had an older sibling diagnosed with ASD.

Compared with children whose older siblings had neither disorder, children with an older sibling with ASD were about 30 times more likely to also be diagnosed with ASD and 3.7 times more likely to be diagnosed with ADHD. Children with an older sibling diagnosed with ADHD were about 13 times more likely to be diagnosed with ADHD and 4.4 times more likely to be diagnosed with ASD.

“[This study] used a simple and transparent design to report novel data on later-born within- and cross-condition recurrence of ASD and ADHD in a way that is useful in the clinic but also motivates research to understand how and why these conditions commonly co-occur both within individuals and within families,” wrote Tony Charman, Ph.D., of King’s College London and Emily Jones, Ph.D., of the University of London in an accompanying editorial.

To read more about this topic, see the Psychiatric News article “Study Examines Connections Between Psychiatric, Neurological Disorders.”

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Cigarette Smoking Associated With Psychotic Experiences in Adolescents, Study Finds

Smoking tobacco is associated with psychotic experiences in adolescents, according to a study published in the Journal of the American Academy of Child & Adolescent Psychiatry.

In the study, Wikus Barkhuizen, M.Sc., of the Centre for Brain and Cognitive Development at the University of London and colleagues analyzed smoking frequency in 3,787 adolescent pairs of twins, with a mean age of roughly 16 years. The adolescents fell into three categories: nonsmokers who had never smoked a cigarette, occasional smokers who had smoked fewer than 50 cigarettes in their lifetimes, and regular smokers who had smoked 50 or more cigarettes in their lifetimes. The researchers used the Specific Psychotic Experiences Questionnaire to assess the adolescents for three positive psychotic experiences (paranoia, hallucinations, and grandiosity), two negative psychotic experiences (self-reported anhedonia and negative symptoms reported by the adolescents’ parents), and cognitive disorganization.

The researchers found that scores for psychotic experiences differed significantly across the three groups. Occasional smokers scored higher than nonsmokers on paranoia, hallucinations, and cognitive disorganization and lower on anhedonia, with no significant differences on grandiosity and parent-rated negative symptoms. Regular smokers scored higher than nonsmokers on paranoia, hallucinations, cognitive disorganization, grandiosity, and parent-rated negative symptoms, but not on anhedonia. Regular smokers scored higher than occasional smokers on all the conditions examined. These results remained after adjusting for variables including sex, age, ethnicity, socioeconomic status, prenatal maternal smoking, cannabis use, sleep disturbances, and stressful life events.

In a secondary analysis, the researchers tested whether shared genetic influences underlie adolescent psychotic experiences and smoking by comparing identical twins and same-sex fraternal twins. They found that the correlations between smoking and paranoia, hallucinations, and cognitive disorganization were higher for identical twins than fraternal twins, suggesting that psychotic experiences “co-occur largely due to shared genetic influences,” Barkhuizen and colleagues wrote.

“Our results suggest that some of the same genetic factors that influence tobacco use in adolescents also influence PE [psychotic experiences],” they added.

For related information, see the Psychiatric News article “FDA’s ‘Real Cost’ Campaign Cuts Cigarette Smoking by Teens.”

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Increased Risk of Mental Illness in Youth Linked to Infection

Children and adolescents with infections appear to be at a heightened risk of mental disorders, suggests a report published Wednesday in JAMA Psychiatry.

“This study found associations between any treated infection and increased risks of all treated childhood and adolescent mental disorders, with the risks differing among specific mental disorders,” wrote Ole Köhler-Forsberg, M.D., of Aarhus University Hospital in Denmark and colleagues.

For the study, Köhler-Forsberg and colleagues analyzed information contained in the Danish nationwide registers on more than one million children and adolescents born in Denmark between January 1, 1995, and June 30, 2012. The researchers focused their analysis on records of infections requiring hospitalizations and less severe infections treated with only anti-infective medications such as antibiotics and antivirals in outpatient settings. They also examined mental health diagnoses made in a hospital and filled prescriptions for psychotropic medications.

The authors found that children who had been hospitalized with a severe infection were 84% more likely to be subsequently diagnosed with a mental disorder than children who had not been hospitalized with a severe infection. Children treated for less severe infections with anti-infective medications were 40% more likely to be subsequently diagnosed with a mental disorder compared with children who had not taken these medications. The disorders associated with the highest risks after infection were autistic spectrum disorder, attention-deficit/hyperactivity disorder, obsessive-compulsive disorder, oppositional defiant disorder, conduct disorder, personality and behavior disorders, schizophrenia spectrum disorders, and tic disorders, Köhler-Forsberg and colleagues noted.

Because this was an observational study, Forsberg and colleagues noted that “the results cannot prove causality.” Nonetheless, “these findings provide evidence for the involvement of infections and the immune system in the etiology of a wide range of mental disorders in children and adolescents,” they added.

“These results bring a sense of urgency to detailing the underlying mechanisms of this association, in particular because of the possibility that these severe and occasionally permanent neuropsychiatric conditions might be rapidly recognized and treated by pharmacological compounds already in clinical use,” Viviane Labrie, Ph.D., and Lena Brundin, M.D., Ph.D., of Van Andel Research Institute, wrote in an accompanying editorial. In the piece, Labrie and Brundin described several mechanisms by which exposure to infections may increase risk of mental illness.

For related information, see the Psychiatric News article “Can Childhood Infections Trigger Mental Disorders?”

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Common Dementia Screening Tests Often Misclassify Patients, Study Finds

About a third of the patients who are screened for dementia by at least one of three short cognitive assessments are misclassified, according to a study in Neurology: Clinical Practice.

The tests examined in the study were the Mini-Mental State Examination (MMSE), which tests memory skills including proper orientation of time and place; the Memory Impairment Screen (MIS), which tests the ability to remember words; and Animal Naming (AN), a verbal fluency test that involves naming as many animals as possible in 60 seconds.

“Our study found that all three tests often give incorrect results that may wrongly conclude that a person does or does not have dementia,” study author David Llewellyn, Ph.D., of the University of Exeter Medical School said in a press release. “Each test has a different pattern of biases, so people are more likely to be misclassified by one test than another depending on factors such as their age, education, and ethnicity.”

Llewellyn and colleagues analyzed data from older adults who participated in the Aging, Demographics, and Memory Study—a population-based longitudinal study of dementia. The participants received a three- to four-hour neuropsychological exam that included all three quick screening tests. A panel of experts then used the neuropsychological data to diagnose dementia in the participants. Of the 824 participants in the study, 291 (35.3%) were diagnosed with dementia.

The researchers found that the MMSE, MIS, and AN misclassified 21%, 16%, and 14% of the participants, respectively; 35.7% of participants were misclassified by at least one assessment, 13.4% were misclassified by at least two, and 1.7% were misclassified by all three.

The researchers identified multiple patient characteristics that contributed to misclassifying a patient with dementia, though most were specific to one or two tests. For example, African Americans were more likely to be mischaracterized by the MMSE, and older people and those with depression were more likely to be mischaracterized by the MIS. People with less education and those with heart problems were more likely to be misclassified by both the MMSE and AN. Only one factor was associated with misclassification in all three assessments, and that was the absence of a report from an outside observer that the participant was having more difficulty with memory or thinking than in the past.

“Knowledge of factors which predict misclassification … may improve clinical decision making by enhancing the selection and interpretation of assessments,” Llewellyn and colleagues concluded. “If an assessment is known to produce biased results for a given patient group, an alternative and more appropriate assessment can be selected.”

To read more about this topic, see the Psychiatric News article “Retinal Thickness May Be a Cognitive Biomarker.”

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APA will be closed on Wednesday, December 5, along with all federal agencies and executive offices, to honor and remember President George H.W. Bush.

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APA Salutes George H.W. Bush for Commitment to Improving Americans’ Lives

George Herbert Walker Bush, the nation’s 41st president, died November 30. He was praised by political and civic leaders of all backgrounds as a modest, fair, and conciliatory leader who embodied a period before American politics became fiercely divisive.

One of Bush’s signature achievements was the passage of the Americans With Disabilities Act of 1990 (ADA), which forbade discrimination based on disability in employment, public accommodations, and transportation. For several years, Congress had been working on a bill for disabled Americans based on the 1964 Civil Rights Act. In his acceptance speech at the 1988 Republican Convention, Bush indicated his support of such a bill, stating, "I am going to do whatever it takes to make sure the disabled are included in the mainstream."

The bill was passed with bipartisan support in Congress. Bush signed the ADA on July 26, 1990.

Bush also championed volunteerism and helped to create the Points of Light Foundation (now known as Points of Light) in 1990 to promote volunteerism. After his presidency, Bush worked on humanitarian projects, in some cases with former President Bill Clinton, working to relieve victims of floods, hurricanes, and tsunamis.

APA CEO and Medical Director Saul Levin, M.D., M.P.A., served in the Bush administration in the Center for Substance Abuse Treatment in what was then the Alcohol and Drug Abuse Administration at the Department of Health and Human Services. Levin credited Bush with creating the “Linkage Initiative”—the integration of primary care with treatment for mental health/substance use disorders, a concept embedded in today’s Collaborative Care Model.

In a statement released this past weekend, Levin hailed Bush as a conciliator. “Our politics today has become increasingly divisive. He was a man who easily walked on both sides of the aisle to get programs and policy done, and he did so because of his love of this great nation. We send his family our deepest condolences.”

APA will be closed on Wednesday, December 5, along with all federal agencies and executive offices, to honor and remember Bush.

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