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’.”

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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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