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

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

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

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

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

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

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

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Autism Linked to Maternal Exposure to DDT, Study Finds

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

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

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

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

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

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

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

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FDA Approves Bedtime ADHD Medication

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

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

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

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

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

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Risk of Suicide Increases After TBI, Study Finds

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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