CME Author: Vicki Brower
Study Authors: Wayne A. Ray, C. Michael Stein, at al.
Target Audience and Goal Statement:
Child psychiatrists and adult psychiatrists, social workers, and family medicine specialists
The goal is to consider the risk of unexpected death in children and young adults who do not have schizophrenia and who are prescribed antipsychotic drugs.
Questions Addressed by this Study:
Are anti-psychotic drugs taken by children and youth who do not have schizophrenia linked to a higher risk of unexpected death, or deaths other than from injuries or suicides? If so, does drug dose matter?
Study Synopsis and Perspective:
Children and young adults taking higher-dose antipsychotics, mood stabilizers, treatments for attention-deficit hyperactivity disorder (ADHD), and depression for diagnoses other than schizophrenia were significantly more likely to die unexpectedly than other youths on low-dose medication, or no medication, according to a retrospective study of Medicaid enrollees in Tennessee. There was a 4.3-fold increased risk of death from cardiovascular or metabolic causes. In this study, unexpected deaths included unintentional drug overdoses.
“Unexpected death was an important study end point because, absent adverse medication events, such deaths should rarely occur in a young population without serious somatic illness,” authors wrote.
The youth in this study, without life-threatening somatic illness or psychosis, who took high-dose drugs had an 80% higher risk of death that was attributed to a more than three-fold increased risk of unexpected deaths, after adjusting for exposure duration and other factors, as compared with patients on low-dose drugs or controls. The risk of unexpected death was 3.51 (95% CI 1.54-7.96) times greater with high-dose antipsychotics than low-dose drugs or controls.
The study included 247,000 youth, ages 5 to 24. Those who received chlorpromazine-equivalent doses of antipsychotics higher than 50 mg (“high dose”) showed a hazard ratio for death of 1.80 (95% CI 1.06-3.07, P<0.001), reported Wayne Ray, PhD, of Vanderbilt University in Nashville, and colleagues. However, risk of death from injuries or suicides was not increased (HR 1.03, 95% CI 0.53-2.01).
Data in this study were drawn from the Tennessee Medicaid enrollment, pharmacy, hospital, outpatient, and nursing home files linked to death certificates. Youths whose records indicated new antipsychotic prescriptions were included, as long as they had been in Medicaid at least 1 year.
A majority of patients in all groups were male (high-dose: 60.8%; low-dose: 67.7%; control: 56.6%). The average age was 12 years in the control group, 11.7 years in the low-dose group (<50 mg in chlorpromazine equivalents), and 14.5 years in the high-dose group, the authors reported.
JAMA Psychiatry, Dec. 12, 2018; DOI:10.1001/jamapsychiatry.2018.3421
Study Highlights: Explanation of Findings:
In this study, it is notable that risks remained low in absolute terms. Out of approximately 27,000 person-years of exposure in the high-dose group, 40 died vs 67 with 123,000 person-years of exposure in controls. Ray and colleagues calculated a number-needed-to-harm (NNH) of 2,283 for all-cause death. NNH values for more specific causes of death ranged from 2,229 for cardiovascular events to nearly 100,000 for injury or suicide.
There were only eight deaths in patients receiving low-dose antipsychotics (<50 mg in chlorpromazine equivalents), with rates not differing significantly from controls; consequently, the researchers focused most of their report on the high-dose group.
“Antipsychotics are prescribed very frequently for children and young adults and in 2010, there were more than 1 million in this age group who received these medications,” Ray told MedPage Today. “The diagnoses for which they receive them are often diagnoses for which other treatments are available, and what we know about the pharmacology of antipsychotics is that they potentially have very dangerous adverse effects.”
Youths with schizophrenia, severe somatic illness, or Tourette syndrome were not included in the study.
The most common diagnoses among youths receiving antipsychotics was ADHD, followed by mood disorders (depression and others), bipolar disorder, and anxiety conditions. Most had received two to three other drugs as well. Ray said unexpected deaths flagged by the study could be an indicator of adverse effects caused by a medication. Since antipsychotics can cause weight gain and diabetes, arrhythmia, and respiratory depression — which can be rapidly fatal — he underscored the importance of physicians following guidelines for careful use of antipsychotics, considering other options when they are available, and not using them for “off-label” purposes.
“The study findings seem to reinforce existing guidelines for improving the outcomes of antipsychotic therapy in children and youths,” Ray and colleagues wrote. “These guidelines include restriction to indications for which there is good evidence of efficacy, adequate trial of alternatives including psychosocial interventions when possible, cardiometric assessment before treatment and monitoring after treatment, and limiting therapy to the lowest dose and shortest duration possible,” they wrote.
The main study limitation was the potential for uncontrolled confounding by differences between antipsychotic users and controls. As the number of deaths during follow-up was relatively small, “the analysis relied on statistical adjustment for an extensive set of covariates to control for the substantially greater psychiatric comorbidities among antipsychotic users,” the researchers stated.
Also, they did not include important details about the patients, such as BMI, family history, undiagnosed cardiovascular problems, nor did they have information on potential drug interactions. Patients may have been underdiagnosed, and the researchers “lacked information needed to refine the end point definitions through psychological autopsies.”
Ray and colleagues concluded that the significantly elevated risk of death in this population due to cardiovascular or metabolic conditions was important “because this end point should be less subject to unmeasured confounding and the finding is consistent with known antipsychotic adverse effects in children and youths.”
They pointed out that in young people, the corrected QT interval increases during treatment with antipsychotic drugs, according to 10 studies. These drugs also cause rapid weight gain and are associated with an increased risk of diabetes, including diabetic ketoacidosis. They noted that these results should be replicated in larger studies because the number of deaths due to cardiovascular or metabolic causes was small.
Barbara Geller, MD, of Washington University in St. Louis, stated in an accompanying editorial that the effects of certain medications such as aripiprazole (Abilify) can affect children more severely because their prefrontal cortices are less developed than adults, which is particularly important since many psychotic disorders require youths to take antipsychotic medication for several decades.
“Intuitively, many consider child psychiatry as a subspecialty that deals with little patients and little problems, but the reality is that psychiatrically ill children are not adult ‘lite,'” she wrote. “Rather, they have the same disorders as adults, including those that have pediatric U.S. Food and Drug Administration indications for antipsychotic use [such as] schizophrenia [and] bipolar disorder.”
The current study is similar to others’ in its consideration of the use of antipsychotic drugs in youth who are not psychotic, in other words, for off-label use, Geller emphasized. Specifically, among patients receiving higher antipsychotic doses, relatively few had diagnoses for which there is an FDA-approved indication (21.9% had bipolar disorder and 6.2% had an autism spectrum disorder). In addition, 45.1% of patients taking high-dose antipsychotics were also taking medications for ADHD, and 42.2% were taking antidepressants, Geller stated.
Geller also highlighted the possibility that some deaths reported in this study could have been undetected suicides, as mood disorders and ADHD are risk factors for childhood suicide. Additionally, a portion of the deaths could have been the result of undetected overdoses, particularly since children in the high-dose group had a greater risk of cardiovascular death compared with controls (HR 4.29, 95% CI 1.33-13.89), she said.
She recommend that “in order to optimize detection of suicide future investigations should include both physical and psychological autopsies and assays for prescribed and illicit drugs.” In addition, future research to confirm the incidence of excess deaths should include cases that represent the entire diagnostic spectrum with sufficiently large sample sizes to detect specific types and doses of drugs and distinct combinations that might increase risk of death. She also recommended analysis by patient age group to get a clearer picture of what occurs with these drugs.
The results “heighten the already increased caution” about prescribing antipsychotics to young people, and overprescribing, Geller stated.
Original story for MedPage Today by Elizabeth Hlavinka
Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner