High doses of a second-generation antipsychotic are associated with a significantly increased risk for death in young adults, adding to long-standing safety concerns regarding the use of higher doses of antipsychotic medication in this age group.
In a large cohort study, people aged 18-24 years had a significantly higher risk for death when starting a second-generation antipsychotic at doses > 100-mg chlorpromazine equivalents, but no increased mortality risk with lower doses.
There was no association with mortality risk in children aged 5-17 years with either dose.
"This finding suggests that antipsychotic medication–related fatalities are rare in healthy children without psychosis," lead investigator Wayne Ray, PhD, from Vanderbilt University School of Medicine in Nashville, Tennessee, and colleagues wrote in a recent study that was published online on November 29, 2023, in JAMA Psychiatry.
"In contrast, young adults aged 18 to 24 years treated with doses greater than 100-mg chlorpromazine equivalents had 127.5 additional deaths for every 100,000 person-years of exposure, suggesting further investigations of antipsychotic medication safety in this population are needed."
Large, Retrospective Study
The researchers compared mortality for more than 2 million Medicaid patients aged 5-24 years (mean age, 13 years; 51% men) starting treatment with a second-generation antipsychotic vs control psychiatric medications. None of them had a diagnosis of severe somatic illness, schizophrenia, or related psychosis.
From January 2004 through September 2013, more than 21 million prescriptions were filled — roughly 5.4 million for antipsychotic doses ≤ 100 mg, 2.8 million for doses > 100 mg, and 13.5 million for control medications.
The most commonly prescribed antipsychotic medication was risperidone, followed by aripiprazole, quetiapine, ziprasidone, and olanzapine. The most commonly prescribed control medication was clonidine, followed by atomoxetine, guanfacine, and sertraline.
In the overall study population, there was no significant association with risk for death for antipsychotic doses ≤ 100-mg chlorpromazine equivalents (hazard ratio [HR], 1.08; 95% CI, 0.89-1.32). However, mortality risk was increased at doses > 100 mg (HR, 1.37; 95% CI, 1.11-1.70).
Looking at mortality risk by age, for children aged 5-17 years, there was no significant association with either antipsychotic dose, whereas young adults aged 18-24 years had increased risk for doses > 100 mg (HR, 1.68; 95% CI, 1.23-2.29).
Start Low, Go Slow
"Start low and go slow is always a good rule of thumb when it comes to the use of these and any medicines, especially among especially among children and adolescents," Caleb Alexander, MD, codirector of the Center for Drug Safety and Effectiveness at Johns Hopkins University in Baltimore, Maryland, who wasn't involved in the study, told Medscape Medical News.
Higher-dose antipsychotic treatment was significantly associated with overdose deaths (HR, 1.57; 95% CI, 1.02-2.42) and other unintentional injury deaths (HR, 1.57; 95% CI, 1.12-2.22), but not with non-overdose suicide deaths or cardiovascular/metabolic deaths.
Death certificates listed opioid involvement in more than half of overdose deaths in those taking higher antipsychotic doses as well as those taking control medications.
"That's a good reminder that the risk of these medicines may increase markedly when they're combined with other treatments, such as prescription opioids," Alexander said.
Also weighing in on the research for Medscape Medical News, Anish Dube, MD, chair of the American Psychiatric Association's Council on Children, Adolescents, and their Families, said the study is "notable for both the increased risk of death among young adults 18-24 prescribed treatment with antipsychotics at doses of > 100-mg chlorpromazine equivalents, but also for the absence of such a finding with antipsychotic use in younger age groups," he said.
"This suggests an interaction between other factors more common to young adults, such as substance use as mentioned by the authors, and concurrent treatment with antipsychotic medications at doses greater than 100-mg chlorpromazine equivalents," said Dube.
"As the authors point out, additional research is needed to help clarify the observed increased risk of death at this developmental juncture so as to allow us to better predict which young adults may be especially vulnerable," Dube said.
The findings also point to a need for caution when prescribing any antipsychotic medications off label, Dube added, especially among people aged 18-24 years, and other treatments should be considered when possible.
"Thankfully, with greater awareness and increased scrutiny, overall prescriptions for antipsychotic medications in the pediatric and young adult populations have likely decreased since the study period," he said.
Limitations of the study include potential residual confounding, confining the study population to Medicaid recipients, restriction to second-generation antipsychotics, and exclusion of individuals with psychoses or severe somatic illness. Also, insufficient numbers of deaths from specific causes precluded an examination of individual antipsychotics or more detailed dose categories.
"No study is perfect," said Alexander, "and some of the findings may be due to unmeasured differences between the groups that were being compared. That's the elephant in the room."
The study was funded by a grant from the National Institute for Child Health and Human Development. Ray, Alexander, and Dube have no relevant conflicts of interest.
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