Increased Mortality Risk for Young Adults on High Doses of Antipsychotics

 Antipsychotic medication-related deaths were rare among children, but young adults on higher doses had a significantly increased risk of death, according to a U.S. national retrospective cohort study of Medicaid patients.

In this cohort of more than 2 million children and young adults without severe somatic disease or diagnosed psychosis, those ages 18 to 24 had increased risk of death with current use of second-generation antipsychotic agents in daily doses of greater than 100-mg chlorpromazine equivalents compared with control medications including antidepressants and mood stabilizers (HR 1.68, 95% CI 1.23-2.29), reported Wayne Ray, PhD, of Vanderbilt University School of Medicine in Nashville, Tennessee, and co-authors.

This amounted to 127.5 additional deaths per 100,000 person-years, they noted in JAMA Psychiatryopens in a new tab or window.

However, the authors observed no increased mortality risk among children ages 5 to 17 with daily doses of less than or equal to 100-mg chlorpromazine equivalents or greater than 100-mg chlorpromazine equivalents compared with control drugs. The mortality rate in children was 32.4 deaths per 100,000 person-years.

"This finding suggests that antipsychotic medication-related fatalities are rare in healthy children without psychosis," Ray and team wrote.

In the total study population, mortality was not associated with antipsychotic doses of 100 mg or less (HR 1.08, 95% CI 0.89-1.32), but was associated with doses greater than 100 mg (HR 1.37, 95% CI 1.11-1.70). For these higher doses, 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 was not associated with non-overdose suicide deaths or cardiovascular/metabolic deaths.

That Ray and his colleagues did not observe an increased risk for cardiovascular deaths was "reassuring," given the findings of a prior single-state study of Medicaid enrolleesopens in a new tab or window, and "good evidence" to suggest that the medications increase the risk of cardiovascular deaths in adults, he told MedPage Today.

The "bad news" was the increased risk of death due to overdose deaths and injury deaths, with 8.3 additional overdose deaths per 100,000 person-years and 12.3 additional unintentional injury deaths per 100,000 person-years, Ray added.

He noted that opioid involvement was listed in more than half of overdose deaths on the death certificates, which suggests concomitant use of opioids and antipsychotics may have been the mechanism of death.

As for the increased risk of non-overdose unintentional injury deaths, Ray and co-authors wrote, "it is uncertain whether or not the association with [these] deaths was due to a drug effect or to unmeasured correlates of antipsychotic treatment."

Antipsychotics are often used to treat agitation, aggression, and anger, and children in high-risk environments with poor parental supervision may be more likely to be prescribed these drugs. While most antipsychotic medications cause sedation, which could raise the risk of unintentional injuries, Ray noted that "it could be those environmental factors ... that increase their risk of death rather than the drugs per se."

For this study, Ray and colleagues used data from the Medicaid Analytic Extract, which includes Medicaid and Children's Health Insurance Program data. They included 2,067,507 patients ages 5 to 24. Mean age was 13.1, 51.3% were male, 57.1% were white, 21.9% were Black, 12.2% were Hispanic, and race and ethnicity were unknown for 8.7%.

Patients were initiated on medication from January 2004 through September 2013 and experienced 817,082 new treatment episodes in the antipsychotic medication group and 1,851,119 treatment episodes in the control group.

Overall, 21,749,825 prescriptions were filled during follow-up. The most commonly filled antipsychotic was risperidone (Risperdal; 45.4%), followed by aripiprazole (Abilify; 25%). The most frequently filled control medications were clonidine (Catapres; 19.7%) and atomoxetine (Strattera; 10.7%).

Those receiving antipsychotic treatment were more frequently male, on Medicaid for a disability or foster care, and living in a metropolitan area.

Participants with schizophrenia were excluded, due to already having a number of risk factors for death. The "lack of a fair comparison group" made it harder to draw "responsible conclusions," Ray said.

As the study was confined to Medicaid patients, generalizability is limited; however, Medicaid provides coverage for nearly one-third of U.S. children.

In the future, Ray suggested that investigating the role of antipsychotics in overdose and injury deaths, and potentially exploring non-fatal outcomes, would be important.

Disclosures

The study was funded by a grant from the National Institute for Child Health and Human Development.

Ray reported no conflicts of interest. Co-authors reported relationships with the National Institute of Child Health and Human Development, the National Institute on Drug Abuse, the Centers for Medicare and Medicaid Innovation, the National Institute of Mental Health, the Agency for Healthcare Research and Quality, the Boedecker Foundation, the Robert Wood Johnson Foundation, and the NIH.

Primary Source

JAMA Psychiatry

Source Reference: opens in a new tab or windowRay WA, et al "Antipsychotic medications and mortality in children and young adults" JAMA Psychiatry 2023; DOI: 10.1001/jamapsychiatry.2023.4573.

https://www.medpagetoday.com/psychiatry/generalpsychiatry/107589