REVIEW OF: Ray WA et al, JAMA Psychiatry 2024;81(3):260–269

STUDY TYPE: Retrospective cohort study

Since 2019, we’ve known high-dose second-generation antipsychotics (SGAs) (over 100 mg of chlorpromazine/CPZ equivalents) increase mortality risk in children and young adults (CCPR March/April 2019). Earlier research indicated a 1.8-fold increased death risk, with cardiovascular and metabolic risks as key contributors. While the FDA’s boxed warning focuses on adult risks, concerns about younger populations persist. Building on earlier work, researchers analyzed a larger cohort of Medicaid recipients to further clarify the risks of high-dose SGAs in youth.

Researchers conducted a retrospective cohort study using Medicaid data from over 2 million patients across 30 US states, ages 5–24 years. The antipsychotic group included those starting oral SGAs (excluding clozapine), divided into low- and high-dose subgroups based on a 100 mg CPZ-equivalent cutoff. The control group received other psychiatric medications, such as alpha-agonists, atomoxetine, antidepressants, or mood stabilizers. The primary outcome was all-cause mortality during active treatment. Common antipsychotics included aripiprazole, quetiapine, and risperidone; control medications included clonidine, guanfacine, atomoxetine, and sertraline. The study period was January 2004 to September 2013.

Low-dose antipsychotic use was not significantly associated with mortality risk (hazard ratio: 1.08; 95% confidence interval: 0.89–1.32). However, in the high-dose group, the death risk increased by 37% in older sample members compared to controls. No increased mortality risk was found in youth ages 5–17, regardless of dose. Among young adults (ages 18–24), high-dose antipsychotics led to a 68% higher mortality risk. Overdose or accidental injury accounted for most of this risk (57% higher than controls), while cardiovascular, metabolic, and nonoverdose suicides were not significant contributors.

Carlat Take

This study reinforces that SGAs, especially at higher doses, are associated with increased mortality risk in young adults, although such deaths remain rare in healthy children and adolescents. When using high-dose SGAs, particularly in those 18–24 years old, careful monitoring for overdose risk and accidental injury is essential.