High doses of antipsychotics may increase mortality among adolescents without diagnosed psychosis: JAMA

Worldwide around 14% to 20% of children and adolescents have a diagnosable mental illness. The FDA has approved the use of antipsychotic medications in some children and adolescents with severe emotional and behavioral disorders. However, dose-related effects of antipsychotic medications may increase mortality in children and young adults.

In a recent cohort published in JAMA Psychiatry of medicaid patients aged 5 to 24 years, antipsychotic treatment was associated with increased risk of death only for patients with doses greater than 100-mg chlorpromazine equivalents. Risk was not significantly associated with lower doses or with either dose in children aged 5 to 17 years.

Researchers conducted a US national retrospective cohort study of Medicaid patients with no severe somatic illness or schizophrenia or related psychoses who initiated study medication treatment. Study data were analyzed from November 2022 to September 2023. Current use of second-generation antipsychotic agents in daily doses of less than or equal to 100-mg chlorpromazine equivalents or greater than 100-mg chlorpromazine equivalents vs that for control medications (α agonists, atomoxetine, antidepressants, and mood stabilizers). Total mortality, classified by underlying cause of death. Rate differences (RDs) and hazard ratios (HRs) adjusted for potential confounders with propensity score–based overlap weights.

The key findings of the study are

• A total of 2 067 507 patients beginning study medication treatment filled 21 749 825 prescriptions during follow-up with 5 415 054 for antipsychotic doses of 100 mg or less, 2 813 796 for doses greater than 100 mg, and 13 520 975 for control medications.

• Mortality was not associated with antipsychotic doses of 100 mg or less (RD, 3.3) but was associated with doses greater than 100 mg (RD, 22.4).

• For higher doses, antipsychotic treatment was significantly associated with overdose deaths (RD, 8.3) and other unintentional injury deaths (RD, 12.3) but was not associated with nonoverdose suicide deaths or cardiovascular/metabolic deaths.

• Mortality for children aged 5 to 17 years was not significantly associated with either antipsychotic dose, whereas young adults aged 18 to 24 years had increased risk for doses greater than 100 mg (RD, 127.5).

Researchers concluded that “In this cohort study of more than 2 million children and young adults without severe somatic disease or diagnosed psychosis, antipsychotic treatment in doses of 100 mg or less of chlorpromazine equivalents or in children aged 5 to 17 years was not associated with increased risk of death. For doses greater than 100 mg, young adults aged 18 to 24 years had significantly increased risk of death, with 127.5 additional deaths per 100 000 person-years.”

Reference: Ray WA, Fuchs DC, Olfson M, et al. Antipsychotic Medications and Mortality in Children and Young Adults. JAMA Psychiatry. Published online November 29, 2023. doi:10.1001/jamapsychiatry.2023.4573.