An article in the Journal of the American Medical Association Psychiatry noted that based on a cohort of more than 2 million Medicaid patients aged 5 to 24 years, antipsychotic treatment was associated with an increased risk of death only for patients with doses greater than 100-mg chlorpromazine equivalents. The article added that the risk was not significantly associated with lower doses or with either dose in children aged 5 to 17 years.
“Antipsychotic treatment of 100-mg chlorpromazine equivalents or less or in children was not associated with increased mortality; further research is needed to better understand the increased risk of death with higher doses in young adults,” advised Vanderbilt University School of Medicine–led researchers.
Data for the U.S. national retrospective cohort study of Medicaid patients with no severe somatic illness or schizophrenia or related psychoses who initiated study medication treatment were analyzed from November 2022 to September 2023.
The focus was on the 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 versus that for control medications (α-agonists, atomoxetine, antidepressants, and mood stabilizers).
The primary outcome was considered to be total mortality, classified by underlying cause of death.
The participants had a mean age of 13.1, and 51.3% of those beginning study medication were male. The patients filled nearly 22 million prescriptions during follow-up, with approximately 5.4 million for antipsychotic doses of 100 mg or less, 2.8 million for doses greater than 100 mg, and 13.5 million for control medications.
The researchers noted that mortality was not associated with antipsychotic doses of 100 mg or less (rate difference [RD], 3.3; 95% CI, –5.1 to 11.7 per 100,000 person-years; hazard ratio [HR], 1.08; 95% CI, 0.89-1.32), but was associated with doses greater than 100 mg (RD, 22.4; 95% CI, 6.6-38.2; HR, 1.37; 95% CI, 1.11-1.70).
“For higher doses, antipsychotic treatment was significantly associated with overdose deaths (RD, 8.3; 95% CI, 0-16.6; HR, 1.57; 95% CI, 1.02-2.42) and other unintentional injury deaths (RD, 12.3; 95% CI, 2.4-22.2; HR, 1.57; 95% CI, 1.12-2.22) but was not associated with nonoverdose suicide deaths or cardiovascular/metabolic deaths,” the authors pointed out. “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; 95% CI, 44.8-210.2; HR, 1.68; 95% CI, 1.23-2.29).”
Background information in the article recounts how the introduction of second-generation antipsychotic medications led to a sharp increase in the treatment of children and young adults with antipsychotic medications. In 2010, more than 1.3 million antipsychotic medication users 24 years or younger filled 7 million antipsychotic prescriptions, the study advised.
Attention-deficit/hyperactivity disorder, disruptive behavior disorder, and depression were the most common diagnoses associated with antipsychotic prescriptions for youths, even though antipsychotic medications often are an off-label or secondary therapeutic choice and other well-defined therapeutic interventions have fewer adverse effects.
The researchers added, “Although more recent data indicate that antipsychotic medication prescribing for children had decreased by 2016, the majority of prescriptions continue to be for off-label indications, potentially exposing children and young adults to unnecessary risks.”
Antipsychotic medications have been linked with elevated risk of cardiovascular and total mortality in older adults, heightening concerns that antipsychotic medications could increase the risk of death in younger populations, according to the authors, who wrote, “Antipsychotic medications have potentially life-threatening cardiovascular, metabolic, respiratory, sedative, and other adverse effects in both children and adults, although many of these are infrequent.” They cite a single-state Medicaid study in Tennessee, published in 2019, which found that new users of antipsychotic medications who were aged 5 to 24 years and taking doses greater than 50-mg chlorpromazine equivalents had an 80% increased risk of death. That included a greater than fourfold increased risk for deaths of cardiovascular or metabolic causes.
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