A new study has found that children and adolescents taking a high dose of antipsychotics are almost twice as likely to die of any cause than children on other types of medications. Perhaps even more striking, children taking high doses of antipsychotics were more than four times as likely to die of cardiovascular or metabolic causes than children on other medications.

The study, published online in JAMA Psychiatry, was led by Wayne A. Ray, PhD, at the Vanderbilt University School of Medicine. The data was captured between 1999 and 2014. The researchers included youths between the ages of 5 and 24 years old, who were recipients of Medicaid insurance in Tennessee. This allowed the researchers to examine their medical records. In total, there were about 250,000 individuals in the study. The researchers excluded children with severe physical illness diagnoses, tic disorders, and schizophrenia. The most common included diagnosis was ADHD.

The study was composed of three groups: a control group who were on medications such as stimulants or antidepressants; a group who were prescribed a low dose of an antipsychotic, and a group prescribed a high dose of an antipsychotic.

The group taking a low dose of antipsychotics did not have a significantly increased risk of death when compared to the group taking other medications. However, children taking a high dose of antipsychotics were 1.8 times more likely to die of any cause, 3.5 times more likely to die of unexpected causes (not including overdose), and 4.29 times more likely to die of cardiovascular or metabolic problems. Deaths from suicide were no different between groups.

In total, there were 40 deaths out of the 27,354 in the higher-dose group (0.15%), compared to 67 deaths out of the 123,005 in the control group (0.05%).

Of course, there could be other confounding factors that led to this effect—something present in the higher-dose group that was not present in the control group. However, the researchers controlled for the most obvious explanations (diagnosis, medical illness, and any medication use). Additionally, after the researchers ran a sensitivity analysis, they concluded that “to explain the risk of unexpected death in the higher-dose group, the confounder would have to increase risk by 5-fold, have a 75% prevalence in the higher-dose antipsychotic treatment group, and not be present in control patients.”

The potentially deadly cardiovascular and metabolic adverse effects of antipsychotic medications are well-documented, but according to the researchers, this is one of the first large studies to examine whether children are at a greater risk of death due to these causes. The researchers write that after the second generation of antipsychotic medications was invented, these drugs began to be prescribed in younger patients for all variety of indications, such as ADHD, depression, and behavioral control—indications for which other, safer therapies might be a better option.

According to the authors,

“The study findings appear to reinforce existing guidelines for improving the outcomes of antipsychotic therapy in children and youths. These guidelines include restriction to indications for which there is good evidence of efficacy, an adequate trial of alternatives including psychosocial interventions when possible, cardiometabolic assessment before treatment and monitoring after treatment, and limiting therapy to the lowest dose and shortest duration possible.”

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Ray, W. A., Stein, M., Murray, K. T., Fuchs, C., Patrick, S. W., Daugherty, J. . . . Cooper, W. O. (2018). Association of antipsychotic treatment with risk of unexpected death among children and youths. JAMA Psychiatry. Published online ahead of print Dec. 12, 2018. doi:10.1001/jamapsychiatry.2018.3421 (Link)