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Children and young adults beginning antipsychotic treatment for diagnoses other than schizophrenia were significantly more likely to die unexpectedly than other youths, according to a retrospective study of Medicaid enrollees in Tennessee.

Among some 247,000 individuals ages 5 to 24, those who received chlorpromazine-equivalent doses of antipsychotics higher than 50 mg ("high dose") showed a hazard ratio for death of 1.80 (95% CI 1.06-3.07, P<0.001) compared with youths receiving other types of drugs (controls), reported Wayne Ray, PhD, of Vanderbilt University in Nashville, and colleagues.

Unexpected deaths other than suicide and injury accounted for virtually all the differences in all-cause mortality. These included deaths from cardiovascular events, unintentional drug overdoses, and a smattering of other causes. Together these comprised about half the deaths in the high-dose group versus one-third of those in controls, they wrote in .

After adjusting for exposure duration and other factors, the risk of unexpected death was 3.51 times greater with high-dose antipsychotics (95% CI 1.54-7.96). Risk of death from injuries or suicides, however, was not increased (HR 1.03, 95% CI 0.53-2.01).

Notably, risks remained low in absolute terms. Out of approximately 27,000 person-years of exposure in the high-dose group, 40 died, versus 67 with 123,000 person-years of exposure in controls. Ray and colleagues calculated a number-needed-to-harm (NNH) of 2,283 for all-cause death. NNH values for more specific causes of death ranged from 2,229 for cardiovascular events to nearly 100,000 for injury or suicide.

There were only eight deaths in patients receiving low-dose antipsychotics (less than 50 mg in chlorpromazine equivalents), with rates not differing significantly from controls; consequently, the researchers focused most of their report on the high-dose group.

"Antipsychotics are prescribed very frequently for children and young adults and in 2010, there were more than 1 million in this age group who received these medications," Ray told MedPage Today. "The diagnoses for which they receive them are often diagnoses for which other treatments are available, and what we know about the pharmacology of antipsychotics is that they potentially have very dangerous adverse effects."

Youths with schizophrenia, severe somatic illness, or Tourette syndrome were excluded. The most common diagnoses among youths receiving antipsychotics was attention deficit-hyperactivity disorder, followed by mood disorders (depression and others), bipolar disorder, and anxiety conditions. Most had received other drugs as well.

Ray said unexpected deaths could be an indicator of adverse effects caused by a medication. Since antipsychotics can cause weight gain and diabetes, arrhythmia, and respiratory depression -- which can be rapidly fatal -- he underscored the importance of physicians following guidelines for careful use of antipsychotics, and considering other options when they are available.

Barbara Geller, MD, of Washington University in St. Louis, noted in an that the effects of certain medications such as aripiprazole (Abilify) can affect children more severely because their prefrontal cortices are less developed than adults, which is particularly important since many psychotic disorders require youths to take antipsychotic medication for several decades.

"Intuitively, many consider child psychiatry as a subspecialty that deals with little patients and little problems, but the reality is that psychiatrically ill children are not adult 'lite,'" she wrote. "Rather, they have the same disorders as adults, including those that have pediatric U.S. Food and Drug Administration indications for antipsychotic use [such as] schizophrenia [and] bipolar disorder."

Geller pointed out the possibility that some deaths reported in this study could have been undetected suicides, as mood disorders and ADHD are risk factors for childhood suicide. Additionally, she noted that a portion of the deaths could have been the result of undetected overdoses, particularly since children in the high-dose group had a greater risk of cardiovascular death compared to controls (HR 4.29, 95% CI 1.33-13.89).

This study used data from the Tennessee Medicaid enrollment, pharmacy, hospital, outpatient, and nursing home files linked to death certificates. Youths whose records indicated new antipsychotic prescriptions were included, as long as they had been in Medicaid at least one year.

A majority of patients in all groups were male (control: 56.6%, low-dose: 67.7%, high-dose: 60.8%), and the average age was 12 years in the control group, 11.7 years in the low-dose group (less than 50 mg in chlorpromazine equivalents), and 14.5 years in the high-dose group, the authors reported.

Geller noted that future investigations should include physical, as well as psychological autopsies and include larger sample sizes across subgroups, in order to determine whether children, adolescents, or young adults are at a higher risk.

The authors acknowledged the study's limitations, including the use of Medicaid data, which lack information on potentially relevant patient characteristics such as body mass index, family histories, or cardiovascular abnormalities. They also noted that the small number of deaths made it impossible to examine associations with dose, potential drug interactions, or individual antipsychotics, which produce differing adverse cardiovascular and metabolic events.