High-Dose Antipsychotics Raise Kids' Risk of Unexpected Death

Pauline Anderson

December 12, 2018

Off-label use of high-dose antipsychotics significantly increases the risk of unexpected death in children and youth, new research shows.

Wayne A. Ray, PhD

Investigators at Vanderbilt University Medical Center in Nashville, Tennessee, found the risk of death associated with off-label antipsychotic use at doses higher than 50 mg in patients age 5 to 24 years was 3.5-fold greater than their counterparts not receiving antipsychotics.

Child and adolescent psychiatrists already exercise "a great deal of caution" when prescribing antipsychotics in young people and can refer to guidelines for evaluation and monitoring when using these drugs, lead author, Wayne A. Ray, PhD, professor, Department of Health Policy, Vanderbilt University School of Medicine, Nashville, told Medscape Medical News.

"These study findings reinforce the importance of adhering to those guidelines for using these medications very carefully," he added.

The study was published online December 12 in JAMA Psychiatry.

Off-Label Use Common

Off-label use of antipsychotics is common. These medications are prescribed to treat children and youth with attention deficit hyperactivity disorder (ADHD), depression, or bipolar disorder.

Antipsychotics tend to have "a calming, tranquilizing effect and actually are effective in controlling behavioral symptoms," said Ray.

"The question is, are there other [medications] that do that as well, so is it worth the risk?"

Those risks, he said, can include potentially life-threatening side effects, including dose-related cardiovascular, metabolic, and other adverse events. However, the investigators note it is unknown whether these medications are associated with an increased risk of death.

Using data from Tennessee Medicaid files, researchers retrospectively analyzed a large cohort of relatively healthy children and youth aged 5 to 24 years who began off-label use of oral antipsychotic therapy and compared them with children who received a control medication for the same indication.

Researchers excluded patients with life-threatening somatic illnesses and those who were in the hospital when the medication was started.

Patients with schizophrenia, other psychoses, and Tourette syndrome were excluded from the study because there are no alternatives to antipsychotics for these conditions.

The analysis included 189,361 patients taking a control medication such as psychostimulants, antidepressants, or mood stabilizers; 28,377 on a lower-dose antipsychotic (50 mg or less of chlorpromazine or its equivalent); and 30,120 taking a higher-dose antipsychotic (50 mg or greater of chlorpromazine equivalent).

The cutoff of 50 mg chlorpromazine was the median dose. About half the study population was taking more than 50 mg, with the remaining half taking less than that amount, said Ray.

The most commonly prescribed medication among the lower-dose antipsychotic group was risperidone (66.0%). The most commonly prescribed antipsychotics in the higher-dose group were quetiapine (34.3%), aripiprazole (23.4%), and olanzapine (16.6%).

In the control group, 43.4% were female and the mean age was 12.0 years. In the lower-dose group, 32.3% were female and the mean age was 11.7 years. And in the higher-dose group, 39.2% were female and the mean age was 14.5 years.

Higher Dose Increases Death Risk

The prevalence of diagnosed or treated cardiovascular illness was low and differed little between study groups.

From death certificate data, researchers determined causes of all deaths. Deaths due to unintentional injury were excluded.

"If you take a cohort of fairly healthy younger people and you look at deaths that are unexpected, then these are a sensitive marker of adverse medication effects," Ray noted.

Included in the unexpected deaths were unintentional drug overdoses. The authors explained that the clinical circumstances with these deaths are often similar to those of deaths due to cardiovascular causes and it can be difficult to distinguish the mechanisms post-mortem.

The researchers also note that antipsychotics are potent central nervous system depressants that can impair respiration and may therefore increase risk of fatal inadvertent overdose.

The analysis used propensity score-based weighting that balanced the distribution of measured comorbidities among the study groups.

After adjustment for covariates, the risk of death in the higher-dose group was 80% greater than that in the control group (hazard ratio [HR], 1.80; 95%, confidence interval [CI], 1.06 - 3.07).

In the higher-dose group, the adjusted risk of unexpected death was significantly increased (HR, 3.51; 95% CI, 1.54 - 7.96). In contrast, the risk of death from injury or suicide was not increased (HR, 1.03; 95% CI, 0.53 - 2.01).

The HR was 4.29 (95% CI, 1.33 - 13.89) for cardiovascular deaths in the higher antipsychotic group compared with the nonantipsychotic group. This finding is consistent with known antipsychotic adverse effects in children and youth.

However, because of the small number of deaths due to cardiovascular or metabolic causes, this finding needs to be replicated in larger populations, the authors note.

Antipsychotics Overused?

Patients in the lower-dose group had no significantly increased risk of total mortality (HR, 1.43; 95% CI, 0.62 - 3.30; P = .41). But the authors note there were few deaths in this group and the 95% CIs were wide.

In a sensitivity analysis performed with an upper age limit of 21 years and a lower age limit of 12 years, the increased risk for unexpected deaths in the higher dose antipsychotic group persisted.

This was also the case for sensitivity analyses that excluded patients with more severe comorbidities — such as bipolar disorder, autism or Asperger syndrome, or intellectual disability — and patients who were taking a mood stabilizer.

Asked if these findings suggest over-prescribing of antipsychotics in young people, Ray said he would leave that question for others to answer. "But it certainly suggests that if they are, there are severe consequences," he said.

Ray noted that in the higher-dose group, the main condition for which an antipsychotic was prescribed was a category called "ADHD, conduct disorder, or impulsivity," which accounted for about 64% of such prescriptions.

Sedating Children Not the Answer

In cases where a young child is disrupting classes at school, "it may come down to keeping the child in Kindergarten."

He suggested that a child's family situation and other interpersonal factors may contribute to behavioral problems.

"There's a long-standing concern that there's not enough priority given to kind of preventing the behavioral outbursts rather than just trying to sedate the children so that they don't have them anymore," he said.

"The thinking is that you can't just carpet bomb with antipsychotics to control these behavioral problems; it's better to try to attack them at the root."

The findings reinforce recommendations for careful prescribing and monitoring of antipsychotic regimens for children and youths and the need for larger antipsychotic safety studies in this population.

In addition, they further underline the importance of caution in prescribing antipsychotics in children with a cardiovascular condition, said Ray. Physicians should monitor patients during treatment for any signs of adverse cardiovascular events, such as arrhythmia.

"It's not just deciding when to prescribe but also the pretreatment evaluation and the posttreatment monitoring," said Ray.

A limitation of the study is the potential for uncontrolled confounding by differences between antipsychotic users and controls.

In addition, the study did not include important patient characteristics, such as body mass index, family history, or undiagnosed cardiovascular abnormalities.

Greater Caution Warranted

In an accompanying editorial, Barbara Geller, MD, Department of Psychiatry, Washington University, St Louis, said these results "heighten the already increased caution about prescribing antipsychotics to children and adolescents."

While alternatives to antipsychotics are available to treat some pediatric conditions, Geller pointed out that for some young patients with bipolar disorder, nonantipsychotic choices are ineffective or clinically inadvisable.

"For example, some patients with mood disorders are unresponsive to lithium for possible genetic and epigenetic reasons, and female patients may not want to risk developing polycystic ovarian syndrome from valproate medications."

Geller questions whether some deaths in the study were undetected suicides. She noted that individuals receiving high doses of antipsychotics had high rates of mood disorders and ADHD, conduct disorders, or impulsivity, which research suggests are risk factors for childhood suicide.

Research to confirm the excess deaths reported in the current study should include cases from across the diagnostic spectrum and have large enough sample sizes to discern specific types and doses of antipsychotics and distinct drug combinations that might increase the risk for excess deaths, Geller notes.

"Investigations will be more informative if they examine outcomes within child, adolescent, and young adult age subgroups, as opposed to combining all youth," she adds.

The study was supported by a grant from the National Heart, Lung, and Blood Institute and a grant from the National Institute for Child Health and Human Development. Ray and Geller have disclosed no relevant financial relationships.

JAMA Psychiatry. Published online December 12, 2018. Full textEditorial

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