Atypical Antipsychotics Increase Cardiometabolic Risk in Children

A study of the adverse effects of 4 second-generation antipsychotics in children and adolescents documented substantial weight gain during 11 weeks of treatment with each agent, with the increased abdominal fat that has been associated with development of metabolic syndrome in adults. Metabolic abnormalities emerged with 3 of the 4 agents, differing in type and severity with the agent and, in some cases, with the dose.

In this analysis from the Second-Generation Antipsychotic Treatment Indications, Effectiveness and Tolerability in Youth (SATIETY) study, 10% to 36% of 272 patients between 4 and 19 years of age (mean, 13.9 years) who had not previously received antipsychotic medication became overweight or obese. There was minimal weight change in a comparison group of patients who had refused the agent, or who discontinued it within 4 weeks.¹

Christoph Correll, MD, Zucker Hillside Hospital, Glen Oaks, NY, and colleagues conducted this observational cohort study as the largest to date of adverse experiences with second-generation antipsychotics in antipsychotic treatment–naive children. The researchers noted that there has been increasing use of these agents in younger patients for psychotic and bipolar disorders as well as nonpsychotic disorders, despite little available age-specific data on adverse reactions.

“Cardiometabolic adverse effects, such as age-inappropriate weight gain, obesity, hypertension, and lipid and glucose abnormalities are particularly problematic during development,” Correll and colleagues indicate, “because they predict adult obesity, the metabolic syndrome, cardiovascular morbidity, and malignancy.”

In an editorial accompanying the study in JAMA, Christopher Varley, MD, and Jon McClellan, MD, Seattle Children’s Hospital, added: “The development of clinically significant hyperlipidemias and insulin resistance after only 12 weeks of treatment portends severe long-term metabolic and cardiovascular sequelae. These results challenge the widespread use of atypical antipsychotic medications in youth.”²

The SATIETY study monitored treatment with aripiprazole (Abilify), olanzapine (Zyprexa), quetiapine (Seroquel), or risperidone (Risperdal), selected and dosed by clinicians to treat psychotic, mood, or aggressive spectrum disorders in this young cohort. After approximately 11 weeks, there was a mean weight gain of 8.5 kg with olanzapine, 6.1 kg with quetiapine, 5.3 kg with risperidone, and 4.4 kg with aripiprazole.

Adverse changes from baseline in levels of total cholesterol, triglycerides, and non–high-density lipoprotein (HDL) cholesterol and also in the ratio of triglycerides to HDL cholesterol were statistically significant with olanzapine and quetiapine. Risperidone was associated with significantly increased triglyceride levels. Olanzapine in dosages greater than 10 mg/d and risperidone in doses greater than 1.5 mg/d were associated with significantly greater increases in total cholesterol and non-HDL cholesterol. There were no metabolic abnormalities or significant changes from baseline with aripiprazole treatment.

Considering atypical antipsychotics for adolescents

This study was published in October, as the FDA continued to consider recommendations from the June meeting of the Psychopharmacologic Drugs Advisory Committee to approve olanzapine, quetiapine, and ziprasidone (Geodon) for indications in children and adolescents, for which-as of this writing-only risperidone and aripiprazole are approved. Although the advisory panel voted to recommend approval of the drugs for treating young patients, a report in JAMA notes that the votes were split over issues of safety.³

Members of the advisory committee had indicated concern, according to the JAMA report, that approval for specific conditions such as bipolar disorder in children would encourage off-label use in this population, or use for approved indications but without rigorous application of diagnostic criteria. Agency representatives at the meeting agreed with the need for approved labeling to narrowly define indications based on DSM-IV criteria.

Correll and colleagues also express concern and suggest that the cardiometabolic risk of these agents in children should be balanced “through careful assessment of the indication for their use, consideration of lower-risk alternatives, and proactive adverse effect monitoring and management.”

References:

References1. Correll CU, Manu P, Olshanskiy V, et al. Cardiometabolic risk of second-generation antipsychotic medications during first-time use in children and adolescents. JAMA. 2009;302:1765-1773.
2. Varley CK, McClellan J. Implications of marked weight gain associated with atypical antipsychotic medications in children and adolescents. JAMA. 2009;302:1811-1812.
3. Kuehn BM. FDA panel OKs 3 antipsychotic drugs for pediatric use, cautions against overuse. JAMA. 2009;302:833-834.