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IN THIS ISSUE:
April 2010

Depression during Pregnancy
New guidelines aid clinicians in treating pregnant women with depression.

SSRIs versus an SNRI
A new study failed to find enhanced benefit from duloxetine (Cymbalta) compared with generic selective serotonin reuptake inhibitors in patients with depression.

Zopiclone and Morning-After Impairment
In a small trial of older adults, driving ability and cognitive performance were impaired the morning after subjects took a dose of zopiclone at bedtime.

In Brief
Antipsychotic Polypharmacy Does Not Increase Mortality Risk in Schizophrenia; Tarenflurbil Fails to Slow Cognitive Decline in Alzheimer’s Disease

Second-Generation Antipsychotics Cause Weight Gain and Adverse Metabolic Effects in Young Patients
Second-generation antipsychotics can be life-saving for youth with serious psychiatric illnesses, but they carry the risk for weight gain and possible long-term cardiovascular and metabolic problems.

Second-Generation Antipsychotics Cause Weight Gain and Adverse Metabolic Effects in Young Patients

April 2010

Antipsychotic medications are increasingly being prescribed for children and adolescents in the United States.1 With the exception of clozapine (Clozaril and others), all second-generation agents now are given to children for multiple behavioral indications. But only two have been approved by the U.S. Food and Drug Administration (FDA) for pediatric use: risperidone (Risperdal and others) for irritability associated with autistic disorder, schizophrenia, and bipolar disorder; and aripiprazole (Abilify) for pediatric schizophrenia and bipolar disorder. Last summer, the FDA Psychopharmacologic Drugs Advisory Committee voted to approve three other antipsychotics for schizophrenia and/or bipolar mania in pediatric patients—quetiapine (Seroquel), ziprasidone (Geodon), and olanzapine (Zyprexa) (BTP 2009;32:39). So far, the FDA has not acted on these recommendations. Good evidence supports the efficacy of second-generation antipsychotics for schizophrenia in young patients. There is some support for their use to treat autism, bipolar disorder, aggression, and tics. Most of the trials in children and adolescents involving antipsychotic drugs, however, are short term.

Correll and coauthors prospectively studied weight and metabolic changes associated with first-time use of four second-generation antipsychotics (aripiprazole, olanzapine, quetiapine, and risperidone) in 272 children and adolescents, aged 4 to 19 years, with funding from the National Institutes of Health and private foundations.2 Clinicians chose treatment in each individual case, and the authors assessed weight and metabolic variables during a 12-week period. Fifteen patients who refused participation or did not adhere to treatment served as a comparison group.

Weight increased substantially with all of the antipsychotics: by an average of 8.5 kg (18.9 lb) with olanzapine, 6.1 kg (13.6 lb) with quetiapine, 5.3 kg (11.8 lb) with risperidone, and 4.4 kg (9.8 lb)

with aripiprazole. Altogether, 10% to 36% of patients crossed the threshold to overweight or obese status within 11 weeks. By comparison, the untreated group of 15 young patients gained an average of only 0.2 kg (0.4 lb). Over half of the patients gained more than 7% of their total body weight.

Significant abnormalities in lipid profiles and other metabolic parameters also occurred, most notably with olanzapine. Olanzapine had the largest effect on weight and also significantly worsened all glucose and lipid parameters except HDL cholesterol. Quetiapine and risperidone significantly increased triglycerides but did not impair glucose homeostasis. Quetiapine was associated with significantly increased total cholesterol, non-HDL cholesterol, and the ratio of triglycerides to HDL cholesterol. As noted earlier, aripiprazole produced substantial weight gain, albeit less than the other three agents, but it did not significantly worsen metabolic indices.

In an accompanying editorial, Varley and McClellan point out that although antipsychotics can be life-saving for youth with serious psychiatric illnesses—such as schizophrenia, bipolar disorder, or severe aggression associated with autism—they carry the risk for weight gain and possible long-term cardiovascular and metabolic problems.1 As we've noted in these pages, patients with chronic mental illnesses, including children and adolescents, often have other risk factors for chronic ill health, which can be additive and include poor nutrition, inadequate exercise, substance abuse, and lack of adequate health monitoring and care.

The study by Correll et al underscores the serious adverse effects associated with antipsychotics in young people. The magnitude of these adverse changes (including those evoked by aripiprazole) is impressive and worrisome. Beyond doubt, antipsychotics should be employed when needed. But the risk/benefit ratio must be considered and discussed with parents or guardians. And the children taking these agents must be monitored routinely for adverse health consequences.

1Varley CK, McClellan J: Implications of marked weight gain associated with atypical antipsychotic medications in children and adolescents. JAMA 2009;302:1811-1812.

2Correll CU, Manu P, Olshanskiy V, Napolitano B, Kane JM, Malhotra AK: Cardiometabolic risk of second-generation antipsychotic medications during first-time use in children and adolescents. JAMA 2009;302:1765-1773.