29 October 2009. Within about 11 weeks of starting treatment with second-generation antipsychotic drugs, children and teens gain a startling amount of excess body weight, according to a study published in JAMA on October 28. Researchers Christoph Correll of Zucker Hillside Hospital in Glen Oaks, New York, and colleagues further link some of these drugs to metabolic disturbances that could burden these young people with heart disease later on. The findings, together with those from the recent TEOSS (Treatment of Early-Onset Schizophrenia Spectrum Disorders) Study, seem to argue against the unfettered use of these drugs in treating various psychiatric disorders in young people.
The supposed superiority of second-generation over first-generation antipsychotics put them front and center in the treatment of schizophrenia. However, recent evidence in adults suggests that most of these second-generation, or “atypical,” antipsychotics work no better than their older, “typical” cousins (see SRF related news story; SRF news story; SRF related news story).
Published last year, the TEOSS trial, one of the few randomized, controlled comparisons of medicines for treating early-onset schizophrenia and schizoaffective disorder, found risperidone and olanzapine, two second-generation drugs, no better at curbing symptoms in youth than the first-generation antipsychotic molindone (see Sikich et al., 2008; Frazier et al., 2007; McClellan et al., 2007). Both second-generation drugs caused more weight gain than molindone did. In fact, subjects in the olanzapine group gained 6.1 kilograms in only eight weeks, prompting the safety board overseeing the study to halt enrollment into that study arm. Olanzapine also increased lipid and insulin levels.
Starting with a clean slate
Unlike the TEOSS study, the one by Correll and colleagues examined only patients who had little to no history of taking antipsychotic drugs. In an interview with SRF, Correll said that their focus on this group came about almost by accident. They had been studying weight gain in children and adolescents who were taking antipsychotic drugs when they realized that those who gained the most weight had been antipsychotic-naïve when they entered the study. This led the researchers to focus on patients with no more than a week’s experience using antipsychotics.
The 272 study participants ranged from four to 19 years old. They included 82 with schizophrenia spectrum, 130 with mood spectrum, and 60 with disruptive or aggressive behavior spectrum disorder. All received treatment with a second-generation antipsychotic.
Instead of randomly assigning treatments, Correll and colleagues let patients’ clinicians decide which drug to prescribe. They chose this approach to maximize generalizability to the real world. Consequently, their sample included patients who were taking other medications, although patients taking more than one antipsychotic drug were excluded.
Too few subjects received ziprasidone to study. The analyses, then, looked at 41 subjects on aripiprazole, 45 on olanzapine, 36 on quetiapine, and 135 on risperidone. An additional 15 subjects either refused treatment or stopped taking their medication within four weeks, but still completed follow-up assessments. They served as the comparison group.
The researchers compared body weight and metabolic outcomes in the different treatment groups using an intent-to-treat approach. The comparison group gained little to no weight during the study. In contrast, after a median of 11 weeks of treatment, subjects taking olanzapine gained, on average, 8.5 kilograms (95 percent confidence interval = 7.4-9.7 kg; for pounds, multiply by 2.2). Weight gain for the other second-generation drugs ranged from 6.1 kilograms (95 percent CI = 4.9-7.2) with quetiapine to 5.3 (95 percent CI = 4.8-5.9) with risperidone and 4.4 (95 percent CI = 3.7-5.2) with aripiprazole. In fact, over half of those on antipsychotic drugs gained more than 7 percent of their body weight.
Not surprisingly, as the pounds piled up, subjects’ waists grew, and they amassed more body fat. Correll and colleagues write, “Altogether, 10 percent to 36 percent of patients transitioned to overweight or obese status within 11 weeks.”
On top of that, the study found metabolic changes. In youngsters on olanzapine or quetiapine, the researchers found significant increases in cholesterol, triglycerides, non-high-density lipoprotein (HDL) cholesterol, and the ratio of triglycerides to HDL cholesterol. They also saw evidence of poor glucose metabolism in those on olanzapine and increased triglycerides in those taking risperidone. In contrast, the metabolic measures remained stable in the aripiprazole and comparison groups. This may seem to make aripiprazole the winner, but a recent meta-analysis found the drug less efficacious than olanzapine (see SRF related news story).
These findings of weight gain and metabolic problems in young people treated with second-generation antipsychotics support similar findings from smaller studies in young people (see, e.g., Sikich et al., 2008; Fraguas et al., 2008). They warn of an unhealthy future for many of these patients. “Cardiometabolic adverse effects, such as age-inappropriate weight gain, obesity, hypertension, and lipid and glucose abnormalities, are particularly problematic during development because they predict adult obesity, the metabolic syndrome, cardiovascular morbidity, and malignancy,” write Correll and colleagues. Even first-generation antipsychotic drugs have been tied to greater cardiac risk (see SRF related news story).
A wake-up call
An editorial in the same issue of JAMA, by Christopher Varley and Jon McClellan of Seattle Children’s Hospital in Washington underscores the importance of these findings. They write, “The magnitude of weight gain is particularly concerning, as is the implication that metabolic adverse events may be underestimated in studies in which participants have had prior atypical antipsychotic exposure.” Correll told SRF that the placebo-controlled trial results that companies submit to gain approval to sell their drugs rely on patients with chronic psychiatric disorders. These patients have likely already gained considerable weight from past antipsychotic drug use.
In light of the side effects, Correll and colleagues call for restraint in the use of second-generation antipsychotics. Varley and McClellan echo that sentiment: “Given the risk for weight gain and long-term risk for cardiovascular and metabolic problems, the widespread and increasing use of atypical antipsychotic medications in children and adolescents should be reconsidered.” The latter note that the use of these drugs has spiraled even as controversy has erupted over the growing number of children and teens diagnosed with bipolar disorder. “Atypical antipsychotic medication use in pediatric bipolar disorder is justified primarily based on the adult literature,” without evidence of “continuity” between pediatric and adult-onset forms of the disease, they write.
The results suggest a need to consider less risky medications as well as non-drug options. However, Correll noted, despite the risks of second-generation antipsychotics, these drugs have brought stability to the lives of many people with severe mental illness. As a result, some families are unwilling to try a different drug once they find one that helps. He said that clinicians should educate them about side effects and lifestyle changes, such as exercise and shunning liquid calories, that could lessen their impact.
Correll thinks that clinicians should not only monitor height and weight at each visit, but also test for the “silent, unseen side effects” that may lead to cardiovascular disease. He and his colleagues recommend obtaining fasting blood work for glucose and lipids at baseline, three months, and every six months thereafter. Until researchers discover better drugs, he said, “We’re between a rock and a hard place.”—Victoria L. Wilcox.
Correll 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 October 28;302(16):1765-73. Abstract
Varley CK, McClellan J. Implications of marked weight gain associated with atypical antipsychotic medications in children and adolescents. JAMA. 2009 October 28;302(16):1811-12. Abstract