Atypical Antipsychotic Medications and Weight Gain

Byron's Comments:

All use of these drugs in children should be banned. The risks far outweigh the benefits.

Study Title:

Cardiometabolic Risk of Second-Generation Antipsychotic Medications During First-Time Use in Children and Adolescents

Study Abstract:

Context Cardiometabolic effects of second-generation antipsychotic medications are concerning but have not been sufficiently studied in pediatric and adolescent patients naive to antipsychotic medication.

Objective To study the association of second-generation antipsychotic medications with body composition and metabolic parameters in patients without prior antipsychotic medication exposure.

Design, Setting, and Patients Nonrandomized Second-Generation Antipsychotic Treatment Indications, Effectiveness and Tolerability in Youth (SATIETY) cohort study, conducted between December 2001 and September 2007 at semi-urban, tertiary care, academic inpatient and outpatient clinics in Queens, New York, with a catchment area of 4.5-million individuals. Of 505 youth aged 4 to 19 years with 1 week or less of antipsychotic medication exposure, 338 were enrolled (66.9%). Of these patients, 272 had at least 1 postbaseline assessment (80.5%), and 205 patients who completed the study (60.7%). Patients had mood spectrum (n = 130; 47.8%), schizophrenia spectrum (n = 82; 30.1%), and disruptive or aggressive behavior spectrum (n = 60; 22.1%) disorders. Fifteen patients who refused participation or were nonadherent served as a comparison group.

Intervention Treatment with aripiprazole, olanzapine, quetiapine, or risperidone for 12 weeks.

Main Outcome Measures Weight gain and changes in lipid and metabolic parameters.

Results After a median of 10.8 weeks (interquartile range, 10.5-11.2 weeks) of treatment, weight increased by 8.5 kg (95% confidence interval [CI], 7.4 to 9.7 kg) with olanzapine (n = 45), by 6.1 kg (95% CI, 4.9 to 7.2 kg) with quetiapine (n = 36), by 5.3 kg (95% CI, 4.8 to 5.9 kg) with risperidone (n = 135), and by 4.4 kg (95% CI, 3.7 to 5.2 kg) with aripiprazole (n = 41) compared with the minimal weight change of 0.2 kg (95% CI, –1.0 to 1.4 kg) in the untreated comparison group (n = 15). With olanzapine and quetiapine, respectively, mean levels increased significantly for total cholesterol (15.6 mg/dL [95% CI, 6.9 to 24.3 mg/dL] P < .001 and 9.1 mg/dL [95% CI, 0.4 to 17.7 mg/dL] P = .046), triglycerides (24.3 mg/dL [95% CI, 9.8 to 38.9 mg/dL] P = .002 and 37.0 mg/dL [95% CI, 10.1 to 63.8 mg/dL] P = .01), non–high-density lipoprotein (HDL) cholesterol (16.8 mg/dL [95% CI, 9.3 to 24.3 mg/dL] P < .001 and 9.9 mg/dL [95% CI, 1.4 to 18.4 mg/dL] P = .03), and ratio of triglycerides to HDL cholesterol (0.6 [95% CI, 0.2 to 0.9] P = .002 and (1.2 [95% CI, 0.4 to 2.0] P = .004). With risperidone, triglycerides increased significantly (mean level, 9.7 mg/dL [95% CI, 0.5 to 19.0 mg/dL]; P = .04). Metabolic baseline-to-end-point changes were not significant with aripiprazole or in the untreated comparison group.

Conclusions First-time second-generation antipsychotic medication use was associated with significant weight gain with each medication. Metabolic changes varied among the 4 antipsychotic medications.

From press release:

Many young children and adolescents taking drugs for severe psychiatric problems gain substantial weight and, in some cases, show increased levels of LDL cholesterol and triglycerides in their blood, researchers report in the Oct. 28 Journal of the American Medical Association.

Although the data from this study need to be replicated over a longer time frame, the findings nonetheless raise worrisome questions about anti-psychotic drugs that often benefit children who have schizophrenia, autism, tics, severe bipolar disorder or aggressive behavior.

“We are between a rock and a hard place here,” says study coauthor Christoph Correll, a psychiatrist at the Zucker Hillside Hospital in Glen Oaks, N.Y. These mental disorders are severe and can lead to suicide or to educational problems and emotional scars, he says. On the other hand, weight gain during youth predisposes an individual to chronic health problems later in life, he says.

Weight gain has been noticed before in children and adolescents taking commonly prescribed drugs for severe psychiatric problems. But studies seeking to link that weight gain to the medications were often muddied because patients had taken one of the drugs beforehand at some point—and may have already put on weight from it or reset their body metabolism to adjust to the drug somehow.

In the new study, Correll and his colleagues monitored 272 children, ages 4 to 19, between 2001 and 2007. Of these, 257 were getting psychotropics for severe problems for the first time, and 15 others refused the drugs but agreed to be seen by a doctor. The drugs were olanzapine (Zyprexa), quetiapine (Seroquel), risperidone (Risperdal) or aripiprazole (Abilify). Restricting the study to first-timers eliminated problems encountered in earlier studies.

After a median follow-up period of nearly 11 weeks, these patients had gained 10 to 19 pounds on average, depending on the drug. Kids on Zyprexa gained the most, on average, while those taking Abilify gained the least. The 15 patients who had refused drug treatment gained less than one pound on average during the monitoring period.

The pace of weight gain seems to level off over time, Correll says, but further study will be needed to clarify that trend.

“This is a really good study of relatively short-term effects,” says Christopher Varley, a child psychiatrist at the University of Washington School of Medicine and Seattle Children’s Hospital. But longer-term data are needed, he says, “because you never really treat a kid with one of these conditions for only 12 weeks—it’s more like six to nine months or a year or two.”

Correll’s team intends to monitor as many of the patients as possible over a longer time period.

Child psychiatrist Linmarie Sikich of the University of North Carolina at Chapel Hill School of Medicine says that she and her colleagues have seen many patients lose weight after coming off these drugs. So far, researchers don’t have enough data to clarify why some patients lose the weight and others don’t, she says.

The biological mechanism underlying the weight gain also remains obscure, Varley says. But some effects are evident, such as carbohydrate cravings. “The appetite of these youngsters dramatically goes up,” he says. At the same time, the drugs have a mild sedative effect. “They’re not out running around, expending calories.”

Sikich says some evidence suggests that the drugs may block the body’s satiety signal.

Meanwhile, patients in this study taking Zyprexa showed increased LDL cholesterol and triglycerides, types of fat in the blood. Patients getting Seroquel also had higher triglycerides. The other drugs showed little change in these metabolic markers.

“This does leave a difficult decision, but I think we’re getting increasing guidance,” Sikich says. Clinicians would prefer to prescribe the drugs with the mildest side effects, she notes.

While all four drugs are cleared for adults, the U.S. Food and Drug Administration has specifically approved only Abilify and Risperdal for pediatric use thus far. Earlier this year, a panel of experts recommended that the FDA approve all four drugs for certain severe psychiatric problems in children. The regulatory body has yet to rule on that.

 

Study Information:

Christoph U. Correll; Peter Manu; Vladimir Olshanskiy; Barbara Napolitano; John M. Kane; Anil K. Malhotra. Cardiometabolic Risk of Second-Generation Antipsychotic Medications During First-Time Use in Children and Adolescents JAMA 2009 November 302(16):1765-1773.
Zucker Hillside Hospital, Psychiatry Research, North Shore-Long Island Jewish Health System, Glen Oaks, New York.




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