Antipsychotics Increase Adiposity, Insulin Resistance in Children


SAN DIEGO – Significant increases in adiposity and insulin resistance quickly became apparent in a 12-week study of low-dose antipsychotics to treat mainly nonpsychotic disorders in 144 children.
Newer, “atypical” antipsychotics increasingly are being used to treat mood and disruptive behavior disorders in children, Dr. John W. Newcomer said at the annual meeting of the American Diabetes Association
“It’s a topic of increasing concern in a number of state Medicaid” systems, he said. Concerns have been generated in part by data showing premature mortality in people with mental disorders that’s related primarily to cardiovascular disease but also to cardiometabolic risk.
Children in the open-label study were randomized to flexibly dosed treatment with risperidone, olanzapine, or aripiprazole. It was their first use of antipsychotics.

Dr. John W. Newcomer
These were “very low doses,” he emphasized. “These are not doses that would be used to treat a psychotic disorder,” said Dr. Newcomer, who led the study while at Washington University, St. Louis. He now is a professor of psychiatry and behavioral sciences at the University of Miami.
The 5-year Metabolic Effects of Antipsychotics in Children (MEAC) study targeted symptoms of aggression and irritability in patients aged 6-18 years. “Typically, they had been suspended from school,” he said.
The main primary diagnosis was treatment-refractory attention deficit hyperactivity disorder (ADHD) in 57% of patients. “This is what clinicians are using these drugs for in this type of public-sector population – kids who fail two or three courses of stimulants who then are looking for some other treatment.”
Other main diagnoses included oppositional defiant disorder in 22%, pervasive developmental disorder in 6%, bipolar disorder in 4%, and major depression in 3%. Smaller proportions of patients were diagnosed with other mood disorders, Asperger’s syndrome, autism, obsessive-compulsive disorder, or Tourette’s syndrome.
Mean doses were 1 mg/day in the 49 patients on risperidone, 6.3 mg/day in the 46 patients on olanzapine, and 6 mg/day in the 49 patients on aripiprazole. Approximately half of patients also were on stable doses of stimulants for ADHD.
Total body percentage of adiposity increased 2.4% after 12 weeks on antipsychotics – slightly less than a standard deviation, and a highly significant change, Dr. Newcomer and his associates reported. Mean total fat increased 2.3 kg, they added.
The percentage body fat increased the most in the youngest children. Greater changes were seen with olanzapine than with risperidone or aripiprazole. About a fourth of patients on risperidone or aripiprazole showed little change in body fat, but three-quarters on those drugs and nearly all patients on olanzapine showed increases.
Whole-body insulin sensitivity decreased approximately from 8 mg/kg per minute to 7 mg/kg per minute, a significant reduction. Olanzapine produced the greatest reduction in whole-body insulin sensitivity.
Importantly, scores for irritability and aggression improved in all groups, he added.
“I’m not a child psychiatrist. I was not terribly sympathetic to this at the beginning” of clinicians’ use of antipsychotics for these indications, said Dr. Newcomer, who chaired the Drug Utilization Review Board for Missouri Medicaid for 14 years. “But I was educated by the psychiatric outcome. There was really profound psychiatric symptom improvement, with kids going back to school and [behaving differently],” he said. The psychiatric response was similar among treatment groups in the study.
As early as 6 weeks after starting therapy, significant changes could be seen on adiposity. Children with the biggest changes in body fat showed effects within the first month of treatment.
Height, weight, waist circumference, body mass index, and BMI percentile were measured at all visits. At baseline and at 12 weeks, investigators performed dual-energy x-ray absorptiometry (DEXA) scans and MRI to assess changes in adiposity, hyperinsulinemic euglycemic clamp with isotopomers to assess changes in insulin sensitivity, plasma sampling (such as oral glucose tolerance test or measuring fasting glucose and lipids), ECG, and psychiatric ratings. At the 6-week follow-up, patients underwent DEXA, oral glucose tolerance testing, and lab measures of fasting status.
A previous nonrandomized study of 272 antipsychotic-naive children and adolescents reported weight gains of 4-8 kg and increases in BMI percentile for patients taking any of four atypical antipsychotics for a median of 11 weeks, compared with a control group (JAMA 2009;302:1811-2).
The study’s design raised concern that the effects could be larger than reported, however, because overweight or obese children were assigned to drugs considered to have the lowest risk for weight gain, Dr. Newcomer said.
In a post-hoc analysis, Dr. Newcomer showed that at the start of the current study, the children had similar rates of overweight or obesity as did children in the general population, but rates were higher in the cohort by the end of the study. The rate of overweight or obese children in the cohort increased from about 33% to 48%.
“I’m personally skeptical about the idea that it’s the psychiatric disorders themselves that are the metabolic challenge, rather than the treatment being the primary effect,” he said.
Medicaid data suggest that 43% of prescriptions for atypical antipsychotics are for indications that are not backed by evidence justifying use, he said. Visits to U.S. physicians that included prescriptions for antipsychotics to patients aged 20 years or younger more than doubled between 1997 and 2002, to a rate greater than 1,400 per 100,000 visits, a separate study reported (Arch Gen. Psych. 2006;63-681).
The National Institutes of Health funded the study. Dr. Newcomer has been a consultant for or received grants from Janssen Pharmaceuticals Inc., Pfizer Inc. , AstraZeneca, Bristol-Myers Squibb, Otsuka Pharmaceutical Co. Ltd., Schering/Merck, Vivus Inc., Obecure Ltd., Biovail Corp., Lundbeck A/S, Sanofi, and Dainippon Sumitomo Pharma Co. Ltd./Sepracor Inc.
Use Judiciously, Monitor Carefully

We know from a variety of studies in adults using atypical antipsychotics that there is a range of potential weight gain seen with this class of agents. With these agents also being used in children for major mental health concerns, it’s important to have information from studies like Dr. Newcomer’s on the metabolic effects in that age group.
The challenge is finding the balance between selecting the agent that works best for the child and monitoring very carefully for things like rapid weight gain, higher blood glucose values, and issues that may be associated with these metabolic disturbances such as high levels of triglycerides or increases in appetite.

Dr. David M. Kendall
Weight gain is part and parcel of our environment, and in many cases is attributed to the availability of calorie-dense foods and decreased physical activity. If we have medications that add to that, in this case the atypical antipsychotics, we have to be judicious about using these medications. Clinicians need to be very attentive, both the in specialty setting and the primary care setting, to watch for changes such as rapid weight gain, and then offer alternative therapies if they are available.
As we’ve learned with adults, anyone who is considering prescribing this class of medications should carefully monitor body weight, plasma glucose (an obvious measure of changing glucose tolerance), and other associated risk factors like blood pressure and blood lipids, which can change as adiposity changes. I think it would be critical to monitor all of those in a situation like this.
Dr. David M. Kendall is chief scientific and medical officer for the American Diabetes Association, Alexandria, Va. He said he has no relevant conflicts of interest.
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