More Proof Antipsychotics Boost Kids' Diabetes Risk

Deborah Brauser

August 22, 2013

Antipsychotic medications place children and young adults at serious risk for type 2 diabetes, new research suggests.

The retrospective cohort study of more than 43,000 individuals between the ages of 6 and 24 years adds to mounting evidence showing that these medications cause rapid metabolic change in young patients, putting them at increased risk for diabetes, overweight, and obesity and subsequent cardiovascular disease.

In this latest report, investigators found that study participants who were prescribed antipsychotics were significantly more likely to develop type 2 diabetes within the first year of use compared with matched control individuals who were not prescribed these medications.

In addition, the researchers found there was a dose-response relationship so that the risk increased with higher medication doses and remained elevated for up to 1 year after the medications were discontinued.

When the investigators assessed only participants who were younger than 18 years, the association between antipsychotic use and type 2 diabetes remained highly significant.

"We found a 3-fold increased risk for type 2 diabetes in the children who were antipsychotic users when compared to a very closely matched group of control children receiving other psychotropic drugs with a similar psychiatric profile," principal investigator Wayne A. Ray, PhD, professor in the Department of Health Policy at the Vanderbilt University School of Medicine in Nashville, Tennessee, told Medscape Medical News.

"This surprised us. Not that the risk was increased but that the magnitude was so great," he added.

Dr. Ray added that the key take-home message for clinicians is to carefully consider the risk/benefit of antipsychotics in this vulnerable population.

"For conditions in which there are other therapeutic alternatives, clinicians and parents should consider those. In some case they may end up using the antipsychotic, but at least they have considered the other options," he said.

The study was published online August 21 in JAMA Psychiatry.

A Perfect Storm

According to the investigators, antipsychotics for children and adolescents used to be prescribed primarily to treat schizophrenia and other psychotic disorders.

However, with the introduction of atypical antipsychotics, the use of this class of medication has "expanded to include bipolar disorders, affective disorders, and symptoms related to behavior and conduct, which now account for the majority of prescriptions."

Previous research has shown that these medications are associated with increased metabolic risks, including weight gain, increased glucose levels, and insulin resistance in this young patient population.

As reported by Medscape Medical News, investigators led by Susan Andrade, ScD, from the University of Massachusetts, published a retrospective study in 2011 in Pediatrics. They found that use of antipsychotics increased the risk for diabetes in a group of children and adolescents between the ages of 5 and 18 years. Out of 9636 of the participants who were taking second-generation antipsychotics (SGAs), 57 were diagnosed with incident diabetes.

"Although we found a potentially 4-fold increased rate of diabetes among children exposed to SGAs, the findings were inconsistent and depended on the comparison group and the outcome definition," the researchers wrote at the time, adding that the small number of cases was a potential study limitation.

Dr. Wayne Ray

The current investigators sought to examine these associations in a larger trial. Dr. Ray noted that the "dramatic increase" in antipsychotic use by children and an increase in pediatric diabetes cases has led to a possible "perfect storm" of problems.

"We thought it was important to clarify this issue for clinicians and for parents. And if this increased risk was really there, they needed to take that information into account when choosing a drug," he explained.

The investigators evaluated records from the Tennessee Medicaid program of 28,858 first-time users of antipsychotic medications and 14,429 1-for-2 matched control individuals who had recently initiated use of a psychotropic other than an antipsychotic. All of the participants were 6 to 24 years of age between 1996 and 2007 (mean age, 14.5 years; 56% boys).

Those who had received a previous diagnosis of diabetes, schizophrenia, or some other condition for which antipsychotics are "the only generally recognizable therapy" were excluded.

Antipsychotics used included risperidone, quetiapine, aripiprazole, and olanzapine; and the median starting dose was 67 mg of chlorpromazine equivalents. Medications used by the control group included mood stabilizers such as lithium, as well as antidepressants, psychostimulants, α-agonists, and benzodiazepines.

Lowest Possible Dose, Shortest Possible Time

Results showed that 106 of the young people receiving antipsychotics were diagnosed and treated for type 2 diabetes (mean age, 16.7 years; 63% girls). This translated into 18.9 cases per 10,000 person-years.

"That's why this study had to be so large, in order to detect clinically meaningful differences in the risk of type 2 diabetes, a relatively uncommon but serious condition for children and youth," explained Dr. Ray in a release.

Still, the group of antipsychotic users had a 3-fold increased risk of developing type 2 diabetes by the end of the study compared with the group of nonusers (hazard ratio [HR], 3.03; 95% confidence interval [CI], 1.73 - 5.32).

And this risk was significant within the first year of follow-up (HR, 2.49; 95% CI, 1.27 - 4.88).

The risk also increased with cumulative dose. For less than 5 grams of chlorpromazine equivalents, the HR was 2.13; for 5 to 99 grams, the HR was 3.42; and for 100 grams or more, the HR was 5.43.

One year after discontinuing use of any antipsychotic, the risk for type 2 diabetes remained elevated (HR, 2.57; 95% CI, 1.34 - 4.91).

Overall risk also remained significant when investigators only evaluated the subgroup of children between the ages of 6 and 17 years (HR, 3.14; 95% CI, 1.50 - 6.56).

A total of 87% of the antipsychotic users used atypicals; and use of this medication classification was associated with significant risk (HR, 2.89).

Risperidone, which was associated with an HR of 2.20 for type 2 diabetes in this study, was also the most frequently prescribed antipsychotic (n = 10,718), followed by quetiapine (n = 5807) and olanzapine (n = 5671).

Interestingly, the difference between HRs for risperidone and aripiprazole was strongly significant (P < .001).

Dr. Ray noted that the results show the need for examining alternatives to antipsychotic use. He added that this is especially important for high-risk children, such as those who are overweight.

"Children should be monitored carefully for metabolic effects predisposing them to diabetes, and use of the drug should be at the lowest possible dose for the shortest possible time," he said.

"Important, Landmark Study"

"Overall, I think this is a really important study. Some would call it a landmark study," Dina Panagiotopoulos, MD, associate professor of pediatrics at the University of British Columbia (BC) and endocrinologist at the BC Children's Hospital in Vancouver, told Medscape Medical News.

Dr. Dina Panagiotopoulos

"It's the largest sample size to date to look at this question, they did very complex statistical analyses to adjust for 151 covariates, and they did very careful subgroup and sensitivity analyses," she said.

She was also impressed that the investigators ensured that the matched control group was as mentally and physically ill as the study group.

"Clearly, these findings are important and clinically relevant."

Dr. Panagiotopoulos, who was not involved with this research, was codeveloper of the Canadian Alliance for Monitoring Effectiveness and Safety of Antipsychotics in children (known as CAMESA) guidelines. She and her colleagues also published a study in 2012 that examined the link between SGAs and cardiometabolic risks in kids.

"My only concern about this study, and it's been echoed by other local and international colleagues, because we've had quite a bit of email interaction about this study already, is with the way the diagnosis of diabetes was made," she said.

She noted that the investigators relied upon a clinical diagnosis, "using an administrator code that a doctor would use for diabetes with use of a medication." However, most cases were not confirmed with blood work.

"So you can't say that there was true ascertainment of diabetes in all of those patients. But because they used the same definition in both groups, you can say that the relative risk has still been increased," said Dr. Panagiotopoulos.

Even with this limitation, she said that the analysis was important — especially because the investigators were able to look at such a young age group.

"This study is adding to the body of literature suggesting that using atypical antipsychotics in children increases diabetes risk. We cannot ignore that," she said.

"There are some very important findings here for clinicians, emphasizing once again that these drugs are dangerous, they should be used only for appropriate indications, and that kids need careful monitoring."

The study was funded by a grant from the Agency for Healthcare Research and Quality, Centers for Education and Research on Therapeutics. The study authors and Dr. Panagiotopoulos have disclosed no relevant financial relationships.

JAMA Psychiatry. Published online August 21, 2013. Abstract

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