Antipsychotics May Boost Incident Diabetes Risk in Kids

Caroline Cassels

November 22, 2011

November 22, 2011 — Initiating therapy with second-generation antipsychotics (SGAs) in children and adolescents has been linked to an increased risk of developing diabetes within 1 year, new research suggests.

A large retrospective study shows previously SGA-naive children and youth may have up to a 4-fold increased rate of incident diabetes mellitus (DM) compared with children not using any psychotropic medications.

"We found an increased incidence of diabetes among children within the first year after initiation of SGA therapy, compared with children who were not using any psychotropic medications. This finding persisted when the incidences of both diabetes and abnormal glucose laboratory values were evaluated," the researchers write.

However, the study showed no difference in DM rates in children and adolescents taking SGAs and their counterparts initiating therapy with antidepressant medications.

With lead author Susan E. Andrade, ScD, the study was published online November 21 in Pediatrics.

Major Public Health Implications

The authors point out that the use of SGAs in children and adolescents in the United States has "increased dramatically" and note most of the use is off-label.

Data from the National Ambulatory Medical Care Survey and the National Hospital Ambulatory Medical Care Survey indicate that antipsychotic prescribing increased from 8.6 cases per 1000 in US children (2 to 18 years of age) in 1995-1996 to 39.4 cases per 1000 US children in 2001-2002.

Research also shows use of SGAs has increased in children ages 2 to 5 years, as has their use in combination with other medications. Data also show that 15% of antipsychotic use in the United States among noninstitutionalized patients is in children and that almost 25% of Medicaid antipsychotic users are children.

A study of a Medicaid population published in 2010 and reported by Medscape Medical News at that time showed a significant proportion of children were prescribed an SGA for conditions that had no published evidence supporting their efficacy.

Research by other investigators, most notably Christoph Correll, MD, Albert Einstein College of Medicine, New York City, has also shown that first-time SGA use in children is associated with rapid metabolic changes, including weight gain and adverse changes in insulin sensitivity and lipid profiles.

SGA use has also been linked to DM, impaired glucose tolerance, and insulin resistance in adults. However, the study authors note, "the evidence has been inconsistent, particularly with respect to the different effects of specific agents."

"Given the clinical complications (cardiovascular, neurologic, and renal) associated with diabetes, the clinical and public health implications of any increased risk in the pediatric population with these agents are large," the investigators write.

Potential 4-Fold Increased Risk

To evaluate the risk for incident DM associated with the use of SGAs, the investigators conducted a retrospective study using the administrative databases of 3 health plans participating in the Health Maintenance Organization Research Network.

A total of 9636 children aged 5 to 18 years who initiated SGA therapy between January 2001 and December 2008 were included in the study. In addition there were 2 comparator groups composed of 38,544 participants who were taking no psychotropic medication and 26,265 patients who began treatment with an antidepressant medication.

The researchers identified cases of diagnosed DM as well as cases with abnormal glucose test results. They then compared the rate of new-onset diabetes in SGA users vs that in the 2 other study groups.

A total of 57 children were diagnosed with incident diabetes. The mean time to diagnosis was 138 days for SGA users (n = 12), 173 days for non–psychotropic medication users (n = 26), and 143 days for antidepressant users (n = 19).

Results showed the risk for incident diabetes was significantly increased among SGA users compared with nonusers of psychotropic medications but was not significantly increased in comparison with antidepressant medication users.

Table. Association Between SGA Use and Incident Diabetes

Patient Group Unadjusted Incidence Rate Ratio (95% CI)
Nonusers of psychotropic medication 4.24 (1.95 - 8.72)
Users of antidepressants 1.74 (0.77 - 3.78)

CI = confidence interval.

"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 investigators write.

The researchers acknowledge that the small numbers of cases was a potential study limitation and acknowledged that "additional research is needed to define the nature and magnitude of the diabetes risk associated with SGA use among children."

Need for Preemptive Lifestyle Counseling

Commenting on the findings for Medscape Medical News, Dina Panagiotopoulos, MD, FRCPC, assistant professor, Department of Paediatrics, University of British Columbia, endocrinologist at BC Children's Hospital and clinician scientist at Child & Family Research Institute, Vancouver, said the study makes "an important and unique contribution to the literature."

"This is the first study in pediatrics to examine the incident risk of diabetes in a cohort of children prescribed second-generation antipsychotics and comparing them to a group of untreated children as well as a group treated with antidepressants," Dr. Panagiotopoulos, who is also a member of the Canadian Alliance for Monitoring Effectiveness and Safety of Antipsychotics (CAMESA), told Medscape Medical News.

She noted that the study also provides important information on the timing to the development of diabetes.

Dr. Panagiotopoulos added that she was not surprised that there was no difference in diabetes risk between the SGA group and the antidepressant group because results from recent adult literature, including a 2011 study published in Diabetologia, suggests individuals treated with antidepressants have an increased risk for type 2 diabetes even after controlling for elevated body mass index (BMI).

"It appears from this study that the risk in kids may be as high [as] or even higher than that in adults but more work needs to be done in that area before any definitive conclusions can be drawn," she said.

Given the evidence from the adult literature, the findings from the current study are "even more important because it is telling us that kids that are treated with SGAs and kids treated with antidepressants seem to have a higher risk and we need to be vigilant and monitor them."

"A study like this one emphasizes once again the importance of metabolic monitoring given the increased risk of diabetes and I suspect that the longer the cohort gets followed, the higher the risk," she said.

She added that every child who begins receiving SGA therapy should have preemptive lifestyle counseling that includes goal setting for optimal nutrition and physical activity guidelines.

Physician Monitoring Poor

Dr. Panagiotopoulos noted that in 2004 the American Diabetes Association and the American Psychiatric Association issued a joint consensus emphasizing the need to monitor anthropometric and laboratory measures in all patients treated with SGAs. However, although these recommendations have been in place for 7 years, physician uptake remains poor.

More recently, she said, the CAMESA released practice and management recommendations guidelines for safety monitoring and management of SGA complications in children.

In addition, a practical tool supported by CAMESA to help facilitate metabolic assessment, screening, and monitoring is available, along with a Healthy Living Toolkits for Professionals and Families to provide resources for clinicians and families working with youth with mental health concerns.

Future research, said Dr. Panagiotopoulos, needs to focus on "developing prospective cohorts of kids — both SGA-treated and non-treated — that are followed longitudinally for several years to understand the natural history of diabetes progression and risk for other metabolic complications."

Furthermore, specific studies conducted to improve understanding of how SGAs affect appetite and pancreatic function are required, as well as studies to see whether different genetic polymorphisms confer different risk in individual patients.

Dr. Panagiotopoulos said the study's strengths include its large sample size and its use of propensity scoring matching. Potential weaknesses include the small number of diabetes cases, which made it difficult to explore diabetes risk by SGA type and dosage.

"Nonetheless, this study makes an important contribution to the literature. This is an important problem, one that requires vigilance and further study but again, I must emphasize the importance of prescribing physicians to monitor for metabolic complications like diabetes and provide lifestyle counseling in advance."

Dr. Andrade reports she has received research funding from Novartis Pharmaceuticals in the past. The disclosures of the other authors can be found in the original paper. Dr. Panagiotopoulos has disclosed no relevant financial relationships.

Pediatrics. Published online November 21, 2011. Abstract

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