Antipsychotics Boost Type 2 Diabetes Risk in Youth

Nancy A. Melville

January 21, 2016

Youth who have been exposed to antipsychotic drugs are at significantly increased risk for type 2 diabetes in comparison with youth who have not been exposed to the drugs, including those who also have psychiatric disorders but who have not been exposed, a new meta-analysis shows.

"The take-away [message] is that type 2 diabetes is a risk when treating youth with antipsychotics, especially long term, and antipsychotics should therefore be used judiciously and for as short a period as necessary and possible," senior author Christoph U. Correll, MD, of the Hofstra Northwell School of Medicine, Hempstead, New York, told Medscape Medical News.

The research was published online January 20 in JAMA Psychiatry.

Significant Increased Risk

The meta-analysis included 13 longitudinal studies reporting on a combined total of 185,105 youth aged 2 to 24 years who were exposed to antipsychotic drugs for at least 3 months. The mean age of the patients was 14 years; 59.5% were male. The mean follow-up was 1.7 years.

The analysis showed that for youth exposed to antipsychotics, the cumulative risk for type 2 diabetes was 5.72 per 1000 patients. The incidence rate was 3.09 cases per 1000 patient years (for both, P < .001).

Dr Christoph U. Correll

The cumulative odds ratio (OR) and incidence rate ratio (IRR) were significantly higher in antipsychotic-exposed youth compared with healthy control persons (OR, 2.58; 95% confidence interval [CI], 1.56-4.24; IRR, 3.02; 95% CI, 1.71 - 5.35; for both, P < .0001).

The increased risk was reduced when compared with patients with psychiatric illness who were not exposed to antipsychotics, but it was still significant (OR, 2.09; 95% CI, 1.50 - 2.90; IRR, 1.79; 95% CI, 1.31 - 2.44; for both, P < .0001).

Factors associated with the highest cumulative risk for type 2 diabetes included a longer follow-up period (P < .001), use of the drug olanzapine (multiple brands) (P < .001), and male sex (P = .002).

Higher incidence of type 2 diabetes was associated with use of second-generation antipsychotics (P ≤ .050). Interestingly, a lower risk was observed for youth with autism spectrum disorder (P = .048).

The reasons for the lower risk associated with autism are uncertain, the authors noted.

"Whether the lower risk in youth with autism spectrum disorder is driven by other diagnostic groups that are associated with a higher type 2 diabetes risk (eg, mood or psychosis spectrum disorders) or by co-medications used for these patients requires further clarification," the investigators note.

Dr Correll speculated that the reduced difference between exposed patients and nonexposed patients with psychiatric diagnoses could reflect various other metabolic risk factors that are linked with psychiatric illness, such as exposure to mood stabilizers and antidepressants.

However, he emphasized that the increased risk in antipsychotic-exposed youth is nevertheless significant.

"The fact that even compared to psychiatrically ill patients, the cumulative type 2 diabetes risk and the exposure-adjusted risk were still 2.1 times and 1.8 times higher in youth exposed to antipsychotics indicates that antipsychotics play a major role," he said.

Dr Correll cited a study by his team that was published in 2009. Mentally ill youth who were prescribed antipsychotic drugs experienced dramatic changes in body weight and blood sugar and blood fat parameters within just 3 months of antipsychotic exposure in comparison with mentally ill youth who were prescribed the drugs but who did not take them or who stopped taking them.

The current analysis showed that the number of excess cases of type 2 diabetes in the antipsychotic-exposed group was relatively low ― an excess of 3.11 and 3.57 new type 2 diabetes cases per 1000 psychiatric control patients and healthy persons, respectively. However, the potential consequences remain serious, the authors assert.

"The clinical importance of these findings is underscored by studies showing increased morbidity and mortality associated with an earlier type 2 diabetes onset," the investigators write.

Dr Correll noted that the analysis did not identify drugs that might be associated with a reduced risk for metabolic effects. However, aripiprazole (Abilify, Otsuka Pharmaceutical Co, Ltd) has been cited as being associated with potentially lower risk.

"Other studies suggest indirectly lower type 2 diabetes risk with aripiprazole than with most other antipsychotics, but in young adults, more data are needed," he said.

"Research is specifically needed that tests lower-risk pharmacologic and nonpharmacologic interventions that may be used effectively before or instead of an antipsychotic when treating nonpsychotic conditions," he added.

"This need pertains especially to youth presenting with severe mood or behavioral dysregulation, irritability, and aggression, for whom antipsychotics are used a lot, often without even providing psychosocial treatments."

Antipsychotics Overused

David Rubin, MD, codirector of PolicyLab at the Children's Hospital of Philadelphia and professor of pediatrics at the Perelman School of Medicine, the University of Pennsylvania, agreed that clinicians need to be more selective in prescribing antipsychotics to the most appropriate patients.

"My major concern is the frequency of use we are seeing for these medications among youth with disruptive behaviors or attention-deficit disorder. I don't believe the evidence supports the use of these medications in many of these cases," Dr Rubin told Medscape Medical News.

"I also worry about how trauma exposure in children can impact the behaviors they display. The answer for this group of youth, and they are many, is not sedation through antipsychotics, it's trauma-focused therapies and the nurturing of stable, attached relationships in their lives."

Dr Rubin, who coauthored research cited in the analysis showing that an increase in the risk for type 2 diabetes in youths who initiated second-generation antibiotics was highest among those who also received antidepressants, agreed that although the incidence of patients developing type 2 diabetes appears relatively small, the risk is still important.

"The authors acknowledge, as we showed in our own study, that the absolute risk for diabetes is low but appears to be real," he said. "That means that clinicians need to weigh that risk against the perceived benefit of using antipsychotics in children.

"At the very least, they should try to minimize the use of these medications to situations that appear to have an evidence base to support their use. They should also try to limit the length of treatment with the antipsychotics, as the longer you treat, the greater the likelihood of harm. Finally, if they are going to treat, they need to be very careful in monitoring for side effects, not just diabetes but other evidence of metabolic dysregulation."

The study received funding from the Zucker Hillside Hospital, the National Institute of Mental Health Advanced Center for Intervention and Services Research for the Study of Schizophrenia and from the Agency of Healthcare Research and Quality. The authors of the study have disclosed numerous financial relationships with industry, which are listed in the original article. Dr Rubin has disclosed no relevant financial relationships.

JAMA Psychiatry. Published online January 20, 2016. Full text

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