Antipsychotic Drugs Linked to Higher Odds for Diabetes in Pregnancy

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U.S. Program Targets Antipsychotic Drug Use in Nursing Homes

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Gene that leads to severe weight gain with antipsychotic treatment discovered

ScienceDaily (May 7, 2012) — Antipsychotic medications are increasingly prescribed in the US, but they can cause serious side effects including rapid weight gain, especially in children. In the first study of its kind, researchers at Zucker Hillside Hospital and the Feinstein Institute for Medical Research identified a gene that increases weight gain in those treated with commonly-used antipsychotic drugs.

See Also:Health & MedicineDiet and Weight LossObesityPersonalized MedicineMind & BrainDieting and Weight ControlObstructive Sleep ApneaSchizophreniaReferenceDopamine hypothesis of schizophreniaDiabetes mellitus type 2PsychopharmacologyStretch marks

These findings were published in the May issue of Archives of General Psychiatry.

Second-generation antipsychotics (SGAs) were used as the treatment in this study. SGAs are commonly used to treat many psychotic and nonpsychotic disorders. However, it is important to note that these SGAs are associated with substantial weight gain, including the development of obesity and other cardiovascular risk factors. The weight gain side effect of SGAs is significant because it often results in a reduced life expectancy of up to 30 years in those who suffer from chronic and severe mental illnesses. The weight gain also prompts some to stop taking the medication, adversely impacting their quality of life.

In this genome-wide association study (GWAS), researchers first evaluated a group of pediatric patients in the US being treated for the first time with antipsychotics. They then replicated the result in three independent groups of patients who were in psychiatric hospitals in the United States and Germany or participating in European antipsychotic drug trials. The gene that was identified to increase weight gain, MC4R or melanocortin 4 receptor, has been previously identified as being linked to obesity and type 2 diabetes. In the new study, it was found that patients gained up to 20 pounds when on treatment.

"This study offers the prospect of being able to identify individuals who are at greatest risk for severe weight gain following antipsychotic treatment," said Anil Malhotra, MD, investigator at the Zucker Hillside Hospital Department of Psychiatry Research and Feinstein Institute for Medical Research. "We hope that those who are at risk could receive more intensive or alternative treatment that would reduce the potential for weight gain and we are currently conducting studies to identify such treatment."

Additional Details About the Study

Researchers conducted the first GWAS of SGA-induced weight gain in patients carefully monitored for medication adherence who were undergoing initial treatment with SGAs. To confirm results, they next assessed three independent replication cohorts: 1) a cohort of adult subjects undergoing their first treatment with a single SGA (clozapine), 2) a cohort of adult subjects treated with the same SGAs as in our discovery sample, and 3) a cohort of adult subjects in the first episode of schizophrenia and enrolled in a randomized clinical trial of antipsychotic drugs. The discovery cohort consisted of 139 pediatric patients undergoing first exposure to SGAs. The 3 additional cohorts consisted of 73, 40, and 92 subjects. Patients in the discovery cohort were treated with SGAs for 12 weeks. Additional cohorts were treated for 6 and 12 weeks.

This GWAS yielded 20 single-nucleotide polymorphisms at a single locus exceeding a statistical threshold of P10-5. This locus, near the melanocortin 4 receptor (MC4R) gene, overlaps a region previously identified by large-scale GWAS of obesity in the general population. Effects were recessive, with minor allele homozygotes gaining extreme amounts of weight during the 12-week trial. These results were replicated in 3 additional cohorts, with rs489693 demonstrating consistent recessive effects; meta-analysis revealed a genome-wide significant effect. Moreover, consistent effects on related metabolic indices, including triglyceride, leptin, and insulin levels were observed.

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Antipsychotic drug may be helpful treatment for anorexia nervosa

ScienceDaily (Apr. 4, 2012) — Low doses of a commonly used atypical antipsychotic drug improved survival in a mouse model of anorexia nervosa, University of Chicago researchers report this month. The result offers promise for a common and occasionally fatal eating disorder that currently lacks approved drugs for treatment.

See Also:Health & MedicineEating Disorder ResearchPharmacologyDiet and Weight LossMind & BrainEating DisordersMental HealthDieting and Weight ControlReferenceEating disorderBulimia nervosaAppetiteAnorexia nervosa

Mice treated with small doses of the drug olanzapine were more likely to maintain their weight when given an exercise wheel and restricted food access, conditions that produce activity-based anorexia (ABA) in animals. The antidepressant fluoxetine, commonly prescribed off-label for anorexic patients, did not improve survival in the experiment.

"We found over and over again that olanzapine was effective in harsher conditions, less harsh conditions, adolescents, adults -- it consistently worked," said the paper's first author Stephanie Klenotich, graduate student in the Committee on Neurobiology at the University of Chicago Biological Sciences.

The study, published in Neuropsychopharmacology, was the product of a rare collaboration between laboratory scientists and clinicians seeking new treatment options for anorexia nervosa. As many as one percent of American women will suffer from anorexia nervosa during their lifetime, but only one-third of those people will receive treatment.

Patients with anorexia are often prescribed off-label use of drugs designed for other psychiatric conditions, but few studies have tested the drugs' effectiveness in animal models.

"Anorexia nervosa is the most deadly psychiatric disorder, and yet no approved pharmacological treatments exist," said Stephanie Dulawa, PhD, assistant professor of Psychiatry & Behavioral Neuroscience at the University of Chicago Medicine and senior author of the study. "One wonders why there isn't more basic science work being done to better understand the mechanisms and to identify novel pharmacological treatments."

One challenge is finding a medication that patients with anorexia nervosa will agree to take regularly, said co-author Daniel Le Grange, PhD, professor of Psychiatry & Behavioral Neuroscience and director of the Eating Disorders Clinic at the University of Chicago Medicine. Drugs that directly cause weight gain or carry strong sedative side effects are often rejected by patients.

"Patients are almost uniformly very skeptical and very reluctant to take any medication that could lower their resolve to refrain from eating," Le Grange said. "There are long-standing resistances, and I think researchers and clinicians have been very reluctant to embark on that course, since it's just littered with obstacles."

Both fluoxetine and olanzapine have been tried clinically to supplement interventions such as family-based treatment and cognitive-behavioral therapy. But their direct effect on anorexia nervosa behavior -- in humans or animals -- is lacking in sufficient data.

To test the effectiveness of these drugs in laboratory mice, Klenotich adapted the ABA protocol from previously published rat studies: Mice given 24-hour access to a running wheel but only six hours a day of food access become hyperactive, eat less and rapidly lose weight, with a 25 percent reduction from baseline considered to be the "drop-out" survival point.

In Klenotich's study, mice were pretreated with fluoxetine, olanzapine or saline before starting the ABA protocol, and treatment continued throughout the ABA period. Researchers then measured how many mice in each group reached the drop-out point for weight loss over 14 days of food restriction and exercise wheel access. Treatment with the antipsychotic olanzapine significantly increased survival over the control group, while fluoxetine treatment produced no significant effects on survival.

Importantly, a low dose of olanzapine did not decrease overall running activity in the mice, indicating that sedative effects of the drug were minimal. In future experiments, the researchers hope to use different drugs and genetic methods to determine exactly how olanzapine is effective against symptoms of anorexia nervosa, perhaps pointing toward a better drug without the negative image or side effects of an antipsychotic.

"We can dissect the effect of olanzapine and hopefully identify the mechanisms of action, and identify what receptor systems we want to target," Klenotich said. "Hopefully, we can develop a newer drug that we can aim towards the eating disorders clinic as an anorexic-specific drug that might be a little more acceptable to patients."

The study offers support for the clinical use of olanzapine, for which clinical trials are already under way to test in patients. Le Grange said the development of a pharmacological variant that more selectively treats anorexia nervosa could be a helpful way to avoid the "stigma" of taking an antipsychotic while giving clinicians an additional tool for helping patients.

"I think the clinical field is certainly very ready for something that is going to make a difference," Le Grange said. "I'm not saying there's a 'magic pill' for anorexia nervosa, but we have been lacking any pharmacological agent that clearly contributes to the recovery of our patients. Many parents and many clinicians are looking for that, because it would make our job so much easier if there was something that could turn symptoms around and speed up recovery."

Additionally, the study demonstrated the innovative experimental design and translational results that can come from a collaboration of laboratory and clinical experts.

"We don't talk to one another often enough in basic science and clinical science," Le Grange said. "More of that would be helpful for clinicians to understand the neurobiology of this disease. I'm very excited about the way this project is going, and I think it's going to be clinically very informative."

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