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Genetic link to drug-related weight gain


Whether a person gains weight while taking antipsychotic medications may depend in part on his or her genes. A new study reports that schizophrenic patients with a particular form of a serotonin receptor gene did not gain weight while others in the study did.

Serotonin pathway

This is the "first real pharmacogenetic finding that could lead directly to an improvement in clinical care" in the domain of schizophrenia, according to Gavin P. Reynolds of the University of Sheffield, U.K., who led the study. He adds that the information may ultimately help doctors determine—through gene tests—which patients are susceptible to the severe side effect.

Doctors consider weight gain due to medications a serious problem because of the health issues associated with being overweight. Weight gain is also "the most worrying side effect for patients," notes Reynolds. The psychological effects associated with gaining weight often cause patients to give up their treatment programs.

The problem of drug-related weight gain has worsened with the increased use of so-called 'atypical antipsychotics,' such as clozapine and olanzapine. These drugs, introduced in the early nineties, work by blocking the action of certain neurotransmitters such as serotonin. Serotonin is involved in regulating mood, appetite, and metabolism, and disrupting this important chemical can lead to severe weight gain.

One serotonin receptor that has been linked to weight gain is the 5-HT2C receptor featured in this study. In particular, the -759T variant of the gene seems to protect against weight gain in non-schizophrenic patients. The reason may be that the variant, located in the promoter region of the gene, causes the receptor to be expressed more often. For patients taking antipsychotic drugs, the increased expression may prevent weight gain because the blocking action of the drugs does not interfere with the transmitter's metabolic control.

In the study, which appears in The Lancet, Reynolds and two colleagues monitored the weights of 123 Chinese patients over a course of drug treatment. They found that the -759T variant was associated with little or no weight gain. After six weeks, none of the individuals with this allele had increased their body weight significantly (by more than 7 percent), compared to 28 percent of the patients with the more common version of the gene. After ten weeks, only 15 percent of the -759T patients had passed the 7 percent mark, while more than half of the others had.

In a second study published this month, researchers found a significantly higher body-mass index among schizophrenics than in the rest of the population. The study investigated changes in body mass index for individuals with and without schizophrenia between 1987 and 1996.

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Homel, P. et al. Changes in body mass index for individuals with and without schizophrenia, 1987-1996. Schizophr Res 55, 277-284 (June 2002).
Reynolds, G.P. et al. Association of antipsychotic drug-induced weight gain with a 5-HT2C receptor gene polymorphism. Lancet 359, 2086-2087 (June 15, 2002).

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