The State of Pharmacogenetics Customizing Treatments

A more common adverse effect is antipsychotic-induced weight gain. Studies have shown that many of the atypical antipsychotics are associated with marked weight gain, particularly in pediatric patients and in those patients with no previous exposure to antipsychotics.²⁰ Reynolds and colleagues²¹ studied 123 antipychotic drug–naive schizophrenic Chinese patients (61 men, 62 women) and reported that a promoter region polymorphism, 2759 C/T in the 5-HT2C receptor gene, significantly influenced weight gain following antipsychotic treatment. Study participants with the T allele at this locus gained significantly less weight than those with the C allele at 6 weeks (P < .0001) and at 10 weeks (P = .0003) of treatment. This effect was observed in 46 patients who received risperidone(Drug information on risperidone) and 69 patients who received chlorpromazine(Drug information on chlorpromazine). The effect remained significant after exclusion of patients who were either underweight or obese at baseline. None of the 27 patients carrying the T allele met criteria for severe weight gain (greater than 7% increase from baseline body weight) after 6 weeks of treatment, compared with 28% of the 96 patients without the T allele.

Templeman and colleagues²² reported similar results in a small first-episode cohort treated with a mix of antipsychotic medications including olanzapine(Drug information on olanzapine). Reynolds and colleagues²³ also demonstrated an association between 2759C/T and weight gain in a small group of clozapine(Drug information on clozapine)-treated patients. However, subsequent studies in previously treated patients have been inconsistent. A critical factor in these studies may be the degree of drug exposure. Studies with previously treated patients may underestimate the amount of true weight liability of each drug; variable histories of drug exposure in each cohort may confound analyses intended to identify subtle genetic effects on a complex phenotype such as weight gain.

A preliminary pharmacogenetic analysis of antipsychotic drug-induced weight gain in patients with first-episode schizophrenia who had little or no prior antipsychotic drug exposure has recently been completed.24 All currently available antipsychotics act on DRD2 and are associated with significant weight gain. Lencz and colleagues24 examined the relationship between DRD2 2141C Ins/Del and weight gain in first-episode patients enrolled in a randomized trial of risperidone (n = 32) and olanzapine (n = 26). DRD2 Del carriers (n = 29) were compared with Ins/Ins homozygotes (noncarriers, n = 29) in a mixed model of 10 measurements over 16 weeks. There were significant main effects of genotype: DRD2 Del carriers demonstrated substantially more weight gain than noncarriers after 6 weeks of treatment, regardless of medication (Figure 2). Mean weight gain in Del carriers at 6 weeks was approximately 6 lb higher than in noncarriers.

Conclusions

Although pharmacogenetics research is still early in its development, the initial results suggest that detection of molecular variants associated with psychotropic drug response may soon be possible. Examination of patients with early illness who have had less drug exposure may enhance the power of this approach. Moreover, a focus on drug-induced adverse effects may be valuable, because these effects may be more amenable to detection than more complex clinical efficacy phenotypes that may require larger study populations.

For those interested in more information on this rapidly developing field, a yearly conference—Pharmacogenetics in Psychiatry—is held in New York. For information, go to www.pharmacogeneticsinpsychiatry.com or call 718-470-8418.