Despite remarkable progress in recentdecades in modern psychopharmacotherapy, patients vary substantially in their response to antidepressants, ranging from total remission to complete treatment failure. Adverse effects, often bothersome and occasionally life-threatening, continue to represent significant challenges to patients and clinicians. Mechanisms responsible for such variability remain poorly understood. In addition, although less appreciated, substantial cross-ethnic variations in psychotropic responses often exist. Recent developments in the field of pharmacogenetics indicate that genetic factors may account for a large part of these differences in response. Specific genetic po'ymorphisms affecting the function of the serotonin (SERT) system has been postulated to predict the effect of antidepressants. Similarly, genetic mutations have been shown to exert a predominant influence on the expression of a number of drug-metabolizing enzymes, including most of the cytochrome P-450 enzymes (e.g., CYP2C 19 and CYP3A4) that are responsible for the biotransformation of most antidepressants. Polymorphisms of genes controlling these enzymes have been found to be strongly associated with the propensity for various kinds of side effects. Capitalizing on these new developments, the proposed study will examine the predictive value of some of these genetic polymorphisms in 400 patients (200 African Americans and 200 Caucasians) with DSM-LV majordepression prospectively treated with citalopram (CIT). It is postulated that mutations affecting the function of SERT will predict responses to CIT, polymorphism of CYP2C 19 will be associated with the side effect profiles and pharmacokinetics of CIT. The inclusion of the two comparison groups, African Americans and Caucasians, whose genetic mutation patterns diverge significantly from each other, will allow us to examine how these differences affect their antidepressant response patterns and whether the associations are 'replicable' across ethnicity. Also, African Americans' response to antidepressants has rarely been studied in a systematic fashion, particularly in the context of controlled clinical trials. Thus, in addition to addressing issues related to clinical pharmacogenetics, data derived from this three-site (Harbor-UCLA, UCLA\King-Drew and Cedars-Sinai Medical Centers) collaborative R0l project should also serve to bridge crucial knowledge gaps regarding the treatment of African American patients suffering from major depression.
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