Genetic predictors of therapeutic response to clozapine: current status of research

Clozapine is one of the most clinically potent drugs currently available for treating the symptoms of schizophrenia. Compared with conventional antipsychotics it surpasses its predecessors in its ability to treat a wider range of symptoms in otherwise refractory patients, while possessing a low propensity to produce extrapyramidal symptoms. Despite its significant advantages, not all patients benefit from treatment. Some patients react adversely to therapy while others fail to respond adequately. If those most likely to benefit from clozapine could be identified prior to treatment, this would significantly improve the clinical management of these patients. Genetic alterations in drug-metabolising enzymes have previously been demonstrated to influence the efficacy of clinically relevant drugs. It is possible that similar alterations in these and other systems may influence the response variability of patients to clozapine. Pharmacogenetic studies are at present investigating genes encoding drug receptors, drug-metabolising enzymes and neurotransmitter transporters to identify genetic variants that may be important. To date polymorphisms within serotonergic and dopaminergic pathways have been implicated, though the involvement of similar variants in other candidate systems is also likely. This information will ultimately enable the genetic prediction of patients most likely to benefit from the drug, and in the process would alleviate the unnecessary exposure of predisposed individuals to potentially serious adverse effects.