How strong is the evidence that genetic factors influence response to psychotropic drugs and susceptibility to adverse effects? The genetic basis of antidepressant response was the focus of several interesting older studies that were reviewed in Lerer and Macciardi (2002). Among patients who had been treated with imipramine(Drug information on imipramine) (Tofranil) or monoamine oxidase inhibitors, Pare and Mack (1971) found concordance of response or nonresponse to drugs from one of these two classes among relative pairs. They also observed a tendency for the same patient to respond (or not respond) to a drug of the same class on repeated administrations. They insightfully suggested, "A patient's response to antidepressant drugs depends to a considerable extent on the fundamental biochemical abnormality of his illness and that this in turn depends on the genetic type of his depression." Several other authors have observed concordance of response to imipramine or MAOIs among relative pairs or within families (Lerer and Macciardi, 2002).
There are a substantial number of clinical studies that have examined the role of genetic factors in the response of patients with bipolar disorder to prophylactic therapy with lithium(Drug information on lithium) (Eskalith, Lithobid) (for a comprehensive review see Alda ). The overall trend of these studies' findings was that a positive family history of bipolar disorder was associated with lithium response, that rates of bipolar disorder were higher among the relatives of lithium-responsive patients than among the relatives of lithium nonresponders and that there was a significantly higher response rate to lithium among the relatives of bipolar probands who were lithium responders than among the relatives of bipolar probands who were not. There are very few studies that have examined the role of family history in response to mood stabilizers other than lithium and in response to antipsychotic drugs.
How far along is the search for specific genes that are implicated in the pharmacogenetics of psychotropic drugs? For several years there has been strong interest in genetic predictors of response to the atypical antipsychotic clozapine(Drug information on clozapine) (Clozaril). Because of its unique binding profile, serotonin and dopamine(Drug information on dopamine) receptors have received particular emphasis. Several reports have implicated polymorphisms in the serotonin 2A and serotonin 2C receptors. Of particular interest are attempts to determine how several genes together contribute to response to a particular drug. Arranz et al. (2000) conducted a series of association studies in multiple candidate genes and attempted to find the combination of polymorphisms that gave the best predictive value of response to clozapine in patients with schizophrenia. Their prediction of response was correct 76.7% of the time (p=0.0001), using a combination of six polymorphisms in neurotransmitter receptor-related genes, with 95% sensitivity for satisfactory response (±0.04). The six polymorphisms included two in the serotonin 2A receptor, two in the 5-serotonin 2C receptor and one each in the serotonin transporter and histamine 2 receptor. There has been little published work on other atypical antipsychotics. Work with the classical antipsychotic drugs has been sporadic with few replicated findings.
An intriguing set of findings has emerged regarding the role of candidate genes in susceptibility to tardive dyskinesia (TD). Steen and colleagues (1997) first reported association of a serine to glycine(Drug information on glycine) polymorphism in the dopamine D3 receptor gene with TD. Carriers of the glycine allele were more likely to have developed the adverse effect. This finding has been replicated by several groups and by a pooled analysis of 780 patients (Lerer et al., 2002). The Figure shows data from this study and demonstrates the greater severity of the abnormal involuntary movements that characterize TD associated with carriage of the glycine allele (Due to copyright concerns, this figure cannot be reproduced online. Please see p38 of the print edition--Ed.) Genetic variation of other receptors has been associated with TD. These include the serotonin 2A and serotonin 2C receptors and the CYP 1A2 enzyme. There are also reports of additive and interactive effects of genes in conferring susceptibility to TD (Segman and Lerer, 2002).
The pharmacogenetics of antidepressants is a rapidly moving area. In 1998, Smeraldi and colleagues reported an association between an insertion deletion polymorphism in the promoter of the serotonin transporter gene and response to antidepressants. They studied 102 patients who met DSM-IV criteria for major depression and found that patients carrying either one or two copies of the long (l) allele of the serotonin transporter gene had a significantly better response to fluvoxamine(Drug information on fluvoxamine) (Luvox) than patients homozygous for the short (s) allele. This genetic variation significantly affects its function, the short (s) allele being associated with less efficient uptake of serotonin. Association of the serotonin transporter gene with response to antidepressants--particularly selective serotonin reuptake inhibitors--has been replicated by several other groups (Lerer and Macciardi, 2002). Other genes have been studied with some positive findings, but these are not yet well replicated.
Overall, the current status of research into the pharmacogenetics of psychotropic drugs may be summarized as very promising but far from definitive (Lerer, 2002). The routine use of genetic information to inform treatment decisions in the field of psychopharmacology is not an immediate prospect. What is not clear is how long it will take. The problem is not technological. Techniques for high throughput genotyping permit very large numbers of samples to be analyzed in a very short time. Once a panel of genetic polymorphisms that reliably predicts response has been identified, it will certainly be possible for them to be tested by means of DNA chips. These can already allow several thousand genes to be analyzed at once. The bottleneck at this point is effective clinical research that will yield reliable and replicable findings. Large samples are needed, and studies need to be designed to take into account potential confounding effects of ethnicity, gender and other variables. The effort that needs to be invested is great but promises very high yields.
Pharmacogenetics addresses a core issue in pharmacotherapeutics--the individualization of drug treatment to the specific patient--and promises to provide the tools for making rational clinical decisions that are based on the patient's genetic profile. This will be a major advance in therapeutics that will have enormous impact on patient care and will also have important pharmacoeconomic implications. Furthermore, the complex and lengthy process of new drug development could be considerably shortened with cost reductions that would be passed on to the consumer. It may take longer than originally anticipated, but ultimately pharmacogenetics and pharmacogenomics will revolutionize the field of clinical psychopharmacology.