Understanding Pharmacogenetics

How feasible is the notion that a clinician prescribing psychotropic medication may take genetic information into account? The idea is not new.

In 1902, British physician Sir Archibald Garrod, D.M., suggested that genetic factors direct chemical transformations in humans and underlie individual variability. In 1957, Arno Motulsky, M.D., demonstrated the relationship between adverse drug reactions and genetically determined variation. Friedrich Vogel coined the term pharmacogenetics in 1959. Werner Kalow, M.D., (1962) showed that an abnormal form of serum cholinesterase leads to catastrophic adverse reactions to succinylcholine (Anectine, Quelicin), and he wrote the first systematic account of pharmacogenetics. Polymorphism of the enzyme now called cytochrome P450 (CYP) 2D6 was first observed in the 1970s in healthy volunteers who developed adverse effects to the antihypertensive agent debrisoquine (Mahgoub et al., 1977). The completion of the human genome sequence and the rapid cataloging of human genetic variation that has followed have given enormous impetus to pharmacogenetics and pharmacogenomics. These developments have ushered in an era of great optimism for the prospect of individualized medicine based on the patient's genetic profile (Roses, 2000). Their potential impact on the pharmaceutical industry and on new drug development is considerable.

Pharmacogenetics is the study of genetically based, inter-individual variability in response to drugs and susceptibility to drug-induced adverse effects (Lerer, 2002). Pharmacogenomics applies genomic technologies to drug development. Genetically based differences between individuals in their response to drugs can be attributed to two classes of factors. Pharmacokinetic factors encompass the processes that influence the bioavailability of a drug (i.e., the concentration that is available at its site of action). Pharmacodynamic factors are differences in the protein targets upon which drugs act. Both sets of factors influence the response of an individual to a given drug and may interact within the same individual and with the environment.

The focus of pharmacogenetics is on genetic polymorphisms that influence the structure or function of the protein for which the gene codes. The most common variation, the single nucleotide polymorphism (SNP), is a single base change in the sequence of the gene, which occurs at a frequency of about one in every 1,000 bases. Less than 10% of SNPs have functional significance. Nonfunctional SNPs are an invaluable resource in genetic mapping, however.

Classical genetics of human disease deals with monogenic disorders in which a single mutation in a single gene is causatively related to the phenotype. This paradigm holds true in pharmacogenetics for pharmacokinetic polymorphisms that have a major effect on drug bioavailability (such as the effect of CYP 2D6 polymorphism on the metabolism of a variety of psychotropic and other drugs, which is inherited as an autosomal recessive trait). For the most part, however, pharmacogenetic traits are polygenic and multifactorial. A polygenic trait is influenced by a number of different genes, each of which contributes a portion of the effect and may do so additively as well as interactively (epistasis). The term multifactorial indicates that both genetic and environmental factors contribute substantially and variably to the phenotype.

Pharmacogenetics has the potential to fill a very important clinical need. For as long as medicine has been practiced, physicians have known that patients respond differently to the same therapeutic agent, even though there are no obvious differences in the nature or severity of their illnesses. Susceptibility to adverse effects is also highly variable. When several drugs from the same or different pharmacological classes are available to treat the same condition, the clinician has virtually no rational basis upon which to make a choice.

Therefore, individual or illness characteristics that might aid in choosing an appropriate treatment have long been sought. The principal objective of pharmacogenetics is to identify and categorize the genetic factors that underlie differences among individuals in their response to drugs and to apply these observations in the clinic. The hoped-for end point is a simple DNA test that can be easily and cheaply performed and will yield results that enable the clinician to make reasonable predictions regarding the outcome of treatment with a particular drug and the likelihood of adverse effects.

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 (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 (Eskalith, Lithobid) (for a comprehensive review see Alda [1999]). 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 (Clozaril). Because of its unique binding profile, serotonin and 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 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 (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.

References:

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