The State of Pharmacogenetics Customizing Treatments

There are limited data on clinical and biological predictors of antipsychotic drug response. The ability to identify those patients who will respond well to psychotropic drug treatment or who will be at a higher risk for adverse effects could help clinicians avoid lengthy ineffective drug trials and limit patients’ exposure to those effects. Moreover, better predictability of treatment response early in the course of a patient’s illness can result in enhanced medication adherence, a significant predictor of relapse prevention.¹

Pharmacogenetics involves the use of molecular genetic informa-tion to predict drug effectiveness and drug-induced adverse events. Pharmacogenetic data could be vital to the development of individualized treatment approaches by providing a better understanding of the molecular substrates of psychotropic drug action.

Pharmacogenetics provides a number of distinct advantages in the search for informative correlates of psychotropic drug response. First, an individual’s genotype is essentially invariable. Collection of the independent measure for analysis versus treatment response can be performed at any time during the treatment (or thereafter), but the genotype remains unaffected by the treatment itself. Second, current molecular biology techniques provide an accurate assessment of an individual’s genotype, and measurement error plays little role in these analyses. Third, the dramatic increase in the amount of publicly available genomic information provides the necessary data to conduct comprehensive studies of individual genes and broad investigation of genome-wide variation. Finally, the ease of accessibility to genotype information by means of peripheral blood or saliva samples, coupled with advances in molecular techniques, has increased the feasibility of routine DNA collection and genotyping in large-scale clinical trials.

Candidate gene approaches to pharmacogenetics

Most pharmacogenetic studies in psychiatry have focused on a candidate gene approach in which single nucleotide polymorphisms within a gene implicated in psychotropic drug action are tested for association to clinical response phenotypes. Candidates may be selected based on a priori hypotheses (such as the known binding sites of psychotropic drugs or reports of association) or because of their location in genomic regions implicated in drug action or disease pathophysiology. Candidate gene approach studies of antidepressant drugs have focused on a polymorphism (5-HTTLPR) in the gene that codes for the serotonin transporter-the putative site of action of serotonin reuptake inhibitors-and many antipsychotic pharmacogenetic drug studies have targeted the dopamine D2 receptor (DRD2) gene, to which all known antipsychotic drugs have binding affinity.

5-HTTLPR and antidepressant drug efficacy

The serotonin transporter gene is located on chromosome 17q and contains a functional polymorphism in the transcriptional control region upstream of the coding sequence. Because SSRIs block reuptake via the serotonin transporter, the 5-HTTLPR polymorphism has been frequently studied in antidepressant pharmacogenetics. Initial results with fluvoxamine indicated that the l allele of 5-HTTLPR was linked with better clinical response. Findings from many subsequent studies with multiple antidepressant agents suggest a similar relationship.²

CHECKPOINTS
? 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.

? Candidate gene approach studies of antidepressant drugs have focused on a polymorphism (5-HTTLPR) in the gene that codes for the serotonin transporter-the putative site of action of serotonin reuptake inhibitors-and many antipsychotic pharmacogenetic drug studies have targeted the dopamine D2 receptor gene, to which all known antipsychotic drugs have binding affinity.

? In contrast to candidate gene studies, the genome-wide association study approach uses recently developed microarrays to interrogate hundreds of thousands of single nucleotide polymorphisms randomly distributed across the genome.

? A potentially more robust phenotype for examination with pharmacogenetics is susceptibility to treatment-related adverse effects.

Serretti and colleagues³ published a meta-analysis of 15 studies that included more than 1400 participants and reported that the l allele was significantly associated with antidepressant response and remission rates. Nevertheless, the relative effect size overall was modest and influenced by factors that included treatment duration, genetic analytic strategy used, and ethnicity. Subsequently, serotonin transporter genotype was not significantly associated with clinical response to the antidepressant citalopram in the large (N = 1914) Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial. Currently, the 5-HTTLPR genotype does not seem to provide sufficient predictive validity for use in clinical practice.⁴

DRD2 and antipsychotic drug efficacy

To date, pharmacogenetic studies in schizophrenia have revealed few compelling candidate genes (or variants) for antipsychotic drug efficacy.⁵ Early studies concentrated on response to the atypical antipsychotic clozapine (in part because of the ease of collecting blood samples from clozapine-treated patients who require regular venipuncture to rule out agranulocytosis). These studies primarily focused on 1 or a few single nucleotide polymorphisms derived from genes encoding dopamine (DRD3, DRD3) or serotonin receptors (HTR2A, HTR2C) for which clozapine has potent affinities.

Later candidate gene studies have followed this basic strategy with olanzapine and risperidone, with mixed results. The lack of compelling results may be related to small sample sizes (often fewer than 100 patients), short trials (4 to 8 weeks), the lack of comprehensive phenotype information with often only a single rating, and the clinical heterogeneity of the study populations (in which patients with early-phase illness are combined with those who have chronic illness).

The largest candidate gene pharmacogenetic study published to date in schizophrenia assessed 678 patients assigned to 1 of 5 antipsychotic drugs as part of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE).⁶ This study was primarily made up of chronically ill patients who were recruited from approximately 50 academic and nonacademic centers across the United States. It focused on the relationship of treatment response to 8 single nucleotide polymorphisms within a candidate gene for schizophrenia susceptibility-regulator of G protein signaling 4 (RGS4). No results survived correction for the number of phenotypes and single nucleotide polymorphisms tested, although nominally significant results (P = .01 and P = .002) were obtained for 2 individual analyses relating specific drugs to a clinical response phenotype.

Taken together, the early pharmacogenetic studies in schizophrenia have not provided any compelling evidence that any gene, or combination of genes, influences treatment response. This is particularly surprising when one considers the fact that all antipsychotic drugs share at least one property (the ability to bind potently to DRD2), although no clear identification of variants within DRD2 that influence antipsychotic response has been reported.⁷ This may be because most pharmacogenetic studies have comprised patients who have chronic schizophrenia and have received multiple antipsychotic drugs. In vivo neuroimaging studies have shown that exposure to treatment influences D2 receptor density. Thus, variation in antipsychotic drug exposure could result in considerable interindividual variation in D2 receptor and would introduce heterogeneity into analyses of single nucleotide polymorphisms that produce functional effects via DRD2 expression.⁸

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