Towards the clinical implementation of pharmacogenetics in bipolar disorder

Abstract

Background: Bipolar disorder (BD) is a psychiatric illness defined by pathological alterations between the mood states of mania and depression, causing disability, imposing healthcare costs and elevating the risk of suicide. Although effective treatments for BD exist, variability in outcomes leads to a large number of treatment failures, typically followed by a trial and error process of medication switches that can take years. Pharmacogenetic testing (PGT), by tailoring drug choice to an individual, may personalize and expedite treatment so as to identify more rapidly medications well suited to individual BD patients.

Discussion: A number of associations have been made in BD between medication response phenotypes and specific genetic markers. However, to date clinical adoption of PGT has been limited, often citing questions that must be answered before it can be widely utilized. These include: What are the requirements of supporting evidence? How large is a clinically relevant effect? What degree of specificity and sensitivity are required? Does a given marker influence decision making and have clinical utility? In many cases, the answers to these questions remain unknown, and ultimately, the question of whether PGT is valid and useful must be determined empirically. Towards this aim, we have reviewed the literature and selected drug-genotype associations with the strongest evidence for utility in BD.

Summary: Based upon these findings, we propose a preliminary panel for use in PGT, and a method by which the results of a PGT panel can be integrated for clinical interpretation. Finally, we argue that based on the sufficiency of accumulated evidence, PGT implementation studies are now warranted. We propose and discuss the design for a randomized clinical trial to test the use of PGT in the treatment of BD.

Figure 1

A pharmacogenetics implementation design. Patients are randomized to pharmacogenetic test (PGT) guided treatment or treatment as usual (TAU). For the PGT group, the physician incorporates the results of the test to make treatment decisions; in the TAU group, the physician treats according to usual practice based on evidence-based treatment guidelines. Subjects are assessed longitudinally and outcome compared after the specified treatment interval.

Figure 2

Integrating pharmacogenetic test results. An algorithm for translating genotypes into specific recommendations for drugs commonly used in BD is illustrated. In making an overall treatment recommendation, all possible drug-genotype combinations are classified into four outcome categories. The overall recommendation is optimized to avoid the worst outcome predicted by PGT. Drug-genotype combinations associated with serious and/or potentially life threatening outcomes are given lowest priority (Use with caution). Drug-genotype combinations with an elevated risk of long term side effects or that are predicted to require higher dosing requirements are given the next lowest priority (Potential limitations to use). Drug-genotype combinations that are not associated with an increase in adverse events are recommended for use in accordance with standard practices (Use as directed), and those without an elevated risk for adverse events, and an association with good psychiatric outcomes are given highest priority (Preferential use). EM, extensive metabolizer; IM, intermediate metabolizer; NA, not available; PM, poor metabolizer; TD, tardive dyskinesia; UM, ultra-rapid metabolizer; UNKN: unknown.