The primary means of treating mental illnesses is with an arsenal of psychotropic medications, including antidepressants, antipsychotics and mood stabilizers. Despite progress over the past several decades in developing new classes of such medications that are presumably safer and more effective, the ability to treat mental illnesses remains clinically sub-optimal. These medications are effective in only a subset of patients or produce partial responses, and they are often associated with debilitating side effects that discourage adherence (1
The results from the latest and largest treatment effectiveness trials of psychotropic medications sponsored by the National Institute of Mental Health (NIMH) reinforce the notion that there is still a long way to go in the war against mental illnesses. In the recently completed Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study in which patients with non-psychotic major depression were followed for up to six years through a sequence of alternative treatment regimens, only 37% achieved remission on first line therapy with a selective serotonin reuptake inhibitor (SSRI) while another 16.3% withdrew completely from treatment due to drug intolerance (2
). Even worse, in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) in which patients with schizophrenia were treated with a menu of leading antipsychotics under conditions meant to reflect realistic clinical practice and followed for up to 18 months, over 74% eventually discontinued their study medication either due to lack of efficacy or tolerability (3
). Similarly, in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) trial in which patients with bipolar disorder were enrolled and provided treatments with mood stabilizers and antidepressants that followed expert consensus guidelines, up to 75% experienced symptom relapse sometime over the course of follow-up (4
). These figures are sobering and suggest considerable room for improvement in psychiatric treatments.
With the advent of the genomics revolution, there has been growing excitement that pharmacogenetics can pave the way to improved treatments. The term pharmacogenetics was first coined nearly a half century ago when it was recognized that inherited variation can influence responses to medications (5
). Since then, an ever growing number of pharmacogenetic traits have been studied. Earlier studies focused on variation in candidate genes or gene systems believed to influence the absorption, distribution, or clearance of drugs (i.e., pharmacokinetics) or mediate their mechanisms of actions via interactions with receptors and/or transporters and downstream second messengers (i.e., pharmacodynamics). However, the completion of the Human Genome Project and the emergence of new tools to interrogate the entire genome on an unprecedented scale have accelerated interest in studying the relevance of variation across the entire genome. These advances have spawned a new term, pharmacogenomics. Pharmacogenomics and pharmacogenetics are used interchangeably, and in both cases refer to the study of how genetic variation influences response to drug treatments in terms of efficacy (i.e., efficacy pharmacogenetics) or tolerability (i.e., safety pharmacogenetics).
The hope is that through pharmacogenetics we will be able to discover genetic profiles that can be determined by simple genetic tests and that predict how patients will respond to different psychotropic treatments before they are initiated. The benefits are obvious as it would allow physicians to tailor medications to their patients in such a way that maximizes their efficacy and tolerability, thus ushering in an era of “personalized medicine.” In addition, by elucidating the pathways by which drugs act to treat illness and provoke unwanted side effects, pharmacogenetics may inform the rational development of new treatments that are ever more safe and efficacious. Thus, the promise of pharmacogenetics in psychiatry is that it will lead to the smarter use of our existing weapons and, in turn, the development of even smarter weapons to combat mental illness.
However, there is clearly still a long way to go before the promise becomes a reality. In this article, we review the progress that has been made in research towards understanding how genetic factors influence psychotropic drug response and the challenges that lie ahead in translating the research findings into clinical practice that yield tangible benefits for patients. We discuss antidepressants, mood stabilizers, and antipsychotics in turn, and for each we review the pharmacogenetic studies that have been carried out on them, including candidate gene studies of pharmakcokinetic or pharmacodynamic factors and genome-wide studies. We then examine the few examples of pharmacogenetic biomarkers and corresponding tests that have begun to penetrate into clinical practice in psychiatry and assess their impact on patient care. Finally, we conclude with a discussion of the challenges to advancing the goals of personalized care in psychiatry.