Psychiatric pharmacogenomics in the age of neuroscience: promises and challenges

Most psychiatric disorders including major depressive disorder (MDD), anxiety disorders, bipolar disorder, obsessive-compulsive disorder (OCD), schizophrenia, autism, and attention-deficit/ hyperactivity disorder (ADHD) are known to be genetically sophisticated disorders. The polygenic architecture of these psychiatric disorders has been determined by the aggregate effect of common genetic variants through various combinations of interacting factors such as numerous single nucleotide polymorphisms (SNPs), copy number variations (CNVs), and rearrangements at chromosomal level [1]. Candidategene studies and genome-wide approaches can disentangle complex genetic architecture and offer insight into the neurobiological underpinnings of psychiatric disorders and their proper management. Pharmacogenomics (PGx) refers to the study of how genetic variation influences response to drug treatments in terms of efficacy (efficacy pharmacogenomics) or tolerability (safety pharmacogenomics). Currently available PGx testing can be divided into two primary categories: metabolic enzymes (cytochrome P450 enzyme system also referred to as pharmacokinetics); and genes that effect neuronal function (dopamine transporter and receptor genes frequently referred to as pharmacodynamics). Recent evidence indicates that genetic factors play a critical role (42–50%) in determining the differences in both response and adverse effects of antidepressants and this evidence serves as the foundation of precision medicine. The benefits are obvious as it would allow psychiatrists to tailor medications to their patients in such a way that maximizes their efficacy and tolerability, thus fulfilling the goals of personalized medicine. In addition; by elucidating the pathways by which drugs act to treat psychiatric disorders or provoke unwanted adverse effects, pharmacogenomics may inform the rational development of new treatments that are ever more safe and efficacious. Precision medicine, a novel approach to disease prevention and treatment, is based on an appreciation of the heterogeneity of disease entities and individual differences in genetic make-up. Psychiatric pharmacogenomics, a gene-based method to improve precision in psychotropic medication prescribing, analyzes polymorphisms in pharmacokinetics and pharmacodynamics of genes that affect the metabolism of and response to antidepressant and antipsychotic medications [2]. This approach is designed to assist clinicians in selecting medications for individual patients based on objective, evidence-based genomic information with the goal of improving clinical outcomes and predicting those drugs that may lead to failed medication trials and poor prognoses [3]. This allows clinicians to optimize the choice of which medications to prescribe and also how to dose them for maximum efficacy and minimal adverse effects. Psychiatric pharmacogenomics is in its infancy due to the fact that there are currently few validated and clinically useful gene-response associations that can be used to reliably guide psychotropic medication choice. Reasons that psychiatry may be lagging behind other specialties such as oncology include the heterogeneity of psychiatric disorders (general syndromes rather than distinct pathophysiologically based disorders), the lack of biomarkers for specific illnesses, and the difficulty in defining and standardizing clinical outcomes [4]. Although numerous biomarkers have been associated with psychiatric disorders such as genes for BDNF (brain-derived neurotrophic factor), COMT, DRD1, DRD2, DISC1, GABABR1 (γ-aminobutyric acid B receptor 1), 5HTR1A, and genes for myelination, glutaminergic and GABAergic neurotransmission, oxidative stress, signal transduction, response to the environment, cell survival and proliferation, and cell shrinkage and apoptosis, no genetic biomarker has yet been shown to be useful in prospectively identifying any specific psychiatric disorders [5]. Genetic predisposition in psychiatry is thinly distributed over thousands of loci, each loci contributing a small effect, with considerable overlap of brain systems and shared common genetic factors. In addition, epigenetic and other factors that alter DNA structure and conformation would determine whether susceptibility genes are expressed or suppressed, further complicating studies of the relationship between genotype and phenotype. Environmental