Psychotropic medication efficacy and tolerability are critical treatment issues faced by individuals with psychiatric disorders and their healthcare providers. For some people, it can take months to years of a trial-and-error process to identify a medication with the ideal efficacy and tolerability profile. Current strategies (e.g. clinical practice guidelines, treatment algorithms) for addressing this issue can be useful at the population level, but often fall short at the individual level. This is, in part, attributed to interindividual variation in genes that are involved in pharmacokinetic (i.e. absorption, distribution, metabolism, elimination) and pharmacodynamic (e.g. receptors, signaling pathways) processes that in large part, determine whether a medication will be efficacious or tolerable. A precision prescribing strategy know as pharmacogenomics (PGx) assesses these genomic variations, and uses it to inform selection and dosing of certain psychotropic medications. In this review, we describe the path that led to the emergence of PGx in psychiatry, the current evidence base and implementation status of PGx in the psychiatric clinic, and finally, the future growth potential of precision psychiatry via the convergence of the PGx-guided strategy with emerging technologies and approaches (i.e. pharmacoepigenomics, pharmacomicrobiomics, pharmacotranscriptomics, pharmacoproteomics, pharmacometabolomics) to personalize treatment of psychiatric disorders.

The implementation of pharmacogenetic testing in psychiatry is underway but is not yet standard protocol. Barriers to pharmacogenetics becoming standard practice are the lack of translation of evidence-based recommendations and standardization of genetic testing panels. As for the latter, there are currently no regulatory standards related to the gene and allele content of testing panels used to derive medication selection and dosing advice. To address these barriers, we summarize the current gene–drug interaction knowledgebase and proposed a minimum gene and allele set for pharmacogenetic testing in psychiatry. The Pharmacogenomics Knowledgebase has cataloged 448 gene–drug interactions relevant to psychiatry based on the current scientific literature, drug labels, and pharmacogenetic-based implementation guidelines. A majority of these interactions involved two cytochrome P450 enzymes (CYP2D6 and CYP2C19) and antidepressant medications, however, CYP2C9, HLA-A, and HLA-B are relevant to mood stabilizers/anticonvulsants. On the basis of evidence base, we proposed a minimum gene and allele set for pharmacogenetic testing in psychiatry that includes 16 variant alleles within five genes (CYP2C9, CYP2C19, CYP2D6, HLA-A, HLA-B). The intent is to assist clinicians in judging the gene and allele content of pharmacogenetic tests and to facilitate pharmacogenetic testing as a standard protocol and companion tool for psychotropic medication selection and dosing.

Methotrexate (MTX) is a folic acid antagonist that is widely used to treat a variety of diseases. One of the most serious side effects of MTX therapy is hepatotoxicity. The potential molecular cytotoxic mechanisms of MTX toward isolated rat hepatocytes were investigated using Accelerated Cytotoxicity Mechanism Screening (ACMS) techniques. A concentration and time dependent increase in cytotoxicity and reactive oxygen species (ROS) formation and a decrease in mitochondrial membrane potential (MMP) were observed with MTX. Furthermore, a significant increase in MTX (300 μM)-induced cytotoxicity and ROS formation were observed when glutathione (GSH)-depleted hepatocytes were used whereas addition of N-acetylcysteine (a GSH precursor) decreased cytotoxicity. Catalase inactivation also increased MTX-induced cytotoxicity, while the direct addition of catalase to the hepatocytes decreased cytotoxicity. MTX treatment in isolated rat mitochondria caused swelling and significantly decreased adenosine triphosphate (ATP) and GSH content, and cytochrome c release. Potent antioxidants such as mesna, resveratrol and Trolox decreased MTX-induced cytotoxicity and ROS formation and increased MMP. This study suggests that MTX-induced cytotoxicity caused by ROS formation and GSH oxidation leads to oxidative stress and mitochondrial injury in rat hepatocytes.