Pharmacogenomics in Psychiatry Practice: The Value and the Challenges

Abstract

The activity of cytochrome P450 enzymes is influenced by genetic and nongenetic factors; hence, the metabolism of exogenous psychotropic medications and potentially some endogenous neuropeptides is variably affected among different ethnic groups of psychiatric patients. The aim of this review is to highlight the most common cytochrome P450 isoenzymes associated with the metabolism of psychotropic medications (antidepressants, antipsychotics, and mood stabilizers), their variations among different populations, their impact on endogenous neurotransmitters (dopamine and serotonin), and the effect of nongenetic factors, particularly smoking, age, and pregnancy, on their metabolic activity. Furthermore, the adverse effects of psychiatric medications may be associated with certain human leukocytic antigen (HLA) genotypes. We also highlight the gene variants that may potentially increase susceptibility to obesity and metabolic syndrome, as the adverse effects of some psychiatry medications. Collectively, the literature revealed that variation of CYP450 activity is mostly investigated in relation to genetic polymorphism, and is directly correlated with individualized clinical outcomes; whereas adverse effects are associated with HLA variants, projecting the value of pharmacogenetics implementation in psychiatry clinics. Only a few previous studies have discussed the impact of such genetic variations on the metabolism of endogenous neuropeptides. In this review, we also report on the prevalence of key variants in different ethnicities, by demonstrating publicly available data from the 1000 Genomes Project and others. Finally, we highlight the future direction of further investigations to enhance the predictability of the individual gene variants to achieve precision therapies for psychiatric patients.

Pharmacogenetics of Long-Term Outcomes of Schizophrenia Spectrum Disorders: The Functional Role of CYP2D6 and CYP2C19

“…This aligns with the recommendations of Siemens et al (2022), who conducted a systematic review of PGx PRS and found large discrepancies between those of candidate gene studies and GWAS, suggesting future studies should be hypothesis-free [ 60 ]. Lastly, as drug metabolism is known to differ by ancestry groups, this study utilized a strict sample of those with European ancestry only, which may increase clinical utility [ 50 , 61 ]. However, we lacked the statistical power to compare individual antipsychotics, which may account for the lack of effect seen in the sensitivity analysis on antipsychotic use as well as on cardiometabolic outcomes.…”

From genes to drugs: CYP2C19 and pharmacogenetics in clinical practice

“…The CYP2C19 enzyme plays a crucial role in the metabolism of many antidepressants, including selective serotonin reuptake inhibitors (SSRIs) such as sertraline, fluoxetine, citalopram, escitalopram, and others. In addition, multiple conventional tricyclic antidepressants such as imipramine, amitriptyline, trimipramine and clomipramine, are known CYP2C19 substrates ( Alchakee et al, 2022 ). Genetic variations of CYP2C19 significantly impact the efficacy and safety of antidepressant medications, thus clinically influencing depression management.…”

The Role of Pharmacogenetics in Personalizing the Antidepressant and Anxiolytic Therapy

“…Various CYP450 enzymes are capable of metabolizing more than one drug, and a single drug can be metabolized by multiple CYP enzymes [15]. The activity of these enzymes could be influenced by genetic variations, which may result in individual differences in antidepressant drug metabolism and responses [15,16]. Most genes encoding CYPs are highly polymorphic [19].…”

“…There are four major CYP phenotypes produced by combinations of various alleles with different degrees of enzymatic activity: poor (PM), intermediate (IM), extensive (normal) (EM), and ultrarapid metabolizer (UM). PMs tend to accumulate higher drug levels in the blood and may require lower drug doses to achieve therapeutic effects, whereas UMs may require higher doses due to faster drug elimination [16,17].…”