Drug hypersensitivity reactions (DHRs) remain a significant hurdle in psychiatric treatment, frequently causing therapy discontinuation, reduced adherence, and suboptimal clinical outcomes. Pharmacogenomics offers a powerful approach to unravel the genetic underpinnings that influence drug metabolism, immune system activation, and individual vulnerability to adverse reactions. This review provides a comprehensive overview of the diverse mechanisms behind DHRs, focusing on immune-mediated pathways—particularly T cell-driven responses—reactive drug metabolite formation, and key genetic determinants. Variations in human leukocyte antigen (HLA) alleles and cytochrome P450 (CYP450) enzymes emerge as central factors in hypersensitivity risk. We examine pharmacogenomic links across commonly used psychiatric medications, including anticonvulsants like carbamazepine and lamotrigine, SSRIs, and newer therapeutics such as vortioxetine, psilocybin, and esketamine. Antipsychotic agents, including clozapine and newer drugs like aripiprazole, brexpiprazole, and cariprazine, are also discussed with regard to gene-drug interactions, highlighting risk alleles such as HLA-B15:02, HLA-A31:01, and CYP2D6 and CYP1A2 polymorphisms. The evidence underscores the potential of pharmacogenomic testing to anticipate and prevent severe reactions, including Stevens-Johnson Syndrome, toxic epidermal necrolysis, agranulocytosis, and liver toxicity. The review also addresses clinical translation, exploring preemptive genetic screening, international guidelines (e.g., CPIC and DPWG), and practical challenges such as test accessibility, ethical considerations, and the absence of standardized protocols globally. Emerging technologies, including next-generation sequencing and integrative multiomic approaches, offer opportunities to refine prediction models and tailor psychiatric therapies more precisely. Finally, population-specific studies and international collaboration are crucial to bridging knowledge gaps, particularly in regions like the Middle East. Altogether, pharmacogenomics holds transformative promise for enhancing psychiatric drug safety and advancing personalized patient care.
