Pharmacogenomics in Psychiatric Disorders

Abstract

The broad arsenal of psychotropic medications is characterised by significant interindividual variability in clinical response and adverse effects, stringent monitoring requirements, potential drug-drug interactions, difficult long-term adherence and high costs. Pharmacogenomics investigates the correlation between genetic polymorphisms and responsiveness to drugs and could provide a valuable guide to fulfill the promise of personalized therapy in the context of the genomic medicine era, by tailoring treatment based on the patient's specific genetic markers. The present paper overviews the current advances in the clinical applications of pharmacogenomics to individualized psychotropic therapy. Material and methods. The relevant recent pharmacogenomics literature is selected and analysed in order to illustrate the impact on the clinical outcomes and quality of life in psychiatric patients of the genetic variants in the neurotransmitter receptors (dopamine and serotonin), metabolic pathways of drugs (cytochrome CYP450 2D6 and 2C19) and the human leukocyte antigen system. The paper focuses on some of the major psychotropic drug classes, such as: antipsychotics, antidepressants and mood stabilizers. Validation of statistically significant pharmacogenomics relationships has enabled the development and market approval of some predictive tests which are already integrated into some psychotropic drugs label. Results and discussions. Predictive pharmacogenomics tests have changed the classical approach of prescription "trial-and error" and "one dose fits all patients" towards personalized therapy. In addition, in new therapeutic candidates' clinical development, pharmacogenomics practically guides the clinical studies design, by substantially reducing the failure rates, costs and exposure risks of non-responders patients to new drugs. Current translation barriers of predictive pharmacogenomic tests from bench to clinical practice are also discussed. Conclusion. The paper emphasizes the current progress and future prospects in the field of pharmacogenomics as a guide to personalized therapy of psychiatric disorders, by: a) pretreatment selection of the right drug, prescribed in its optimized dose, to the right patient, according to one's specific genetic biomarkers; b) by improved clinical trials design based on genetic stratification of patients' population into responders versus nonresponders, especially in the costly phases III and IV.

Pharmacogenomics of Dementia: Personalizing the Treatment of Cognitive and Neuropsychiatric Symptoms

“…It has also been reported that responsiveness to antipsychotics is higher in Ins/Ins carriers (−141C Ins/ins), as well as in A1 carriers of the Taq 1 A SNP of the DRD2 gene. The Ser allele of the Ser9Gly SNP in the DRD3 gene was associated with a better response to clozapine, while the Gly allele was associated with a higher risk for tardive dyskinesia [268]. Several SNPs in the SLC6A4 and SLC6A3 genes showed an association between clozapine responsiveness and genotype or allele frequencies [8,266].…”

“…More than 100 different CYP2D6 alleles might show deficient (poor metabolizer, PM), normal (extensive metabolizer, EM), intermediate (intermediate metabolizer, IM), or increased (ultra-rapid metabolizer, UM) enzymatic activity, meaning that different patients will require different dosages [218,268]. While the majority of the general population shows normal enzymatic activity [265,268], the proportion of extensive metabolizers and ultrarapid metabolizers is slightly higher in the general population compared to AD cases [265]. On the other hand, the proportion of intermediate metabolizers and poor metabolizers is vaguely lower in the general population compared to AD cases.…”

“…Moreover, repeat-length polymorphisms in the serotonin transporter gene have been associated with responses to certain antidepressants and antipsychotics. For example, a long allele is associated with a better response to citalopram, paroxetine, fluoxetine, risperidone, and clozapine [268], while CYP2D6 and CYP2C19 variants are associated with antidepressantinduced symptoms, such as nightmares, anxiety, and panic attacks [8]. Furthermore, polymorphisms in the genes SCN1A, ABCB1, UGT2B7, ABCC2, CYP1A2, HNF4A, and CYP3A5 are associated with altered drug metabolism of carbamazepine.…”