Pharmacogenomic Update On Antidepressant and Antipsychotic Medications

Abstract

Psychiatric medications continue to be prescribed on a ‘trial-and-error’ fashion, with virtually no predictive tools available allowing to select type and dose of medications for any given individual.An increasing amount of evidence support an important role for genetic markers to improve outcome to many antidepressant and antipsychotic used for depression and schizophrenia, respectively. High levels of clinical evidence in favor of genetic associations are particularly reported for drug metabolizing genes. Another example are patients of Asian ancestry who receive carbamazepine and where the HLA-B*1502 marker substantially increases risk of serious skin disorders (Stevens Johnson Syndrome and toxic epidermal necrolysis), leading to policies where genetic testing is now mandatory in some Asian countries.This presentation will begin by reviewing the state of the current research with a focus on drug metabolizing enzymes and highlight expert consensus guidelines and recommendations provided by national drug and safety administrative institutions.CYP450 enzymes, and in particular CYP2D6 and CYP2C19, are responsible for metabolizing most psychiatric medications. Data will be shown from 383 physicians (mostly psychiatrists and family general practitioners) from the greater Toronto area returning surveys following genetic testing for CYP2D6 and CYP2C19 genes (among others) of their patients treated with antidepressants and antipsychotic medications. Questionnaires where retrieved 6-8 weeks later and results indicate that whenever genetic information was considered in their treatment decisions, improvement of drug treatment was seen in 122 cases compared to only 2 cases where a slight symptom deterioration was reported (p < 0.01).Next, results from genetic analyses in noradrenergic and serotonergic genes will be shown from 350 adults diagnosed with late life depression (LLD). Participants received open-label venlafaxine, a serotonin-norepinephrine reuptake inhibitor, for up to 12 weeks. After adjusting for multiple comparisons, the norepinephrine variant rs2242446 (T-182C) was significantly associated with remission (odds ratio=1.66, 95% CI=1.13, 2.42). Individuals with the rs2242446 C/C genotype were more likely to remit (73.1%) than those with either the C/T (51.8%) or the T/T genotype (47.3%). Individuals with the C/C genotype also had a shorter time to remission than those with the C/T or T/T genotypes and had a greater percentage change in depressive symptom scores from baseline to end of treatment (up to week 12). We are currently testing selected microRNA plasma level changes at baseline and end of treatment and these results will be presented at the conference.Overall, pharmacogenomics is being recognized by many stakeholders to bear the potential to improve psychiatric medication treatments. While this notion has become increasingly supported for some important gene-drug pairs through thorough reviews provided by expert panels, more research is required to develop, improve and validate multi-gene algorithms in order to overcome the current trial-and-error approaches in psychiatric medicine. Limitations such as lack of consensus' to select for actionable gene-drug pairs, which genotypes best to select, how to assign metabolizer status and how to effectively develop algorithms to guide treatment decisions will be discussed.