The pharmacogenetics of CYP2D6 and CYP2C19 in a case series of antidepressant responses

Abstract

Pharmacogenetics has potential for optimizing use of psychotropics. CYP2D6 and CYP2C19 are two clinically relevant pharmacogenes in the prescribing of antidepressants. Using cases recruited from the Understanding Drug Reactions Using Genomic Sequencing (UDRUGS) study, we aimed to evaluate the clinical utility of genotyping CYP2D6 and CYP2C19 in antidepressant response. Genomic and clinical data for patients who were prescribed antidepressants for mental health disorders, and experienced adverse reactions (ADRs) or ineffectiveness, were extracted for analysis. Genotype-inferred phenotyping of CYP2D6 and CYP2C19 was carried out as per Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines. A total of 52 patients, predominantly New Zealand Europeans (85%) with a median age (range) of 36 years (15–73), were eligible for analysis. Thirty-one (60%) reported ADRs, 11 (21%) ineffectiveness, and 10 (19%) reported both. There were 19 CYP2C19 NMs, 15 IMs, 16 RMs, one PM and one UM. For CYP2D6, there were 22 NMs, 22 IMs, four PMs, three UMs, and one indeterminate. CPIC assigned a level to each gene-drug pair based on curated genotype-to-phenotype evidence. We analyzed a subgroup of 45 cases, inclusive of response type (ADRs/ineffectiveness). Seventy-nine (N = 37 for CYP2D6, N = 42 for CYP2C19) gene-drug/antidepressant-response pairs with CPIC evidence levels of A, A/B, or B were identified. Pairs were assigned as ‘actionable’ if the CYP phenotypes potentially contributed to the observed response. We observed actionability in 41% (15/37) of CYP2D6-antidepressant-response pairs and 36% (15/42) of CYP2C19-antidepressant-response pairs. In this cohort, CYP2D6 and CYP2C19 genotypes were actionable for a total of 38% pairs, consisting of 48% in relation to ADRs and 21% in relation to drug ineffectiveness.

The Utility of CYP2D6 and CYP2C19 Variants to Guide Pharmacological Treatment in Complex Unipolar Major Depression: A Pilot Longitudinal Study

“…It is of interest that 66% of the tested patients had at least one impaired function allele at CYP2C19 and CYP2D6. This observation is consistent with previous reports that almost 70-80% of individuals affected by mental health conditions, carry at least one impaired allele at CYP2C19 and/or CYP2D6 [24]. Indeed, both genes show high interethnic variability.…”

From genes to drugs: CYP2C19 and pharmacogenetics in clinical practice

“…The discontinuation of antidepressant treatment is a common behavior in people with depression, mainly due to adverse drug reactions. Nearly 50% of undesirable drug reactions can be attributed to the differences in drug metabolism between individuals ( Solomon et al, 2019 ; Kee et al, 2023 ). A clinical study was conducted to explore the association of CYP2C19 actionable variants translated into phenotypes with suicidal behavior in patients with depression who were using citalopram.…”

The Role of Pharmacogenetics in Personalizing the Antidepressant and Anxiolytic Therapy

“…Ahmed et al showed that CYP2D6 UM status contributes to venlafaxine treatment remission in patients with major depressive disorder [46]. Therefore, when prescribing SSRIs and other antidepressants, clinicians must consider a patient's CYP2D6 genotype and adjust the dose or choose an alternative medication, if necessary, to minimize the risk of adverse effects while maximizing therapeutic benefit [6,7,20]. Despite the growing literature on the clinical implications of the CYP2D6 genotype and phenoconversion on patient-related outcomes, implementation of pharmacogenetics to guide antidepressant prescribing is rare.…”

“…In addition to various environmental, physiological, and psychological factors, these individual differences might be largely due to genetic factors [3,4]. Therefore, various pharmacogenetic studies have been conducted to identify genetic variants that can predict patients who may optimally benefit from specific, individually tailored treatments [5][6][7][8][9] (Figure 1).…”

“…Identifying SNPs associated with variability in drug response and toxicity has been the primary focus of a The molecules involved in ADME processes include enzymes responsible for drug metabolism and drug transport molecules that mediate drug uptake and efflux [4]. In this context, the cytochrome P450 (CYP) and multidrug resistance (MDR) gene families have been extensively studied [6,12]. The CYP450 enzyme family in the liver is responsible for the metabolism of many psychotropic drugs [13].…”