Optimizing drug selection in psychopharmacology based on 40 significant CYP2C19- and CYP2D6-biased adverse drug reactions of selective serotonin reuptake inhibitors

Abstract

Background Selective serotonin reuptake inhibitors (SSRIs) are among the most widely prescribed class of drugs in the practice of psychiatry. Cytochrome P450 (CYP) 2C19 and CYP2D6 are established as clinically relevant drug metabolizing enzymes (DMEs) that influence the pharmacokinetics of SSRIs and may either be grouped as being primarily metabolized by CYP2C19 or CYP2D6. The aim of this study is to test the hypothesis that the primary drug metabolizing pathway for SSRI antidepressants are associated with adverse drug reactions (ADRs) related to physiological modulation of organs with the highest gene tissue expression. Methods Post-marketing ADR cases were obtained from the United States Food and Drug Administration’s Adverse Events Reporting System from each of the four quarters for the years 2016 and 2017. Cases were grouped based on one of two primary pharmacokinetic pharmacogenomic pathway biomarkers CYP2C19 and CYP2D6. Citalopram, escitalopram, and sertraline were grouped as CYP2C19 substrates and fluvoxamine, fluoxetine, and paroxetine as CYP2D6 substrates. Logistic regression was computed for the reported SSRI ADRs associated with one of two aforementioned DMEs. All data homogenization and computations were performed in R for statistical programming. Results The most commonly reported ADR among the SSRIs was anxiety (n = 3,332). The top two ADRs associated with SSRIs metabolized by CYP2D6 are: nightmare (n = 983) reporting odds-ratio (OR) = 4.37 (95% confidence interval (CI) [3.67–5.20]) and panic attack (n = 1,243) OR = 2.43 (95% CI [2.11–2.79]). Contrastingly, the top two ADRs for CYP2C19 metabolized SSRIs are: electrocardiogram QT prolonged (n = 351) OR = 0.18 (95% CI [0.13–0.24]) and small for dates baby (n = 306) OR = 0.19 (95% CI [0.14–0.26]). The study tested and produced 40 statistically significant CYP2C19- and CYP2D6-biased ADRs. In overall context, the results suggest that CYPC19 SSRI substrates are associated with ADRs related to modulation of the autonomic nervous system, seizure, pain, erectile-dysfunction, and absorption. Contrastingly, CYP2D6 SSRI substrates are associated with ADRs related to nightmares, withdrawal syndrome, and de-realization of cognitive processes. The results of this study may aid as guidance to optimize drug selection in psychopharmacology.

Head-to-Head Comparison of Sedation and Somnolence Among 37 Antipsychotics in Schizophrenia, Bipolar Disorder, Major Depression, Autism Spectrum Disorders, Delirium, and Repurposed in COVID-19, Infectious Diseases, and Oncology From the FAERS, 2004–2020

“…Both aripiprazole and brexpiprazole are CYP2D6 substrates and would result in a drug-drug-interaction (DDI) if combined with fluoxetine, paroxetine, sertraline, bupoprion, and duloxetine due to the antidepressants being CYP2D6 inhibitors. The pharmacokinetic outcomes of increased an AUC and Cmax would be even further exacerbated if the patient is a CYP2D6 Intermediate Metabolizer or CYP2D6 Poor Metabolizer (Hefner, 2018;Eugene, 2019).…”

Pharmacogenomics of Cognitive Dysfunction and Neuropsychiatric Disorders in Dementia

“…Properties Pharmacogenetics (minor), CYP2C8 (minor), CYP2D6 (minor), CYP2J2 (minor), CYP3A4 (major) Transporter genes: SLC6A2, SLC6A4 CYP2C19 and CYP2D6 variants affect the occurrence of ADRs in patients treated with selective serotonin reuptake inhibitors (SSRIs) (citalopram, escitalopram, sertraline, fluvoxamine, fluoxetine, and paroxetine), including anxiety, nightmares, and panic attacks associated with CYP2D6 and electrocardiogram (ECG)-prolonged QT associated with CYP2C19 [231]. Prolonged QTc interval is prevalent in patients with moderate-severe dementia, with behavioral symptoms, with global and temporal atrophy, and with leukoaraiosis [232]. A pharmacogenetic risk score has been proposed with top-scoring SNPs (rs12248560, rs878567, and rs17710780).…”

Fluoxetine pharmacokinetics and tissue distribution suggest a possible role in reducing SARS-CoV-2 titers

“…Given this information, drug interactions associated with fluoxetine are due to inhibition of the cytochrome P450 (CYP) system, specifically CYP2C19 and CYP2D6 which may have interactions such as in patients taking tamoxifen in oncology – by inhibiting conversion to the active endoxifen metabolite via CYP2D6 – or in cases of clopidogrel – inhibiting the conversion to the active 2-oxo-clopidogrel metabolite – in cardiology. (Spina, Trifirò & Caraci, 2012; Eugene, 2019; United States Food and Drug Administration, 2020).…”

“…The most common adverse drug event reported for fluoxetine is Drug Interaction and amounts to 3,798 cases (4.75% of total). Given this information, drug interactions associated with fluoxetine are due to inhibition of the cytochrome P450 (CYP) system, specifically CYP2C19 and CYP2D6 which may have interactions such as in patients taking tamoxifen in oncology -by inhibiting conversion to the active endoxifen metabolite via CYP2D6 -or in cases of clopidogrelinhibiting the conversion to the active 2-oxo-clopidogrel metabolite -in cardiology (Spina, Trifirò & Caraci, 2012;Eugene, 2019;. United States Food and Drug Administration, 2020).Extrapolating from in vitro to in vivo concentrations are dependent on intracellular versus extracellular concentrations, as well as methodology of quantifying either whole-blood versus plasma concentrations in human pharmacokinetic studies.…”