Influence of combined CYP2C19 and CYP2D6 phenotypes on adverse drug reactions in patients with major depressive disorder: a clinical cohort study

Influence of combined CYP2C19 and CYP2D6 phenotypes on adverse drug reactions in patients with major depressive disorder: a clinical cohort study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Influence of combined CYP2C19 and CYP2D6 phenotypes on adverse drug reactions in patients with major depressive disorder: a clinical cohort study Carolin Görnert, Maike Scherf-Clavel, Heike Weber, Sibylle Roll, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6406316/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 09 Apr, 2026 Read the published version in The Pharmacogenomics Journal → Version 1 posted 11 You are reading this latest preprint version Abstract Variants in cytochrome P450 enzymes are known risk factors for developing adverse drug reactions (ADR). Most antidepressants (AD) are simultaneously metabolized by major or minor pathway of CYP2C19 and CYP2D6, resulting in a complex interplay of metabolites. This study is one of the first to investigate and demonstrate the combined CYP 2C19/2D6 functional metabolic status as a risk factor for ADR in AD treatment of major depressive disorder. Most prescribed AD venlafaxine underwent subgroup analysis. Significantly more ADR in non-normal metabolizers (nNM) for one or both CYP enzymes compared with normal metabolizers ( p = 0.039) were observed. Both slow (PM and IM) and rapid metabolizers (RM and UM) were affected. There were non-significant trends for CYP2C19 RM and UM with ADR in venlafaxine, which may be avoided in CYP2C19 nNM. More research is required to identify risk variants for personalized and safe AD treatment. Health sciences/Risk factors Biological sciences/Genetics/Genotype Biological sciences/Drug discovery/Drug safety Biological sciences/Drug discovery/Pharmacology/Pharmacogenetics Health sciences/Diseases/Psychiatric disorders/Depression Figures Figure 1 Figure 2 INTRODUCTION Treatment with antidepressants (AD) may go along with poor efficacy and tolerability ( 1 ). Almost half of adverse drug reactions (ADR) can be attributed to interindividual variations in hepatic drug metabolism ( 2 ). At least 20% of these ADR are preventable ( 3 ). To enhance safety of drug therapy, the Clinical Pharmacogenomics Implementation Consortium (CPIC) and the Dutch Pharmacogenetics Working Group (DPWG) have published pharmacogenetic-guided decision support tools. These guidelines provide dosage and action recommendations for prescribing certain AD based on CYP genotypes ( 4 – 7 ). The two highly polymorphic cytochrome P450 isoenzymes CYP2C19 and CYP2D6 are particularly important in the metabolism of AD ( 8 – 10 ). Divergent (= non-normal-metabolizer (nNM)) genotypes are common in patients suffering from severe mental disorders ( 11 , 12 ). Isolated studies indicate that poor metabolizers of CYP2C19 or CYP2D6 experience more ADR on AD therapy than normal metabolizers ( 13 – 18 ). This is attributed to increased serum concentrations of the active drug moieties ( 19 – 21 ). Rapid CYP2C19 or CYP2D6 metabolizers have been associated with insufficient clinical response and drug discontinuation due to sub-therapeutic serum concentrations ( 22 , 23 ). An increased risk of ADR has not been demonstrated for UM ( 13 , 24 ). Although phenoconversion (PC) occurs in up to 44.9% of patients undergoing psychopharmacotherapy, studies have often utilized CYP genotype instead of phenotype ( 13 , 18 , 25 , 26 ). Inhibitors decrease the CYP activity, leading to higher drug concentrations of the substrate ( 27 – 30 ). In addition to these drug-gene interactions, drug-gene-gene interactions (DDGI) may also occur because the metabolism of certain AD, such as venlafaxine (VEN), is catalyzed by several CYP isoenzymes ( 31 ). Impaired CYP enzyme activity can lead to ADR and activation of an alternative pathway, altering serum levels of the parent drug, metabolites, and parent-metabolite ratios ( 32 ). Studies have investigated serum concentrations in relation to two CYP isoenzyme phenotypes, but the impact on clinical tolerability is limited ( 33 – 35 ). The influence of combined functional CYP 2C19/2D6 enzyme status on VEN tolerability has only been investigated in case studies ( 36 – 38 ). There are also no controlled studies on tolerability based on combined CYP isoenzymes for most other AD, except for amitriptyline, where combined pharmacogenomic (PGx) testing for CYP 2C19/2D6 revealed risk constellations for ADR ( 14 ). PGx-guided therapies can lead to better response, faster remission rates, lower incidence of ADR, and thus significant long-term cost savings for healthcare system ( 39 – 44 ). A better understanding of gene-gene interaction of functional CYP 2C19/2D6 enzyme status on AD tolerability may contribute to an improved therapy of major depressive disorder (MDD). Cross-tabulations based on combined phenotypes of CYP 2C19/2D6 for amitriptyline and CYP 2B6/2C19 for sertraline have already been published by CPIC ( 4 , 5 ). This study investigates the frequency and intensity of ADR during AD therapy in a cohort of hospitalized psychiatric patients regarding their CYP2C19 and CYP2D6 functional status. Pharmacodynamic and pharmacokinetic factors were considered. Furthermore, a drug-specific subgroup analysis was performed for VEN. METHOD Study design 104 adult patients voluntarily admitted to the Department of Psychiatry at the University Hospital Frankfurt were recruited for the FACT-PGx clinical cohort study between July 2021 and July 2022. The sample size was chosen because rare genotypes CYP2D6 UM and CYP2C19 PM statistically occur at least once in 100 European Caucasian individuals, allowing all different genotypes to be included in the study. Patients were treated for MDD according to ICD-10 F32.x and F33.x criteria, regardless of whether AD or other psychotropics had been taken at the time of admission. There were no restrictions on ethnicity and choice, number, or dosage of AD prescribed. Patients were asked to complete the subjective questionnaire “ SeIf-Rating Scale for Adverse Drug Effects “ developed by Dreher et al. for AD treatment ( 45 ). It examines 16 defined and up to two individual ADR based on their incidence (yes/no), intensity (not disturbing/unpleasant/very unpleasant/unbearable), and likelihood of a causal drug effect (probable/possible/improbable). ADR reported as unlikely to be medication-related were corrected for further analysis. Patients who did not complete the questionnaire or submitted it incompletely were excluded from the analysis ( n = 42). Data collection was one-pointed. The clinical response to AD typically occurs within 14 days, and initial ADR usually subside after this period ( 46 ). Therefore, only patients who had not taken a new AD in the previous 14 days were considered for statistical analysis of stable ADR ( n = 41). On the same day, blood was drawn for genotyping. Genotyping was performed in the laboratory of the Department of Psychiatry at University Hospital Würzburg, which was certified by a quality control program ( 48 ). DNA was isolated from EDTA blood samples, and relevant gene variants (single nucleotide polymorphisms) in CYP2C19 and CYP2D6 were genotyped using a MassArray Analyzer 4 system (Agena Bioscience GmbH, Hamburg, Germany). This process employed a self-designed panel utilizing SpectroCHIP®-96 Arrays and iPLEX® Pro chemistry, following the provided instructions manufacturer. Moreover, copy number variations (CNV) were determined using CYP2D6 RealFast™ CNV Assay ( 47 ). Single nucleotide polymorphisms were translated into star alleles using the Pharmacogene Variation Consortium website ( www.pharmvar.org ). Haplotype tables were reported elsewhere ( 28 , 30 ). Each star allele was assigned an activity value based on CPIC definition table (5), and an activity score was calculated by summing all allelic activity values of the diplotype ( 49 , 50 ). Finally, the genetic phenotype was calculated by considering PC. The Flockhart table published by the Food and Drug Administration (FDA) was used to identify CYP enzyme-specific inducers and inhibitors in the current medication, and the genotype-predicted phenotype of CYP2C19 and CYP2D6 was calculated ( 31 , 51 , 52 ). The inhibitor strength level of promethazine is currently under review. Therefore, it was not considered in PC calculation. All following analyses regarding CYP enzyme status were performed considering PC. Phenotypes were classified as PM (poor metabolizer), IM (intermediate metabolizer), NM (normal metabolizer), UM (ultrarapid metabolizer), and CYP2C19 additionally RM (rapid metabolizer) ( 53 ). CYP2C19 UM and RM were grouped as rapid metabolizers (RM). Due to the small number of PM, these were grouped with IM as slow metabolizers (SM). The genotyping result was unknown to the participants when they completed the questionnaire. To evaluate ADR depending on functional CYP enzyme status, we considered only those patients whose AD are known to be mainly metabolized by CYP2C19 and/or CYP2D6 ( n = 35). All study participants gave informed consent. The study was approved by the Ethics Committee of the Goethe University Frankfurt (2021 − 138) and was conducted following the Declaration of Helsinki 2013. Statistical analyses Data were collected, processed, and analyzed descriptively and statistically using Microsoft Excel version 16.66.1. Independent t-tests were performed to analyze continuous parametric discrete variables, whilst chi-square tests were used to analyze categorical dichotomous variables. A P-value of < 0.05 (*) was considered significant for all tests performed. An Odds Ratio (OR [95% confidence interval]) greater than 1 indicated that the ADR was more likely to occur in the exposure group. For this purpose, the Haldane correction was applied if the observed event did not occur once in a group ( 54 ). Data are presented as mean ± standard deviation unless specified otherwise. RESULTS Patient characteristics 55 of 104 genotyped patients (52.9%) completed the questionnaire. Of these patients, 41 had been taking an AD for at least two weeks. Their mean age was 41.6 years (± 14.3, range 19-77), with 58.5% identifying as male and 39.0% as current smokers. In the context of a first depressive episode, 12.2% were first hospitalized and treatment naïve. AD were primarily used as monotherapies (82.9%), with VEN ( n = 12), sertraline ( n = 8), and escitalopram ( n = 7) being administered most frequently. Mirtazapine was the most common combination partner (57.4%). Augmentation with second or third-generation antipsychotics ( n = 15) and lithium ( n = 4) occurred in 46.3%. Demographic and drug use characteristics are shown in Table 1 . Characteristics Responses Total (%) of participants Age 41.6 ± 14.3 years, range 19-77 Sex Male 17 (41.5) Female 24 (58.5) Smoking status Smoker 16 (39.0) Non-smoker 25 (61.0) Clinical parameters Renal impairment (GFR < 60 ml/min) 0 (0.0) Hepatic impairment (liver enzymes 3-fold upper normal limits) 0 (0.0) Diagnosis according to ICD-10 Depressive episode (ICD-10 F32.x) 5 (12.2) Recurrent depressive disorder (ICD-10 F33.x) 36 (87.8) Antidepressant medication Selective Serotonin Reuptake Inhibitors (SSRI) Sertraline ( n = 8) Escitalopram ( n =7) Fluoxetine ( n = 3) 18 (43.9) Serotonin Noradrenalin Reuptake Inhibitors (SNRI) Venlafaxine ( n = 12) Duloxetine ( n = 2) 14 (34.1) Alpha-2-Antagonist (A2A) Mirtazapine ( n = 7) 7 (17.1) Tricyclic Antidepressants (TCA) Amitriptyline ( n = 1) Clomipramine ( n = 1) 2 (4.9) Not mainly metabolized by CYP2C19/CYP2D6 Agomelatine ( n = 2) Bupropion ( n = 1) Tianeptine ( n = 1) Trazodone ( n = 1) Tranylcypromine ( n = 1) 6 (14.6) Form of antidepressant treatment Monotherapy 34 (82.9) Combination with other antidepressants 7 (17.1) Psychotropic comedication Antipsychotics First-generation Promethazine ( n = 9) Prothipendyl ( n = 7) Pipamperone ( n = 3) 19 (46.3) Second-generation Quetiapine immediate release ( n = 12) Quetiapine extended release ( n = 1) Risperidone ( n = 1) Olanzapine ( n = 1) 15 (34.1) Third-generation Aripiprazole ( n = 1) 1 (2.4) Anxiolytics Lorazepam ( n = 6) 6 (14.6) Lithium 4 (9.8) Anticonvulsants Valproic acid ( n = 1) Lamotrigin ( n = 1) 2 (4.9) CYP enzyme status in patients whose antidepressants are mainly metabolized by CYP2C19 and/or CYP2D6 ( n = 35) Genotype-predicted CYP2C19 phenotype NM 13 (37.1) IM 12 (34.3) PM 0 (0.0) RM 7 (20.0) UM 3 (8.6) Genotype-predicted CYP2D6 phenotype NM 23 (65.7) IM 10 (28.7) PM 1 (2.9) UM 1 (2.9) Phenoconversion-predicted CYP2C19 phenotype NM 12 (34.3) IM 11 (31.4) PM 2 (5.7) RM 7 (20.0) UM 3 (8.6) Phenoconversion-predicted CYP2D6 phenotype NM 11 (31.4) IM 19 (54.3) PM 5 (14.3) UM 0 (0.0) Table 1 Characteristics of patients ( n = 41) As illustrated in Figure 1 , patients were asked to rate the causality of AD for each symptom. The three most prevalent ADR were inner unrest ( n = 48, 87.3%), sleepiness ( n = 42, 76.4%), and sleep disturbances ( n = 41, 74.5%), which, according to DSM-5, are similar to characteristic symptoms of depression (55). Following the exclusion of ADR that were considered unlikely to be medication-related by the patients, most frequently reported symptoms were still sleepiness ( n = 26, 63.4%), inner unrest ( n = 23, 56.1%), and reduced salivation ( n = 23, 56.1%). The group reported suffering from an average of 5.7 (± 3.1) ADR. Of these, 10.3% were classified as not disturbing, 44.0% as unpleasant, 36.8% as very unpleasant, and 6.8% as unbearable. No statistically significant difference was observed between genders. However, the analysis showed that females were more likely to experience libido loss (OR = 2.84, CI 0.76-10.58, p = 0.063) and headache (OR = 1.95, CI 0.48-7.85, p = 0.178), while males had a higher incidence of nausea (OR = 2.15, CI 0.41-11.2, p = 0.184). The only significant difference related to smoking status was nausea, which was more common among non-smokers (OR = 13.38, CI 0.71-252.72, p = 0.010*). Pharmacodynamic factors influencing the occurrence and intensity of ADR included combinations with a second AD (8.1 ± 2.5 ADR, OR = 2.04, CI 1.34-3.11, p = 0.012* and p = 0.001*) or with at least one psychotropic drug from another substance class (6.6 ± 2.8 ADR, OR = 2.32, CI 1.59-3.39, p = 0.002*). CYP2C19 and CYP2D6 phenotypes For CYP2D6 and CYP2C19, we observed a high PC rate ( n = 17, 48.57%) in the context of concomitant use of perpetrator drugs ( Table 2 ). Perpetrator drugs on the CYP2D6 genotype Total (%) Inhibitors Sertraline 3 Escitalopram 3 Bupropion 1 Fluoxetine 1 Duloxetine 1 Promethazine 4 33 (73.3) 9 7 4 3 2 8 Perpetrator drugs on the CYP2C19 genotype Inhibitors Pantoprazole 3 Fluoxetine 2 Oral contraceptive 3 Inducer Prednisolone 11 (24.4) 6 4 1 1 (2.2) 1 1 Strong inhibitor: causes a > 5-fold increase in the plasma area under the curve (AUC) values or more than 80% decrease in clearance; 2 Moderate inhibitor: causes a > 2-fold increase in the plasma AUC values or 50-80% decrease in clearance; 3 Weak inhibitor: causes a > 1.25-fold but < 2-fold increase in the plasma AUC values or 20-50% decrease in clearance; 4 Inhibitor strength level is under review. Source: The Flockhart Cytochrome P450 Drug-Drug Interaction Table Table 2 Perpetrator drugs on the CYP2D6 and CYP2C19 genotype-predicted phenotype ( n = 35) CYP2D6 was most frequently affected ( n = 14). Inhibition led to a twofold rise in the proportion of CYP2D6 SM, from 31.9% to 68.57%. CYP2D6 UM could no longer be observed after PC. CYP2C19 genotype exhibited minimal susceptibility to DDGI, resulting in no alteration in the number of SM and RM. Phenotype combinations occurring in the study population and their respective OR for ADR were cross-tabulated ( Tables 3 and 4 ). The control combination CYP 2C19/2D6 NM/NM occurred three times. All following analyses regarding CYP enzyme status were performed considering PC. Phenotype CYP2D6 PM n (%) OR (95% CI) IM n (%) OR (95% CI) NM n (%) OR (95% CI) UM n (%) OR (95% CI) CYP2C19 PM n (%) OR (95% CI) 2 (5.7) 0.52 (0.13-2.12) - - - IM n (%) OR (95% CI) 1 (2.9) 9.04 (2.7-30.27) 6 (17.1) 3.38* (1.45-7.88) 4 (11.4) 2.53 (1.03-6.24) - NM n (%) OR (95% CI) 2 (5.7) 3.66* (1.34-10.01) 7 (20.0) 3.19* (1.39-7.36) 3 (8.6) 1.00 - RM n (%) OR (95% CI) - 4 (11.4) 2.06 (0.83-5.15) 3 (8.6) 4.6 (1.83-11.58) - UM n (%) OR (95% CI) - 2 (5.7) 1.64 (0.55-4.87) 1 (2.9) 9.04 (2.7-30.27) - Table 3 Observed CYP 2C19/2D6 phenotypes predicted following phenoconversion and Odds Ratio (OR) of adverse drug reactions ( n = 35) Adverse side effect Phenotype CYP2C19/CYP2D6 CYP2C19 CYP2D6 Headache 0.91 (0.07-11.23) 0.88 (0.20-3,89) 1.33 (0.28-6.44) Reduced Salivation 2.92 (0.24-35.68) 0.93 (0.23-3,82) 0.68 (0.16-2.93) Sleepiness/Sedation 4.40 (0.36-54.37) 0.94 (0.21-4.10) 1.14 (0.26-5.09) Dizziness 7.00 (0.33-146.45) 0.46 (0.11-1.90) 1.75 (0.40-7.58) Constipation 0.46 (0.04-5.97) 3.88 (0.41-36.79) 0.25 (0.04-1.40) Visual Disorders 2.83 (0.13-60.2) 5.87* (0.64-54.00) 0.46 (0.10-2.22) Tremor 2.57 (0.21-31.33) 2.18 (0.53-9.02) 0.57 (0.13-2.48) Nausea 1.72 (0.08-37.54) 1.05 (0.16-6.78) 0.90 (0.14-5.84) Loss of Appetite 1.40 (0.06-31.12) 0.75 (0.11-5.24) 0.64 (0.09-4.53) Heart Troubles 2.43 (0.11-52.01) 0.83 (0.16-4.30) 1.50 (0.25-8.98) Inner Unrest 10.11* (0.48-212.09) 0.78 (0.19-3.19) 1.68 (0.40-7.07) Sleep Disturbances 3.74 (0.18-78.94) 1.60 (0.34-7.64) 2.70 (0.47-15.40) Increased Sweating 7.00 (0.33-146.45) 2.18 0.51-9.33) 1.02 (0.24-4.26) Disturbance of Micturition 0.57 (0.02-14.53) 2.91 (0.13-65.53) 0.43 (0.02-7.66) Reduced Sexual Desire 0.50 (0.04-6.08) 0.21 (0.05-1.01) 2.45 (0.56-10.68) Erection Problems 0.57 (0.02-14.53) 2.91 (0.13-65.53) 2.56 (0.11-57.78) Other 1.15 (0.12-10.8) 1.22 (0.33-4.45) 0.46 (0.13-1.56) Total 2.99* (1.38-6.46) 1.11 (0.78-1.58) 0.98 (0.69-1.40) Table 4 Odds Ratio (95% CI) of phenoconversion predicted NM/NM phenotype compared to non-Normal Metabolizers ( n = 35) Functional nNM for CYP2C19 and CYP2D6 had an average of 6.2 (± 3.2) ADR. This was 2.3 times more common than in NM/NM (2.7 ± 1.9) with an OR of 2.99 (CI 1.38-6.46, p = 0.039*) ( Figure 2) . ADR were observed more frequently with both slow (6.1 ± 2.8) and fast (6.2 ± 3.8) combined partners. The combination CYP 2C19/2D6 NM/IM or IM/NM already increased the OR for ADR (OR = 3.19, CI 1.39-7.36, p = 0.006*; OR = 2.53, CI 1.03-6.24, p = 0.166). ADR risk was highest for CYP 2C19/2D6 IM/PM and UM/NM (OR = 9.04, CI 2.7-30.27, p = 0.044*). Due to autoinhibition, PM/PM was observed twice when fluoxetine was taken, but it was not associated with a higher number of ADR (OR = 0.52, CI 0.13-2.12, p = 0.278). For individual ADR such as inner unrest (OR = 10.11, CI 0.48-212.09, p = 0.025*), increased sweating (OR = 7.00, CI 0.33-146.45, p = 0.051), and sleepiness (OR = 4.40, CI 0.36-54.37, p = 0.114), OR was notably increased in combination with a nNM for CYP2C19 or CYP2D6. CYP2C19 SM were significantly associated with visual disturbances (OR = 5.87, CI 0.64-54.00, p = 0.018*). Venlafaxine subgroup VEN was the most prescribed AD in the cohort. In the drug-specific analysis for VEN ( n = 12), the appearance of a nNM, whether for CYP2C19 or CYP2D6, reported on average 4.4 more ADR (OR = 4.41, CI 1.49-13.04, p = 0.108) ( Table 5 ). In particular, reduced salivation (OR = 10.71, CI 0.4-287.83, p = 0.038*), increased sweating, and inner unrest (both OR = 7.22, CI 0.28-189.19, p = 0.072) occurred more frequently in this constellation. Descriptively, only CYP2C19 nNM status had influence on increased ADR with VEN, especially RM (OR = 1.30, CI 0.70-2.42, p = 0.356). CYP2D6 nNM occurred only as IM, an actionable genotype (AG) according to DPWG ( Table 6 ), which had no effect on ADR (OR = 0.87, CI 0.44-1.69, p = 0.448). Adverse side effect Phenotype CYP2C19/CYP2D6 CYP2C19 CYP2D6 Headache 0.25 (0.01-5.98) 1.00 (0.06-15.99) 0.27 (0.01-6.74) Reduced Salivation 10.71* (0.4-287.83) 1.67 (0.15-18.87) 1.60 (0.10-24.70) Sleepiness/Sedation 1.50 (0.07-31.57) 1.67 (0.15-18.87) 0.25 (0.02-4.00) Dizziness 3.46* (0.13-90.68) 1.80 (0.12-26.20) 1.00 (0.06-15.99) Constipation 1.47 (0.05-41.83) 3.46 (0.13-90.68) 0.40 (0.01-10.81) Visual Disorders 3.46 (0.13-90.68) 1.80 (0.12-26.20) 1.00 (0.06-15.99) Tremor 1.50 (0.07-31.57) 1.67 (0.15-18.87) 0.25 (0.02-4.00) Nausea 0.79 (0.02-25.90) 1.80 (0.06-54,33) 0.81 (0.03-25.10) Loss of Appetite 2.33 (0.09-62.68) 1.00 (0.06-15.99) 1.75 (0.10-30.84) Heart Troubles 2.33 (0.09-62.68) 1.00 (0.06-15.99) 1.75 (0.10-30.84) Inner Unrest 7.22 (0.28-189.19) 1.00 (0.09-11.03) 2.50 (0.16-38.60) Sleep Disturbances 2.33 (0.09-62.68) 1.00 (0.06-15.99) 1.75 (0.10-30.84) Increased Sweating 7.22 (0.28-189.19) 1.00 (0.09-11.03) 2.50 (0.16-38.60) Disturbance of Micturition 0.79 (0.02-25.9) 1.80 (0.06-54.33) 0.81 (0.03-25.10) Reduced Sexual Desire 0.43 (0.02-9.36) 0.33 (0.03-4.19) 1.00 (0.06-15.99) Erection Problems 0.24 (0-15.19) 0.53 (0.01-31.41) 2.71 (0.04-164.94) Other 5.00 (0.24-106.11) 1.36 (0.20-9.28) 1.00 (0.14-7.10) Total 4.41 (1.49-13.04) 1.30 (0.70-2.42) 0.87 (0.44-1.69) Table 5 Odds Ratio (95% CI) of phenoconversion predicted NM/NM phenotype compared to non-Normal Metabolizers for the venlafaxine subgroup ( n = 12) Besides CYP2D6 IM in VEN, our cohort included with CYP2D6 IM one AG for clomipramine, showing more ADR (OR = 1.3, CI 0.31-5.39). There were no AG for selective serotonin reuptake inhibitors (SSRI). Antidepressant Phenotype Total of participants (OR, 95% CI) Guideline recommendation References Venlafaxine CYP2D6 PM - Avoid or reduce dose Bousman et al. 2023 Beunk et al. 2024 CYP2D6 IM 3 (0.87, CI 0.44-1.69) Avoid or reduce dose Beunk et al. 2024 Tricyclic antidepressants CYP2D6 PM - Avoid or reduce dose by 50% and use therapeutic drug monitoring (TDM) to adjust dosing Hicks et al. 2018 CYP2D6 IM 1 (1.3, CI 0.31-5.39) Reduce dose by 25% and use TDM to adjust dosing CYP2D6 UM - Avoid or use TDM to adjust dosing CYP2C19 PM - Avoid or reduce dose by 50% and use TDM to adjust dosing CYP2C19 RM and UM - Avoid or use TDM to adjust dosing Citalopram Escitalopram CYP2C19 PM - Select another antidepressant not predominantly metabolized by CYP2C19 or reduce dose by 50% Bousman et al. 2023 CYP2C19 UM - Select another antidepressant not predominantly metabolized by CYP2C19 Sertraline CYP2C19 PM - Reduce dose by 50% Bousman et al. 2023 CYP2B6 PM - Select another antidepressant not predominantly metabolized by CYP2B6 or reduce dose by 25% Table 6 Actionable CYP-enzyme phenotypes and dose recommendations based on CPIC and DPWG guidelines DISCUSSION This study shows that AD treatment is highly associated with ADR, which are perceived as severe in over 40% of cases. Identifying individual risk factors is essential for preventing ADR and enhancing depression treatment adherence. The study shows that variants of CYP2C19 and CYP2D6 phenotypes increase ADR risk for psychotropic drugs. Our findings demonstrate that nNM metabolic phenotypes are associated with a significantly increased risk of ADR. Particularly for CYP2C19, an elevated ADR risk was observed for both SM and RM. Consistent with previous studies, CYP2C19 SM are associated with intolerances due to increased serum concentrations ( 13 ). To our knowledge, this study is the first to demonstrate clearly that individuals who are RM may also exhibit an elevated number of ADR. This divergent observation may be attributable to DDGI and PC, which have not been adequately considered in numerous studies, including that of Joković et al. ( 13 ). Given the accelerated degradation of AD and the resulting lower serum concentration, it appears counterintuitive that RM are more susceptible to ADR. However, the CYP system is complex, with many CYP isoenzymes involved in the degradation of an active substance. For instance, VEN is degraded to 90% via CYP2D6 and 10% via CYP2C19 in O-desmethyl-venlafaxine (ODV). Surprisingly, CYP2C19 RM had a greater effect on ADR incidence than CYP2D6. An alternative metabolic pathway for VEN involves N-demethylation by CYP2C19 and CYP3A4, resulting in N-desmethyl-venlafaxine (NDV), which has no antidepressant effect ( 56 ). Accordingly, a rapid CYP2C19 phenotype could lead to a relative increase in NDV concentration. It is not sufficiently clear how the ratio of VEN to its metabolites and the stereoselectivity of the enantiomers contribute to ADR. Studies suggest that exposure to VEN, and possibly NDV, is more important for treatment tolerability than exposure to ODV ( 15 , 57 ). This may provide a rationale for increased ADR in CYP2C19 RM. Compared with ODV, VEN has a higher affinity for the noradrenergic system, which has been implicated in symptoms such as reduced salivation and increased sweating in CYP2D6 SM ( 58 ). It is important to recognize that VEN serum concentration and effect cannot be explained by isolated CYP2C19 or CYP2D6 phenotype. A comprehensive consideration of both enzymes is essential ( 32 ). Current guidelines for VEN dosing are limited to recommendations for CYP2D6 ( 5 , 7 ). CPIC and DPWG both advise against using VEN in PM, while DPWG also advises against its use in IM (Table 6 ). Both define IM as having a gene activity score of 0.25 through 1. The VEN subgroup contained no CYP2D6 PM, but IM. Our results did not show an increased ADR risk with IM compared to NM, which supports CPIC position using the standard dose. However, current guidelines do not provide any recommendations for VEN use in CYP2C19 nNM, which was identified as the primary cause of ADR in this study. Furthermore, most AD lack therapy adjustment recommendations in RM or UM due to insufficient data evidence. An exception are tricyclic antidepressants (TCA), which should be avoided in UM for CYP2C19 or CYP2D6. In our findings, established AG alone do not fully explain ADR risk in AD treatment, underscoring the need for guidelines considering broader factors. Divergent combinations of CYP2C19 and CYP2D6 phenotypes appear to have additive adverse effects on AD pharmacokinetics, as shown in Tables 3 and 4 or in the previous example of VEN. This finding may also apply to other substance classes of AD. PGx-guided dose recommendations are currently available from CPIC for most SSRI and TCA based on CYP2C19, CYP2D6, or CYP2B6 ( 4 , 5 ). While an isolated phenotype is usually considered, cross-tabulations already exist for amitriptyline (CYP 2C19/2D6) and sertraline (CYP 2B6/2C19) ( 4 , 5 ). Hicks et al. described CYP2C19, and CYP2D6 combined gene-based recommendations for amitriptyline with levels of recommendation of optional, moderate, and strong. TCA should be avoided in patients with CYP2D6 PM or UM and CYP2C19 PM. While amitriptyline therapy can be initiated without restriction when CYP2D6 in NM is considered alone (strong), it should be avoided in combination with CYP2C19 PM (moderate). Amitriptyline should also be avoided in CYP 2C19/2D6 NM/PM (severe) and NM/UM (severe). The authors note that clinical and pharmacokinetic data are currently lacking for stronger recommendations, mainly due to the rare occurrence of UM in previous studies. However, it can be deduced that extreme metabolizers such as PM and UM pose a risk for both CYP enzymes, as evidenced by pharmacokinetic observations of their metabolites. CYP2C19 metabolizes amitriptyline into active nortriptyline (NT), which is associated with a higher ADR prevalence than amitriptyline; the hydroxylated metabolites produced by CYP2D6 have a strong affinity for muscarinic receptors and have been associated with cardiotoxicity ( 59 ). Steimer et al. hypothesized that CYP2C19 RM are linked with more ADR than CYP2C19 SM ( 14 , 35 ). Their study cohort had an absence of UM and a paucity of PM. They showed that CYP 2C19/2D6 IM/NM was the most beneficial combination for the tolerability of TCA. Dosage recommendations are not available for all SSRI. There is no guideline for fluoxetine, as there is no evidence that CYP2C19 or CYP2D6 significantly impact clinical outcome ( 5 ). The sum of active fluoxetine metabolites appears mainly independent of CYP2D6 metabolism status ( 60 ). According to this, this study found no positive correlation with ADR in PM/PM. However, this group included only two patients genotyped for both enzymes as NM and only became PM/PM due to fluoxetine autoinhibition. Besides CYP2D6, CYP2C9 is significantly involved in fluoxetine metabolism without being autoinhibited by its substrate ( 61 , 62 ). CYP2C9 converts fluoxetine to R-norfluoxetine, which is less pharmacologically active than S-norfluoxetine produced by CYP2D6 ( 63 ). Therefore, the CYP2C9 pathway could lead to a regular degradation of fluoxetine without an increased risk of ADR. This consideration is speculative, as our study did not include genotyping for CYP2C9. However, it highlights again that metabolism cannot be considered linear and that a gene panel is required to account for DGGI. Besides amitriptyline and sertraline, combined gene-based recommendations have also been published by CPIC for other common drugs such as rosuvastatin (SLCO1B1/ABCG2) and fluvastatin (SLCO1B1/CYP2C9) to prevent statin-associated musculoskeletal symptoms and for thiopurines (TPMT/NUDT15) to prevent severe myelosuppression ( 64 , 65 ). A double-slow combination appears to be associated with additive negative pharmacokinetic effects. For example, fluvastatin is not recommended for individuals with CYP2C9 PM and reduced SLO1B1 function ( 64 ). Combined genetic considerations also exist for warfarin, where CYP2C9 and VKORC1 genotypes have been associated with an increased risk of bleeding ( 66 , 67 ). Another risk factor for ADR is polypharmacy ( 68 ). This can lead not only to drug-drug interactions but also to drug-gene interactions. Many psychotropic drugs are both substrates and inhibitors of CYP2D6 and CYP2C19. In our cohort, PC resulted in a deviation from the genetic phenotype in 48.57% of patients. This observation is representative of psychiatric inpatients ( 25 , 26 ). There is evidence that PGx-guided therapies reduce polypharmacy, making implementation even more important ( 42 ). The study is limited by its small sample size due to excluded patients who did not complete the questionnaire. Explanations for this may include the linguistic barrier or a disease-related decline in motivation. However, the balanced gender distribution, broad age range, and heterogeneity of the medications prescribed allowed a cross-section of the population to be represented. Despite the small sample, the data are valuable because of the good gene-panel using modern CNV analysis and considering interacting factors. ADR rating was done by the patients, which is a limitation of the results. Future studies should use self and observer ratings to verify the results. Not all CYP phenotypes were represented. SM were overrepresented due to PC. There were no UM for CYP2D6 and only three CYP 2C19/2D6 NM/NM as controls. The influence of PC on functional CYP enzyme status has rarely been considered in previous studies but is crucial for interpreting study results on PGx-related ADR. Some inhibitors, such as promethazine, require a clear FDA statement of inhibition strength for accurate phenotype calculation. This study demonstrates the correlation of ADR with the combined phenotypes of CYP 2C19/2D6, considering both psychiatric and non-psychiatric medication. Combined divergent CYP 2C19/2D6 enzyme status was significantly associated with increased ADR. Further and larger cohort studies must follow to provide sufficient evidence for generating phenotype-specific cross-tabulations. CONCLUSION The complex pharmacokinetic interaction of the CYP2C19 and CYP2D6 functional status is relevant for the intolerance of AD. A combined nNM enzyme status is associated with a significantly higher ADR risk than a combined NM enzyme status. One potential cause is the alteration of exposure to the metabolites and a shift in metabolite to parent drug ratio. Furthermore, we recommend avoiding venlafaxine in nNM patients due to highly elevated risk for ADR. Alternatives are not primarily CYP2C19 or CYP2D6 metabolized drugs. This might also apply to other AD, but larger studies are needed to support these findings. This study highlights the need for larger controlled trials to identify risk variants for drug-specific subgroups and provide further evident PGx guidelines for AD. Implementing genetic information into clinical decision-making may enhance the safety of AD therapy. Declarations COMPETING INTERESTS MH and MSC are CPIC members. AR has received funding from Janssen. AUTHOR CONTRIBUTIONS Project administration: MH; data collection: AE, MH, MSC, HW; analysis and interpretation of the data: CG; manuscript writing CG; review and editing: CG, MH, MSC, HW, AE, AR, SCR. All authors made significant contributions to the study and have approved the final manuscript. References Ramos M, Berrogain C, Concha J, Lomba L, García CB, Ribate MP. Pharmacogenetic studies: A tool to improve antidepressant therapy. Drug Metab Pers Ther. 2016;31(4):197–204. Phillips KA, Veenstra DL, Oren E, Lee JK, Sadee W. Potential role of pharmacogenomics in reducing adverse drug reactions: A systematic review. Jama. 2001;286(18):2270–9. M. T, A.A. B, B. D, S. S. Adverse drug reactions in hospitalized psychiatric patients. Ann Pharmacother [Internet]. 2010;44(5):819–25. 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Cite Share Download PDF Status: Published Journal Publication published 09 Apr, 2026 Read the published version in The Pharmacogenomics Journal → Version 1 posted Editorial decision: revise 09 Oct, 2025 Review # 3 received at journal 06 Oct, 2025 Reviewer # 3 agreed at journal 14 Sep, 2025 Review # 1 received at journal 31 Jul, 2025 Reviewer # 2 agreed at journal 31 Jul, 2025 Reviewer # 1 agreed at journal 29 Jul, 2025 Reviewers invited by journal 23 Jun, 2025 Submission checks completed at journal 11 Apr, 2025 First submitted to journal 10 Apr, 2025 Unknown event 10 Apr, 2025 Editor assigned by journal 08 Apr, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6406316","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":474966262,"identity":"bfa02f6e-7719-4f36-bbea-ccaa0cc0145c","order_by":0,"name":"Carolin Görnert","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABFUlEQVRIie3Pz0rDMBzA8YxAd0nJ9TeQ9RVSCmVv4GtkDOolw4EXD2MUAttNr4G9hI8wKMZLvQccUhV6FgqeZBiLgyJtvQrL95I/5EMShFyu/1rBGgsK9QBnvYQ3CIwUGqR2JP2kMQdmaoI6Cd08vhR8sUfBudTV4vp5FT3Jh1eznBA0zO7vWgjkFxHjrERhrmdblV9BvNdTKbR9GEkS00IYSjzgLEOhEhH21xxiI0IpPEuAxK2ElkdyWWH/wCFS3+TQQ+DnlgAExn7KgYEl83U3AVNi+5eMMKIjTDQfKZNMt/MbIF7HX+htMijeP7NxsJFvmCw5pWq2q8THakyHmW4jxwjb/d7yeo7XBelfJ1wul+tk+wLddVrUrkvaAwAAAABJRU5ErkJggg==","orcid":"","institution":"University Hospital Frankfurt, Goethe University","correspondingAuthor":true,"prefix":"","firstName":"Carolin","middleName":"","lastName":"Görnert","suffix":""},{"id":474966263,"identity":"06113acb-e704-429c-b65b-fbbd5b2270f8","order_by":1,"name":"Maike Scherf-Clavel","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Maike","middleName":"","lastName":"Scherf-Clavel","suffix":""},{"id":474966264,"identity":"1bb351a6-adac-4be2-a46b-6207c19b9315","order_by":2,"name":"Heike Weber","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Heike","middleName":"","lastName":"Weber","suffix":""},{"id":474966265,"identity":"bf253869-9e17-4e09-a95e-575bb433026a","order_by":3,"name":"Sibylle Roll","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Sibylle","middleName":"","lastName":"Roll","suffix":""},{"id":474966266,"identity":"046603ec-586a-4700-8149-5138e79c4a4b","order_by":4,"name":"Andreas Eckert","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Andreas","middleName":"","lastName":"Eckert","suffix":""},{"id":474966267,"identity":"ad9d9662-8ede-4953-a34f-f6afa03ff7bf","order_by":5,"name":"Andreas Reif","email":"","orcid":"https://orcid.org/0000-0002-0992-634X","institution":"University Hospital Frankfurt, Germany","correspondingAuthor":false,"prefix":"","firstName":"Andreas","middleName":"","lastName":"Reif","suffix":""},{"id":474966268,"identity":"50b35c73-4c0a-4a54-b85d-99bd68619c2e","order_by":6,"name":"Martina Hahn","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Martina","middleName":"","lastName":"Hahn","suffix":""}],"badges":[],"createdAt":"2025-04-08 20:55:24","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6406316/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6406316/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41397-026-00407-3","type":"published","date":"2026-04-09T04:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":85636428,"identity":"4bb64583-012d-493f-afaf-0b5d5cee1c3e","added_by":"auto","created_at":"2025-06-30 06:02:54","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":114133,"visible":true,"origin":"","legend":"\u003cp\u003eOverview of ADR incidence as reported in the \u003cem\u003e\"SeIf-Rating Scale for Adverse Drug Effects\"\u003c/em\u003eby Dreher et al. Patients rated the causality of ADR with their prescribed antidepressants (n = 41).\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6406316/v1/b0cbc8850843b2c4ba1ce814.jpg"},{"id":85636971,"identity":"5ecd6297-91c1-47ab-a45d-81255fd1999f","added_by":"auto","created_at":"2025-06-30 06:10:54","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":113170,"visible":true,"origin":"","legend":"\u003cp\u003eNumber of ADR depending on the combined phenoconversion predicted CYP 2C19/2D6 phenotype (n = 35).\u003cstrong\u003e \u003c/strong\u003eCombined CYP 2C19/2D6 phenotypes predicted following phenoconversion are shown. Compared to combined NM/NM, divergent phenotypes had a significantly higher number of ADR.\u003c/p\u003e\n\u003cp\u003e(A) NM/NM (median: 4, IQR: 2) vs divergent phenotypes (median: 6, IQR: 3.5), p = 0.039*; (B) SM/SM (median: 6, IQR: 7) vs one SM (median: 6, IQR: 2) vs NM/NM (median: 4, IQR: 2) vs one RM (median: 6, IQR: 7)\u003c/p\u003e\n\u003cp\u003eMean (x); median (−); *p \u0026lt; 0.05; SM = Slow Metabolizers (PM, IM); NM = Normal Metabolizers; RM = Rapid Metabolizers (RM, UM).\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-6406316/v1/f473b17f22c5af5aac3bf8d3.png"},{"id":106583859,"identity":"47e2a396-2399-490e-b0b7-385d52b2cc3d","added_by":"auto","created_at":"2026-04-10 07:12:58","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1326743,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6406316/v1/e19b2b77-deb4-4437-8eca-95ee3534107f.pdf"}],"financialInterests":"\u003cb\u003eYes\u003c/b\u003e there is potential conflict of interest.","formattedTitle":"Influence of combined CYP2C19 and CYP2D6 phenotypes on adverse drug reactions in patients with major depressive disorder: a clinical cohort study","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eTreatment with antidepressants (AD) may go along with poor efficacy and tolerability (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). Almost half of adverse drug reactions (ADR) can be attributed to interindividual variations in hepatic drug metabolism (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). At least 20% of these ADR are preventable (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). To enhance safety of drug therapy, the Clinical Pharmacogenomics Implementation Consortium (CPIC) and the Dutch Pharmacogenetics Working Group (DPWG) have published pharmacogenetic-guided decision support tools. These guidelines provide dosage and action recommendations for prescribing certain AD based on CYP genotypes (\u003cspan additionalcitationids=\"CR5 CR6\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). The two highly polymorphic cytochrome P450 isoenzymes CYP2C19 and CYP2D6 are particularly important in the metabolism of AD (\u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). Divergent (=\u0026thinsp;non-normal-metabolizer (nNM)) genotypes are common in patients suffering from severe mental disorders (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIsolated studies indicate that poor metabolizers of CYP2C19 or CYP2D6 experience more ADR on AD therapy than normal metabolizers (\u003cspan additionalcitationids=\"CR14 CR15 CR16 CR17\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). This is attributed to increased serum concentrations of the active drug moieties (\u003cspan additionalcitationids=\"CR20\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). Rapid CYP2C19 or CYP2D6 metabolizers have been associated with insufficient clinical response and drug discontinuation due to sub-therapeutic serum concentrations (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e). An increased risk of ADR has not been demonstrated for UM (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAlthough phenoconversion (PC) occurs in up to 44.9% of patients undergoing psychopharmacotherapy, studies have often utilized CYP genotype instead of phenotype (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e). Inhibitors decrease the CYP activity, leading to higher drug concentrations of the substrate (\u003cspan additionalcitationids=\"CR28 CR29\" citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e). In addition to these drug-gene interactions, drug-gene-gene interactions (DDGI) may also occur because the metabolism of certain AD, such as venlafaxine (VEN), is catalyzed by several CYP isoenzymes (\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e). Impaired CYP enzyme activity can lead to ADR and activation of an alternative pathway, altering serum levels of the parent drug, metabolites, and parent-metabolite ratios (\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e). Studies have investigated serum concentrations in relation to two CYP isoenzyme phenotypes, but the impact on clinical tolerability is limited (\u003cspan additionalcitationids=\"CR34\" citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e). The influence of combined functional CYP 2C19/2D6 enzyme status on VEN tolerability has only been investigated in case studies (\u003cspan additionalcitationids=\"CR37\" citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e). There are also no controlled studies on tolerability based on combined CYP isoenzymes for most other AD, except for amitriptyline, where combined pharmacogenomic (PGx) testing for CYP 2C19/2D6 revealed risk constellations for ADR (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e).\u003c/p\u003e \u003cp\u003ePGx-guided therapies can lead to better response, faster remission rates, lower incidence of ADR, and thus significant long-term cost savings for healthcare system (\u003cspan additionalcitationids=\"CR40 CR41 CR42 CR43\" citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e). A better understanding of gene-gene interaction of functional CYP 2C19/2D6 enzyme status on AD tolerability may contribute to an improved therapy of major depressive disorder (MDD). Cross-tabulations based on combined phenotypes of CYP 2C19/2D6 for amitriptyline and CYP 2B6/2C19 for sertraline have already been published by CPIC (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThis study investigates the frequency and intensity of ADR during AD therapy in a cohort of hospitalized psychiatric patients regarding their CYP2C19 and CYP2D6 functional status. Pharmacodynamic and pharmacokinetic factors were considered. Furthermore, a drug-specific subgroup analysis was performed for VEN.\u003c/p\u003e"},{"header":"METHOD","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design\u003c/h2\u003e \u003cp\u003e104 adult patients voluntarily admitted to the Department of Psychiatry at the University Hospital Frankfurt were recruited for the FACT-PGx clinical cohort study between July 2021 and July 2022. The sample size was chosen because rare genotypes CYP2D6 UM and CYP2C19 PM statistically occur at least once in 100 European Caucasian individuals, allowing all different genotypes to be included in the study.\u003c/p\u003e \u003cp\u003ePatients were treated for MDD according to ICD-10 F32.x and F33.x criteria, regardless of whether AD or other psychotropics had been taken at the time of admission. There were no restrictions on ethnicity and choice, number, or dosage of AD prescribed.\u003c/p\u003e \u003cp\u003ePatients were asked to complete the subjective questionnaire \u0026ldquo;\u003cem\u003eSeIf-Rating Scale for Adverse Drug Effects\u003c/em\u003e\u0026ldquo; developed by Dreher et al. for AD treatment (\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e). It examines 16 defined and up to two individual ADR based on their incidence (yes/no), intensity (not disturbing/unpleasant/very unpleasant/unbearable), and likelihood of a causal drug effect (probable/possible/improbable). ADR reported as unlikely to be medication-related were corrected for further analysis. Patients who did not complete the questionnaire or submitted it incompletely were excluded from the analysis (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;42). Data collection was one-pointed. The clinical response to AD typically occurs within 14 days, and initial ADR usually subside after this period (\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e). Therefore, only patients who had not taken a new AD in the previous 14 days were considered for statistical analysis of stable ADR (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;41).\u003c/p\u003e \u003cp\u003eOn the same day, blood was drawn for genotyping. Genotyping was performed in the laboratory of the Department of Psychiatry at University Hospital W\u0026uuml;rzburg, which was certified by a quality control program (\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e). DNA was isolated from EDTA blood samples, and relevant gene variants (single nucleotide polymorphisms) in CYP2C19 and CYP2D6 were genotyped using a MassArray Analyzer 4 system (Agena Bioscience GmbH, Hamburg, Germany). This process employed a self-designed panel utilizing SpectroCHIP\u0026reg;-96 Arrays and iPLEX\u0026reg; Pro chemistry, following the provided instructions manufacturer. Moreover, copy number variations (CNV) were determined using CYP2D6 RealFast\u0026trade; CNV Assay (\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e). Single nucleotide polymorphisms were translated into star alleles using the Pharmacogene Variation Consortium website (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e\u003ca href=\"http://www.pharmvar.org\" target=\"_blank\"\u003ewww.pharmvar.org\u003c/a\u003e\u003c/span\u003e\u003cspan address=\"http://www.pharmvar.org\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). Haplotype tables were reported elsewhere (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e). Each star allele was assigned an activity value based on CPIC definition table (5), and an activity score was calculated by summing all allelic activity values of the diplotype (\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e, \u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e). Finally, the genetic phenotype was calculated by considering PC. The Flockhart table published by the Food and Drug Administration (FDA) was used to identify CYP enzyme-specific inducers and inhibitors in the current medication, and the genotype-predicted phenotype of CYP2C19 and CYP2D6 was calculated (\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e, \u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e). The inhibitor strength level of promethazine is currently under review. Therefore, it was not considered in PC calculation. All following analyses regarding CYP enzyme status were performed considering PC. Phenotypes were classified as PM (poor metabolizer), IM (intermediate metabolizer), NM (normal metabolizer), UM (ultrarapid metabolizer), and CYP2C19 additionally RM (rapid metabolizer) (\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e). CYP2C19 UM and RM were grouped as rapid metabolizers (RM). Due to the small number of PM, these were grouped with IM as slow metabolizers (SM). The genotyping result was unknown to the participants when they completed the questionnaire. To evaluate ADR depending on functional CYP enzyme status, we considered only those patients whose AD are known to be mainly metabolized by CYP2C19 and/or CYP2D6 (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;35).\u003c/p\u003e \u003cp\u003e All study participants gave informed consent. The study was approved by the Ethics Committee of the Goethe University Frankfurt (2021\u0026thinsp;\u0026minus;\u0026thinsp;138) and was conducted following the Declaration of Helsinki 2013.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eStatistical analyses\u003c/h3\u003e\n\u003cp\u003eData were collected, processed, and analyzed descriptively and statistically using Microsoft Excel version 16.66.1. Independent t-tests were performed to analyze continuous parametric discrete variables, whilst chi-square tests were used to analyze categorical dichotomous variables. A P-value of \u0026lt;\u0026thinsp;0.05 (*) was considered significant for all tests performed. An Odds Ratio (OR [95% confidence interval]) greater than 1 indicated that the ADR was more likely to occur in the exposure group. For this purpose, the Haldane correction was applied if the observed event did not occur once in a group (\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e). Data are presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation unless specified otherwise.\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cp\u003e\u003cstrong\u003ePatient characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e55 of 104 genotyped patients (52.9%) completed the questionnaire. Of these patients, 41 had been taking an AD for at least two weeks. Their mean age was 41.6 years (\u0026plusmn; 14.3, range 19-77), with 58.5% identifying as male and 39.0% as current smokers. In the context of a first depressive episode, 12.2% were first hospitalized and treatment na\u0026iuml;ve. AD were primarily used as monotherapies (82.9%), with VEN (\u003cem\u003en\u003c/em\u003e = 12), sertraline (\u003cem\u003en\u003c/em\u003e = 8), and escitalopram (\u003cem\u003en\u0026nbsp;\u003c/em\u003e= 7) being administered most frequently. Mirtazapine was the most common combination partner (57.4%). Augmentation with second or third-generation antipsychotics (\u003cem\u003en\u003c/em\u003e = 15) and lithium (\u003cem\u003en\u003c/em\u003e = 4) occurred in 46.3%. Demographic and drug use characteristics are shown in \u003cstrong\u003eTable 1\u003c/strong\u003e.\u003c/p\u003e\n\u003cdiv\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"538\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCharacteristics\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 343px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eResponses\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTotal (%) of participants\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 129px;\"\u003e\n \u003cp\u003eAge\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 343px;\"\u003e\n \u003cp\u003e41.6 \u0026plusmn; 14.3 years, range 19-77\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 129px;\"\u003e\n \u003cp\u003eSex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 343px;\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e17 (41.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 343px;\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e24 (58.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 129px;\"\u003e\n \u003cp\u003eSmoking status\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 343px;\"\u003e\n \u003cp\u003eSmoker\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e16 (39.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 343px;\"\u003e\n \u003cp\u003eNon-smoker\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e25 (61.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 129px;\"\u003e\n \u003cp\u003eClinical parameters\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 343px;\"\u003e\n \u003cp\u003eRenal impairment (GFR \u0026lt; 60 ml/min)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 343px;\"\u003e\n \u003cp\u003eHepatic impairment (liver enzymes 3-fold upper normal limits)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 129px;\"\u003e\n \u003cp\u003eDiagnosis according to ICD-10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 343px;\"\u003e\n \u003cp\u003eDepressive episode (ICD-10 F32.x)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e5\u0026nbsp;(12.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 343px;\"\u003e\n \u003cp\u003eRecurrent depressive disorder (ICD-10 F33.x)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e36\u0026nbsp;(87.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"5\" style=\"width: 129px;\"\u003e\n \u003cp\u003eAntidepressant medication\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 343px;\"\u003e\n \u003cp\u003eSelective Serotonin Reuptake Inhibitors (SSRI)\u003c/p\u003e\n \u003cp\u003eSertraline (\u003cem\u003en\u003c/em\u003e = 8)\u003c/p\u003e\n \u003cp\u003eEscitalopram (\u003cem\u003en\u003c/em\u003e =7)\u003c/p\u003e\n \u003cp\u003eFluoxetine (\u003cem\u003en\u003c/em\u003e = 3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e18 (43.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 343px;\"\u003e\n \u003cp\u003eSerotonin Noradrenalin Reuptake Inhibitors (SNRI)\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eVenlafaxine (\u003cem\u003en\u003c/em\u003e = 12)\u003c/p\u003e\n \u003cp\u003eDuloxetine (\u003cem\u003en\u003c/em\u003e = 2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e14 (34.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 343px;\"\u003e\n \u003cp\u003eAlpha-2-Antagonist (A2A)\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eMirtazapine (\u003cem\u003en\u003c/em\u003e = 7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e7 (17.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 343px;\"\u003e\n \u003cp\u003eTricyclic Antidepressants (TCA)\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eAmitriptyline (\u003cem\u003en\u003c/em\u003e = 1)\u003c/p\u003e\n \u003cp\u003eClomipramine (\u003cem\u003en\u003c/em\u003e = 1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e2 (4.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 343px;\"\u003e\n \u003cp\u003eNot mainly metabolized by CYP2C19/CYP2D6\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eAgomelatine (\u003cem\u003en\u003c/em\u003e = 2)\u003c/p\u003e\n \u003cp\u003eBupropion (\u003cem\u003en\u003c/em\u003e = 1)\u003c/p\u003e\n \u003cp\u003eTianeptine (\u003cem\u003en\u003c/em\u003e = 1)\u003c/p\u003e\n \u003cp\u003eTrazodone (\u003cem\u003en\u003c/em\u003e = 1)\u003c/p\u003e\n \u003cp\u003eTranylcypromine (\u003cem\u003en\u003c/em\u003e = 1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e6 (14.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 129px;\"\u003e\n \u003cp\u003eForm of antidepressant treatment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 343px;\"\u003e\n \u003cp\u003eMonotherapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e34 (82.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 343px;\"\u003e\n \u003cp\u003eCombination with other antidepressants\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e7 (17.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"6\" style=\"width: 129px;\"\u003e\n \u003cp\u003ePsychotropic comedication\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eAntipsychotics\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 258px;\"\u003e\n \u003cp\u003eFirst-generation\u0026nbsp;\u003c/p\u003e\n \u003cp\u003ePromethazine (\u003cem\u003en\u003c/em\u003e = 9)\u003c/p\u003e\n \u003cp\u003eProthipendyl (\u003cem\u003en\u003c/em\u003e = 7)\u003c/p\u003e\n \u003cp\u003ePipamperone (\u003cem\u003en\u003c/em\u003e = 3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e19 (46.3)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 258px;\"\u003e\n \u003cp\u003eSecond-generation\u003c/p\u003e\n \u003cp\u003eQuetiapine immediate release (\u003cem\u003en\u003c/em\u003e = 12)\u003c/p\u003e\n \u003cp\u003eQuetiapine extended release (\u003cem\u003en\u003c/em\u003e = 1)\u003c/p\u003e\n \u003cp\u003eRisperidone (\u003cem\u003en\u003c/em\u003e = 1)\u003c/p\u003e\n \u003cp\u003eOlanzapine (\u003cem\u003en\u003c/em\u003e = 1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e15 (34.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 258px;\"\u003e\n \u003cp\u003eThird-generation\u003c/p\u003e\n \u003cp\u003eAripiprazole (\u003cem\u003en\u003c/em\u003e = 1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e1 (2.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 343px;\"\u003e\n \u003cp\u003eAnxiolytics\u003c/p\u003e\n \u003cp\u003eLorazepam (\u003cem\u003en\u003c/em\u003e = 6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e6 (14.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 343px;\"\u003e\n \u003cp\u003eLithium\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e4 (9.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 343px;\"\u003e\n \u003cp\u003eAnticonvulsants\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eValproic acid (\u003cem\u003en\u003c/em\u003e = 1)\u003c/p\u003e\n \u003cp\u003eLamotrigin (\u003cem\u003en\u003c/em\u003e = 1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e2 (4.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" style=\"width: 538px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCYP enzyme status in patients whose antidepressants are mainly metabolized by CYP2C19 and/or CYP2D6\u003c/strong\u003e (\u003cem\u003en\u003c/em\u003e = 35)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"5\" style=\"width: 129px;\"\u003e\n \u003cp\u003eGenotype-predicted CYP2C19 phenotype\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 343px;\"\u003e\n \u003cp\u003eNM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e13 (37.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 343px;\"\u003e\n \u003cp\u003eIM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e12 (34.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 343px;\"\u003e\n \u003cp\u003ePM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 343px;\"\u003e\n \u003cp\u003eRM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e7 (20.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 343px;\"\u003e\n \u003cp\u003eUM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e3 (8.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"4\" style=\"width: 129px;\"\u003e\n \u003cp\u003eGenotype-predicted CYP2D6 phenotype\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 343px;\"\u003e\n \u003cp\u003eNM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e23 (65.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 343px;\"\u003e\n \u003cp\u003eIM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e10 (28.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 343px;\"\u003e\n \u003cp\u003ePM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e1 (2.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 343px;\"\u003e\n \u003cp\u003eUM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e1 (2.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"5\" style=\"width: 129px;\"\u003e\n \u003cp\u003ePhenoconversion-predicted CYP2C19 phenotype\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 343px;\"\u003e\n \u003cp\u003eNM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e12 (34.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 343px;\"\u003e\n \u003cp\u003eIM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e11 (31.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 343px;\"\u003e\n \u003cp\u003ePM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e2 (5.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 343px;\"\u003e\n \u003cp\u003eRM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e7 (20.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 343px;\"\u003e\n \u003cp\u003eUM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e3 (8.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"4\" style=\"width: 129px;\"\u003e\n \u003cp\u003ePhenoconversion-predicted CYP2D6 phenotype\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 343px;\"\u003e\n \u003cp\u003eNM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e11 (31.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 343px;\"\u003e\n \u003cp\u003eIM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e19 (54.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 343px;\"\u003e\n \u003cp\u003ePM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e5 (14.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 343px;\"\u003e\n \u003cp\u003eUM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1\u0026nbsp;\u003c/strong\u003eCharacteristics of patients (\u003cem\u003en\u003c/em\u003e = 41)\u003c/p\u003e\n\u003cp\u003eAs illustrated in \u003cstrong\u003eFigure 1\u003c/strong\u003e, patients were asked to rate the causality of AD for each symptom. The three most prevalent ADR were inner unrest (\u003cem\u003en\u003c/em\u003e = 48, 87.3%), sleepiness (\u003cem\u003en\u003c/em\u003e = 42, 76.4%), and sleep disturbances (\u003cem\u003en\u003c/em\u003e = 41, 74.5%), which, according to DSM-5, are similar to characteristic symptoms of depression (55). Following the exclusion of ADR that were considered unlikely to be medication-related by the patients, most frequently reported symptoms were still sleepiness (\u003cem\u003en\u003c/em\u003e = 26, 63.4%), inner unrest (\u003cem\u003en\u003c/em\u003e = 23, 56.1%), and reduced salivation (\u003cem\u003en\u003c/em\u003e = 23, 56.1%). The group reported suffering from an average of 5.7 (\u0026plusmn; 3.1) ADR. Of these, 10.3% were classified as not disturbing, 44.0% as unpleasant, 36.8% as very unpleasant, and 6.8% as unbearable. No statistically significant difference was observed between genders. However, the analysis showed that females were more likely to experience libido loss (OR = 2.84, CI 0.76-10.58, \u003cem\u003ep\u003c/em\u003e = 0.063) and headache (OR = 1.95, CI 0.48-7.85, \u003cem\u003ep\u003c/em\u003e = 0.178), while males had a higher incidence of nausea (OR = 2.15, CI 0.41-11.2, \u003cem\u003ep\u003c/em\u003e = 0.184). The only significant difference related to smoking status was nausea, which was more common among non-smokers (OR = 13.38, CI 0.71-252.72, \u003cem\u003ep\u003c/em\u003e = 0.010*).\u003c/p\u003e\n\u003cp\u003ePharmacodynamic factors influencing the occurrence and intensity of ADR included combinations with a second AD (8.1 \u0026plusmn; 2.5 ADR, OR = 2.04, CI 1.34-3.11, \u003cem\u003ep\u003c/em\u003e = 0.012* and \u003cem\u003ep\u003c/em\u003e = 0.001*) or with at least one psychotropic drug from another substance class (6.6 \u0026plusmn; 2.8 ADR, OR = 2.32, CI 1.59-3.39, \u003cem\u003ep\u003c/em\u003e = 0.002*).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCYP2C19 and CYP2D6 phenotypes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFor CYP2D6 and CYP2C19, we observed a high PC rate (\u003cem\u003en\u003c/em\u003e = 17, 48.57%) in the context of concomitant use of perpetrator drugs (\u003cstrong\u003eTable 2\u003c/strong\u003e).\u0026nbsp;\u003c/p\u003e\n\u003cdiv\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 245px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePerpetrator drugs on the CYP2D6 genotype\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTotal (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 245px;\"\u003e\n \u003cp\u003eInhibitors\u003c/p\u003e\n \u003cp\u003eSertraline\u003csup\u003e3\u003c/sup\u003e\u003c/p\u003e\n \u003cp\u003eEscitalopram\u003csup\u003e3\u003c/sup\u003e\u003c/p\u003e\n \u003cp\u003eBupropion\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e\n \u003cp\u003eFluoxetine\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e\n \u003cp\u003eDuloxetine\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e\n \u003cp\u003ePromethazine\u003csup\u003e4\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e33 (73.3)\u003c/p\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 245px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePerpetrator drugs on the CYP2C19 genotype\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 245px;\"\u003e\n \u003cp\u003eInhibitors\u003c/p\u003e\n \u003cp\u003ePantoprazole\u003csup\u003e3\u003c/sup\u003e\u003c/p\u003e\n \u003cp\u003eFluoxetine\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e\n \u003cp\u003eOral contraceptive\u003csup\u003e3\u003c/sup\u003e\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eInducer\u003c/p\u003e\n \u003cp\u003ePrednisolone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e11 (24.4)\u003c/p\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1 (2.2)\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003csup\u003e1\u003c/sup\u003eStrong inhibitor: causes a \u0026gt; 5-fold increase in the plasma area under the curve (AUC) values or more than 80% decrease in clearance;\u003csup\u003e\u0026nbsp;2\u003c/sup\u003eModerate inhibitor: causes a \u0026gt; 2-fold increase in the plasma AUC values or 50-80% decrease in clearance;\u003csup\u003e\u0026nbsp;3\u003c/sup\u003eWeak inhibitor: causes a \u0026gt; 1.25-fold but \u0026lt; 2-fold increase in the plasma AUC values or 20-50% decrease in clearance;\u003csup\u003e\u0026nbsp;4\u003c/sup\u003eInhibitor strength level is under review.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSource: The Flockhart Cytochrome P450 Drug-Drug Interaction Table\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2\u0026nbsp;\u003c/strong\u003ePerpetrator drugs on the CYP2D6 and CYP2C19 genotype-predicted phenotype (\u003cem\u003en\u003c/em\u003e = 35)\u003c/p\u003e\n\u003cp\u003eCYP2D6 was most frequently affected (\u003cem\u003en\u003c/em\u003e = 14). Inhibition led to a twofold rise in the proportion of CYP2D6 SM, from 31.9% to 68.57%. CYP2D6 UM could no longer be observed after PC. CYP2C19 genotype exhibited minimal susceptibility to DDGI, resulting in no alteration in the number of SM and RM. Phenotype combinations occurring in the study population and their respective OR for ADR were cross-tabulated (\u003cstrong\u003eTables 3 and 4\u003c/strong\u003e). The control combination CYP 2C19/2D6 NM/NM occurred three times. All following analyses regarding CYP enzyme status were performed considering PC.\u003c/p\u003e\n\u003cdiv\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"571\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" rowspan=\"2\" valign=\"top\" style=\"width: 149px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePhenotype\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 422px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCYP2D6\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 105px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePM\u003c/strong\u003e \u003cem\u003en\u003c/em\u003e (%)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eOR (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 105px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eIM\u003c/strong\u003e \u003cem\u003en\u003c/em\u003e (%)\u003c/p\u003e\n \u003cp\u003eOR (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 105px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNM\u003c/strong\u003e \u003cem\u003en\u003c/em\u003e (%)\u003c/p\u003e\n \u003cp\u003eOR (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 105px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eUM\u0026nbsp;\u003c/strong\u003e\u003cem\u003en\u003c/em\u003e (%)\u003c/p\u003e\n \u003cp\u003eOR (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"5\" valign=\"top\" style=\"width: 59px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCYP2C19\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePM\u003c/strong\u003e \u003cem\u003en\u003c/em\u003e (%)\u003c/p\u003e\n \u003cp\u003eOR (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 105px;\"\u003e\n \u003cp\u003e2 (5.7)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.52 (0.13-2.12)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 105px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 105px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 105px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eIM\u003c/strong\u003e \u003cem\u003en\u003c/em\u003e (%)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eOR (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 105px;\"\u003e\n \u003cp\u003e1 (2.9)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e9.04 (2.7-30.27)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 105px;\"\u003e\n \u003cp\u003e6 (17.1)\u003c/p\u003e\n \u003cp\u003e3.38* (1.45-7.88)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 105px;\"\u003e\n \u003cp\u003e4 (11.4)\u003c/p\u003e\n \u003cp\u003e2.53 (1.03-6.24)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 105px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNM\u003c/strong\u003e \u003cem\u003en\u003c/em\u003e (%)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eOR (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 105px;\"\u003e\n \u003cp\u003e2 (5.7)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e3.66* (1.34-10.01)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 105px;\"\u003e\n \u003cp\u003e7 (20.0)\u003c/p\u003e\n \u003cp\u003e3.19* (1.39-7.36)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 105px;\"\u003e\n \u003cp\u003e3 (8.6)\u003c/p\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 105px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRM\u003c/strong\u003e \u003cem\u003en\u003c/em\u003e (%)\u003c/p\u003e\n \u003cp\u003eOR (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 105px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 105px;\"\u003e\n \u003cp\u003e4 (11.4)\u003c/p\u003e\n \u003cp\u003e2.06 (0.83-5.15)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 105px;\"\u003e\n \u003cp\u003e3 (8.6)\u003c/p\u003e\n \u003cp\u003e4.6 (1.83-11.58)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 105px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eUM\u003c/strong\u003e \u003cem\u003en\u003c/em\u003e (%)\u003c/p\u003e\n \u003cp\u003eOR (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 105px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 105px;\"\u003e\n \u003cp\u003e2 (5.7)\u003c/p\u003e\n \u003cp\u003e1.64 (0.55-4.87)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 105px;\"\u003e\n \u003cp\u003e1 (2.9)\u003c/p\u003e\n \u003cp\u003e9.04 (2.7-30.27)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 105px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3\u003c/strong\u003e Observed CYP 2C19/2D6 phenotypes predicted following phenoconversion and Odds Ratio (OR) of adverse drug reactions (\u003cem\u003en\u003c/em\u003e = 35)\u003c/p\u003e\n\u003cdiv\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eAdverse side effect\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 408px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePhenotype\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCYP2C19/CYP2D6\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCYP2C19\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCYP2D6\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003eHeadache\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003e0.91 (0.07-11.23)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e0.88 (0.20-3,89)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.33\u0026nbsp;\u003c/strong\u003e(0.28-6.44)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003eReduced Salivation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e2.92\u0026nbsp;\u003c/strong\u003e(0.24-35.68)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e0.93 (0.23-3,82)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e0.68 (0.16-2.93)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003eSleepiness/Sedation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e4.40\u0026nbsp;\u003c/strong\u003e(0.36-54.37)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e0.94 (0.21-4.10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.14\u0026nbsp;\u003c/strong\u003e(0.26-5.09)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003eDizziness\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e7.00\u0026nbsp;\u003c/strong\u003e(0.33-146.45)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e0.46 (0.11-1.90)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.75\u0026nbsp;\u003c/strong\u003e(0.40-7.58)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003eConstipation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003e0.46 (0.04-5.97)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e3.88\u0026nbsp;\u003c/strong\u003e(0.41-36.79)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e0.25 (0.04-1.40)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003eVisual Disorders\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e2.83\u0026nbsp;\u003c/strong\u003e(0.13-60.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e5.87*\u0026nbsp;\u003c/strong\u003e(0.64-54.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e0.46 (0.10-2.22)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003eTremor\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e2.57\u0026nbsp;\u003c/strong\u003e(0.21-31.33)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e2.18\u0026nbsp;\u003c/strong\u003e(0.53-9.02)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e0.57 (0.13-2.48)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003eNausea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.72\u0026nbsp;\u003c/strong\u003e(0.08-37.54)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.05\u0026nbsp;\u003c/strong\u003e(0.16-6.78)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e0.90 (0.14-5.84)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003eLoss of Appetite\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.40\u0026nbsp;\u003c/strong\u003e(0.06-31.12)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e0.75 (0.11-5.24)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e0.64 (0.09-4.53)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003eHeart Troubles\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e2.43\u0026nbsp;\u003c/strong\u003e(0.11-52.01)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e0.83 (0.16-4.30)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.50\u0026nbsp;\u003c/strong\u003e(0.25-8.98)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003eInner Unrest\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e10.11*\u0026nbsp;\u003c/strong\u003e(0.48-212.09)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e0.78 (0.19-3.19)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.68\u0026nbsp;\u003c/strong\u003e(0.40-7.07)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003eSleep Disturbances\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e3.74\u0026nbsp;\u003c/strong\u003e(0.18-78.94)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.60\u0026nbsp;\u003c/strong\u003e(0.34-7.64)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e2.70\u0026nbsp;\u003c/strong\u003e(0.47-15.40)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003eIncreased Sweating\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e7.00\u0026nbsp;\u003c/strong\u003e(0.33-146.45)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e2.18\u0026nbsp;\u003c/strong\u003e0.51-9.33)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.02\u003c/strong\u003e (0.24-4.26)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003eDisturbance of Micturition\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003e0.57 (0.02-14.53)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e2.91\u0026nbsp;\u003c/strong\u003e(0.13-65.53)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e0.43 (0.02-7.66)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003eReduced Sexual Desire\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003e0.50 (0.04-6.08)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e0.21 (0.05-1.01)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e2.45\u0026nbsp;\u003c/strong\u003e(0.56-10.68)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003eErection Problems\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003e0.57 (0.02-14.53)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e2.91\u0026nbsp;\u003c/strong\u003e(0.13-65.53)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e2.56\u0026nbsp;\u003c/strong\u003e(0.11-57.78)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003eOther\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.15\u0026nbsp;\u003c/strong\u003e(0.12-10.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.22\u0026nbsp;\u003c/strong\u003e(0.33-4.45)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e0.46 (0.13-1.56)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eTotal\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e2.99* (1.38-6.46)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e1.11 (0.78-1.58)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e0.98 (0.69-1.40)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cstrong\u003eTable 4\u003c/strong\u003e Odds Ratio (95% CI) of phenoconversion predicted NM/NM phenotype compared to non-Normal Metabolizers (\u003cem\u003en\u003c/em\u003e = 35)\u003c/p\u003e\n\u003cp\u003eFunctional nNM for CYP2C19 and CYP2D6 had an average of 6.2 (\u0026plusmn; 3.2) ADR. This was 2.3 times more common than in NM/NM (2.7 \u0026plusmn; 1.9) with an OR of 2.99 (CI 1.38-6.46, \u003cem\u003ep\u003c/em\u003e = 0.039*) (\u003cstrong\u003eFigure 2)\u003c/strong\u003e. ADR were observed more frequently with both slow (6.1 \u0026plusmn; 2.8) and fast (6.2 \u0026plusmn; 3.8) combined partners. The combination CYP 2C19/2D6 NM/IM or IM/NM already increased the OR for ADR (OR = 3.19, CI 1.39-7.36, \u003cem\u003ep\u003c/em\u003e = 0.006*; OR = 2.53, CI 1.03-6.24, \u003cem\u003ep\u003c/em\u003e = 0.166). ADR risk was highest for CYP 2C19/2D6 IM/PM and UM/NM (OR = 9.04, CI 2.7-30.27, \u003cem\u003ep\u003c/em\u003e = 0.044*). Due to autoinhibition, PM/PM was observed twice when fluoxetine was taken, but it was not associated with a higher number of ADR (OR = 0.52, CI 0.13-2.12, \u003cem\u003ep\u003c/em\u003e = 0.278).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFor individual ADR such as inner unrest (OR = 10.11, CI 0.48-212.09, \u003cem\u003ep\u003c/em\u003e = 0.025*), increased sweating (OR = 7.00, CI 0.33-146.45, \u003cem\u003ep\u003c/em\u003e = 0.051), and sleepiness (OR = 4.40, CI 0.36-54.37, \u003cem\u003ep\u003c/em\u003e = 0.114), OR was notably increased in combination with a nNM for CYP2C19 or CYP2D6. CYP2C19 SM were significantly associated with visual disturbances (OR = 5.87, CI 0.64-54.00, \u003cem\u003ep\u003c/em\u003e = 0.018*).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eVenlafaxine subgroup\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eVEN was the most prescribed AD in the cohort. In the drug-specific analysis for VEN (\u003cem\u003en\u003c/em\u003e = 12), the appearance of a nNM, whether for CYP2C19 or CYP2D6, reported on average 4.4 more ADR (OR = 4.41, CI 1.49-13.04, \u003cem\u003ep\u003c/em\u003e = 0.108) (\u003cstrong\u003eTable 5\u003c/strong\u003e). In particular, reduced salivation (OR = 10.71, CI 0.4-287.83, \u003cem\u003ep\u003c/em\u003e = 0.038*), increased sweating, and inner unrest (both OR = 7.22, CI 0.28-189.19, \u003cem\u003ep\u003c/em\u003e = 0.072) occurred more frequently in this constellation. Descriptively, only CYP2C19 nNM status had influence on increased ADR with VEN, especially RM (OR = 1.30, CI 0.70-2.42, \u003cem\u003ep\u003c/em\u003e = 0.356). CYP2D6 nNM occurred only as IM, an actionable genotype (AG) according to DPWG (\u003cstrong\u003eTable 6\u003c/strong\u003e), which had no effect on ADR (OR = 0.87, CI 0.44-1.69, \u003cem\u003ep\u003c/em\u003e = 0.448).\u0026nbsp;\u003c/p\u003e\n\u003cdiv\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"516\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eAdverse side effect\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 393px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePhenotype\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 125px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCYP2C19/CYP2D6\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 134px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCYP2C19\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 134px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCYP2D6\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eHeadache\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 125px;\"\u003e\n \u003cp\u003e0.25 (0.01-5.98)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 134px;\"\u003e\n \u003cp\u003e1.00 (0.06-15.99)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 134px;\"\u003e\n \u003cp\u003e0.27 (0.01-6.74)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eReduced Salivation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 125px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e10.71*\u0026nbsp;\u003c/strong\u003e(0.4-287.83)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 134px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.67\u0026nbsp;\u003c/strong\u003e(0.15-18.87)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 134px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.60\u0026nbsp;\u003c/strong\u003e(0.10-24.70)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eSleepiness/Sedation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 125px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.50\u0026nbsp;\u003c/strong\u003e(0.07-31.57)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 134px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.67\u0026nbsp;\u003c/strong\u003e(0.15-18.87)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 134px;\"\u003e\n \u003cp\u003e0.25 (0.02-4.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eDizziness\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 125px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e3.46*\u0026nbsp;\u003c/strong\u003e(0.13-90.68)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 134px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.80\u0026nbsp;\u003c/strong\u003e(0.12-26.20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 134px;\"\u003e\n \u003cp\u003e1.00 (0.06-15.99)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eConstipation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 125px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.47\u003c/strong\u003e (0.05-41.83)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 134px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e3.46\u003c/strong\u003e (0.13-90.68)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 134px;\"\u003e\n \u003cp\u003e0.40 (0.01-10.81)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eVisual Disorders\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 125px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e3.46\u0026nbsp;\u003c/strong\u003e(0.13-90.68)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 134px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.80\u0026nbsp;\u003c/strong\u003e(0.12-26.20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 134px;\"\u003e\n \u003cp\u003e1.00 (0.06-15.99)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eTremor\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 125px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.50\u0026nbsp;\u003c/strong\u003e(0.07-31.57)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 134px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.67\u0026nbsp;\u003c/strong\u003e(0.15-18.87)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 134px;\"\u003e\n \u003cp\u003e0.25 (0.02-4.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eNausea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 125px;\"\u003e\n \u003cp\u003e0.79 (0.02-25.90)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 134px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.80\u0026nbsp;\u003c/strong\u003e(0.06-54,33)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 134px;\"\u003e\n \u003cp\u003e0.81 (0.03-25.10)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eLoss of Appetite\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 125px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e2.33\u003c/strong\u003e (0.09-62.68)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 134px;\"\u003e\n \u003cp\u003e1.00 (0.06-15.99)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 134px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.75\u0026nbsp;\u003c/strong\u003e(0.10-30.84)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eHeart Troubles\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 125px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e2.33\u003c/strong\u003e (0.09-62.68)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 134px;\"\u003e\n \u003cp\u003e1.00 (0.06-15.99)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 134px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.75\u0026nbsp;\u003c/strong\u003e(0.10-30.84)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eInner Unrest\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 125px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e7.22\u003c/strong\u003e (0.28-189.19)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 134px;\"\u003e\n \u003cp\u003e1.00 (0.09-11.03)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 134px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e2.50\u0026nbsp;\u003c/strong\u003e(0.16-38.60)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eSleep Disturbances\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 125px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e2.33\u0026nbsp;\u003c/strong\u003e(0.09-62.68)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 134px;\"\u003e\n \u003cp\u003e1.00 (0.06-15.99)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 134px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.75\u0026nbsp;\u003c/strong\u003e(0.10-30.84)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eIncreased Sweating\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 125px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e7.22\u0026nbsp;\u003c/strong\u003e(0.28-189.19)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 134px;\"\u003e\n \u003cp\u003e1.00 (0.09-11.03)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 134px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e2.50\u0026nbsp;\u003c/strong\u003e(0.16-38.60)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eDisturbance of Micturition\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 125px;\"\u003e\n \u003cp\u003e0.79 (0.02-25.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 134px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.80\u0026nbsp;\u003c/strong\u003e(0.06-54.33)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 134px;\"\u003e\n \u003cp\u003e0.81 (0.03-25.10)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eReduced Sexual Desire\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 125px;\"\u003e\n \u003cp\u003e0.43 (0.02-9.36)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 134px;\"\u003e\n \u003cp\u003e0.33 (0.03-4.19)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 134px;\"\u003e\n \u003cp\u003e1.00 (0.06-15.99)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eErection Problems\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 125px;\"\u003e\n \u003cp\u003e0.24 (0-15.19)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 134px;\"\u003e\n \u003cp\u003e0.53 (0.01-31.41)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 134px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e2.71\u003c/strong\u003e (0.04-164.94)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eOther\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 125px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e5.00\u0026nbsp;\u003c/strong\u003e(0.24-106.11)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 134px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.36\u0026nbsp;\u003c/strong\u003e(0.20-9.28)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 134px;\"\u003e\n \u003cp\u003e1.00 (0.14-7.10)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eTotal\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 125px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e4.41 (1.49-13.04)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 134px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e1.30 (0.70-2.42)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 134px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e0.87 (0.44-1.69)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cstrong\u003eTable 5\u003c/strong\u003e Odds Ratio (95% CI) of phenoconversion predicted NM/NM phenotype compared to non-Normal Metabolizers for the venlafaxine subgroup (\u003cem\u003en\u003c/em\u003e = 12)\u003c/p\u003e\n\u003cp\u003eBesides CYP2D6 IM in VEN, our cohort included with CYP2D6 IM one AG for clomipramine, showing more ADR (OR = 1.3, CI 0.31-5.39). There were no AG for selective serotonin reuptake inhibitors (SSRI).\u003c/p\u003e\n\u003cdiv\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"627\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAntidepressant\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePhenotype\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTotal of participants\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(OR, 95% CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 235px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGuideline recommendation\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eReferences\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003eVenlafaxine\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003eCYP2D6 PM\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 235px;\"\u003e\n \u003cp\u003eAvoid or reduce dose\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003eBousman et al. 2023\u003c/p\u003e\n \u003cp\u003eBeunk et al. 2024\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003eCYP2D6 IM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e3\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(0.87, CI 0.44-1.69)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 235px;\"\u003e\n \u003cp\u003eAvoid or reduce dose\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003eBeunk et al. 2024\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"5\" valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003eTricyclic antidepressants\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003eCYP2D6 PM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 235px;\"\u003e\n \u003cp\u003eAvoid or reduce dose by 50% and use therapeutic drug monitoring (TDM) to adjust dosing\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"5\" valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003eHicks et al. 2018\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003eCYP2D6 IM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e1\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(1.3, CI 0.31-5.39)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 235px;\"\u003e\n \u003cp\u003eReduce dose by 25% and use TDM to adjust dosing\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003eCYP2D6 UM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 235px;\"\u003e\n \u003cp\u003eAvoid or use TDM to adjust dosing\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003eCYP2C19 PM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 235px;\"\u003e\n \u003cp\u003eAvoid or reduce dose by 50% and use TDM to adjust dosing\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003eCYP2C19 RM and UM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 235px;\"\u003e\n \u003cp\u003eAvoid or use TDM to adjust dosing\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003eCitalopram\u003c/p\u003e\n \u003cp\u003eEscitalopram\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003eCYP2C19 PM\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 235px;\"\u003e\n \u003cp\u003eSelect another antidepressant not predominantly metabolized by CYP2C19 or reduce dose by 50%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003eBousman et al. 2023\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003eCYP2C19 UM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 235px;\"\u003e\n \u003cp\u003eSelect another antidepressant not predominantly metabolized by CYP2C19\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003eSertraline\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003eCYP2C19 PM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 235px;\"\u003e\n \u003cp\u003eReduce dose by 50%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003eBousman et al. 2023\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003eCYP2B6 PM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 235px;\"\u003e\n \u003cp\u003eSelect another antidepressant not predominantly metabolized by CYP2B6 or reduce dose by 25%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cstrong\u003eTable 6\u0026nbsp;\u003c/strong\u003eActionable CYP-enzyme phenotypes and dose recommendations based on CPIC and DPWG guidelines\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThis study shows that AD treatment is highly associated with ADR, which are perceived as severe in over 40% of cases. Identifying individual risk factors is essential for preventing ADR and enhancing depression treatment adherence.\u003c/p\u003e \u003cp\u003eThe study shows that variants of CYP2C19 and CYP2D6 phenotypes increase ADR risk for psychotropic drugs. Our findings demonstrate that nNM metabolic phenotypes are associated with a significantly increased risk of ADR. Particularly for CYP2C19, an elevated ADR risk was observed for both SM and RM. Consistent with previous studies, CYP2C19 SM are associated with intolerances due to increased serum concentrations (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eTo our knowledge, this study is the first to demonstrate clearly that individuals who are RM may also exhibit an elevated number of ADR. This divergent observation may be attributable to DDGI and PC, which have not been adequately considered in numerous studies, including that of Joković et al. (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). Given the accelerated degradation of AD and the resulting lower serum concentration, it appears counterintuitive that RM are more susceptible to ADR. However, the CYP system is complex, with many CYP isoenzymes involved in the degradation of an active substance. For instance, VEN is degraded to 90% via CYP2D6 and 10% via CYP2C19 in O-desmethyl-venlafaxine (ODV). Surprisingly, CYP2C19 RM had a greater effect on ADR incidence than CYP2D6. An alternative metabolic pathway for VEN involves N-demethylation by CYP2C19 and CYP3A4, resulting in N-desmethyl-venlafaxine (NDV), which has no antidepressant effect (\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e). Accordingly, a rapid CYP2C19 phenotype could lead to a relative increase in NDV concentration. It is not sufficiently clear how the ratio of VEN to its metabolites and the stereoselectivity of the enantiomers contribute to ADR. Studies suggest that exposure to VEN, and possibly NDV, is more important for treatment tolerability than exposure to ODV (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e). This may provide a rationale for increased ADR in CYP2C19 RM. Compared with ODV, VEN has a higher affinity for the noradrenergic system, which has been implicated in symptoms such as reduced salivation and increased sweating in CYP2D6 SM (\u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e). It is important to recognize that VEN serum concentration and effect cannot be explained by isolated CYP2C19 or CYP2D6 phenotype. A comprehensive consideration of both enzymes is essential (\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e). Current guidelines for VEN dosing are limited to recommendations for CYP2D6 (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). CPIC and DPWG both advise against using VEN in PM, while DPWG also advises against its use in IM (Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e6\u003c/span\u003e). Both define IM as having a gene activity score of 0.25 through 1. The VEN subgroup contained no CYP2D6 PM, but IM. Our results did not show an increased ADR risk with IM compared to NM, which supports CPIC position using the standard dose. However, current guidelines do not provide any recommendations for VEN use in CYP2C19 nNM, which was identified as the primary cause of ADR in this study.\u003c/p\u003e \u003cp\u003eFurthermore, most AD lack therapy adjustment recommendations in RM or UM due to insufficient data evidence. An exception are tricyclic antidepressants (TCA), which should be avoided in UM for CYP2C19 or CYP2D6. In our findings, established AG alone do not fully explain ADR risk in AD treatment, underscoring the need for guidelines considering broader factors. Divergent combinations of CYP2C19 and CYP2D6 phenotypes appear to have additive adverse effects on AD pharmacokinetics, as shown in Tables\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e and 4 or in the previous example of VEN. This finding may also apply to other substance classes of AD.\u003c/p\u003e \u003cp\u003ePGx-guided dose recommendations are currently available from CPIC for most SSRI and TCA based on CYP2C19, CYP2D6, or CYP2B6 (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). While an isolated phenotype is usually considered, cross-tabulations already exist for amitriptyline (CYP 2C19/2D6) and sertraline (CYP 2B6/2C19) (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). Hicks et al. described CYP2C19, and CYP2D6 combined gene-based recommendations for amitriptyline with levels of recommendation of optional, moderate, and strong. TCA should be avoided in patients with CYP2D6 PM or UM and CYP2C19 PM. While amitriptyline therapy can be initiated without restriction when CYP2D6 in NM is considered alone (strong), it should be avoided in combination with CYP2C19 PM (moderate). Amitriptyline should also be avoided in CYP 2C19/2D6 NM/PM (severe) and NM/UM (severe). The authors note that clinical and pharmacokinetic data are currently lacking for stronger recommendations, mainly due to the rare occurrence of UM in previous studies. However, it can be deduced that extreme metabolizers such as PM and UM pose a risk for both CYP enzymes, as evidenced by pharmacokinetic observations of their metabolites. CYP2C19 metabolizes amitriptyline into active nortriptyline (NT), which is associated with a higher ADR prevalence than amitriptyline; the hydroxylated metabolites produced by CYP2D6 have a strong affinity for muscarinic receptors and have been associated with cardiotoxicity (\u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e). Steimer et al. hypothesized that CYP2C19 RM are linked with more ADR than CYP2C19 SM (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e). Their study cohort had an absence of UM and a paucity of PM. They showed that CYP 2C19/2D6 IM/NM was the most beneficial combination for the tolerability of TCA.\u003c/p\u003e \u003cp\u003eDosage recommendations are not available for all SSRI. There is no guideline for fluoxetine, as there is no evidence that CYP2C19 or CYP2D6 significantly impact clinical outcome (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). The sum of active fluoxetine metabolites appears mainly independent of CYP2D6 metabolism status (\u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e60\u003c/span\u003e). According to this, this study found no positive correlation with ADR in PM/PM. However, this group included only two patients genotyped for both enzymes as NM and only became PM/PM due to fluoxetine autoinhibition. Besides CYP2D6, CYP2C9 is significantly involved in fluoxetine metabolism without being autoinhibited by its substrate (\u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e61\u003c/span\u003e, \u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e62\u003c/span\u003e). CYP2C9 converts fluoxetine to R-norfluoxetine, which is less pharmacologically active than S-norfluoxetine produced by CYP2D6 (\u003cspan citationid=\"CR63\" class=\"CitationRef\"\u003e63\u003c/span\u003e). Therefore, the CYP2C9 pathway could lead to a regular degradation of fluoxetine without an increased risk of ADR. This consideration is speculative, as our study did not include genotyping for CYP2C9. However, it highlights again that metabolism cannot be considered linear and that a gene panel is required to account for DGGI.\u003c/p\u003e \u003cp\u003eBesides amitriptyline and sertraline, combined gene-based recommendations have also been published by CPIC for other common drugs such as rosuvastatin (SLCO1B1/ABCG2) and fluvastatin (SLCO1B1/CYP2C9) to prevent statin-associated musculoskeletal symptoms and for thiopurines (TPMT/NUDT15) to prevent severe myelosuppression (\u003cspan citationid=\"CR64\" class=\"CitationRef\"\u003e64\u003c/span\u003e, \u003cspan citationid=\"CR65\" class=\"CitationRef\"\u003e65\u003c/span\u003e). A double-slow combination appears to be associated with additive negative pharmacokinetic effects. For example, fluvastatin is not recommended for individuals with CYP2C9 PM and reduced SLO1B1 function (\u003cspan citationid=\"CR64\" class=\"CitationRef\"\u003e64\u003c/span\u003e). Combined genetic considerations also exist for warfarin, where CYP2C9 and VKORC1 genotypes have been associated with an increased risk of bleeding (\u003cspan citationid=\"CR66\" class=\"CitationRef\"\u003e66\u003c/span\u003e, \u003cspan citationid=\"CR67\" class=\"CitationRef\"\u003e67\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAnother risk factor for ADR is polypharmacy (\u003cspan citationid=\"CR68\" class=\"CitationRef\"\u003e68\u003c/span\u003e). This can lead not only to drug-drug interactions but also to drug-gene interactions. Many psychotropic drugs are both substrates and inhibitors of CYP2D6 and CYP2C19. In our cohort, PC resulted in a deviation from the genetic phenotype in 48.57% of patients. This observation is representative of psychiatric inpatients (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e). There is evidence that PGx-guided therapies reduce polypharmacy, making implementation even more important (\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe study is limited by its small sample size due to excluded patients who did not complete the questionnaire. Explanations for this may include the linguistic barrier or a disease-related decline in motivation. However, the balanced gender distribution, broad age range, and heterogeneity of the medications prescribed allowed a cross-section of the population to be represented. Despite the small sample, the data are valuable because of the good gene-panel using modern CNV analysis and considering interacting factors. ADR rating was done by the patients, which is a limitation of the results. Future studies should use self and observer ratings to verify the results.\u003c/p\u003e \u003cp\u003eNot all CYP phenotypes were represented. SM were overrepresented due to PC. There were no UM for CYP2D6 and only three CYP 2C19/2D6 NM/NM as controls. The influence of PC on functional CYP enzyme status has rarely been considered in previous studies but is crucial for interpreting study results on PGx-related ADR. Some inhibitors, such as promethazine, require a clear FDA statement of inhibition strength for accurate phenotype calculation.\u003c/p\u003e \u003cp\u003eThis study demonstrates the correlation of ADR with the combined phenotypes of CYP 2C19/2D6, considering both psychiatric and non-psychiatric medication. Combined divergent CYP 2C19/2D6 enzyme status was significantly associated with increased ADR. Further and larger cohort studies must follow to provide sufficient evidence for generating phenotype-specific cross-tabulations.\u003c/p\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003eThe complex pharmacokinetic interaction of the CYP2C19 and CYP2D6 functional status is relevant for the intolerance of AD. A combined nNM enzyme status is associated with a significantly higher ADR risk than a combined NM enzyme status. One potential cause is the alteration of exposure to the metabolites and a shift in metabolite to parent drug ratio. Furthermore, we recommend avoiding venlafaxine in nNM patients due to highly elevated risk for ADR. Alternatives are not primarily CYP2C19 or CYP2D6 metabolized drugs. This might also apply to other AD, but larger studies are needed to support these findings.\u003c/p\u003e \u003cp\u003e This study highlights the need for larger controlled trials to identify risk variants for drug-specific subgroups and provide further evident PGx guidelines for AD. Implementing genetic information into clinical decision-making may enhance the safety of AD therapy.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eCOMPETING INTERESTS\u003c/h2\u003e \u003cp\u003eMH and MSC are CPIC members. AR has received funding from Janssen.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eAUTHOR CONTRIBUTIONS\u003c/h2\u003e \u003cp\u003eProject administration: MH; data collection: AE, MH, MSC, HW; analysis and interpretation of the data: CG; manuscript writing CG; review and editing: CG, MH, MSC, HW, AE, AR, SCR. All authors made significant contributions to the study and have approved the final manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eRamos M, Berrogain C, Concha J, Lomba L, Garc\u0026iacute;a CB, Ribate MP. Pharmacogenetic studies: A tool to improve antidepressant therapy. Drug Metab Pers Ther. 2016;31(4):197\u0026ndash;204.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePhillips KA, Veenstra DL, Oren E, Lee JK, Sadee W. Potential role of pharmacogenomics in reducing adverse drug reactions: A systematic review. 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Neuropharmacology. 1992;31(10):997\u0026ndash;1000.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCooper-DeHoff RM, Niemi M, Ramsey LB, Luzum JA, Tarkiainen EK, Straka RJ, et al. The Clinical Pharmacogenetics Implementation Consortium Guideline for SLCO1B1, ABCG2, and CYP2C9 genotypes and Statin-Associated Musculoskeletal Symptoms. Clin Pharmacol Ther. 2022;111(5):1007\u0026ndash;21.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRelling M V., Schwab M, Whirl-Carrillo M, Suarez-Kurtz G, Pui CH, Stein CM, et al. Clinical Pharmacogenetics Implementation Consortium Guideline for Thiopurine Dosing Based on TPMT and NUDT15 Genotypes: 2018 Update. Clin Pharmacol Ther. 2019;105(5):1095\u0026ndash;105.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMega JL, Walker JR, Ruff CT, Vandell AG, Nordio F, Deenadayalu N, et al. Genetics and the clinical response to warfarin and edoxaban: Findings from the randomised, double-blind ENGAGE AF-TIMI 48 trial. Lancet [Internet]. 2015;385(9984):2280\u0026ndash;7. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://dx.doi.org/10.1016/S0140-6736(14)61994-2\u003c/span\u003e\u003cspan address=\"10.1016/S0140-6736(14)61994-2\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVandell AG, Walker J, Brown KS, Zhang G, Lin M, Grosso MA, et al. Genetics and clinical response to warfarin and edoxaban in patients with venous thromboembolism. Heart. 2017;103(22):1800\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSisay T, Wami R. Adverse drug reactions among major depressive disorders: patterns by age and gender. Heliyon [Internet]. 2021;7(12). Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.heliyon.2021.e08655\u003c/span\u003e\u003cspan address=\"10.1016/j.heliyon.2021.e08655\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"the-pharmacogenomics-journal","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"tpj","sideBox":"Learn more about [The Pharmacogenomics Journal](http://www.nature.com/tpj/)","snPcode":"41397","submissionUrl":"https://mts-tpj.nature.com/cgi-bin/main.plex","title":"The Pharmacogenomics Journal","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-6406316/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6406316/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eVariants in cytochrome P450 enzymes are known risk factors for developing adverse drug reactions (ADR). Most antidepressants (AD) are simultaneously metabolized by major or minor pathway of CYP2C19 and CYP2D6, resulting in a complex interplay of metabolites. This study is one of the first to investigate and demonstrate the combined CYP 2C19/2D6 functional metabolic status as a risk factor for ADR in AD treatment of major depressive disorder. Most prescribed AD venlafaxine underwent subgroup analysis. Significantly more ADR in non-normal metabolizers (nNM) for one or both CYP enzymes compared with normal metabolizers (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.039) were observed. Both slow (PM and IM) and rapid metabolizers (RM and UM) were affected. There were non-significant trends for CYP2C19 RM and UM with ADR in venlafaxine, which may be avoided in CYP2C19 nNM. More research is required to identify risk variants for personalized and safe AD treatment.\u003c/p\u003e","manuscriptTitle":"Influence of combined CYP2C19 and CYP2D6 phenotypes on adverse drug reactions in patients with major depressive disorder: a clinical cohort study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-30 05:54:50","doi":"10.21203/rs.3.rs-6406316/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"revise","date":"2025-10-09T15:01:24+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"This content is not available.","date":"2025-10-06T07:46:38+00:00","index":3,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2025-09-14T09:10:08+00:00","index":3,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2025-07-31T22:03:08+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2025-07-31T07:30:21+00:00","index":2,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2025-07-29T12:37:00+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewersInvited","content":"","date":"2025-06-23T07:13:17+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-04-11T11:41:52+00:00","index":"","fulltext":""},{"type":"submitted","content":"The Pharmacogenomics Journal","date":"2025-04-10T18:26:19+00:00","index":"","fulltext":""},{"type":"checksFailed","content":"","date":"2025-04-10T08:52:05+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-04-08T20:52:43+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"the-pharmacogenomics-journal","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"tpj","sideBox":"Learn more about [The Pharmacogenomics Journal](http://www.nature.com/tpj/)","snPcode":"41397","submissionUrl":"https://mts-tpj.nature.com/cgi-bin/main.plex","title":"The Pharmacogenomics Journal","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"df4293da-8d02-4a6b-9787-be57f003756a","owner":[],"postedDate":"June 30th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":50430966,"name":"Health sciences/Risk factors"},{"id":50430967,"name":"Biological sciences/Genetics/Genotype"},{"id":50430968,"name":"Biological sciences/Drug discovery/Drug safety"},{"id":50430969,"name":"Biological sciences/Drug discovery/Pharmacology/Pharmacogenetics"},{"id":50430970,"name":"Health sciences/Diseases/Psychiatric disorders/Depression"}],"tags":[],"updatedAt":"2026-04-10T07:12:53+00:00","versionOfRecord":{"articleIdentity":"rs-6406316","link":"https://doi.org/10.1038/s41397-026-00407-3","journal":{"identity":"the-pharmacogenomics-journal","isVorOnly":false,"title":"The Pharmacogenomics Journal"},"publishedOn":"2026-04-09 04:00:00","publishedOnDateReadable":"April 9th, 2026"},"versionCreatedAt":"2025-06-30 05:54:50","video":"","vorDoi":"10.1038/s41397-026-00407-3","vorDoiUrl":"https://doi.org/10.1038/s41397-026-00407-3","workflowStages":[]},"version":"v1","identity":"rs-6406316","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6406316","identity":"rs-6406316","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}