CYP2C19 slow metabolizer phenotype is associated with lower antidepressant efficacy and tolerability

Joković, Danilo; Milosavljević, F.; Stojanovic, Zvezdana; Šupić, Gordana; Vojvodić, Danilo; Uzelac, Bojana; Jukić, Marin M.; Ćurčin, Aleksandra Petković

doi:10.1016/j.psychres.2022.114535

Cited by 12 publications

(12 citation statements)

References 35 publications

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“…A great majority of psychiatrists claimed that they do recognize the need for dose personalization in depression treatment by means of therapeutic drug monitoring and genotyping. This is in accordance with our recently published results (10,14,15,16) on an altered drug blood levels in individuals with variant enzyme capacity to metabolize such drugs. Still, these results have several limitations such as (i) the unknown impact of other genetic and environmental factors on clinical outcomes of pharmacotherapy, (ii) the fact that the relationship between drug concentration and clinical outcomes for many drugs is still not conclusively determined (17,18,19), and (iii) the problem of translation of genetic test results into clinical recommendations (20).…”

Section: Discussionsupporting

confidence: 93%

Patients' and psychiatrists' stance on the current state of pharmacological depression treatment in Serbia and prospects of introduction of personalized pharmacotherapy and its potential effects

Jeremić¹,

Milosavljević²,

Opanković³

et al. 2022

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The use of antidepressants has been steadily increasing. Even though the amount of evidence on the usefulness of personalized drug dosing in depression treatment is growing, there is still resistance and skepticism among physicians and regulators regarding the implementation of CYP450 genotyping and therapeutic drug monitoring in psychiatric clinical practice. The aim of this study was to quantify the opinions of psychiatrists and patients from three large psychiatric clinics in Belgrade, Serbia, and to examine what requirements need to be met to make changes in clinical guidelines or recommendations. All participants completed an anonymous questionnaire that was developed at the Faculty of Pharmacy, University of Belgrade. Fourteen practicing psychiatrists and 30 patients currently treated for depression completed the questionnaire. Distributions of opinion scores were compared between the psychiatrists and patients upon the visual inspection of the violin plots. Our results show that psychiatrists predominantly have a positive opinion on personalized dosing in psychiatry and that patients are most likely to comply with new approaches in depression pharmacotherapy. However, due to the long time needed for regulatory change, it is very unlikely that personalized dosing would be rapidly implemented in clinical practice, even if adequate evidence was to emerge.

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Section: Discussionsupporting

confidence: 93%

Patients' and psychiatrists' stance on the current state of pharmacological depression treatment in Serbia and prospects of introduction of personalized pharmacotherapy and its potential effects

Jeremić¹,

Milosavljević²,

Opanković³

et al. 2022

Arhiv za farmaciju

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“…Our findings from this real-world case series highlights the predictive value of CYP2D6 and CYP2C19 pharmacogenetics. This is supported by literature where the genotypes of either CYP2D6 and CYP2C19 were associated with the efficacy and tolerability profile of antidepressants ( Shams et al, 2006 ; Penas-Lledo et al, 2013 ; He et al, 2017 ; Fabbri et al, 2018 ; Jukic et al, 2018 ; Zastrozhin et al, 2021 ; Campos et al, 2022 ; Jokovic et al, 2022 ; Thiele et al, 2022 ). However, there were also negative and mixed findings reported ( Brandl et al, 2014 ; Hodgson et al, 2015 ; Taranu et al, 2017 ; Maggo et al, 2019a ).…”

Section: Discussionsupporting

confidence: 70%

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

et al. 2023

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

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“…However, for adverse effects, we observed a different pattern in severity over time, suggesting that patients in the PIT group experienced gradually fewer and less severe adverse effects compared with those in the control group. In addition, it is clear that clinical outcome is influenced by many other biological and nonbiological factors in addition to antidepressant plasma concentrations …”

Section: Discussionmentioning

confidence: 99%

“…In addition, it is clear that clinical outcome is influenced by many other biological and nonbiological factors in addition to antidepressant plasma concentrations. 5,[34][35][36][37][38] Most previous studies [39][40][41][42] of treatment for MDD guided by pharmacogenetics examined the use of combinatorial pharmacogenetic tests (ie, multigene testing). Other studies 14,[43][44][45] found promising results regarding remission rates; however, questions have been raised about whether the studies were properly randomized and blinded.…”

Section: Main Findingsmentioning

confidence: 99%

Effectiveness of Genotype-Specific Tricyclic Antidepressant Dosing in Patients With Major Depressive Disorder

et al. 2023

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ImportanceEvidence of the clinical benefit of pharmacogenetics-informed treatment (PIT) with antidepressants is still limited. Especially for tricyclic antidepressants (TCAs), pharmacogenetics may be of interest because therapeutic plasma concentrations are well defined, identification of optimal dosing can be time consuming, and treatment is frequently accompanied by adverse effects.ObjectiveTo determine whether PIT results in faster attainment of therapeutic TCA plasma concentrations compared with usual treatment in patients with unipolar major depressive disorder (MDD).Design, Setting, and ParticipantsThis randomized clinical trial compared PIT with usual treatment among 111 patients at 4 centers in the Netherlands. Patients were treated with the TCAs nortriptyline, clomipramine, or imipramine, with clinical follow-up of 7 weeks. Patients were enrolled from June 1, 2018, to January 1, 2022. At inclusion, patients had unipolar nonpsychotic MDD (with a score of ≥19 on the 17-item Hamilton Rating Scale for Depression [HAMD-17]), were aged 18 to 65 years, and were eligible for TCA treatment. Main exclusion criteria were a bipolar or psychotic disorder, substance use disorder, pregnancy, interacting comedications, and concurrent use of psychotropic medications.InterventionIn the PIT group, the initial TCA dosage was based on CYP2D6 and CYP2C19 genotypes. The control group received usual treatment, which comprised the standard initial TCA dosage.Main Outcomes and MeasuresThe primary outcome was days until attainment of a therapeutic TCA plasma concentration. Secondary outcomes were severity of depressive symptoms (measured by HAMD-17 scores) and frequency and severity of adverse effects (measured by Frequency, Intensity, and Burden of Side Effects Rating scores).ResultsOf 125 patients randomized, 111 (mean [SD] age, 41.7 [13.3] years; 69 [62.2%] female) were included in the analysis; of those, 56 were in the PIT group and 55 were in the control group. The PIT group reached therapeutic concentrations faster than the control group (mean [SD], 17.3 [11.2] vs 22.0 [10.2] days; Kaplan-Meier χ21 = 4.30; P = .04). No significant difference in reduction of depressive symptoms was observed. Linear mixed-model analyses showed that the interaction between group and time differed for the frequency (F6,125 = 4.03; P = .001), severity (F6,114 = 3.10; P = .008), and burden (F6,112 = 2.56; P = .02) of adverse effects, suggesting that adverse effects decreased relatively more for those receiving PIT.Conclusions and RelevanceIn this randomized clinical trial, PIT resulted in faster attainment of therapeutic TCA concentrations, with potentially fewer and less severe adverse effects. No effect on depressive symptoms was observed. These findings indicate that pharmacogenetics-informed dosing of TCAs can be safely applied and may be useful in personalizing treatment for patients with MDD.Trial RegistrationClinicalTrials.gov Identifier: NCT03548675

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CYP2C19 slow metabolizer phenotype is associated with lower antidepressant efficacy and tolerability

Cited by 12 publications

References 35 publications

Patients' and psychiatrists' stance on the current state of pharmacological depression treatment in Serbia and prospects of introduction of personalized pharmacotherapy and its potential effects

Patients' and psychiatrists' stance on the current state of pharmacological depression treatment in Serbia and prospects of introduction of personalized pharmacotherapy and its potential effects

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

Effectiveness of Genotype-Specific Tricyclic Antidepressant Dosing in Patients With Major Depressive Disorder

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