Dose-Dependent Inhibition of CYP2D6 by Bupropion in Patients With Depression

Hole, Kristine; Arnestad, Marianne; Molden, Espen; Haslemo, Tore

doi:10.1097/jcp.0000000000001387

Cited by 9 publications

(4 citation statements)

References 23 publications

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“…This coincides well with a previous report of the potent CYP‐inhibitor paroxetine leading to a 60% elevation in the duloxetine area under the concentration‐time curve (AUC) 15 . It is not surprising that having PM phenotype would be of more consequence than use of an inhibitor, as several studies have reported a slightly higher CYP2D6 activity in patients using potent CYP2D6 inhibitors compared with patients who have genotype‐assigned PM phenotype 16,17 . Furthermore, a pharmacokinetic model developed by Stingl et al estimated that duloxetine oral clearance in CYP2D6 PMs was 69% of the average patient 18 .…”

Section: Discussionsupporting

confidence: 89%

“…15 It is not surprising that having PM phenotype would be of more consequence than use of an inhibitor, as several studies have reported a slightly higher CYP2D6 activity in patients using potent CYP2D6 inhibitors compared with patients who have genotype-assigned PM phenotype. 16,17 patient. 18 The results from our study are close to this estimation, with a C/D ratio that was almost doubled in PMs compared with NMs.…”

Section: Discussionmentioning

confidence: 99%

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Effect of CYP2D6 genotype on duloxetine serum concentration

Hole,

Gangsø,

Jensstuen

et al. 2023

Basic Clin Pharma Tox

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Duloxetine is metabolized by cytochrome P450 (CYP)1A2 and CYP2D6. The aim of this study was to investigate the effect of CYP2D6 genotype on duloxetine serum concentration adjusting for age and sex. Patients were included retrospectively from a therapeutic drug monitoring service. Multiple linear regression analysis was used to investigate the effect of CYP2D6 genotype, age and sex on duloxetine concentration‐to‐dose (C/D) ratio. In total, 269 patients were included and assigned to the following genotype‐predicted phenotype subgroups: CYP2D6 poor metabolizers (PMs, n = 23), intermediate metabolizers (IMs, n = 121), normal metabolizers (NMs, n = 120), and ultrarapid metabolizers (UMs, n = 5). Multiple linear regression analysis revealed a 95% higher duloxetine C/D ratio in PMs compared with NMs (P = 0.009). Patients ≥65 years had a 56% higher C/D ratio than younger patients (P = 0.01), while women had a 46% higher C/D ratio than men (P = 0.04). In conclusion, CYP2D6 PM phenotype is associated with a twofold higher concentration at recommended dosing compared with NM phenotype. CYP2D6 PM females above 65 years are at particular risk of high duloxetine levels as they may obtain threefold higher C/D ratio compared with younger, male NMs.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Effect of CYP2D6 genotype on duloxetine serum concentration

Hole,

Gangsø,

Jensstuen

et al. 2023

Basic Clin Pharma Tox

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“…Based on these findings, a DM/bupropion combination medication under the brand name Auvelity was approved by the US Food and Drug Administration in August 2022 to treat MDD in adults. Auvelity's recent approval suggests that DM may be a viable adjunctive therapy for individuals receiving a stable dose of bupropion without remission of their depressive symptoms, although the dose of DM would need to be titrated in accordance with the dose-dependent CYP2D6 inhibition activity of bupropion 16 . As with all serotonergic compounds, prescribers and patients should be informed about the theoretical risks of serotonin syndrome associated with adjunctive DM use.…”

Section: Discussionmentioning

confidence: 99%

An Open-Label Study of Adjunctive Dextromethorphan/Quinidine in Treatment-Resistant Depression

Wang,

Yavi,

Lee

et al. 2023

J Clin Psychopharmacol

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Background Approximately one third of individuals with major depressive disorder have treatment-resistant depression (TRD). Glutamatergic modulators such as the N-methyl-d-aspartate receptor antagonist ketamine have rapid and robust antidepressant effects, but their use has been limited by accessibility and route of administration. This open-label pilot study assessed the adjunctive antidepressant efficacy of dextromethorphan/quinidine (DM/Q) in TRD. Methods Inpatients with TRD (n = 17, 40.8 ± 12.3 years; 9 females/8 males) received adjunctive open-label DM/Q (20 mg/10 mg) up to 3 times daily. The study had no set endpoint; participants were followed until they discontinued DM/Q or were discharged. Montgomery-Asberg Depression Rating Scale (MADRS) scores were obtained at baseline (before DM/Q administration) and regularly during hospitalization. Full response was defined as a ≥50% reduction in baseline MADRS score, partial response as a 25% to 50% decrease in baseline MADRS score, and nonresponse as a <25% reduction or an increase in baseline MADRS score. Results The 17 inpatients received open-label DM/Q for 5.1 ± 2.7 weeks. Forty-seven percent of participants responded to DM/Q—12% achieved a full response and 35% achieved a partial response. The largest MADRS difference observed at any time point was −6.4 ± 8.4 (−21.0% ± 29.9%), and the MADRS difference observed at time of DM/Q discontinuation or hospital discharge was −4.8 ± 8.4 (−15.9% ± 29.7%). Twenty-four percent of participants experienced a nonserious adverse event; none experienced a serious adverse event. Conclusions In this open-label pilot study, 47% of participants responded to adjunctive DM/Q, which was well tolerated. Larger placebo-controlled trials are needed to determine the real-world efficacy of DM/Q.

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“…A limitation of our study is that daily doses of the inhibitors/inducers of CYP2C19 were not recorded due to the retrospective nature of this study. However, a recent study showed that the phenoconversion effect might be dose-dependent [44]. Also, the phenoconversion was calculated based on the genetic phenotype, not on haplotypes due to the low number of patients; however, a study of de Jong showed that the phenoconversion might depend upon the specific polymorphism (e. g.,*1/*17 vs.*2/*17) [45].…”

Section: Strengths and Limitationsmentioning

confidence: 99%

The Relevance of Integrating CYP2C19 Phenoconversion Effects into Clinical Pharmacogenetics

Scherf-Clavel,

Weber,

Unterecker

et al. 2024

Pharmacopsychiatry

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Introduction CYP2D6 and CYP2C19 functional status as defined by genotype is modulated by phenoconversion (PC) due to pharmacokinetic interactions. As of today, there is no data on the effect size of PC for CYP2C19 functional status. The primary aim of this study was to investigate the impact of PC on CYP2C19 functional status. Methods Two patient cohorts (total n=316; 44.2±15.4 years) were investigated for the functional enzyme status of CYP2C19 applying two different correction methods (PCBousman, PCHahn&Roll) as well as serum concentration and metabolite-to-parent ratio of venlafaxine, amitriptyline, mirtazapine, sertraline, escitalopram, risperidone, and quetiapine. Results There was a decrease in the number of normal metabolizers of CYP2C19 and an increase in the number of poor metabolizers. When controlled for age, sex, and, in the case of amitriptyline, venlafaxine, and risperidone, CYP2D6 functional enzyme status, an association was observed between the CYP2C19 phenotype/functional enzyme status and serum concentration of amitriptyline, sertraline, and escitalopram. Discussion PC of CYP2C19 changes phenotypes but does not improve correlations with serum concentrations. However, only a limited number of patients received perturbators of CYP2C19. Studies with large numbers of patients are still lacking, and thus, it cannot be decided if there are minor differences and which method of correction to use. For the time being, PC is relevant in individual patients treated with CYP2C19-affecting drugs, for example, esomeprazole. To ensure adequate serum concentrations in these patients, this study suggests the use of therapeutic drug monitoring.

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Dose-Dependent Inhibition of CYP2D6 by Bupropion in Patients With Depression

Cited by 9 publications

References 23 publications

Effect of CYP2D6 genotype on duloxetine serum concentration

Effect of CYP2D6 genotype on duloxetine serum concentration

An Open-Label Study of Adjunctive Dextromethorphan/Quinidine in Treatment-Resistant Depression

The Relevance of Integrating CYP2C19 Phenoconversion Effects into Clinical Pharmacogenetics

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