CYP2D6 Inhibition in Patients Treated With Sertraline

Abstract

Sertraline, a selective serotonin reuptake inhibitor used to treat depression, inhibits CYP2D6 in vitro (Ki = 1.2 microM) less potently than fluoxetine (Ki = 0.15 microM). To determine the extent and time course of CYP2D6 inhibition in patients, six males (mean age: 40 years, range: 29-64 years), who were starting treatment for depression with sertraline, were phenotyped on five occasions (once before treatment and approximately 3, 7, 14, and 21 days later). Phenotype status was determined using oral dextromethorphan (30 mg) by calculating the urinary ratio of O-demethylated metabolites to parent drug (i.e., log ODMR). CYP2D6 genotype was determined by leukocyte DNA analysis using polymerase chain reaction amplification. Compliance was confirmed by sertraline plasma levels. Daily sertraline dosages ranged from 50 to 150 mg. Genotype results indicated all subjects were extensive metabolizers (four homozygous wild type [wt], two heterozygous wt/B mutation). Phenotype results showed that CYP2D6 inhibition in patients treated with sertraline appeared to be related to baseline CYP2D6 activity and sertraline dosage. Some patients with high CYP2D6 activity can demonstrate inhibition with sertraline dosages as low as 50 mg.

Antidepressants, metoprolol and the risk of bradycardia

“…Sertraline is not as strong a CYP2D6 inhibitor as fluoxetine or paroxetine. However, there is evidence that it is a weak inhibitor [Sproule et al 1997]. A sensitivity analysis removing sertraline from the non-CYP2D6-inhibiting antidepressant category did not change the results.…”

“…Although bupropion is also a CYP2D6-inhibiting antidepressant [Kotlyar et al 2005], we included it as a covariate with other CYP2D6 inhibitors rather than as an exposure antidepressant per se because its use as an adjunct for smoking cessation may have introduced bias if patients treated with bupropion were systematically different from those prescribed other antidepressants. Finally, because sertraline exhibits some CYP2D6 inhibition, particularly at high doses [Sproule et al 1997], we conducted a sensitivity analysis by removing sertraline exposure and repeating the multivariate analysis.…”

“…Fluoxetine and paroxetine (strong CYP2D6 inhibitors) constituted one group, while fluvoxamine, citalopram, venlafaxine, and sertraline collectively constituted the reference group. In a secondary analysis, we excluded patients treated with sertraline because the reported effect of sertraline on CYP2D6 activity varies among publications [Alfaro et al 2000;Sproule et al 1997].…”

Multifunctional Pharmacotherapy: What Can We Learn from Study of Selective Serotonin Reuptake Inhibitor Augmentation of Antipsychotics in Negative-Symptom Schizophrenia?

“…Several SSRI antidepressants inhibit cytochrome P-450 enzymes, mainly CYP1A2 and CYP2D6 isozymes, which are metabolizers of antipsychotic drugs. [21][22][23] Adding an SSRI antidepressant drug often results in an increase in plasma levels of the antipsychotic, 24,25 which could underlie the superior efficiency of the augmentation treatments. However, improvement in negative symptoms of schizophrenic patients treated with SSRI and haloperidol did not correlate with the increase of antipsychotic levels in plasma.…”

The importance of cytochrome P450 monooxygenase CYP2D6 in palliative medicine

“…Fluoxetine is activated to norfluoxetine by CYP2D6; paroxetine is inactivated by CYP2D6; fluvoxamine is inactivated by CYP1A2 and CYP2D6, sertraline by CYP3A4, and citralopram by CYP2C19 and CYP3A4 [38,71]. The inhibitory potency of SSRI agents to CYP2D6 occurs in the following order: paroxetine greater than fluoxetine and norfluoxetine greater than sertraline greater than fluvoxamine greater than venlafaxine [3,27,71,84]. Individuals with CYP2D6 #10 isomers will have higher concentrations of paroxetine per dose than patients with the wild type CYP2D6 #1 [103].…”