CYP 2D6 PM Status and Antidepressant Response to Nortriptyline and Venlafaxine

Abstract

W e propose that cytochrome P450 (CYP) 2D6 poor metabolizers (PMs) are inherently resistant to the beneficial effects of antidepressants that act by altering serotonin-norepinephrine neurotransmission and that this phenomenon is responsible for the curvilinear concentration-antidepressant response relationship observed with nortriptyline over 30 years ago.The impetus for this hypothesis was the recent finding by Lobello and colleagues 1 that CYP 2D6 PMs treated with venlafaxine (VEN) have low antidepressant response and remission rates: 2-to 3-fold lower than those achieved in CYP 2D6 extensive metabolizers (EMs) and comparable to rates seen in placebo-treated patients. The details concerning the work that lead to the finding of poor antidepressant response to VEN in CYP 2D6 PMs is summarized next. VENLAFAXINE AND CYP 2D6Venlafaxine is a model substrate of CYP 2D6, and the ratio of VEN to its major metabolite O-desmethylvenlafaxine (ODV) can be used to phenotype individuals as CYP 2D6 EMs or PMs as follows: ODV/VEN ratios greater than 1 predict EM status, whereas ratios less than 1 predict PM status. 2 Using this approach to phenotype patients, Lobello and colleagues 1 conducted a secondary analysis of the registration trial data of VEN to treat major depressive disorder, reassessing the data after dividing the VEN-treated population into 2 groups: phenotypic CYP 2D6 EMs and PMs. The analysis was based on 4 large placebo-controlled, double-blind, efficacy trials of VEN in which a plasma level of VEN and ODV was measured at the time of the trial. EMs had a 2-to 3-fold higher antidepressant response and remission rate on 4 of 5 efficacy measures when compared with PMs (P e 0.015). Both groups received the same average dose of VEN, achieved the same total concentration of VEN plus ODV, and had the same tolerability profile, ruling out differences in those parameters as an explanation for the differences in antidepressant efficacy observed. 1 Although the total concentration of VEN plus ODV was the same in both groups, the EMs achieved higher levels of ODV and lower levels of VEN, whereas the converse was true for the PMs. Of note, the finding by Lobello and colleagues was a replication of an earlier, smaller study by Borgherini and colleagues. 3 There are 2 possible explanations for the finding of poor antidepressant response to VEN in CYP 2D6 PMs. The first is VEN could be a prodrug that requires biotransformation to ODV to be an effective antidepressant. However, this explanation is inconsistent with the known pharmacology of VEN and ODV. The second is that CYP 2D6 PMs, for as yet unknown reasons, are less responsive to antidepressants, such as VEN, which are thought to work by affecting central serotonin and norepinephrine neurotransmission.Consistent with this second explanation, CYP 2D6 is expressed in the brain and is involved in the metabolism of serotonin. In addition, EMs and PMs are reported to differ in terms of personality type and to have differences in regional brain metabolism as determined using fu...

PharmGKB summary

“…In contrast, other studies have not been able to link VEN response with ODV and VEN plasma levels or the CYP2D6 genotype [11,14,15]. An accompanying editorial proposes that CYP2D6 PM patients are less responsive to VEN because CYP2D6 has pharmacodynamics effects on the metabolism of serotonin in the brain [51]. …”

How Pharmacogenomics (PG) Are Changing Practice

“…14,15 These differences can explain why some patients do not experience antidepressant efficacy when treated with drugs such as venlafaxine at usually effective doses, or tumor suppression when treated with drugs such as tamoxifen, or why patients experience toxicity when treated with what are usually safe doses of other drugs such as pimozide. 5,[23][24][25][26] In addition to leading to revisions in the special populations sections of PLs, PGI can also have an impact on warnings, dosing recommendations, and information on adverse reactions.…”

Recent examples on the clinical relevance of the CYP2D6 polymorphism and endogenous functionality of CYP2D6

“…The evidence for the effects of CYP2D6 polymorphism on the PK of CNSactive CYP2D6 substrates is clearly given [14][15][16][17][18][19][20][21][24][25][26][27][28][29][30][31][32], and CYP2D6 genotyping can definitely help avoid serious adverse reactions. However, the ultimate proof for a clear link to the clinical outcome/endpoints is still lacking.…”

“…The risk is not limited to the direct use in children after tonsillectomy but also applies to breastfeeding mothers treated with codeine [15][16][17][18][19][20][21]. Other examples are tardive dyskinesia after metoclopramide in PMs [22,23]; cardiac and neurotoxic effects with tricyclic antidepressants in PMs [24][25][26], but also with some newer antidepressants such mirtazapine [27,28] in UMs and venlafaxine in PMs [29,30]; and the higher incidence of Parkinson-like symptoms in PMs treated with typical antipsychotics such as haloperidol [31]. While in the beginning, mostly CNS and cardiovascular drugs were in the focus [32], the efficacy of the antiestrogen tamoxifen has been shown to be linked to the CYP2D6 genotype [33].…”