Combination therapy with venlafaxine and carbamazepine in depressive patients not responding to venlafaxine: pharmacokinetic and clinical aspects

Abstract

The chiral antidepressant venlafaxine (VEN) is both a serotonin and a norepinephrine uptake inhibitor. CYP2D6 and CYP3A4 contribute to its metabolism, which has been shown to be stereoselective. Ten CYP2D6 genotyped and depressive (F32x and F33x, ICD-10) patients participated in an open study on the pharmacokinetic and pharmacodynamic consequences of a carbamazepine augmentation in VEN non-responders. After an initial 4-week treatment with VEN (195 +/- 52 mg/day), the only poor metabolizer out of 10 depressive patients had the highest plasma concentrations of S-VEN and R-VEN, respectively, whereas those of R-O-demethyl-VEN were lowest. Five non-responders completed the second 4-week study period, during which they were submitted to a combined VEN-carbamazepine treatment. In the only non-responder to this combined treatment, there was a dramatic decrease of both enantiomers of VEN, O-demethylvenlafaxine, N-desmethylvenlafaxine and N, O-didesmethylvenlafaxine in plasma, which suggests non-compliance, although metabolic induction by carbamazepine cannot entirely be excluded. The administration of carbamazepine [mean +/- SD, range: 360 +/- 89 (200-400) mg/day] over 4 weeks did not result in a significant modification of the plasma concentrations of the enantiomers of VEN and its O- and N-demethylated metabolites in the other patients. In conclusion, these preliminary observations suggest that the combination of VEN and carbamazepine represents an interesting augmentation strategy by its efficacy, tolerance and absence of pharmacokinetic modifications. However, these findings should be verified in a more comprehensive study.

GABAergic Contributions to the Pathophysiology of Depression and the Mechanism of Antidepressant Action

“…In another clinical pilot study, as an augmentation to citalopram treatment, carbamazepine has been found to be clinically effective in depressed patients with comorbid anxiety disorders [218]. Similar to this study, carbamazepine augmentation provided clinical improvement in the majority of depressed patients non-responsive to venlafaxine treatment [219].…”

Blood–brain barrier penetration of the enantiomers of venlafaxine and its metabolites in mice lacking P-glycoprotein

“…Gex-Fabry et al investigated 35 patients on chronic medication with 14 venlafaxine and they reported S/R concentration ratios between 0.4-2.5 (median 1.1) (GexFabry et al, 2004;Gex-Fabry et al, 2002). Ciusani and co-workers studied 5 patients receiving individually adapted doses between 75-225 mg/day and they found mean plasma S/R ratios of 1.16, 0.94 and 1.01 for venlafaxine, Odm-venlafaxine and Ndm-venlafaxine, respectively (Ciusani et al, 2004). Taken together, there seems to be both species differences and inter-individual variability in the S/R disposition that need to be considered when results from different studies are compared.…”

Depressive effect of an antidepressant: therapeutic failure of venlafaxine in a case lacking CYP2D6 activity

“…18,19 A more plausible explanation is the fact that patients can also be non-responders to venlafaxine therapy, not linked to a certain CYP450 genotype, but in combination with a poor metabolizer the risk of a maintained depression and acquiring ADRs is increased substantially. 8,20 Other more rare ADRs include pulmonary (e.g. interstitial pneumonia) and cardiovascular (e.g.…”