Interaction of valproic acid and the antidepressant drugs doxepin and venlafaxine: analysis of therapeutic drug monitoring data under naturalistic conditions

Abstract

Valproic acid and the antidepressants doxepin and venlafaxine are frequently used psychotropic drugs. In the literature, an influence of valproic acid on serum levels of antidepressants has been described, although studies have focused on amitriptyline. The authors assessed their therapeutic drug monitoring (TDM) database for patients receiving a combination of doxepin or venlafaxine and valproic acid and compared these samples with matched controls without valproic acid comedication in terms of the serum concentration of antidepressants. The mean dose-corrected serum concentration of doxepin+N-doxepin in 16 patients who received valproic acid comedication was higher (2.171±1.482 ng/ml/mg) than that in the matched controls (0.971±0.857 ng/ml/mg, P<0.003). We also found a significant correlation between valproic acid serum level and dose-corrected doxepin+N-doxepin serum level (Spearman's ρ r=0.602, P<0.014). The mean dose-corrected serum level of venlafaxine+O-desmethylvenlafaxine in 41 patients who received valproic acid comedication did not differ significantly from that of the matched controls (P<0.089), but there was a significant difference between both groups in the dose-corrected serum level of O-desmethylvenlafaxine (1.403±0.665 vs. 1.102±0.444, P<0.017). As a consequence, if a combination of valproic acid with doxepin or venlafaxine is administered, cautious dosing is advisable and TDM should be performed.

Fig. 1

Serum level of doxepin (DOX)+N-DOX (ng/ml) as a function of DOX dose in patients with and without valproic acid (VPA) comedication (dashed lines: lower and upper limit of the therapeutic range).

Fig. 2

Serum level of venlafaxine (VEN)+O-desmethylvenlafaxine (ODV) (ng/ml) as a function of VEN dose in patients with and without valproic acid (VPA) comedication (dashed lines: lower and upper limit of the therapeutic range).

Fig. 3

Scatterplot of dose-corrected serum level of doxepin (DOX)+N-DOX [(ng/ml)/(mg/day)] and serum level of valproic acid (VPA) (Spearman’s ρ r=0.602, P<0.014, n=16).