Venlafaxine (brand name Effexor) is an antidepressant used in the treatment of major depressive disorder, anxiety, and panic disorders. Venlafaxine belongs to the drug class of serotonin and norepinephrine reuptake inhibitors (SNRIs), as does its major metabolite, desvenlafaxine (brand name Pristiq).
The recommended starting dose for venlafaxine is 75 mg/day, divided into 2 or 3 doses. Depending on tolerability and clinical response, the dose may be increased to 150 mg/day, and if needed, further increased up to 225 mg/day. Only the more severely depressed individuals may respond to higher doses, up to a maximum of 375 mg/day.
Venlafaxine is metabolized into its major active metabolite, O-desmethylvenlafaxine (ODV), primarily by the CYP2D6 enzyme. As such, individuals that have high plasma concentrations of venlafaxine and low plasma concentrations of ODV when taking venlafaxine, indicates they have reduced or absent CYP2D6 activity. This can be caused by concomitant use of medications that inhibit the CYP2D6 enzyme or by germline genetic variation in the CYP2D6 gene. Individuals who have genetic variants associated with no enzyme activity are called “CYP2D6 poor metabolizers” and account for approximately 7% of Caucasians.
The FDA-approved drug label for venlafaxine does not provide dose adjustments for CYP2D6 poor metabolizers, and states that no dose adjustment is required when venlafaxine is coadministered with a CYP2D6 inhibitor (Table 1) (1). The label states that although imipramine (an antidepressant that inhibits CYP2D6) was found to partially inhibit venlafaxine metabolism, the total concentration of active compounds (venlafaxine plus ODV) was not affected. In addition, the label cites a clinical study comparing venlafaxine use in CYP2D6 poor metabolizers and normal metabolizers, which found that the total concentration of active compounds (venlafaxine plus ODV) was similar in both metabolizer groups.
However, the Dutch Pharmacogenetics Working Group (DPWG) of the Royal Dutch Association for the Advancement of Pharmacy has published venlafaxine dosing recommendations based on CYP2D6 genotype. For CYP2D6 poor and intermediate metabolizers, DPWG recommends that an alternative drug is used. If an alternative medication is not an option and side effects occur, DPWG recommends a venlafaxine dose reduction based on clinical response and drug levels. For individuals who are CYP2D6 ultrarapid metabolizers (increased CYP2D6 activity), the DPWG recommends increasing the dose of venlafaxine up to 150% of the standard dose, or using an alternative drug if dose adjustment based on therapeutic drug monitoring is not possible (Table 2) (2).