The pharmacokinetics of standard antidepressants with aripiprazole as adjunctive therapy: studies in healthy subjects and in patients with major depressive disorder

Possible effects of the atypical antipsychotic aripiprazole on the pharmacokinetics of standard antidepressant therapies (ADTs) were assessed in two open-label, non-randomised studies in healthy subjects (Studies 1 and 2) and two placebo-controlled studies in patients with major depressive disorder (MDD) (Studies 3 and 4). Healthy subjects received venlafaxine 75 mg/day (Study 1; N = 38) or escitalopram 10 mg/day (Study 2; N = 25) with the addition of aripiprazole 10-20 mg/day (10 mg/day fixed dose in Study 2) for 14 days. Patients with MDD (N = 498; Studies 3 and 4) received escitalopram (10-20 mg/day), fluoxetine (20-40 mg/day), paroxetine controlled-release (37.5-50 mg/day), sertraline (100-150 mg/day) or venlafaxine extendedrelease (150-225 mg/day) for 8 weeks plus placebo. Incomplete responders were randomised (1: 1) to placebo or adjunctive aripiprazole 2-20 mg/day. Blood samples were collected for pharmacokinetic analysis of ADTs. Plasma concentration-time data from Studies 3 and 4 were combined for statistical analysis. In healthy subjects, point estimates [90% CI] for the ratios of geometric means of C-max (venlafaxine 1.148 [1.083-1.217]; escitalopram 1.04 [0.99-1.09]) and AUCTAU (venlafaxine 1.183 [1.130-1.238]; escitalopram 1.07 [1.04-1.11]) indicated no meaningful increase in ADT exposure in the presence of aripiprazole. In patients, point estimates for mean plasma concentration ratios indicated no substantial effect of aripiprazole on any ADT escitalopram 0.970 [0.911-1.033], fluoxetine 1.177 [1.049-1.321], paroxetine 0.730 [0.598-0.892], sertraline 0.958 [0.887-1.035] or venlafaxine 0.966 [0.887-1.051]. Aripiprazole had no meaningful effects on the pharmacokinetics of standard ADTs in either healthy subjects or patients with MDD.