Mirtazapine in combination with amitriptyline: a drug-drug interaction study in healthy subjects

Objective To assess the steady‐state pharmacokinetics of mirtazapine (30 mg/day orally) and amitriptyline (75 mg/day orally) during combined administration compared with that of either drug administered alone. To evaluate the tolerability and effects on psychometric tests of acute and subchronic administration of both drugs combined and alone. Methods In a single‐blind, three‐way cross‐over study, 24 (12 male and 12 female) healthy subjects were randomly assigned to six different sequences of three 9‐day treatments, i.e. racemic mirtazapine (30 mg/day), amitriptyline (75 mg/day) or the combination of these drugs. To control for acute pharmacodynamic assessments, during the first treatment period, a placebo group (n = 8; 4 females and 4 males) was added. Serial blood samples were drawn for plasma level measurements that were subsequently subjected to pharmacokinetic analysis. Psychometric tests assessed attentional performance, and a computer‐assisted telephone questionnaire assessed self‐ratings of drowsiness/alertness and sleep quality. Results Amitriptyline increased the Cmax of mirtazapine (+ 36%, p