OBJECTIVETo evaluate the efficacy and safety of venlafaxine, a new-generation antidepressant that selectively inhibits serotonin and norepinephrine reuptake, in the treatment of premenstrual dysphoric disorder (PMDD).METHODWe conducted a randomized, double-blind, placebo-controlled, parallel-group, flexible-dose trial. After three screening cycles, including a single-blind placebo cycle, 164 women were randomly assigned to double-blind treatment with venlafaxine (50–200 mg/day) or placebo for four menstrual cycles. Primary outcome measures were the total premenstrual symptom scores as assessed by a daily symptom report (DSR) and the Hamilton Rating Scale for Depression.RESULTSVenlafaxine was significantly more effective than placebo in reducing PMDD symptoms as assessed by DSR scores (P< .001 for last observation carried forward and observed analyses). Sixty percent of venlafaxine versus 35% of placebo subjects improved >50% (P= .003). Forty-three percent of venlafaxine subjects versus 25% of placebo subjects experienced symptom remission, defined as reduction of DSR scores to the postmenstrual level (P= .034). Venlafaxine treatment was significantly better than placebo for all statistically derived DSR factors (mood, function, pain, and physical symptoms). Improvement was relatively swift, with approximately 80% symptom reduction in the first treatment cycle. Mean venlafaxine doses ranged from 50 mg/day in the first treatment cycle to 130 mg/day in the fourth treatment cycle. Adverse events such as nausea, insomnia, and dizziness were mild and transient.CONCLUSIONSVenlafaxine is significantly more efficacious than placebo for PMDD treatment. Response to treatment can occur in the first treatment cycle, and venlafaxine is well tolerated. Further studies are needed to evaluate the potential of intermittent (luteal phase) dosing for this cyclic disorder and the efficacy of long-term maintenance treatment with venlafaxine.