Background: Citalopram, the most selective serotonin reuptake inhibitor (SSRI), is a bicyclic phthalane derivative with a chemical structure that is unrelated to that of Ether SSRIs and available antidepressants. The drug is approved for use in 69 countries. This 6-week, fixed-dose, placebo-controlled, parallel-arm, multicenter trial was performed to confirm its efficacy and safety in treatment of outpatients with major depression in the United States. Method: Six hundred and fifty adult outpatients with moderate-to-severe major depression (DSM-III-R) were randomly assigned to receive citalopram at doses of 10 mg (N = 131), 20 mg (N = 130), 40 mg (N = 131), or 60 mg (N = 129) or placebo (N = 129) once daily. Outcome assessments were the 21-item Hamilton Rating Scale for Depression (HAM-D), the Montgomery-Asberg Depression Rating Scale (MADRS), and the Clinical Global Impressions scale. Results: Between-group comparisons of the change from baseline to endpoint revealed significantly greater improvement in the citalopram patients relative to the placebo patients on all 3 efficacy measures. Patients randomly assigned to 40 mg/day and 60 mg/day of citalopram showed significantly greater improvement than placebo on all efficacy measures, as well as on the HAM-D symptom clusters measuring depressed mood, melancholia, cognitive disturbance, and psychomotor retardation Patients who received 10 mg/day and 20 mg/day of citalopram also showed consistent improvement relative to placebo on all efficacy ratings, with statistical significance demonstrated in the MADRS response rate, the HAM-D depressed mood item, and the HAM-D melancholia subscale. Citalopram was well tolerated, with only 15% of patients discontinuing for adverse events. The side effects most commonly associated with citalopram treatment were nausea, dry mouth, somnolence, insomnia, and increased sweating. Conclusion: Citalopram was significantly more effective than placebo in the treatment of moderate-to-severe major depression, especially symptoms of depressed mood and melancholia, with particularly robust effects shown at doses of 40 and 60 mg/day. Citalopram was well tolerated in spite of forced upward titration to fixed-dose levels, with a low incidence of anxiety, agitation, and nervousness.
