The cost-effectiveness of tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) has not been compared in a prospective study in primary care. Aims To determine the relative cost-effectiveness of TCAs, SSRIs and lofepramine in UK primary care. Method An open-label, three-arm randomised trial with a preference arm. Practitioners referred 327 patients with incident depression. Results No significant differences were found in effectiveness or cost-effectiveness. The

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... mbers of depression-free weeks over 12 months (on the Hospital Anxiety and Depression Scale) were 25.3 (95% CI 21.3–29.0) for TCAs, 28.3 (95% CI 24.3–32.2) for SSRIs and 24.6 (95% CI 20.6–28.9) for lofepramine. Mean health service costs per patient were $762 (95% CI 553–1059) for TCAs, $875 (95% CI 675–1355) for SSRIs and $867 (95% CI 634–1521) for lofepramine. Cost-effectiveness acceptability curves suggested SSRIs were most cost-effective (with a probability of up to 0.6). Conclusions The findings support a policy of recommending SSRIs as first-choice antidepressants in primary care.