Are two antidepressant mechanisms better than one? Issues in clinical trial design and analysis

The introduction of newer antidepressants that affect both serotonergic and noradrenergic neurotransmission has prompted the question of whether two antidepressant mechanisms of action are better than one for the treatment of depression. Existing data do not provide a definitive answer. Whether future studies provide the answer will depend largely on the quality of trial designs. Some design aspects are dictated by the nature of such a study (e.g., superiority vs. equivalence trial), and others are somewhat more discretionary (e.g., assessment tools, statistical procedures). Issues in the design and analysis of clinical trials comparing dual- and single-action antidepressants are discussed.