The National Institute of Mental Health (NIMH) has embarked upon a new venture—effectiveness trials, large-scale trials to test more than one treatment option for individuals affected with diverse major mental disorders. The launch follows a recent report by the NIMH National Advisory Mental Health Council, which emphasized the failure within routine clinical care to widely implement findings of randomized, controlled efficacy trials (RCTs)—perhaps, in part, because of reduced generalizability that leaves real-world application unclear.

Efficacy trials do not answer a number of key clinical questions, including: (1) Are the treatments as effective and safe in representative patient groups? (2) How does the new treatment fit within the treatment armamentarium? (3) When should the new treatment be combined with existing interventions? (4) What are the long-term benefits? (5) Do treatments differ regarding their effectiveness in patients with comorbid general medical or psychiatric disorders? (6) How do these newer treatments affect costs of routine care? Effectiveness trials can address a number of these issues and incorporate a broad range of outcomes, including symptom reduction, day-to-day function, side effect burden, and patient satisfaction.

With a major aim of effectiveness trials being increased generalizability, selection of participants is crucial. Since symptomatic volunteers, who are typically used in efficacy RCTs for major depressive disorder, may be more responsive to either the nonspecific aspects of treatment or to the treatment itself than self-declared patients with concomitant comorbidities, setting minimal exclusion criteria, recruiting large samples of patients from representative practices, and excluding symptomatic volunteers assures that patients are representative, while protecting the internal validity of the trial. In addition, treatments must be reasonably well delivered so that outcomes can be attributed to the treatment per se and not to improper implementation of an otherwise effective treatment. Frequent clinic visits, patient/family educational efforts, universal access to all protocol recommended treatments (including psychotherapy), and adequate provider compensation can ensure that treatments are reasonably well delivered.