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.

Different lines of evidence suggest that human immunodeficiency virus type 1 (HIV-1) infection is complicated by a variety of adverse effects on neuroendocrine systems. Soon after the discovery of HIV-1, reports began to appear suggesting that a number of neurotransmitter and neuroendocrine activities were negatively impacted by this infection. In 1987 it was observed that fine-needle aspiration of the lung in patients with acquired immunodeficiency syndrome resulted in syncopal reactions. Subsequently, an abnormality in the autonomic nervous system was reported in these patients. However, investigations in this area have remained limited due to the assumption that HIV-1–mediated activation of various endocrine systems was related to the major life stressor of living with a fatal disease. Evidence accumulated over the years has indicated, instead, that there are various other mechanisms in addition to life stressors that also play an important role in negatively impacting the neuroendocrine systems in this infection. This article examines various developments that have taken place in this area in order to provide avenues for future research.

Can timely diagnosis and treatment of depression reduce the risk of suicide? Studies of treatment effects on mortality in major mood disorders remain rare and are widely considered difficult to carry out ethically. Despite close associations of suicide with major affective disorders and related comorbidity, the available evidence provides little support for sustained reductions of suicide risk by most mood-altering treatments, including antidepressants. Studies designed to evaluate clinical benefits of mood-stabilizing treatments in bipolar disorders, however, provide comparisons of suicidal rates with and without treatment or under different treatment conditions. This emerging body of research provides consistent evidence of reduced rates of suicides and attempts during long-term treatment with lithium. This effect may not generalize to proposed alternatives, particularly carbamazepine. Our recent international collaborative studies found compelling evidence for prolonged reduction of suicidal risks during treatment with lithium, as well as sharp increases soon after its discontinuation, all in close association with depressive recurrences. Depression was markedly reduced, and suicide attempts were less frequent, when lithium was discontinued gradually. These findings indicate that studies of the effects of long-term treatment on suicide risk are feasible and that more timely diagnosis and treatment for all forms of major depression, but particularly for bipolar depression, should further reduce suicide risk.

Which mood stabilizers are the most effective in reducing suicide rates in patients with bipolar disorder? This paper reviews the literature and compares the data on two types of mood-stabilizing agents, lithium and anticonvulsants. Compared with the large amount of data on lithium, there is surprising little information available on the effects of anticonvulsants on mortality in manic-depressive illness. Each was also assessed in terms of suicide risk factors such as depression and mixed episodes, rapid cycling, substance abuse, anxiety and panic, and central serotonergic function. Only two studies that provide data demonstrating anticonvulsant efficacy in preventing suicide in bipolar disorder are available, and the data are incomplete at best. Further research in this area should include an emphasis on the outcome of mortality in patients treated with any of the anticonvulsants or with lithium-anticonvulsant combinations.