A curbstone consult to applicants for National Institute of Mental Health grant support.

With research budgets tight and review procedures being streamlined, applicants for research funds, especially newer investigators, may become disheartened. This article provides advice that we believe improves the quality of a written application. We detail ideas for how to develop applications that are complete and most easily understood by reviewers. Important elements include: a focus on selected, specific critical hypotheses that have both clinical and theoretical significance, documenting feasibility, establishing reliable effect sizes, providing specific analyses for each hypothesis, and writing a clear, well-articulated, "reader-friendly" application. In addition, we emphasize the value of collegial review and critique of the application prior to submission. We believe this "curbstone" advice will facilitate a well-reasoned review and if funds are available, eventual funding.

From scientific knowledge to the clinical practice of psychopharmacology: can the gap be bridged?

This paper examines the nature and types of information and syntheses relevant to the strategic and tactical decisions required in the treatment of depression with medication. Strategic decisions (What to do?) include determining what is wrong, defining treatment objectives, selecting the first treatment, deciding the next best treatment (should the first treatment fail), and deciding when to discontinue a successful treatment. Tactical decisions (How to do?) include determining where and by whom treatment is conducted, and the specific steps involved (e.g., dosing, frequency of visits, assessment of outcome, recognition and management of side effects, compliance, etc.) in the treatment as well as in the discontinuation of treatment (e.g., taper schedule, frequency of visits, etc.). The treatment of each patient is inherently an experimental single case study. Because individual patients differ, the most luxuriant data bases cannot fully address all strategic and tactical decisions with certainty. Thus, practitioners must apply general principles and group (nomothetic) data to individual patients. The relationship between research efforts and the information needed by clinicians is examined. Suggestions for developing and reporting more clinically relevant information from efficacy trials and other research are made.

The definition and operational criteria for treatment outcome of major depressive disorder. A review of the current research literature.

A review of research articles published in nine journals over a 2-year period was conducted to determine how critical changes in the clinical course of depressive disorder are defined in the research literature. These change points, labeled by terms such as response, recovery, and relapse, are critical for evaluation and communication of study results. The review focused on studies of unipolar depression that used a criterion-based diagnostic system and involved some form of therapeutic maneuver. The review showed significant inconsistency in the labeling and definition of change points and indicated the need for more precise conceptual definitions and operational criteria to enhance comparison, generalization, and application of results from clinical studies of depression.

Conceptualization and rationale for consensus definitions of terms in major depressive disorder. Remission, recovery, relapse, and recurrence.

In 1988, the MacArthur Foundation Research Network on the Psychobiology of Depression convened a task force to examine the ways in which change points in the course of depressive illness had been described and the extent to which inconsistency in these descriptions might be impeding research on this disorder. We found considerable inconsistency across and even within research reports and concluded that research on depressive illness would be well served by greater consistency in the definition change points in the course of illness. We propose an internally consistent, empirically defined conceptual scheme for the terms remission, recovery, relapse, and recurrence. In addition, we propose tentative operational criteria for each term. Finally, we discuss ways to assess the usefulness of such operational criteria through reanalysis of existing data and the design and conduct of new experiments.

Methodologic issues in maintenance therapy clinical trials.

In the early 1980s, the National Institute of Mental Health supported a multicenter, randomized, controlled, clinical trial on unipolar and bipolar disorder to evaluate the comparative efficacies of lithium carbonate, imipramine hydrochloride, a lithium-imipramine combination, and placebo in preventing the recurrence of affective disorders. The objective of this report is to present a reanalysis of the relative efficacies of these treatments in patients with unipolar disorder to focus attention on general issues related to the design and conduct of maintenance therapy trials. We show that the earlier conclusions of that study that imipramine and the combination therapy are more effective than lithium and placebo in preventing the recurrence of depression in unipolar patients can be accounted for by alternative explanations that are a consequence of the design of the study. Our findings have important implications for the design, conduct, and interpretation of results of maintenance therapy clinical trials in general.

Efficacy of continuation drug therapy of depression and anxiety: issues and methodologies.

Continuation treatment is the continued administration of a drug after disappearance of acute symptoms for the purpose of maintaining control over the episode. This critical phase of treatment constitutes a neglected area of research concerned with depression and anxiety disorders. Most therapeutic studies focus on the treatment of acute symptoms, using designs of only 4-8 weeks' duration. These studies provide little information on the effectiveness and use of continuation treatment for the duration of an episode, which may extend for months following control of acute symptoms. Furthermore, the relatively few continuation drug therapy studies deal primarily with depressive disorders, leaving anxiety disorders almost two decades behind depressive disorders in terms of published research in this critical area of treatment. This report reviews the current status of continuation drug treatment for anxiety and depression and examines research needs, issues, and problems. It also presents a design model for evaluating the need for and duration of continuation treatment for both depressive and anxiety disorders.

Alternatives to lithium for preventive treatment of bipolar disorder.

The authors review the research literature on drug treatment for the prevention of recurrences in bipolar disorder, emphasizing the available alternatives to lithium therapy. They discuss the need for alternative treatments and the current status of promising agents. Carbamazepine receives special attention because of its status as the most promising backup treatment for lithium. The authors conclude that despite the extensive literature on carbamazepine, there is strong need for carefully designed, prospective, double-blind studies to establish the efficacy of carbamazepine alone and in combination with lithium as a prophylactic treatment for bipolar disorder. Difficulties in developing and evaluating preventive maintenance are discussed.

Treatment of mixed mania.

Mixed mania (i.e., a manic syndrome accompanied by depressive symptoms) and its response to long-term preventive drug treatment was studied as part of a larger NIMH collaborative study. Following recovery from a manic episode, patients received either lithium, imipramine, or the combination of lithium and imipramine for a 2-year period. It was found that patients who had recovered from a mixed manic state were at significantly higher risk for recurrences than patients who had recovered from a pure (non-mixed) manic state. Lithium and the combination of lithium and imipramine were highly effective preventive treatments for the pure manic group and poor treatments for the mixed group. Imipramine was ineffective for both the pure and mixed groups. The need for identifying mixed mania in therapeutic trials and in evaluating alternative treatments for lithium with this subgroup is discussed.

Bipolar disorder: are there manic-prone and depressive-prone forms?

Descriptive studies from the prelithium era and lithium prophylactic studies were reviewed to look for evidence that there are manic-prone and depressive-prone subtypes of bipolar illness. The manic-prone subtype has a high ratio of manic to depressive episodes, and a depressive-prone subtype has the reverse. Although data from the prelithium era are suggestive, the evidence is insufficient to accept or reject the relevance of this hypothesis. Data from the lithium era suggest that there is a relationship between the type of index episode and future episode on placebo as well as drug. The clinical and heuristic implications of the relationship of index to subsequent episode and manic proneness and depressive proneness are discussed. Its relevance for planning prophylactic drug studies is also examined. The suggestive evidence presented here will hopefully encourage other investigators to collect the data necessary to test the possibility that manic-prone and depressive-prone subtypes of bipolar illness exist.

Continuation drug therapy for major depressive episodes: how long should it be maintained?

A major problem for the practitioner is the lack of satisfactory guidelines as to how long continuation drug treatment of depressive episodes must be maintained to ensure that the episode is over. This often leads to either premature withdrawal of the drug and subsequent relapse or unnecessarily prolonged treatment. Results from a collaborative project of the National Institute of Mental Health provide the first study-derived guidelines on the length of continuation therapy. Findings indicate that withdrawal of such therapy is safe only after the patient has been free of significant symptoms for 16 to 20 weeks and that focusing on mild as well as severe symptoms is critical in this decision.

Antidepressant drug therapy: the role of the new antidepressants.

Three new antidepressants have been marketed in the United States since 1980, and about two dozen more are being evaluated. In a 1983 workshop convened by the National Institute of Mental Health, participants examined the claims made for the newer antidepressants in relation to clinical efficacy, speed of onset, cardiovascular effects, and other adverse reactions. In this summary report of the workshop, primarily covering amoxapine, maprotiline, trazodone, and the investigational drug bupropion, the authors note that none of the new antidepressants demonstrate greater effectiveness than standard tricyclics, although some produce a different profile of side effects. The main benefit of the newer drugs is that they offer new options for the treatment of patients who cannot tolerate side effects of the traditional drugs or have responded unsatisfactorily to them.