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Executive Summary

Lithium is the drug of choice for prevention of recurrences of bipolar mood disorders, while both lithium and tricyclic antidepressants "have been shown to be effective for prevention" of unipolar depressive disorders, a Natl. Institutes of Health Consensus Development Conference on Mood Disorders concluded after its meeting April 24-26. In its draft consensus statement, the conference panel noted that "in a summary of 14 studies of bipolar disorder the percentage of patients having a recurrent episode of either mania or depression during one year after the start of treatment was greatly reduced by lithium maintenance in contrast to placebo." In most of the studies, the panel observed, "the number of recurrences was reduced by 50% compared to placebo, and the recurrences were less severe." However, the panel added, "rapidly cycling bipolar patients, i.e., those who have three or more episodes per year, often respond poorly." Discussing the pharmacologic prevention of recurrences of mood disorders, the NIH conference distinguished between bipolar affective disorders (episodes of depression and mania or mania alone) and unipolar affective disorders (episodes of depression alone). Although the panel found "antidepressants are significantly less effective than lithium in preventing recurrence of bipolar disorder," it noted that many controlled studies have shown imipramine and amitriptyline, as well as lithium, "can substantially prevent recurrent episodes of unipolar depression." The consensus statement noted that "one multicenter study suggests that patients with severe initial episodes [of unipolar disorder] have a better response to imipramine and that patients with moderately severe initial episodes respond equally to lithium and tricyclics." The panel added that "most studies, however, find lithium and tricyclics to be equally effective or lithium to be superior." The multicenter study cited is the Natl. Institutes of Mental Health (NIMH) collaborative study of long-term maintenance drug therapy in recurrent affective illness. The NIMH study involved 150 patients with recurrent unipolar affective disorder assigned to one of four treatments -- lithium, imipramine, a combination of lithium and imipramine, or placebo. NIMH's Robert Prien, PhD, reported that imipramine and the imipramine-lithium combination were more effective than either lithium or placebo in preventing depressive recurrences. He noted, however, that in preventing recurrence of manic episodes (in patients with no history of mania or hypomania) lithium tended to be more effective than the other treatment therapies. The consensus panel addressed specific questions in its draft statement, such as: what groups of patients with mood disorders should be considered for preventive maintenance medication?; how effective are the medications in modifying the course of recurrent illness?; what additional or alternative strategies are available for breakthrough episodes and treatment failures?; and what are the long-term risks and complications of maintenance therapy? With respect to preventive maintenance medication, the panel said "the occurrence of a manic episode should always raise the question of preventive therapy," since such patients are at high risk for recurrences. Preventive therapy should also be considered for patients who have had a hypomanic and a depressive episode as they are "also at high risk for recurrence and are more likely to become psychotic when depressed than are patients with unipolar disorder," the panel stated. Carbamazepine, Monoamine Oxidase Inhibitors Offer Alternatives For Treatment Failures Other factors among patients with hypomanic or depressive episodes that may indicate a need for preventive therapy include "number and recency of prior episodes of depression, family history of bipolar disorder, past suicide attempts, past psychotic episodes, past functional incapacity, associated with episodes, and level of social functioning or affective symptoms between episodes." If lithium or tricyclic antidepressant treatment fails "two reasonable alternatives are the addition of carbamazepine to lithium or the replacement of tricyclic antidepressants with monoamine oxidase inhibitors," the panel stated. The panel also noted that "maintenance electroconvulsive therapy may be used for either manic or depressive treatment failures." During a press conference following the conference, the panel said electrical shock therapy remains a useful clinical device, but is only a backup treatment. With respect to psychotherapy, the panel said "for nearly all patients, such treatments should be adjunctive to and not substitutes for pharmacotherapy." FDA Neuropharmacologic Div. Director Paul Leber, MD, commented from the audience that "perhaps it should be left that we don't know what the long-term consequences of lithium treatment are." He said he realized the panel's conclusion that kidney disease is not a major problem from lithium treatment "is based on followup studies that have gone on as long as 10 years." However, he stated, "if you have the onset of the use of lithium chronically beginning early in adult life, the period of risk may be well beyond 10 years or so." In response to a question from Leber as to whether any of the antidepressants have adverse consequences that would disqualify them as drugs of first choice, Alan Gelenberg, MD, Harvard, said the three newer antidepressants that have come to market should not be drugs of first choice because they "carry associated risks that are greater than those with the standard drug." Gelenberg said the risk of tardive dyskinesia with amoxapine (Lederle's Asendin), priapism with trazodone (Mead Johnson's Desyrel), and seizures with maprotiline (Ciba's Ludiomil) "render all of them far down on the list of preferences." He added that desipramine and nortriptyline "look more and more attractive in contrast." The panel concluded that top priority should be placed on "basic research aimed at elucidating the etiology and pathogenesis of major mood disorders and the development of more effective treatments." The panel also suggested "studies of high-risk populations (children of a parent with a mood disorder), the development and testing of new therapeutic approaches, and identification of clinical and biochemical predictors of recurrence" be undertaken.

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