Introduction and Conclusions

Mood disorders, also called affective illnesses, are common and serious conditions. It is estimated that at any given time 3 to 4 percent of the nation’s population will be suffering from a major depressive or manic episode. Recurrences are frequent. During the past decade, clinical and research interest in mood disorders has expanded beyond the treatment of acute episodes to include consideration of long-term maintenance treatment aimed at preventing or reducing the frequency and intensity of further attacks. This broadening of focus has occurred in the context of improved approaches to the description and classification of these disorders and newer epidemiologic studies.

Recent evidence has demonstrated the recurrent and chronic nature of these illnesses and the extent to which they represent a continual source of distress and dysfunction for affected individuals and their families, as well as a substantial burden to society. Interest in preventive maintenance treatment has been stimulated further by results from recent long-term trials involving antidepressant drugs and lithium.

The need to consider the longitudinal nature of affective disorders in treatment planning has raised many issues of concern about whether, when, and how to use psychopharmacologic agents to protect patients against recurring episodes of depression or mania. In an effort to resolve questions surrounding these issues, the National Institutes of Health in conjunction with the National Institute of Mental Health convened a Consensus Development Conference on Mood Disorders: Pharmacologic Prevention of Recurrences on April 24-26, 1984. After a day and a half of presentations by experts in the field, a consensus panel including representatives of psychiatry, psychology, pharmacology, epidemiology, internal medicine, and the general public considered the scientific evidence and agreed on answers to the following key questions:

1. How common are recurrent mood disorders, and what are the variations in the course of these illnesses?

2. What groups of patients with mood disorders should be considered for preventive maintenance medication?

3. How effective are these medications in modifying the course of recurrent affective illness?

4. What principles guide selection of specific therapeutic agents for these groups?

5. What are the treatment strategies for using these medications on a long-term basis? What additional or alternative strategies are available for breakthrough episodes, treatment failures, or aspects of the illness unresponsive to medication?

6. What are the long-term risks and complications of maintenance therapy? How should these be assessed and managed?

7. What research areas need further development?

Panel’s Conclusions

Recurrent mood disorders have high prevalence and serious consequences but are currently underdiagnosed and undertreated. There are groups of patients with recurrent mood disorders for whom treatments are available which effectively reduce the frequency and intensity of subsequent episodes. Complete evaluation and careful differential diagnosis are required before initiating long-term preventive treatment. For patients with bipolar disorders, who are particularly likely to suffer recurrences, extensive studies have supported the efficacy of lithium in preventing recurrences.
While unipolar disorder is associated with a reduced rate of recurrence, both lithium and the tricyclic antidepressants have been shown to be effective as long-term preventive treatments for recurrent unipolar disorder.

Although the long-term use of these agents poses certain risks, they are not appreciably different from their use in acute situations. Applying appropriate strategies to the management and use of these drugs will enhance the likelihood of compliance and consequent prevention of recurrences with a minimum of bothersome side effects. Such strategies must be used within the context of an ongoing, supportive relationship among the doctor, the patient, and the family.

Research priorities should be placed on basic research aimed at elucidating the etiology and pathogenesis of major mood disorders and the development of more effective treatments.

How Common Are Recurrent Mood Disorders, And What Are The Variations In The Course Of These Illnesses?

Recurrent major mood (affective) disorders are highly prevalent and have serious consequences. These conditions often are not accurately identified by either patients or clinicians and even when correctly diagnosed are often undertreated or not treated at all. Precision in differential diagnosis using explicit inclusion and exclusion criteria is essential to the identification and optimal treatment of these disorders.

“Depression” can refer either to a normal mood or to an illness requiring treatment. The normal mood, which consists of those transitory feelings of sadness or discouragement that everyone experiences during difficult times of life, is not what is being discussed in this report but rather the specific clinical syndromes of depression and mania. Within this clinical context, the symptoms of depression are many and varied. They may include loss of interest or pleasure in almost all usual activities; poor appetite or weight loss or increased appetite or weight gain; insomnia or hypersomnia; psychomotor agitation or retardation; decrease in sexual drive; loss of energy; fatigue; feelings of worthlessness, self-reproach, or excessive or inappropriate guilt; difficulty thinking or concentrating; and, most serious, suicidal thinking or attempts. Some individuals with manic syndromes may be euphoric, overconfident, and optimistic. However, their mood is typically brittle and deteriorates rapidly into irritability. Others may only be angry or irritable. These individuals may become more active, restless, and talkative; feel that their thoughts are racing; have an inflated sense of self-esteem; be distracted easily; and engage impulsively in activities that could have severe consequences, such as buying sprees, sexual indiscretions, violent behaviors, or foolish business investments. As a result, mania can be devastating to personal relationships and careers.

For the purposes of this report, a major recurrent mood disorder represents a full-blown syndrome of depression or mania, as defined by criteria set forth in the Diagnostic and Statistical Manual of Mental Disorders, Third Edition (DSM-III). Other affective disorders, such as single episodes of depression, chronic milder depression of at least 2 years’ duration (dysthymic disorder), and mild depressive or hypomanic syndromes, are discussed only when they occur in patients who also have a recurrent major mood disorder. These other affective disorders also should be recognized as important causes of emotional impairment and often will benefit from treatment, but they are beyond the scope of this consensus statement. Depressive and manic states caused by medical disorders (e.g., hypothyroidism) or exogenous agents (e.g., amphetamines) also are not considered.

The division of major mood disorders into unipolar and bipolar subtypes is clinically useful. Patients with unipolar disorder have episodes of depression only; patients with bipolar disorder have either episodes of mania or hypomania and depression or episodes of mania alone. Unipolar disorder is reported to be considerably more prevalent than bipolar disorder. Family and genetic (twin, adoption, and pedigree) studies provide compelling support for strong heritability of these disorders, especially bipolar disorder.

The rates of recurrence, variations in course of illness, and the results of clinical trials in this report are based on studies involving patients who sought treatment at inpatient and outpatient units affiliated with university medical centers. It is premature to generalize from these data on course and outcome for the entire population of persons with recurrent mood disorders, which presumably includes a substantial number whose conditions remit spontaneously, who never seek treatment, or who are treated in other settings. However, the treatment recommendations derived from these studies are applicable to patients who suffer major recurrent mood disorders regardless of the setting in which they are seen.

Variations in Patterns of Course of Illness

Relapse refers to the exacerbation of an ongoing episode after an initial suppression of symptoms. Recurrence refers to a new episode that follows a complete recovery that has lasted for at least several months. Treatment for preventing a relapse is called continuation therapy and is distinguished from longer term efforts to prevent completely or reduce the intensity and frequency of recurrence (preventive treatment). Thus, the sequence of treatment may be: (a) an acute phase to control disabling symptoms (may be measured in weeks), (b) a continuation phase to avoid relapses of a single episode (may be measured in months), and (c) a preventive phase to avoid recurrences of new episodes over time (may be measured in years). This report addresses only the third item in the sequence-the preventive treatment of recurrent episodes of affective disorders.

Most of the information presented in this section on course of illness is based on the study of patients whose treatment was not under the control of research investigators, and a substantial proportion of these patients received either minimal or no treatment.

Most patients who have a manic episode go on to have a course marked by multiple recurrences of major depressive and manic episodes. The course of unipolar depression is more variable and less well established. Studies suggest that between 50 and 85 percent of patients with a major depressive episode who seek treatment at university medical centers will have at least one subsequent episode of depression in their lifetime. Between 10 and 15 percent of unipolar patients will have subsequent episodes that will involve manic or hypomanic symptoms, at which point they are reclassified as having a bipolar disorder. This reclassification occurs less frequently as patients become older and have an increased number of depressive episodes.

Although there are fewer studies of affective disorder in children and adolescents than in adult populations, emerging evidence suggests that these disorders do occur in childhood and, when present, may have a chronic, recurring course. It is reported that the lifetime incidence of major depression is as high as 30 percent by late adolescence in children who have at least one parent with a major affective illness.

Once mood disorders become recurrent, they have a course marked by high rates of relapse and recurrence and significant morbidity in subsequent episodes and in the intervals between episodes.

Fifteen to 20 percent of patients with a recurrent unipolar disorder do not recover fully from any given episode and have persistent symptoms for at least 2 years. Recently, similar rates have been reported for patients with bipolar disorder who formerly were believed to have much higher rates of full recovery between episodes.

As many as 50 percent of patients with recurrent unipolar disorders who recover from a given episode are reported to have a recurrence within the first 2 years after recovery. The likelihood of recurrence is greatest in the 4 to 6 months following initial symptomatic recovery; this risk levels off markedly between 6 and 12 months and is still lower after the patient has been well for 18 months. Some evidence suggests that the length of well intervals between episodes decreases for the first few episodes and then remains steady, while the duration of episodes remains fairly constant. The rate of recurrence in bipolar patients is greater than in unipolar conditions and does not decrease over time.

Some recurrent affective disorders have courses of illness marked by discrete episodes with minimal or no symptoms or impairment in social functioning in the intervals between episodes. Other patients have more insidious onsets of episodes, as well as less complete symptomatic recovery and more impairment in social functioning in the intervals between episodes. The proportion of patients in each of these groups is unknown. Patients who have either of these patterns also may have antecedent or concurrent nonaffective mental disorders.

Factors That Increase Risk of Recurrence

A substantial proportion of patients with recurrent mood disorders also suffer from a dysthymic disorder. If dysthymic symptoms persist after recovery from the major depressive syndrome, the risk of developing new episodes of major depression is especially high. The presence of a nonaffective psychiatric disorder such as alcoholism, drug dependence, or anxiety disorder and an older age of onset also substantially increase the risk of recurrence in unipolar or bipolar recurrent disorders. In addition, the greater the number of previous episodes, the higher the risk of recurrence.

Health and Social Consequences

Complications of affective disorders include attempted and completed suicide, increase in deaths from nonpsychiatric medical causes and accidents, impaired social functioning, impaired occupational functioning, impaired parenting, and marital discord. The rates of these events and their severity are substantial.

What Groups Of Patients With Mood Disorders Should Be Considered For Preventive Maintenance Medication?

Before preventive medication is begun, the patient should have a careful medical evaluation to search for organic cause(s) of the affective syndrome or conditions that would contraindicate the use of one or another of the proposed treatments. A comprehensive medical history, physical examination, and appropriate laboratory tests are indicated. This evaluation should include an assessment by, or consultation with, a clinician skilled in the differential diagnosis of mental disorders.

Bipolar Disorder

Patients who have a manic episode are at high risk for recurrences. Manic episodes themselves are very disruptive. The likelihood of becoming psychotic (i.e., having delusions or hallucinations) when manic or depressed is great, and suicide risk is high. Therefore, the occurrence of a manic episode should always raise the question of preventive therapy.

Patients who have not had a full-blown manic episode, but have had a hypomanic and a depressive episode, are also at high risk for recurrence and are more likely to become psychotic when depressed than are patients with unipolar disorder. Therefore, careful consideration should be given to implementing preventive therapy in these patients. Other factors in this patient group that indicate a need to consider 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. Each of these factors tends either to increase the likelihood of recurrence or to be associated with considerable disability and risk should a new episode occur.

Unipolar Disorder

This condition is less frequently recurrent than the bipolar disorders, and the efficacy of the preventive treatments is less clearly established. Therefore, the decision of whether and when to initiate preventive therapy is more highly individualized for patients with unipolar disorders. It depends on identifying those unipolar patients with a high risk of recurrence. The presence of another mental disorder, a chronic medical disorder, or chronic affective symptoms each increases the rate of recurrence, as does older age at the onset of the first depressive episode. Psychotic features, serious suicide attempts, or serious functional impairment during recent episodes all predict increased severity in subsequent episodes. A family history of suicide, bipolar disorder, or psychotic affective episodes also is predictive of increased severity.

Additional Considerations

Additional factors also play a role in the timing and decision to begin preventive therapy in patients who have never had a manic episode. A slow or incomplete response to treatment for a prior episode of depression would lead one to consider preventive therapy more closely. A rapid therapeutic response in a patient with long intervals between episodes argues against the initiation of preventive therapy. The potentially irreparable disruption that a depressive episode may exact on a patient’s work, family, and social relationships also would increase the need for preventive therapy. The decision to use preventive treatment is complicated in women who are, or may become, pregnant. Special consideration is also needed for patients who find the presence of side effects disruptive or highly unpleasant For such patients the decision involves the careful weighing of the potential benefits and risks of preventive treatment.

How Effective Are These Medications In Modifying The Course Of Recurrent Affective Illness?

Bipolar Disorder

In a summary of 14 studies of bipolar disorder, the percentage of patients having a recurrent episode of either mania or depression during 1 year after the start of treatment was greatly reduced by lithium maintenance in contrast to placebo. In most of these studies, the number of recurrences was reduced by 50 percent compared to placebo, and the recurrences were less severe. However, rapidly cycling bipolar patients, i.e., those who have three or more episodes a year, often respond poorly.

Preventive treatment with lithium is equally effective against both manic and depressive recurrences in male and female bipolar patients of all ages from early adulthood to old age, but few data are available for children and adolescents and for the elderly.

The preventive effect of lithium may not develop fully for several months. An early recurrence of bipolar illness following initiation of treatment should not necessarily lead to its abandonment. Antidepressants have not been shown to be effective in preventing recurrence of manic episodes in bipolar disorder.

Unipolar Disorder

Many controlled studies have shown that preventive treatment with lithium or antidepressants (imipramine and Amitriptyline HCL) can substantially prevent recurrent episodes of unipolar depression. In most patients, lithium and tricyclics decrease the frequency and/or intensity of recurrences. In six studies with follow-up periods ranging from 5 months to 3 years, the percentages of patients who relapsed or had a recurrence on placebo were significantly greater than the percentages of patients who relapsed or had a recurrence on lithium. In a similar manner, a significant difference between tricyclic however, find lithium and tricyclics to be equally effective or lithium to be somewhat superior.

Individual patients may respond better to either lithium or tricyclics. One multicenter study suggests that patients whose last episode was severe have a better response to imipramine and that patients whose last episode was of only moderate intensity respond equally well to lithium and tricyclics. Research to date has not produced clear-cut guidelines for choosing one over the other when all other factors are equal, nor has it supported the combination of the two as superior to either alone.

Tricyclic antidepressants and lithium prevent recurrences of unipolar depression in both men and women of all ages from early adulthood to old age; however, few data are available for children and adolescents and for the elderly.

Successful prevention of recurrence may involve other important gains, including increased stability of mood during intervals between episodes, regained self-esteem, renewed hope for the future, improved social relations, enhanced vocational abilities, and increased enjoyment of recreational activities.

Because the preventive treatment of recurrent mood disorders is clearly effective for large numbers of persons suffering from these conditions, and because a substantial proportion do not now seek treatment or are not accurately diagnosed, systematic efforts should be made to bring about a greater awareness and understanding by both health professionals and the public of the nature and effective treatment of these illnesses.

What Principles Guide Selection Of Specific Therapeutic Agents For These Groups?
Decision to Initiate Preventive Treatment

Repeated and candid discussions with the patient and the patient’s spouse or other relatives are mandatory to ensure full understanding of potential advantages and risks of preventive treatment as well as of no treatment. These discussions should begin as early as possible after an acute episode is under control. The clinician should have complete information regarding the illness from the patient’s and the family’s perspective, and it is essential that patients and their families share in the decisionmaking process. The possible salutary effects on family and job stability should be explained thoroughly, and the known serious and troublesome side effects of each drug under consideration should be made clear. The necessity and importance of long-term monitoring, including required laboratory tests, should be understood fully. Compliance during treatment is improved greatly when all parties understand the therapeutic goals.

Choice of Drugs

Lithium is the drug of choice for preventing recurrences of bipolar disorder. In treating unipolar disorders, both lithium and tricyclic antidepressants have been shown to be effective for prevention. Since most patients will have been treated previously with tricyclic drugs for their depressive episodes, it is usually most appropriate to continue with the same drug, provided it has been effective and is well tolerated. Tricyclic antidepressants also may be preferable in older patients in whom renal function shows a normal decline with age. In addition, elderly individuals are more likely to be using other drugs to treat concurrent illnesses. Either these other agents or the illnesses themselves could interfere with lithium excretion and, thereby, predispose to toxicity. On the other hand, some older patients may be more vulnerable to certain side effects of the tricyclic antidepressants, such as urinary retention, cardiac arrhythmias, and increased intra-ocular pressure. Some clinicians recommend that lithium be used in both bipolar and unipolar cases to minimize the risk of an unexpected manic episode in a patient considered to be unipolar. In particular, lithium may be preferable for patients who have first degree relatives with a history of bipolar illness or whose psychiatric history is uncertain, since some previously diagnosed unipolar depressions ultimately may prove to be bipolar. The consequences of an unexpected manic episode, which lithium is likely to prevent, are generally serious.

Only a few tricyclic antidepressants have been used in controlled studies of the preventive effect of these agents. It is likely, however, that all standard tricyclic drugs are equally effective, although the question has not been studied empirically. On the other hand, some patients seem to respond to one tricyclic antidepressant after receiving no benefit from another, and side effects will differ from patient to patient and agent to agent. Thus, close monitoring is required, and some sequential courses of treatment with different antidepressants may be indicated.

What Are The Treatment Strategies For Using These Medications On A Long-Term Basis? What Additional Or Alternative Strategies Are Available For Breakthrough Episodes, Treatment Failures, Or Aspects Of The Illness Unresponsive To Medication?

Use of Lithium and Tricyclic Antidepressants

Specific clinical guidelines for the use of lithium and tricyclic antidepressants are available in various pharmacologic and psychiatric textbooks as well as articles in professional journals. Unfortunately, despite the interest in various biological tests for the diagnosis and treatment of mood disorders (dexamethasone suppression test, thyrotropin releasing hormone test, thyroid stimulating hormone test, measurement of 3-methoxy-4-hydroxyphenethyleneglycol), no clear-cut guidelines for their use in the treatment of recurrent mood disorders have been established. What follows is only a brief outline of the use of these drugs as preventive agents.

Preventive doses of tricyclic antidepressants have not been adequately defined and, thus, physicians must be flexible in seeking to achieve optimal control. In general, doses similar to or somewhat lower than those used in treating the acute episode have been found effective. Studies of long-term preventive maintenance treatment with tricyclics have not adequately evaluated the effectiveness of dosages greater than 150 mg/day. Lithium in conventional forms is satisfactory. The goal in lithium treatment is to achieve serum concentrations between 0.6 and 0.8 mEq/L in most patients. While some patients may require higher concentrations, in general the physician is advised to maintain the patient on the lowest dose that prevents the return of symptoms since these lower concentrations are associated with fewer side effects.

Duration of Treatment

Duration of treatment must be determined on an individual basis, depending on the previous pattern of episodes, degree of impairment produced, the adverse consequences of a new recurrence, and the patient’s ability to tolerate the drug. Data concerning the optimal duration of treatment are lacking. Most clinicians, as well as patients, would be loath to embark on a lifetime course of treatment. If the patient remains free of recurrences during a period equivalent to several of the previous cycle lengths, a decision may be reached to discontinue treatment, provided that a family member or friend of the patient is available to alert the patient and, if necessary, the physician to symptoms of recurrence. In general, the stronger the indications for initiating preventive treatment, the longer its duration should be.

When tricyclics are discontinued after long-term exposure to the drug, the process should be gradual to avoid symptoms that sometimes occur after sudden cessation. Thus, decreases in doses may be spread over weeks or months, with larger decrements early in the withdrawal phase and smaller decrements once the daily dose becomes 50 mg or less. Discontinuation of lithium can be done abruptly or spread out over a couple of weeks. The latter is probably advisable for patients receiving relatively high doses. Neither drug is addictive or prone to abuse.

Breakthrough Episodes

Breakthrough episodes during preventive treatment are manifested by the emergence of clinically significant signs and symptoms of either mania or depression. Purely symptomatic treatment (e.g., sedative hypnotics or anxiolytics) should be delayed at this stage since close assessment over several weeks is desirable to be sure that a clinically significant recurrence of symptoms has occurred. When such breakthroughs occur during lithium treatment, the first step is to check serum lithium levels either to assure compliance or to justify an increased dose. The second step is to check the thyroid status, since hypothyroidism may mimic depression. The third step would be to add to the lithium an antipsychotic for manic breakthroughs or an antidepressant for depressive breakthroughs. These agents, however, should be used only temporarily for relief of the acute symptoms and should be withdrawn when these symptoms abate.

Treatment Failures

If the aforementioned measures fail, other treatments should be tried. Although many alternatives have been suggested, none has been extensively tested. Several reasonable alternatives are the replacement of lithium with carbamazepine, the addition of carbamazepine to lithium, or the replacement of tricyclic antidepressants with monoamine oxidase inhibitors for depressive treatment failures. Electroconvulsive therapy may also be considered for either manic or depressive treatment failures, particularly where suicidal risks seem high.

Some patients, usually those who have frequent and severe recurrences of depression that require large doses of tricyclic antidepressants, may experience more frequent episodes after use of these agents. When such a pattern is recognized, the minimal effective dose of tricyclic should be used. In some cases, allowing a depressive episode to run its course without antidepressant treatment will break the cycle.

Psychological Management of Patients in Preventive Therapy

The problem of patient compliance, especially with lithium, has been well documented in several studies. Medication side effects as well as patient and family attitudes toward these illnesses and their treatment may each contribute to noncompliance. It is believed that the treating physician can make a considerable impact on treatment efficacy by counseling patients who are on preventive therapy, interviewing carefully, asking directly about particular side effects, eliciting patients’ concerns, treating side effects as indicated, and providing information to ensure optimal adherence.

More specific psychotherapies or brief counseling sessions may be helpful in reducing the secondary consequences of chronic conditions that are often associated with recurrent major affective illness (e.g., occupational or marital disruptions). This treatment may be provided either by the treating physician or by another professional skilled in such services.

Three types of psychotherapy (cognitive, interpersonal, and behavioral) have been found helpful in alleviating depressive symptoms. Whether these specific psychotherapies or others also play an adjunctive role with pharmacotherapy in preventing recurrence has not been firmly established. Based on our present state of knowledge, for nearly all patients suffering from major recurrent mood disorders, psychotherapy should be used in combination with, not as a substitute for, pharmacotherapy for long-term preventive treatment.

What Are The Long-Term Risks And Complications Of Preventive Therapy? How Should These Be Assessed And Managed? Adverse Effects of Preventive Treatment

The risks of preventive therapy with lithium or tricyclic antidepressants do not appear to differ appreciably from the adverse reactions to these drugs for treatment of acute episodes of mood disorders, with the exception of impaired thyroid function, which may increase in frequency over time on preventive lithium therapy. Because lower doses are frequently successful for prevention, side effects may, in fact, be less of a problem. The earlier fears of irreversible renal damage now seem to be unwarranted. Except during the first trimester of pregnancy, there are few significant permanent risks with either lithium or tricyclic therapy. There may be minor renal tubular defects and hypothyroidism brought on by long-term lithium therapy, and a few patients may be at minimal risk for arrhythmias with extended treatment with tricyclic antidepressants. Tricyclics may lead to weight gain, orthostatic hypotension, subtle confusional states, and exacerbation of mania. Lithium may create symptoms of thirst, polyuria, tremor, diarrhea, weight gain, or, less commonly, hypothyroidism. Memory problems, tiredness, and a dulling of senses have been reported as additional complications of lithium that may contribute to noncompliance. Separation of these possible side effects from symptoms of the illness needs to be explored. A carefully supervised reduction in dose, revaluation of thyroid status, or a therapeutic trial of antidepressants are ways in which the distinction may be achieved. Because patients with mania and depression are at high risk for suicide, supplies of medication should be limited. Adverse consequences of lithium on the fetus and nursing newborn should be made known to women who may become pregnant. Preventive use of lithium and tricyclic antidepressants in children and adolescents must be based on clinical judgment, as risks and benefits have yet to be firmly established. Preliminary studies suggest that the potential problems are similar to those seen in adults.

Monitoring for Adverse Effects

Follow-up visits at regular intervals provide an opportunity to assess changes in clinical status, resolve compliance issues, institute appropriate medical interventions, and establish a basis for treatment during breakthrough episodes. More frequent contact is clearly necessary during periods of potential recurrence or change in clinical status. Clinical observation and laboratory tests provide useful benchmarks in the event of complications during long-term treatment. Current practice during treatment with lithium is to monitor serum lithium levels at intervals of 1 to 3 months and to assess serum creatinine values and thyroid stimulating hormone (TSH) values every 6 to 12 months. Additional studies such as EKGs may be needed to elucidate other adverse effects.

Lithium intoxication is less likely in patients on low doses and with low serum concentrations as recommended here for preventive treatment. Patients should be advised always to keep well hydrated and to report immediately intercurrent illnesses that cause vomiting, diarrhea, or fever, or treatment with or use of new drugs.

What Research Areas Need Further Development?

There are many deficiencies in our knowledge of how best to prevent recurrent mood disorders.

The fundamental questions that underlie these deficiencies and need to be investigated are:

1. Why do some patients develop severe recurrent illnesses while others do not?

2. Why do some patients respond well to preventive treatment while others do not?

3. Why do some patients lose benefits after an initial response to treatment?

Answers to these questions will require information from therapeutic, epidemiologic, neurobiologic, and genetic studies. The results of such studies should elucidate basic mechanisms of the disorders themselves.

Some research strategies would include, for example, studies of high risk populations (e.g., 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. The panel feels that priority should be given to the search for new knowledge about the pathogenesis of mood disorders. Such knowledge might then lead to new and more effective therapies for their treatment.