by Joshua D. McDavid, M.D., M.P.H. & Michael E. Thase, M.D.

Our sense of personal and physical integrity is undermined by chronic illness. The fragility and temporality of life is intimated, and the inviolability of the body and the belief in our autonomy is threatened. Manic depression, or bipolar affective disorder, is a chronic illness that displays a highly variable course and generally manifests in the second or third decade of life. Perhaps more prominently than other chronic medical illnesses, people with manic depression are perplexed by whether they have engendered the illness and whether it is an integral part of their personality, temperament, or nature. This disquieting ambiguity can be difficult to resolve, and often has a profound emotional impact.

The last forty years, beginning with the discovery of the therapeutic effects of lithium, has seen encouraging developments in the treatment of bipolar disorder. Although there are no cures, significant pharmacological and psychotherapeutic advances have led to the reduction of the frequency, severity, and morbidity of episodes. In the following, we will summarize some of the important contemporary themes of long term treatment that we believe are important for doctors, patients, and families to know.

Treatment Goals and Principles
The treatment plan for a person with bipolar disorder may be complex, and includes consideration of several important factors: assessment, statement of treatment goals, the forging of a therapeutic alliance, provision of psychoeducation, the ongoing attention to psychosocial factors, and the ongoing management of medication.

Proper assessment is an important preliminary component of the treatment, and we cannot emphasize how much it helps to guide subsequent management.

Manic depression, or bipolar affective disorder, is a chronic illness
that displays a highly variable course and generally manifests in the second or third decade of life.

For example, the treatment of a "mixed state" (i.e., an episode with an admixture of depressive and manic features) usually differs from that of a "pure" depressive episode. Initial determination of the duration and severity of episodes of mania, hypomania (i.e., a milder form of mania), depression, or mixed state is a requirement. Further investigation should focus on the level of distress, amount of dysfunction at home and in the workplace, deterioration of interpersonal relationships, family history and other history of medical illnesses, risk of dangerousness to self or others, presence of psychosis, and need for hospitalization or commitment. Definitive diagnosis of acute states of depression and mania requires discrimination from medical causes of mania and depression, such as substance abuse or hypothyroidism, with a thorough physical exam and laboratory studies. People with a history of depression, substance abuse, psychosis, or a childhood diagnosis of attention deficit disorder may be at particularly high risk to develop bipolar disorder.

Presently, the goals of treatment are: first, reduction in symptoms; second, decreasing the frequency or preventing future episodes; and third, optimizing overall functioning, especially during episode intervals. Treatment thus may be thought of as having three stages: acute, continuation and maintenance.

The major goal of the acute stage is to achieve a significant response to treatment. The acute treatment phase may be completed in as little as two or three weeks or it may take months to find the right combination of therapies. A complete recovery, whenever possible, is the goal of continuation treatment, which may require two to six months or even longer. However, as the patient's improvement continues to consolidate towards a complete recovery, the frequency of continuation therapy visits may decrease from every other week to monthly.

Maintenance treatment, which can last for decades, is intended to prevent recurrent episodes of illness. Maintenance treatment may involve as little medical contact as twice yearly visits. The goals of this stage of treatment are best fulfilled by helping the patient to learn to monitor symptoms as potential early warning signs of a recurrent episode of illness. Teaching patients to be vigilant about their own symptoms helps to foster a collaborative therapeutic relationship. Moreover, rapid interventions triggered by such warning signs may prevent full blown recurrent episodes.

Given the long term nature of manicdepression, the therapeutic relationship between patient and doctor (or therapist or treatment team) is pivotal for establishing a solid treatment foundation. We have found that it is best very early in treatment to address several issues: course of the illness, confidentiality, the need to establish a contact person (family member or friend) who can provide collateral information, frank discussion of the expectations for benefit and the limits of treatments, and the potential need for hospitalization and commitment.

Quite often, ethical concerns (i.e., poorly controlled or reckless behavior, or the decision to hospitalize involuntarily) and complex decisions (i.e. treatment during pregnancy or genetic counseling) emerge, and as much as possible we try to anticipate them by engaging the person with manic depression and their loved ones in frank discussions.

People with bipolar affective disorder do not experience their episodes of illness in a vacuum and, as a result, family, friends, and colleagues invariably bear some of the disruption, too, often with great distress. Attention to occupational, social, family, and interpersonal problems and ethical or legal difficulties is critical in maintaining long term progress. We have found that it is best to involve the family or significant others in the treatment alliance, without, of course, compromising the confidentiality of the doctor patient relationship.

The management of bipolar disorder almost always requires a psychiatrist, preferably one experienced with the disorder. We prefer a treatment team approach within the setting of a specialty clinic, although we recognize that such an approach may not be practical in rural or underserved areas. There are many advantages to having care provided at a mood disorder clinic: experienced staff who are familiar with the management and ethical issues that frequent the illness, the possibility of forming peer and family support groups, and especially the provision of continuity of care.

Milder exacerbations of symptoms and full fledged major episodes (especially mania) often unravel psychological defenses and may de stabilize the patient's or family's coping mechanisms. It is particularly common for people with mania, despite frequent and severe episodes, to deny they have an illness, to only intermittently follow through with treatment, or to resist treatment altogether. Persistent, stubborn, or intractable denial requires skilled clinicians experienced with bipolar illness. Our impressions are that a specialty clinic is better equipped to work with people with such attitudes, helping the patient to accept the illness more easily, and reducing concerns such as suffering alone without support.

Perhaps more prominently than other chronic medical illnesses, people with manicdepression are perplexed by whether they have engendered the illness and whether it is an integral part of their personality, temperament, or nature. This disquieting ambiguity can be difficult to resolve, and often has a profound emotional impact.

Pharmacotherapy
Medication treatment of bipolar disorder currently is the cornerstone of all modern therapeutic approaches, especially among long term treatments. Americans are particularly reluctant to accept pharmacologic treatments for conditions that they view as having emotional or psychologic origins and recent surveys suggest that between 30 and 50% of individuals with manicdepression are not receiving any current pharmacotherapy. Thus, it is not surprising that some individuals will seek unconventional treatments that emphasize macrobiotic, "holistic" or natural remedies. While keeping an open mind about new developments is a good general principal, we wish to emphasize strongly that the only scientifically proven treatments for bipolar disorder are pharmacologic and we similarly strongly discourage the use of such "natural" remedies, without the collaboration of a competent, boardcertified psychiatrist.

Research and clinical experience clearly supports the use of mood stabilizers in the long term prophylaxis or prevention of new episodes of bipolar disorder. The three most effective mood stabilizers are: lithium, carbamazepine (Tegretol), and valproate( Depakote). These agents are equally effective as acute phase treatments for mania, although lithium is usually used as the "first line" of treatment because of its long track record, relative safety, and inexpensiveness. All three mood stabilizers are reliably measured by simple blood tests, a significant advantage for treatment. When these mood stabilizers are used for maintenance therapy they have been shown to reduce the number and severity of subsequent episodes, as well as improve mood stability between episodes.

The mood stabilizers are also somewhat effective for treatment of acute bipolar depression. They are generally not fast acting. They may take at least two weeks or even longer to be effective in diminishing manic symptoms and up to eight weeks to diminish depression symptoms. During acute episodes of illness, and depending on the nature of the mood instability, mood stabilizers are frequently supplemented with antipsychotic, benzodiazepines, or antidepressants.

Electroconvulsive therapy (ECT) is a rapid and powerfully effective treatment for both mania and bipolar depression. It is probably underused in the 1990's because of the stigma of "Shock treatments" and because many severely ill people with manic depression will not consent to the treatment. The dangers of ECT have been greatly exaggerated by "antipsychiatry" groups. However, ECT is an expensive treatment and its major side effect, memory loss, can be transiently disabling. Further, ECT only treats the current episode and does not solve the problem of relapse or cycling into recurrent episodes. Effective ECT must be followed by treatment with a mood stabilizer. On occasion, weekly or monthly sessions of maintenance ECT are recommended for people who have had multiple relapses despite use of preventative medications.

Prior to initiation of any mood stabilizer a careful medical history concentrating on cardiac, liver, renal, thyroid and the central nervous system should be undertaken. There should be a review of present and past drug use encompassing prescription drugs, over the counter preparations, illicit drugs, alcohol, caffeine, and nicotine usage. Other areas also need to be explored, for example, dietary habits, weight change, exercise and recreational habits, and sexual habits. Additionally, laboratory investigation of medical causes of mood elevation or depression, and pregnancy status are considered. Depending on the mood stabilizer to be prescribed specific tests may be supplemented. The use of mood stabilizers during pregnancy is a complex issue and requires careful collaboration between the OB GYN and psychiatrists. In elderly patients or those with suspected cardiovascular abnormalities, an electrocardiogram is an important pre treatment assessment. As noted earlier, blood level monitoring of mood stabilizers facilitates treatment especially during initiation, after any dosage changes, after the development of significant side effects, or following clinical changes in a patient's mood. Side effects that do not improve may prompt changing dosage schedule, lowering of the dosage, or additional or substitute medications. Patient education is particularly important here.

Premature or abrupt discontinuation of an effective mood stabilizer is of particular concern and may precipitate new episodes of mania, depression, or mixed states. On occasion, these new episodes may "explode" almost overnight. A small number of people are fortunate enough to have only a single significant episode of mania or episodes as infrequently as every ten years. For these individuals, a slow taper off a mood stabilizer over several months may be worth attempting after a sustained period of recovery. But for most, episodes occur in cycles of one to three years, and each new episode appears to convey added risks of suicide or development of a refractory (i.e., not responsive to medication) stage of illness. Some have speculated that repeated, stressful episodes of manic depression actually changes brain function, resulting in more severe and less treatment responsive episodes. Therefore, many specialists recommend maintenance treatment after only one episode of mania or two episodes of depression. This may be particularly important for those who first become ill at a young age (e.g., 25 or younger) who seem to be at an even higher level of vulnerability.

Of the three mood stabilizer, most psychiatrists have much more experience with the use of lithium as a long term treatment of bipolar disorder. Lithium is a metallic element of the same family as sodium. It is abundant on the earth's surface, and is administered as a medication frequently in the form of a salt, lithium carbonate. Those seeking a "natural" treatment cannot find a more elemental treatment in all of modern medicine!
The precise manner in which lithium works is not completely understood. It is clear that lithium effects the activity of neurotransmitters, the brain's chemical messengers, and more specifically regulates the responsiveness of brain cells. We suspect that further research will reveal that lithium works because it stabilizes or helps to properly regulate brain systems, governing excitement, pursuit of goals, restfulness, and pleasure.

Lithium does cause a number of common side effects: nausea, diarrhea, increased urination, acne, thirstiness, muscle weakness, tremor, sedation and/ or confusion. Most side effects subside or dissipate over time and dosage adjustment often helps those that do not. Weight gain, hypothyroidism, and increased urination are side effects that are more common long term concerns. Longer term treatment may cause scarring of the kidneys, although this side effect does not cause kidney failure, nevertheless, most doctors obtain annual or semi annual laboratory tests to monitor these changes. Overdose can be a serious medical emergency and toxic doses may lead to confusion, marked morbidity and even death. However, if taken as prescribed, lithium is quite safe. Fortunately, most side effects are manageable and the majority of people tolerate it well. More importantly, most people come to appreciate how much better they feel after taking an appropriate dosage for an extended period.

MEDICAL TREATMENTS FOR BIPOLAR DISORDERS

Recommended Prophylactic Treatments (also used for acute exacerbations):

• Lithium (Eskalith, Lithobid)
  
• Carbamazepine (Tegretol)
• Valproate (Depakene, Depakote)
  

Recommended Adjuvants in Acute Exacerbations (occasionally used as long term adjuvants):

• Anti-psychotics (Mellaril, Trilafon, Haloperidol, Clozaril, Risperdal, etc.)
  
• Benzodiazepines (Clonazepam, Lorazepan, Diazepam, etc.)
  
• Electroconvulsive Therapy
  
• Thyroid Hormone Anti depressants MAOIs (Parnate, Nardil) Tricyclics (Imipramine, Nortriptyline, etc.)
  
• SSRIs (Prozac, Paxil, Zoloft)
  
• Other (Effexor, Wellbutrin)
  

Promising future agents:

• Calcium Channel Blockers (Verapamil)
  
• Moclobemide
  
  

In the last decade, two other medications, effective for long term treatment of bipolar disorder, have been promoted. The anti convulsant carbamazepine comes close to being an alternative first line therapy to lithium. Although its usefulness to treat acute bipolar depression is still under investigation, carbamazepine is as effective as lithium for the treatment of mania. Moreover, carbamazepine is possibly more effective than lithium for treatment of rapid mood cycling and mixed mood states. The mechanism of carbamazepine's anti-manic action is also unknown, but it is believed to help stabilize the inner workings of nerve cells, thus modulating brain signals.

Carbamazepine and lithium may be used together when these medications have not been effective as single drug strategies. Carbamazepine may have fewer day to day side effects than lithium for people who have not done well on lithium. The principal side effects are dizziness, drowsiness, clumsiness, double vision, nausea, and vomiting. Most of these symptoms occur during the initial few days of carbamazapine treatment and soon resolve. However, carbamazepine has less common side effects that include potentially lethal forms of anemia, decreased white blood cell production (granulocytopenia), and a severe skin reaction know as the Stevens Johnson syndrome. Initially, blood levels of red and white blood cells are monitored closely, about every two weeks, along with carbamazepine levels. In addition to these precautions, carbamazepine has significant interactions with other medications and may alter their effectiveness.

Valproate has increasingly found a place as a potential alternative to lithium and carbamazepine. Like carbamazepine, it is an anti convulsant and has been shown to be effective for mania. Less certain is its effectiveness for acute bipolar depression and long term studies of its effect as a maintenance treatment are underway. Even less is known about its mechanism of action, but presumably it also effects brain cell responsiveness to neurotransmitters and modifies signals.

Available evidence suggests that lithium, carbamazepine, and valproate all have different mechanisms of action. Like carbamazepine, valproate may be combined with lithium to help those with harder to treat conditions. Sometimes carbamazepine and valproate are combined as well, although blood levels need to be monitored carefully. Valproate's side effect profile is generally favorable and (unlike carbamazepine) it has no catastrophic side effects in adults. (In children, however, it rarely may cause liver failure.) The most common side effects are gastrointestinal distress, anorexia, nausea, vomiting, indigestion, and diarrhea. Other side effects are occasional sedation, weight gain, tremors and hair loss. Most of the side effects remit over time. Like carbamazepine, use with other medications requires monitoring.

People with a history of depression, substance abuse, psychosis, or a childhood diagnosis of attention deficit disorder may be at particularly high risk to develop bipolar disorder.

As mentioned earlier, antipsychotics, benzodiazepines, anti depressants, ECT, and other agents are frequently urged treatment for acute episodes in combination with one or more mood stabilizers. Occasionally, for patients with refractory or unstable moods, these agents must be used for long periods of time to augment the mood stabilizers. Antipsychotics are typically used to help treat hallucinations and/ or delusions. These severe and frightening symptoms are the most disabling faced by people with manic depression. Of the additive or adjunctive medications, anti psychotics are probably the most widely used for long term mood instability. Long term usage does raise the concern of inducing tardive dyskinesia, which is characterized by irreversible, abnormal muscle movements, particularly of the face, hands, and neck.

Antidepressants are used when acute bipolar depression does not respond to a mood stabilizer or a new episode of depression develops despite maintenance treatment. The major types of anti depressants include both older (tricyclics [TCA's] and monoamine oxidase inhibitors [MAOI's]) and newer (selective serotonin reuptake inhibitors [SSRI's], venlafaxine, and bupropion) types of drugs.

The value of the newer agents is that they tend to have fewer side effects and are much safer if they are taken in overdose. Most American psychiatrists now prefer to use the SSRI's first, although we do not think that their effectiveness has been proved for bipolar depression. For depressed episodes characterized by fatigue, slowed thought and action, increased sleep, and/or increased weight, we still favor the older MAGI tranylcypromine (Parnate). The MAOI's require special caution however, because they alter one's capacity to metabolize a protein subunit, tyramine, and chemically related drugs. Thus people who take an MAGI must also follow a diet low in foods rich in tyramine (i.e., aged cheeses, overripe bananas, liver, and fava beans). They must also avoid beer and most alcohol, cocaine, diet pills and certain cold remedies, Although inconvenient, most people are able to follow the MAGI diet without difficulty.

Benzodiazepines such as diazepam (Valium), lorazepam (Ativan), and clonazepan (Klonopin), are given to induce sleep and to calm agitation. Benzodiazepines may be used to reduce the dosage of anti psychotics. However, they are not good maintenance medications because their benefits tend to decrease over time and they also may lead to depression. They have some potential for abuse, and some people may develop physiologic dependence.

Psychotherapeutic treatments
Another, often overlooked, component of long term pharmacologic treatment for bipolar disorder is psychotherapy. Psychotherapy may be individual, group or couples/family oriented, depending on the needs of the patient and the talents of the therapist. Specific types of therapy include: medical management, supportive, interpersonal, dynamic, cognitivebehavioral, and behavioral approaches. Most approaches focus on "here and now" issues that confront people who have bipolar disorder. These issues include the social and emotional consequences of current and past episodes, apprehension about future episodes, loss of the ideal "healthy self" and the stigma of a psychiatric illness.

It is important to keep in mind that the match of the patient and therapist may be as important as the methods or techniques. Does the therapist listen? Does he/she seem to understand? Can she/he provide a comfortable balance of structure and support? A poor match with one therapist does not mean that therapy per se will not be helpful.
Although, intuitively, one would expect that psychotherapeutic approaches would be beneficial in promoting favorable long term outcomes, research in this area is still in its infancy. Some of the areas under evaluation are the impact of family therapy, behavioral therapy and interpersonal therapy on functioning, mood exacerbations, and symptoms.

Summary
Bipolar affective disorder has a lifetime prevalence of at least 1%. Its severity ranges from mild, readily controllable episodes, to rapidly cycling and/or psychotic states that are incapacitating. For most persons, one episode of mania or two episodes of depression mean a significantly increased risk of repeated cycles of illness. Suicide, drug and alcohol abuse, and loss of family and/or occupation are not uncommon consequences. More treatment options exist today than ever before and most people with this illness can be treated effectively. For many, a long term treatment plan including daily use of a mood stabilizer, practical psychotherapy, and judicious use of other medications to quell minor mood swings provides a level of benefit superior to that of people treated for high blood pressure, diabetes, or other common chronic or recurrent medical illnesses.

(This article was first published in 1995)

JOSHUA D. McDAVID, M.D., M.RH. is Acting Assistant Professor of Psychiatry in the Department of Psychiatry at the University of Washington in Seattle. MICHAEL E. THASE, M.D. isAssociate Professor of Psychiatry at the University of Pittsburgh, School of Medicine, and Diyector of the Division of Mood, Anxiety, and Related Syndromes where and his associates are currently funded by the National Institute of Mental Health and the Stanley Foundation to conduct research on the treatment of depression and manic depression.