by Michael Gitlin, M.D.

During the 1950's extending to the 1970's, lithium was demonstrated as the first effective treatment for bipolar disorder, initially in treating acute mania, and later in preventing both manic and depressive episodes. Looking back at the early papers and books about lithium written no more than twenty to thirty years ago one might imagine that daily doses of lithium would virtually eradicate the symptoms of bipolar disorder with no more than minor, generally tolerable side effects, and that little else was needed for the vast majority of bipolar patients.

Now, in the 1990's, it is obvious how wonderfully optimistic and amazingly naive were many of those early statements. Even as we discovered other effective medications for treating bipolar disorder, the limitations of medication treatment and the complexities of the disorder became increasingly apparent. Some of these complexities include: when to start preventive treatment, how to best treat bipolar depression, how to deal with pregnancy in bipolar women, understanding the genetic patterns of bipolar disorder and explaining the seeming change in clinical outcome of bipolar patients over the last twenty years. This article will summarize our state of knowledge in each of these areas.

Maintenance (Preventive) Medication Treatment in Bipolar Disorder

Since bipolar disorder is virtually always recurrent (only a very small percentage of bipolar individuals will have only one episode in a lifetime), the typical question for preventive treatment with medication is rarely if but when. There is a clear consensus that after a number of recurrent manic episodes for the vast majority of patients, the benefits of preventive treatment outweigh the risks of further episodes.

Treating bipolar depression is far more complicated than unipolar depression
since the treatment (antidepressants) can be helpful, by alleviating the depression,
as well as hurtful, by triggering off manic episodes.

Whether to treat more aggressively with preventive medication treatment after the first manic episode or after only one manic and one depressive episode is a topic of some dispute. On one hand, we know that the longest period of time between episodes (without preventive treatment) is usually between the first and second episodes. Therefore, it is after the first episode that patients are most likely to remain episode free for a number of years without preventive treatment.

On the other hand, two considerations would encourage preventive treatment, even after the first episode. First, the initial episode of bipolar disorder typically occurs when patients are in their late teens to mid20's. The period of time after that, when the question of preventive treatment arises is a critical one for school, early occupational choices and relationships. A destructive episode in such an important and sensitive time of life might risk important hard won gains. Second, some researchers speculate that later episodes might be more difficult to control than earlier ones. If this were true, a reasonable recommendation would be to treat more aggressively earlier meaning starting preventive medication after one episode in the hope that the entire course of the disorder would be milder and less destructive over a lifetime. This second train of logic is, at this time, simply a hypothesis, not a well documented finding. Thus, there are good rationales to both treat preventively after a first episode, and to not treat. The ultimate decision therefore is an individual one to be made by patient and doctor collaboratively. Hopefully, research into the potential importance of aggressive preventive treatment will give us firmer guidelines as to how to optimally proceed in this critical area.

Bipolar Depression

Among the least explored areas of optimal pharmacological treatment of bipolar disorder is the treatment of bipolar depression. While studies on unipolar depression are published regularly, there is little solid information to guide the treatment of bipolar patients when they become depressed. Treating bipolar depression is far more complicated than unipolar depression since the treatment (antidepressants) can be helpful, by alleviating the depression, as well as hurtful, by triggering off manic episodes or inducing a more pervasive mood instability. Because of this, if bipolar depressions are mild, serious consideration should be given to avoiding antidepressants, using mood stabilizers or psychotherapy alone or in combination. Unfortunately, many patients require the use of antidepressants to alleviate significant depressive episodes. In evaluating antidepressants for bipolar depression, the proper questions to ask are:
1) Are some antidepressants more effective than others?; and
2) Regardless of efficacy, are some antidepressants more likely to trigger destructive manias than others?

In the little research published so far, MAO inhibitors seem to be more effective than tricyclic antidepressants for those patients who have "anergic" features such as psychomotor retardation, profound fatigue or hypersomnia (sleeping too much). Yet, we know virtually nothing about the comparative efficacy of the newer medications such as bupropion (Wellbutrin) and the serotonin active agents such as fluoxatine (Prozac), sertraline (Zoloft), paroxetine (Paxil) and venlafaxine (Effexor). Similarly, in answering the second question, there is very soft, preliminary evidence that bupropion and the serotonin active agents may be less likely to cause mania than the tricyclics. However, we do not have enough information to meaningfully compare tricyclics to MAO inhibitors to serotonin active medications to bupropion in their likelihood to trigger manic episodes. Until more is known, we must treat bipolar depression cautiously, relying on careful observation and individualized treatment decisions.

Bipolar Disorder and Pregnancy

With an average age of onset in the mid 20's, and 50% of bipolar individuals being women, the question of how to treat bipolar disorder around the time of pregnancy has become increasingly important. In some ways, the surprise is that this topic has not been a more serious topic for research, discussion and thought before. All three major mood stabilizers have been documented as teratogenic (causing fetal abnormalities.) Lithium can cause Ebstein's anomaly, a cardiovascular malformation; valproate causes spina bifida, a neurological disorder associated with spinal cord dysfunction; while carbamazapine is associated with a variety of neurological defects. For many years, lithium was thought to be the most teratogenic of these three medications. Recent studies have now caused a revision of these relative risks; some investigators now feel lithium may be the safest of the three.

Yet, even these few generalizations do not begin to describe the complexity of the dilemmas for the risks of treating must be weighed against the risks of not treating. It was once thought that during pregnancy, a woman's risk of having a manic or depressive episode was less than at other times. Here, too, the field is questioning this assumption, thereby requiring the potential consequences of a manic or depressive episode to be considered in the overall treatment decision.

There is no doubt that bipolar disorder is familial; it runs in families.
Two thirds of bipolar individuals have a positive family history of the disorder.

Given these uncertainties, how should a bipolar woman wanting to become pregnant proceed so as to minimize risks to herself and her unborn child? If a woman becomes manic each time she goes off her mood stabilizer, thereby causing extreme life disruption (and typically preventing her from becoming pregnant), should she stay on the mood stabilizer with the potential small risk to the fetus?; should she discontinue her medication and hope for a quick pregnancy and a time of clinical stability?; or should she stay on the mood stabilizer and discontinue it only when she becomes pregnant, thereby minimizing (but not eliminating) the exposure of the fetus to the medication? Another approach would be to discontinue the medication for the first trimester, the most critical time for organ formations, restarting it at the beginning of the second trimester. This strategy would virtually eliminate the risk of organ malformation but would not address the concerns about the possible effects of medications on more subtle aspects of development when fetuses are exposed during the second and third trimesters of pregnancy (an area about which we have virtually no information).

Clearly, no single answer will be right for all women. For now, as with the other critical areas already discussed, the best approach is a careful discussion by the woman, her spouse and psychiatrist, examining the comparative risks and benefits of each option and deciding on a course that seems safest for that individual woman.

Genetics of Mood Disorder

Among the most exciting areas of active investigation in the biology of all psychiatric disorders, including mood disorders is the search for genetic markers. There is no doubt that bipolar disorder is familial; it runs in families. Two thirds of bipolar individuals have a positive family history of the disorder. Furthermore, a significant part of this risk is explained by genetic, not environmental considerations. As an example, the identical (or monozygotic) twin of an individual with bipolar disorder is at much higher risk to have a major mood disorder than is the nonidentical (fraternal or dizygotic) twin of a bipolar person.

Much research over the last decade and continuing currently has been to identify the site of the gene (or genes) that carry the risk for bipolar disorder. Identifying the location of the gene and subsequently identifying those that carry the gene would allow those individuals with bipolar disorder in their families to know if they are at risk to develop the disorder (as well as informing those not at risk). Those individuals at risk and their families could then become more aware of the early signs of the disorder. At some time in the future, interventions to prevent the emergence of the disorder for those at risk to develop it might be constructed. (Presently, there is no knowledge as to what these strategies might be.) Some individuals documented to be at risk might elect preventive treatment with a mood stabilizer even prior to a first episode. Genetic counseling about the potential risk to children would be far more accurate.

Unfortunately, despite the intermittent discovery of a specific genetic marker in large extended families where bipolar disorder is common (an example was the report of a marker for bipolar disorder on Chromosome 11 in a group of Amish families), none of these markers could be replicated in other families from different regions. Whether this is due to the existence of multiple forms of bipolar disorder, the risk for each of which is carried at different genetic sites or whether the risk for bipolar disorder is characterized by alterations at multiple genetic sites is unknown. The research is ongoing, but for now, it must be acknowledged that no established genetic marker for bipolar disorder has yet been discovered.

How Effective Are Our Treatments? What Determines Outcome?

A review of the early studies of the efficacy of lithium in the prevention of episodes of bipolar disorder suggested that bipolar disorder is exceedingly treatable, and that lithium is very effective at preventing episodes. The best summary statement from the controlled studies published in the 1970's is that the relapse rate on lithium was 34% compared to 81% for those treated with placebo. With the discovery of the mood stabilizing properties of carbamazepine (Tegretol) and valproate (Depakote) in the 1980's, it would be logical to assume that with three effective mood stabilizers, bipolar disorder would be even more treatable and that the relapse rates in individuals in ongoing treatment would decrease. Unfortunately, this has not seemed to be the case.

A number of studies published within the last five years have examined relapse rates in bipolar patients treated naturalistically i.e., they were treated according to the best judgment of the treating doctors in a variety of settings (typically university affiliated clinics) and without placebo treated or other control groups. Surprisingly, the percentage of patients in ongoing treatment suffering at least one relapse averaged 55% over one year and approximately 75% over four to five years, far higher than expected.

What explains these discrepant findings? At first glance, it appears that as increasing numbers of effective medications were available, the relapse rates of those treated increased. Yet, a number of possible factors may contribute to explaining this paradox.

Even as we discovered other effective medications for treating bipolar disorder,
the limitations of medication treatment and the complexities
of the disorder became increasingly apparent.

First, the controlled studies such as those done twenty years ago were likely to include less complicated patients. Those individuals with other psychiatric or medical disorders are typically excluded from controlled studies. Thus, the more recent reports probably more accurately reflect the spectrum of those with bipolar disorder, including those with more complicated disorders.

Second, medication noncompliance is typically higher in noncontrolled studies, such as those published recently, and may be more representative of true treatment outcome.

Third, every study that has examined the issue has concluded that drug and alcohol abuse predicts a poor outcome for bipolar patients with or without treatment. It is possible that in more naturalistic settings, the rates of drug and alcohol abuse are higher compared to those who participated in the earlier controlled studies.

Fourth, it is increasingly well documented that, despite the essential biological nature of bipolar disorder, episodes are often triggered by psychological and psychosocial stressors. Thus, bipolar patients in these naturalistic settings (typically clinic settings) may lead more stressful lives, leading to higher relapse rates despite ongoing treatment.

Where does that leave patients, families and clinicians? Since the simple availability of effective medications has not enhanced the outcome of those with bipolar disorder, it would behoove all involved parties to be more attentive to the issues just noted. Compliance to treatment is vital and can be enhanced by a variety of educational techniques, be they individual treatments or in groups such as NDMDA (National Depressive and Manic Depressive Association) and CAMI.

Drug and alcohol abuse is common, profoundly destructive and frequently unrecognized in those with mood disorders. More attention to the recognition of drug abuse and more vigorous treatment is likely to enhance outcome. Finally, the stresses of both life itself and the specific stresses associated with having a major mood disorder can in turn trigger further episodes in a vicious circle (with more stress leading to more episodes leading to more stress, etc.). There must be more attention to these nonbiological factors and the development of methods of decreasing the destructive effects of these stressors.

Summary

Over the last few decades, our understanding about bipolar disorder has increased greatly. A naive optimism in the power of lithium has been replaced by a more mature, complex understanding of this difficult but treatable disorder. Hopefully, over the next decade, the issues noted above will be better understood and better treatment interventions, both pharmacological and psychological, will be developed so as to enhance the quality of life for those with bipolar
disorder and for their families.

(This article was first published in 1995)

MICHAEL GITLIN, M.D. is Clinical Professor of Psychiatry at UCLA School of Medicine where he directs the Affective Disorders Clinic at the Neuropsychiatric Hospital.