by Trisha Suppes, M.D., Ph.D.

Managing Bipolar Disorder
I first became interested in the nervous system and behavior and emotions when I did volunteer work with autistic children as a high school student. My early training was in the neurosciences, and my work focused on neuronal excitability and modulation. In particular, I studied neurophysiological events that occurred over many seconds (e.g. electrical potentials lasting seconds that effected the threshold of neighboring cells), and thus happened in a time frame relevant to people.

Following my medical training, I decided to focus my research on bipolar manic depressive disorder. I found myself fascinated by this psychiatric illness characterized by changes in behavior, activity, mood and thinking. It was particularly interesting to me that many people with this illness could have long periods of complete wellness followed by unexpected and marked changes in behavior, activity, and mood. It is my expectation that the
study of bipolar disorder will allow us to bridge how changes in brain activity lead to altered behavior, emotions and perceptions.

During my residency and fellowship training at McLean Hospital in Boston, I had the opportunity to be involved with a wide range of patients with bipolar disorder. At that time hospital stays were much longer than they are currently, and thus I was able to observe a patient during both the acute and stabilization phase of a manic or depressive episode. While some of the patients had very severe illness unresponsive to virtually any medications available at that time, an experience that helped create my interest in developing new significant treatments for these individuals (see below), other patients were functioning at a very high level between episodes. Given the degree and normalization for long periods during which some patients had few or any symptoms, I began to wonder if all patients with bipolar disorder would need on going lifetime medications.

Brian (not his real name) was a 24 year old young man with a high school diploma, who had attended a local junior college for a few courses. He developed bipolar disorder eight years previously. Brian came from a large family which was supportive of him and encouraged him to stay on his medication in a consistent way. When taking his lithium, he had few or no symptoms, and functioned well in the world. However, Brian had difficulty accepting that he might need medications in an on going way and stopped his lithium about once a year. When he stopped his lithium, within days he developed symptoms of mania, including decreased sleep, increased activity and altered judgment leading him to take trips spontaneously or go into debt. He also became delusional and sometimes aggressive. With each of his lithium discontinuation episodes, he required re hospitalization. As he became older, each hospitalization was longer in duration and he was taking more time to stabilize once his medications were restarted.

I was a resident at McLean Hospital while I was treating Brian and saw him both as an inpatient and an outpatient over a four year period. The question he raised in my mind was whether his experience of a very quick return of symptoms after lithium discontinuation would be true for all patients with bipolar disorder. In some sense, I was asking whether the physiological changes associated with bipolar disorder were representative of an underlying persistent and permanent brain malfunction, or might be due to a temporary malfunction which did not require on going medications for the person's lifetime. When I reviewed the literature, I was unable to find a clear answer as to whether a patient with bipolar disorder needed medication for their entire life, or if medications could be used only during an episode of mania or depression.

My collaborators at Harvard Medical School, including Ross Baldessarini, Gianni Faedda, Leonardo Tondo and Mauricio Tohen, and I discussed these issues and developed a research study to address this question. The research project we developed was to review the world literature of studies where patients with clearly identified bipolar disorder were well stabilized on lithium and symptom free (maintenance phase treatment), and then lithium was discontinued. At the outset of the study, my own hypothesis was not all patients would need lithium throughout their lifetime.

...patients with well proven illness need to stay on their medications indefinitely...

Scouring the literature, we found fourteen studies where the diagnosis was clearly defined, patients had been symptom free for an average of three years (thus, they were in maintenance treatment), and in the majority of cases the patients were on lithium as their only medication. In ten of the studies we reviewed discontinuation had been done blindly (neither patient or doctor knew when lithium was stopped), and four studies were open. What we found was striking. We showed that despite long periods of prior remission, more than 50% of the patients had a return of significant symptoms by five months after stopping lithium. The severity of symptoms was enough to require either rehospitalization or reinstitution of medications. Additionally, over 90% of the patients had a return of symptoms over the next two to three years.

While we were carrying out this study, our Italian collaborators, Leonardo Tondo and Gianni Faedda, were examining clinical findings from Dr. Tondo's clinic in Sardinia. The majority of patients were on lithium alone. Their study involved discontinuing patients with bipolar disorder in maintenance phase treatment (e.g. well stabilized and essentially symptom free), at a rapid rate over about one week versus tapering over a month. We found a difference in recurrence rate or return of symptoms depending on whether medications were stopped quickly or tapered more slowly. While this finding needs to be confirmed and replicated in more controlled studies, medication adjustments are increasingly tapered more slowly when possible.

At this time we make the recommendation that patients with well proven illness need to stay on their medications indefinitely, but that if a medication change is needed (e.g. medical reasons), or if the patient feels very strongly they want to try a period without medication, that any changes be done in a very gradual manner.

New Treatments In Bipolar Disorder
Many patients with bipolar disorder may do very well on lithium alone, or one of the anticonvulsants. Unfortunately, however, there is also a substantial minority of patients where even combining lithium and the anticonvulsants (valproate, carbamazepine), and typical antipsychotic medication will not adequately treat all their symptoms. That is, while the combination of medications may prevent acute episodes, many patients will still be plagued by continued mood lability, poor concentration, episodes of hypomania and depression, and continued difficulty functioning. During the 1980's clozapine (Clozaril) was available for use at McLean Hospital due to an FDA compassionate use waiver for patients who were treatment resistant to all other medications.

During much of the long term treatment I did with patients who had bipolar disorder, I frequently found that the combination of lithium plus anticonvulsants was adequate, but for a few patients these medications were not enough.

Bridgette (an alias) was a 32 year old woman with a 15 year history of bipolar disorder living in a halfway house, and attending a day treatment program. Despite a high level of intelligence and interest in the world, due to persistence of symptoms on her regime of lithium and thioridazine (Mellaril), she was unable to resume independent adult functioning. Her medications prevented acute episodes, but she continued to experience very poor concentration, easy distractibility, periodic trouble sleeping, and mild psychotic symptoms, including heightened sensitivity to stimulation, feeling people could read her mind, and becoming mildly delusional about other people's attentions and motivations.

I first added valproate which helped her to do more stimulating things, such as attend a concert or go to a museum, and her concentration improved, allowing her to read again and pursue interests she had developed while in college. However, she continued to experience mood lability and the symptoms above, though in lessened intensity. I initiated clozapine and tapered off her thioridazine. During the first couple of months of clozapine, plus valproate and lithium treatment, she experienced side effects, including increased sleeping and salivation, but chose to continue the medication because she felt generally better able to concentrate, had less distractibility, and improved mood stabilization.

Throughout the first year on clozapine she made incremental improvements, for example, modulating her food intake leading to a needed weight loss. Over the next two years, she had such a significant improvement in mood stabilization and ability to function that for the first time in ten years she transitioned to living in her own apartment and part time work, and was able to take up hobbies which she had been unable to do for the last ten years. At this time, she continues on a moderate dose of clozapine, valproate and lithium and feels that her illness is stabilized for the first time since she became ill over fifteen years ago.

I left Boston in 1992 because of a unique opportunity to work with Drs. Ken Altshuler and John Rush at the University of Texas Southwestern Medical School, in collaboration with Dallas County Mental Health Mental Retardation (the local public health facility) to study how effective clozapine would be in severely ill bipolar patients. We are carrying out a study where patients who have proven treatment resistant to usual treatments, (including a combination of lithium plus anticonvulsants, and standard neuroleptics in those with psychotic symptoms), are randomized to either "treatment as usual" (anything except clozapine), or a clozapine treatment arm (clozapine plus anything). We then follow patients closely for one year, and plan to continue the follow up less frequently throughout a second year.

We are impressed with the likelihood that clozapine will be an important new medication option for those patients with treatment resistant bipolar disorder. (ed. note - there are now many other newer antipsychotic medications available now).

We have just closed entry into our clozapine study. At this point, I am impressed by how effective clozapine can be to markedly decrease symptoms for many of these severely ill patients, and thus enable them to start a new life for themselves. In fact, many of the patients we have seen have had more dramatic clearing of symptoms and change towards health than I have observed in patients who have schizophrenia. We have not yet analyzed the findings statistically because the study is still ongoing, but we have observed significant improvement in a majority of our patients ranging from marked to moderate. We are impressed with the likelihood that clozapine will be an important new medication option for those patients with treatment resistant bipolar disorder.

Additionally, many of the patients who entered the treatment as usual arm, despite strenuous efforts on our part (including electroconvulsive therapy and calcium channel blockers) were unable to stabilize. We have pulled these patients from the study and started them on clozapine treatment. The treatment as usual patients, who have left the study will not be analyzed as part of the original study, but their response to clozapine reinforces our general impression that this medication may provide help for patients who have not responded to anything else.

One of the very first patients that we screened (1992) was a woman in her early 40's who had never been psychotic, but had a very severe rapid cycling bipolar disorder, with homicidal urges when dysphorically manic (monthly), and suicidal impulses when depressed (monthly). She had been incapacitated for over ten years, and was frequently unable to leave her house or carry out even simple household duties. She had one to three days per month in which she felt relatively mood stable and able to carry out more usual tasks, such as taking care of her home, socializing, and dealing with bills. We initially hesitated to put her in the study because there was no history of psychosis, and I'd been used to thinking of clozapine as both a mood stabilizer and an antipsychotic. However, the clozapine study I designed with John Rush in Dallas was to test the efficacy of this drug for mood stabilization, and she was mood unstable. We entered and randomized her into the study, and she received the clozapine treatment arm.

Our patient had such remarkable mood stabilization from the clozapine that we initially attributed her symptom changes to decreasing other medications, such as an antidepressant. However, not only did her mood cycling stop, impressively she has been without symptoms of mania or depression for over eighteen months. This period of stability is the longest period of mood stabilization since the onset of her illness in her midtwenties. This case was so striking to us that I discussed it with other clinicians, and in fact recently published, with Katherine Phillips and Catherine Judd, a case series of three patients, all of whom had severe rapid cycling, but without a significant history of psychosis. Two of these patients responded in a dramatic fashion to starting clozapine. Controlled trials are needed to more clearly define who will benefit from this medication, but it appears from our experience that clozapine may be helpful to some of those rapidly cycling bipolar patients who are among the most difficult of all to treat.

I think for those patients with the more severe forms of the illness, which may be as many as 20 to 30% of all patients with bipolar disorder, clozapine may herald a new treatment era. Clozapine is the beginning of a whole new generation of drugs, and like chlorpromazine in the 1950's represents a class of medications with improved useful clinical efficacy. Some of these new medications may include olanzepine, sertindole, and a number of atypical antipsychotics that are currently under development. Equally important, there are a number of new anticonvulsant medications, which have just received approval in this country, plus more under study in Europe. There is already early indication that some of these anticonvulsants, many of which have different mechanisms from those currently used for mood stabilization, may be helpful for patients not fully responsive to lithium, valproate, or carbamazepine.

My interest and fascination in the illness itself continues unchanged, as we enter this new treatment era. It is with deep appreciation and considerable awe that I bear witness to the difficulties that many patients with bipolar disorder endure as they make often heroic efforts to manage their illnesses and to lead
fulfilling lives.


(This article was first published in 1995)

TRISHA SUPPES, M.D., Ph.D. is Assistant Professor of Psychiatry at the University of Texas Southwestern Medical Center in Dallas.