Husseini K. Manji, MD, Chief of the Laboratory of Molecular Pathophysiology and Director of the Mood & Anxiety Disorders Program for the National Institute of Mental Health, talks with Jessica Gould (on behalf of Medscape) about the complexity of bipolar disorder and its effect on research and treatment. Dr. Manji addresses such topics as pathophysiology and the medications of the future.
Medscape: Could you describe the challenges inherent to treating bipolar disorder, specifically mania?
Dr. Manji: Bipolar disorder is difficult to treat because it is so complex at different times of the illness. For example, when individuals are in the depressed phase, their thoughts are slowed down, their movements are slowed down, they are not interested in anything, they have problems with sleep and appetite, and they can be suicidal. Then, in the same person in the manic stage, it is almost as if a switch has been turned on and their thoughts are moving a mile a minute. They are full of energy, they are not sleeping, and sometimes they hear voices. It is an interesting challenge: to figure out how the same individual can have a clinical picture that looks so different at different times.
Medscape: How has that complexity informed research on the subject?
Dr. Manji: The fact that the clinical picture can be so different in one person has made researchers think that bipolar disorder cannot be as simplistic as "too much of one chemical or too little of another." It has got to be more complex than that. A lot of the previous research had been on specific chemicals, like serotonin, norepinephrine, and dopamine. Now investigators are looking at the machinery inside the cells.
Medscape: Tell me a bit about treatment for mania.
Dr. Manji: Until recently, we have not had any effective treatments that work within a reasonable timeframe. Almost everything we use takes 3 weeks or so to work. When manic patients are admitted to the hospital, they are given medications that are highly sedating to calm them down, as well as other medications that will take 3 weeks or more to work. Lithium and valproate -- both of which are mood stabilizers -- definitely work to treat mania, but again, the onset of action is several weeks. These medications eventually work correctly, but they go through a lot of steps to get there. What tends to happen, therefore, is that people's lives get lost in mania; they make bad decisions, lose jobs and marriages, or get arrested. For that reason we need to be able to treat mania more rapidly.
In addition, some patients can recognize that they are getting manic. They notice that they are becoming more irritable and are not sleeping well. If they could do something right at that moment, it might prevent a more manic episode from coming on. If we had something that could work on mania right away, it might also cut down on the time that people spend in the hospital. That is one of the challenges we wanted to tackle; we thought that if we could target something that specific about the illness, we could, hopefully, end up with a better treatment.
Medscape: So what did you do?
Dr. Manji: Initially, we undertook animal research to understand which molecule bipolar disorder treatments affect. Years of work along those lines suggested that a molecule called protein kinase C, or PKC, might be the molecule to target. If we could reduce PKC activity in the brain, we hypothesized, we might have medication that would not only be effective in mania, but might also be effective immediately because it hits the target right away. A lot of animal data suggested that this was the case. So we started to look for molecules that are safe to use, can get into the brain, and inhibit PKC activity.
The only one available was the breast cancer drug tamoxifen. Tamoxifen is well known to block estrogen, but it also inhibits PKC. It has been used for decades, so we knew all about its safety and side-effect profiles. We decided to use tamoxifen with the idea that if tamoxifen was given to individuals who are manic, it might treat the manic episode as soon as the right dose was achieved.
We brought in bipolar patients experiencing a manic episode; if they were already on medications that were working, we took them off those medications. Then, we treated them with either tamoxifen or placebo. Our target dose of tamoxifen was 100 mg a day. We started with 20 mg on the first day, 40 mg the next day, 60 mg the third day, etc. We got to our correct dose at day 5, and not only did we see a very significant anti-manic effect, but it also occurred at almost the precise time we predicted. As for the placebo group, not only did those patients not get better, they got worse. It was a very striking finding.
Medscape: What did these findings tell you?
Dr. Manji: The findings provide strong support for the idea that inhibiting PKC is highly relevant to treating mania. If one can inhibit PKC quickly, one can have a very rapid anti-manic effect. The hope would be that PKC inhibitors might become emergency room treatments for mania. Furthermore, it might be possible for patients with bipolar disorder to have this medication on hand. If they sensed a manic episode coming on, they could take it right away and, perhaps, even prevent the emergence of full-blown mania.
Medscape: Why did you use tamoxifen?
Dr. Manji: We used tamoxifen because it was available. Our hope is that this research will lead to an investigation of even better molecules that inhibit PKC but do not block estrogen receptors like tamoxifen does. The hope, once again, is that we will develop improved and much more rapid-acting treatments for mania.
Medscape: Why not stick with tamoxifen?
Dr. Manji: Tamoxifen use, in the short term, is very safe. Usually treatment for mania is only used for days or weeks, and once the mania is under control people are maintained on mood stabilizers. For short periods, tamoxifen is very well tolerated. However, for long-term use (ie, years) there are concerns about certain gynecologic cancers in which blocking estrogen receptors might not be a good idea. That is why tamoxifen would not be recommended for long-term use. Still, we felt confident about our study design because it only involved treating people for 3 weeks. The ethics committee felt that there was no concern for short-term use.
Medscape: In the field of research for bipolar disorder treatment, what are you most excited about?
Dr. Manji: It is a very exciting time because the genes for bipolar disorder have been identified. Interestingly, a lot of them are exactly in the area I mentioned earlier; they affect the machinery inside cells. For a long time, a lot of our focus was outside the nerve cell on the different neurotransmitters. Now, the genetic studies, the animal studies, and the tamoxifen study all suggest that most of the action in bipolar disorder actually occurs inside the nerve cell. That might be why, to date, we have not been able to treat bipolar disorder so well. Most of our treatments work outside the cell and are largely symptomatic. They treat flare-ups. If the underlying disease involves the machinery inside the cells, then maybe long-term improvement requires targeting that faulty machinery.
Right now, the statistics are quite grim in terms of patients with bipolar disorder. We are able to get individuals out of mania or out of their bad depressions, but they often do not go back to their normal levels of functioning in terms of education, work, or relationships. The thought has been that perhaps we are not doing enough about the underlying disease. So, again, much of the research is moving towards targeting machinery inside the cells.
Interestingly, some of the machinery inside the cell is also responsible for helping nerve cells grow or protecting them from shrinking when they are exposed to things like free radicals. A lot of brain-imaging studies in the last few years have shown that patients with bipolar disorder have some degree of brain shrinkage going on as well. It is not like Alzheimer's disease or Huntington's disease, where in a few years you have got a large amount of brain shrinkage. It is a more subtle shriveling up of some of the nerve cells. The thought is that if we target the machinery inside the nerve cells, it may prevent shrinkage or, in some cases, reverse it.
Many patients with bipolar disorder first present with depression, which makes it hard to distinguish whether someone has depression or whether they have bipolar disorder and they have not yet had their first manic episode. That is a very important question, because sometimes when you treat bipolar patients with antidepressants and without mood stabilizers, you trigger manic episodes. There is a lot of work to be done to determine whether a biomarker can be found -- something to measure chemicals in the blood that would tell us that it is 70% likely that this person is bipolar vs 30%. Information like that would guide the correct treatment right from the start.
Unfortunately, many bipolar patients still go through trial and error with respect to treatments before they get the correct diagnosis.
This interview is published in collaboration with NARSAD, the World's Leading Charity Dedicated to Mental Health Research.
Medscape Psychiatry © 2008 Medscape
Cite this: New Medications for Mania: An Expert Interview With Husseini K. Manji, MD - Medscape - Feb 13, 2008.