The pharmacotherapy of patients with bipolar disorder is sometimes very challenging for the psychiatrist or primary care provider. The number of available medication options continues to expand, but knowing how and when to apply them requires knowledge and skill. On behalf of Medscape, Randall F. White, MD, FRCPC, obtained advice on this matter from expert psychopharmacologist Stephen M. Stahl, MD, PhD, Professor of Psychiatry at the University of California, San Diego.
Dr. White: The first specific treatment for bipolar disorder was lithium, approved by the US Food and Drug Administration (FDA) in 1970. What other medications are now approved by the FDA for the treatment of bipolar disorder?
Dr. Stahl: The answer depends on the phase of the disorder and is in flux, but of course lithium was the first, and the evidence is good that it is effective for the manic and maintenance phases. The evidence for its utility in the depressed phase is perhaps not as robust, but I think that it works in that phase. It's also been used to prevent suicide, for which there is good evidence but no FDA approval.
All of the atypical antipsychotics except clozapine are approved for treatment of the manic phase in bipolar I disorder. Chlorpromazine is approved for the manic phase, but it's not used very much, and I don't advocate using it, given the other options.
In the depressed phase, lamotrigine is thought to work but is only approved for maintenance. In fact, the only currently approved medication for bipolar depression is the combination of olanzapine plus fluoxetine, but we believe that the FDA will rule very shortly on quetiapine, which has 2 positive studies. The other atypical antipsychotics probably work for bipolar depression and are under study, but they are not yet approved.
Divalproex is used for maintenance treatment but not approved for that, and it may work for the depressed phase, but it is approved for the manic phase. Carbamazepine was actually one of the first anticonvulsants widely used for bipolar disorder, but only recently was it approved as a controlled-release formulation for just the manic phase. It may also work in the depressed phase or maintenance. Many other anticonvulsants are used but not approved.
The approvals are for bipolar I disorder. Quetiapine has been studied in bipolar I and II disorders. A lot of clinicians believe that much of bipolar disorder is best diagnosed as not otherwise specified (NOS), and although there are many such patients, no drugs are approved for that indication.
Dr. White: Bipolar disorder has many manifestations and distinct phases of treatment. Which medications have the best evidence as acute antimanic agents, and how does the clinician choose among them?
Dr. Stahl: The best ones are probably divalproex, lithium, and the 5 atypical antipsychotics that the FDA approved for mania. In hospital settings, people tend to prefer olanzapine and risperidone, probably because they came to the market first, often in combination with divalproex. The combination tends to work quickly and provides some sedation.
Dr. White: Does the evidence suggest that patients with nonpsychotic mania should receive both a mood stabilizer and an antipsychotic?
Dr. Stahl: In the past, before atypical antipsychotics were available, we used typical antipsychotics as briefly as possible and only for psychotic mania because of concern about tardive dyskinesia. People with mood disorders may be more vulnerable to tardive dyskinesia than people with schizophrenia when treated with drugs, such as haloperidol. It was a surprise to find that the atypical antipsychotics work not only for psychotic mania but for nonpsychotic mania. They don't treat just the psychosis.
Dr. White: Is a mood stabilizer also necessary then?
Dr. Stahl: Some people quibble about what a mood stabilizer is: If a medication works for mania, is it a mood stabilizer? If so, all 5 atypical antipsychotics are [mood stabilizers]. Does it mean that a medication must work for mania, depression, and maintenance? No drug has all 3 of those claims yet, although some soon may.
The FDA requires evidence and approval for the individual phases of bipolar disorder. Although studies for such purposes have been done with individual medications, most patients are actually on 2 or 3 drugs. One of the atypical antipsychotics is given for mania, and unfortunately, because many patients have difficult-to-treat illness, they will need a second medication. Divalproex is used if the mood is too high, and lamotrigine is often used if the mood is low. Lithium can be added as a third agent if the others are inadequate. Some younger physicians don't know much about lithium because it's been off-patent for a while and isn't actively promoted.
Dr. White: The treatment of bipolar depression is often difficult, yet many bipolar patients spend more time struggling with depression than with mania. What does the existing scientific work suggest is the best approach to treatment of acute bipolar depression?
Dr. Stahl: Lithium or lamotrigine is often used, but neither is approved for acute bipolar depression — only for maintenance. The use of antidepressants is a huge controversy. I think that most experts recommend against antidepressant monotherapy for a patient with bipolar depression, but most would add an antidepressant second or third in line if other agents don't work. Studies have shown that atypical antipsychotics are effective but are not yet approved by the FDA.
The answer to your question is that lithium, lamotrigine, or any atypical antipsychotic is probably adequate first- and second-line treatment for acute bipolar depression. If one or two of those put together is not useful, the next step is adding an antidepressant.
Dr. White: According to one systematic review, tricyclic antidepressants have a high risk of causing a mood switch. Does the evidence say that other antidepressants are in fact less likely to cause mood instability?
Dr. Stahl: Tricyclics are powerful antidepressants. Some evidence suggests that venlafaxine also causes more mood switching, and some suggests that bupropion causes a little less mood switching than others. Even though monoamine oxidase inhibitors are quite powerful, there is little evidence that they cause mood switching, perhaps because they are used infrequently. I think that for someone who is not adequately stabilized, effective antidepressants all have the potential to cause mania. Tricyclics may be worst, but because some evidence exists that bupropion is a little less risky, it may be used preferentially in bipolar depression.
Dr. White: Do existing empirical data provide guidance on the best approach to an acute mixed mood disorder in a bipolar patient?
Dr. Stahl: Unfortunately, very little. Mixed mood states are common, poorly defined, and difficult to manage. According to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), this diagnosis means that the patient simultaneously meets the full criteria for major depression and mania. Many clinical trials of bipolar mania put mixed patients in as well, and therefore some medications have indications for what I call full mixed patients. Quetiapine is the only agent not approved for both mania and mixed states. I believe that's not necessarily because it doesn't work, but because mixed patients were excluded from the trials. Another kind of mixed state is often called dysphoric mania, which is when a patient meets the criteria for mania but has a little depression, too. Some people may meet the criteria for major depression but have a few manic symptoms.
We studied ziprasidone in dysphoric mania, and ratings of both depression and mania went down. You will see in the literature smaller case studies of mixed states, but more common are less-than-full mixed states, which are sometimes called bipolar disorder not otherwise specified. Sometimes these patients are rapid-cycling, going from mania to a mixed state before they crash into full depression.
Dr. White: What about patients with rapid-cycling bipolar disorder?
Dr. Stahl: Four mood switches in a year, as the DSM-IV requires for the diagnosis, are not all that rapid. Some people may change mood 4 times in a day. Mood switches can occur precipitously; people move within hours from one pole to another, and some can have a surge of mania during depression. It's very common for manic patients to crash into depression.
Sometimes drugs will cause rapid cycling, which has been an accusation about too much antidepressant — or any antidepressant at all. You can treat this by removing the antidepressant, but it's not necessarily progress to make a rapid-cycling patient unremittingly depressed. You sometimes need to treat for both mania and depression to avoid causing a switch or increasing the rate of cycling.
Dr. White: Are there data on that?
Dr. Stahl: There are almost no data to support what I just said. Some of the early research on divalproex suggested that it was better than lithium for mixed states and rapid cycling, but more recent studies have indicated that they are equally good. The American Psychiatric Association treatment guidelines suggest using lithium for euphoric mania and divalproex for dysphoric mania and rapid cycling. However, that is irrelevant, because in the real world, someone with rapid cycling is unlikely to get along with 1 drug anyway. The reality is that everybody is treated with 2 or 3 drugs, yet few have done studies on polytherapy.
The only 2-drug studies are with atypical antipsychotics combined with lithium or divalproex for treating mania, not rapid cycling. I'm not aware of any studies suggesting how to mix divalproex with lithium, so we're left with art and anecdote.
Dr. White: According to a recent meta-analysis, lithium is the only true mood stabilizer, meaning that it is effective in mania, depression, and for maintenance. Do you think that other agents may eventually be recognized as true mood stabilizers?
Dr. Stahl: Again, it depends on how one defines a mood stabilizer. I would agree that the level of evidence is best for lithium, and yet it probably is grossly underutilized. You could argue that's because of its adverse effects or lack of promotion. I think that many agents will eventually be found to be mood stabilizers. Some are coming off-patent, such as risperidone and divalproex, so the reality is that those drugs may never get adequate testing. Even lamotrigine is coming off-patent. Could those 3 drugs work for all 3 phases? Maybe we'll never know.
Most likely to be investigated are the atypical antipsychotics with some patent life. I think that the first through the post will be quetiapine. I actually believe that all 5 atypical antipsychotics are true mood stabilizers, just as is lithium; however, none of them are FDA-approved for use in all 3 phases of the disorder. I think that it's very likely that ziprasidone, aripiprazole, and quetiapine will all get there, and maybe olanzapine, but I don't think that the company is trying to get monotherapy approval for bipolar depression.
Dr. White: Many patients are treated for an acute episode with several medications, but do they need to stay on them?
Dr. Stahl: We don't know. The only real evidence that I can cite is current prescribing practice, and it may be ignorance on the part of physicians, but I don't think so. In my practice and that of other psychiatrists who I know, we use more than 1 medication because patients are dissatisfied with outcomes or sometimes with side effects. Studies of monotherapy show that the approved agents are more effective than placebo, but a patient who is only 30% better will ask for more: "I want to be 70% or even 100% better." This leads clinicians to either raise the dose of the drug, which may then become intolerable, or add a second one. The sad thing is that it's difficult for some patients with bipolar disorder to achieve full remission with even 3 or 4 agents.
The effectiveness of polypharmacy has been shown for atypical antipsychotics plus lithium or divalproex in treating mania. I can tell you that most psychiatrists believe that the combination is also effective in the depressed and maintenance phases, but I don't know of any randomized controlled trials to prove it.
Dr. White: When should a psychiatrist turn to clozapine for a patient with difficult-to-treat bipolar mood disorder?
Dr. Stahl: If this is an evidence-based discussion, I'd have to say that we do not have the same level of evidence for bipolar disorder as for schizophrenia. For schizophrenia, clozapine works better than other antipsychotics, as shown by classic studies comparing it with first-generation antipsychotics, and it is probably more effective than other atypical antipsychotics. Despite the lack of evidence, many experts would use clozapine for bipolar disorder somewhat as they would for schizophrenia, namely, after failure of multiple atypical antipsychotics, especially in patients with psychotic mania.
Of course, the medication carries significant risks, including metabolic disorder. The risk vs benefit analysis is not as favorable for bipolar disorder as for schizophrenia because, although the risks are known, the exact benefits are not clearly known. I suspect that most patients who receive clozapine are very treatment-refractory, those for whom it would be worth the risk of developing diabetes. Printer- Friendly Email This
Medscape Psychiatry & Mental Health. 2006;11(2) ©2006 Medscape
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