EDITORIAL

Bipolar Disorder Treatment Update

Charles B. Nemeroff, MD, PhD, Reunette W. Harris Professor and Chairman, Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia

When compared to research on unipolar depression, anxiety disorders, or schizophrenia, investigation-both psychobiologically and psychopharmacologically-in bipolar disorder is generally considered more difficult. There are a multitude of reasons for this; they include: (1) the presence of subtypes which makes it difficult to recruit a homogeneous patient population to study; (2) the cyclical nature of the disorder; (3) the increasing patient drop out rate in studies as the patients cycle from mania to depression or vice versa, a particularly serious problem in long term longitudinal studies; and (4) the use of multiple psychopharmacological agents to treat the disorder, usually greater than that observed in patients with unipolar depression or schizophrenia.

This concentration of factors has conspired to limit large-scale studies of bipolar disorder, with the consequent relative dearth of knowledge in the area. The present summary of research on bipolar disorder presented at the American Psychiatric Association's (APA) annual meeting represents a radical departure from the aforementioned poverty of research in this area.

I have been proud to serve on the National Institute of Mental Health (NIMH) Advisory Council during a time when Steven T. Hyman, MD, NIMH Director, had taken the Institute to an unprecedented level of investigative rigor in basic neuroscience and clinical research. As Dr. Nassir Ghaemi described, Dr. Hyman's support and enthusiasm for bipolar disorder research has already produced results-an increase in funded NIMH research on basic neuroscience relevant to this disorder, as well as clinical research on pathophysiology and treatment.

There is a consensus among investigators and patient advocacy groups-the latter exemplified by the National Depressive and Manic Depressive Disorders Association (NDMDA)-that this vision extolled by Dr. Hyman, is filled with promise for all stakeholders. One major component of Hyman's vision is the funding of large scale, multicenter effectiveness trials to guide the field in development of rational treatment algorithms for psychoses, refractory depression, and bipolar disorder.

Dr. Gary Sachs comprehensively described the latter program, the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), a clear breakthrough in the field. This program will contribute novel and important information on antidepressant treatment of bipolar depression, the utility of psychotherapy in preventing relapse, and naturalistic and combination therapy to treat the overall disorder. In terms of psychotherapy, cognitive, behavioral, interpersonal, and family-focused therapies will be evaluated. Several other breakthroughs in the management of bipolar disorder were discussed during the APA. One such topic area is the use of novel anticonvulsants-including topiramate (Topamax®)1, lamotrigine (Lamictal®)1, and gabapentin (Neurontin®)1-in the management of bipolar disorder. Several controlled studies have now demonstrated the efficacy of lamotrigine in bipolar depression and in the treatment of rapid-cycling bipolar disorder. In contrast, the controlled studies with gabapentin have not confirmed the earlier impression of efficacy in acute mania. Topiramate has not yet been extensively studied, but results from open trials and clinical anecdotes serve as an impetus for subsequent scrutiny of this compound. Its association with weight loss, in contrast to the weight gain characteristic of so many anticonvulsants, is an obvious major potential advantage in a drug used to treat bipolar disorder.

Another topic focused on the role of atypical antipsychotics in the management of bipolar disorder. Olanzapine (Zyprexa®)1 is already FDA-approved for acute mania, and apparently possesses not only antimanic but antidepressant properties. There is evidence that risperidone (Risperda®)1 also possesses efficacy in the treatment of mania; it is as effective as haloperidol (Haldol®)1 with a more favorable side effect profile. Dr. Sachs presented data of a pilot study indicating greater efficacy of risperidone concurrently administered with a mood stabilizer when compared to mood stabilizer monotherapy in patients with bipolar disorder. Dr. Charles Bowden, who highlighted the safety of risperidone-mood stabilizer combination therapy, echoed Sachs' findings.

In a final presentation, Dr. Joseph Goldberg discussed medication compliance in bipolar patients. He made the excellent point that compliance is intimately related to efficacy, even when more than one medication is prescribed.

There is considerable excitement in the field about the recent advances in research on bipolar disorder. Further advances are sure to follow.

THE SYSTEMATIC TREATMENT ENHANCEMENT PROGRAM FOR BIPOLAR DISORDER (STEP-BD)

Gary Sachs, MD, Director, Harvard Bipolar Research Program, Assistant Professor of Psychiatry, Harvard Medical School and Massachusetts General Hospital, Boston, with Nassir Ghaemi, MD, Instructor in Psychiatry at Harvard Medical School, and Researcher in Psychopharmacology at Cambridge Hospital, MA

Bipolar disorder, until recently a relatively neglected area of major psychiatric research, took its rightful place as a major topic at the American Psychiatric Association (APA) 2000 Annual Meeting held in Chicago, IL, from May 13-18.

According to Dr. Nassir Ghaemi, recent efforts by pharmaceutical companies and leadership from the National Institutes of Mental Health's (NIMH) new Director, Dr. Steven Hyman, including unprecedented NIMH financial support, have communicated clear signals to the mental health research community that BD merits increased attention.

"This illness is probably the least studied major psychiatric disorder that clinicians deal with," Dr. Ghaemi said. "Essentially, the field is still wide open for researchers, and a number of agents have come along-notably antipsychotics and third generation anticonvulsants-that have provided psychiatrists with new treatment options for BD."

Until about 20 years ago, he added, schizophrenia remained a less than precise diagnosis in the United States. Psychiatrists directed little effort in differentiating schizoaffective and bipolar disorders until DSM-III was introduced in 1980. The resulting failure of physicians to recognize BD contributed to its neglect. Further, researchers have mainly focused on unipolar depression during the last decade, spurred on by the introduction of a number of new antidepressant medications.

Historically, physicians have regarded BD as less important than other psychiatric disorders because epidemiological research suggested that it affected less than one percent of the general population, Dr. Ghaemi added. "Even if that were true," he pointed out, "it would still make BD equivalent to schizophrenia [in prevalence rates]. But many, including myself, now challenge the studies that [revealed a] one percent [prevalence rating] because they concentrated primarily on 'pure' mania. There are at least two [major] subtypes of BD-type 1 and type 2-and the latter is comprised of patients who [alternately] have [depressive episodes and] hypomania, a milder form of the illness often not treated. Epidemiological studies that have included both subtypes put the prevalence at three to five percent, close to the frequency of unipolar depression, which is believed to affect between five to ten percent of the population, [which] makes BD a major public health problem. [If we] combine [the two major forms of affective disorders,] unipolar depression and bipolar depression, we are talking about a significant number of people."

The NIMH recently pledged $20 million for the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD)-the largest contract ever awarded by the agency for a BD investigation-confirming the importance of BD research.

In fact, Dr. Ghaemi believes Dr. Hyman has been instrumental in building interest in BD research. "When he took over as director, Dr. Hyman noticed that [the majority of research grant proposals] were for schizophrenia, anxiety disorders, and depression, with very few for BD," Dr. Ghaemi explained, "so even if NIMH wanted to fund research in the area, they had few [such] opportunities."

Dr. Hyman generated interest in BD by pooling the equivalent of ten to 20 grants under one funding arrangement and requesting proposals from the research community. He hoped that ten to 20 institutions would design a collaborative study to help answer as many questions as possible about the illness. This plan gave birth to STEP-BD, a large-scale longitudinal project designed to carry out studies that will improve BD treatment.

At present, about 15 centers around the US have united for the trial, with head sites located at Harvard and Massachusetts General Hospital, Boston, Dr. Gary Sachs; the University of Pittsburgh, PA, Dr. Michael Thase; and the University of Colorado, Dr. David Miklowitz. Because 5,000 patients will be enrolled and data will be gathered over five to eight years, the trial has the potential to become a landmark study in the management of BD, Dr. Ghaemi said.

STEP-BD has three major investigative arms:

• Standard clinical trials using double-blind protocols will recruit about 500 patients and follow them for five years. Initial studies will focus on strategies for treatment of bipolar depression and relapse prevention, and will assess symptomatic, functional, and economic outcomes via a number of treatment pathways. Among other investigations, researchers will focus on the efficacy of two antidepressants-paroxetine (Paxil®)1 and bupropion (Wellbutrin®)1-for acute bipolar depression, with additional studies planned to evaluate interventions for rapid-cycling and psychotherapy treatments for prevention of relapse. The psychotherapy component will involve, in part, a collaborative treatment approach between physicians, patients, and the patients' families. Participants will receive education about BD and attend sessions with a psychologist.

• A second aspect of STEP-BD will involve conventional psychotherapy, where patients elect cognitive, behavioral, interpersonal, or family-focused psychotherapy. The latter is a treatment approach devised by Dr. Miklowitz to enlist family members as a support for patients, particularly at times when patients become resistant to therapy. Dr. Sachs, who presented various aspects of the study at a number of APA 2000 poster sessions and symposia, described family-focused psychotherapy as "a collaborative care plan built on a therapeutic alliance among doctor, patient, and family which allows adjustment of care with each new episode."

• A third major component of the study will take a naturalistic approach and involve 4,500 patients over five years. Dr. Ghaemi said investigators would gather data on patients' responses to monotherapy or combination therapy prescribed by their physicians. "Although the information will be less scientifically rigorous, it will be considerable in volume and very clinically relevant," he added. Dr. Sachs pointed out that as science elucidates the mechanisms responsible for BD, researchers would begin to more accurately subcategorize the condition, providing the opportunity to tailor pharmacological treatments to individual patient needs.

"Unfortunately, few bipolar patients respond adequately to one medication," he added, "and most will do best with skillful polypharmacy, including the use of atypical antipsychotics and third generation anticonvulsants. In STEP-BD, we start with a systematic assessment and move toward treatment pathways. We're not trying to find multiple recipes; we want to link systematic assessments with individual treatments targeted to obstacles that become present with each phase of bipolar disease."

Does STEP-BD have the potential to do for BD what the Framingham study has done for heart disease? "Framingham was, of course, a much larger trial, but that's the hope," Dr. Ghaemi said. "After five years, we'll have vast amounts of data we can analyze in various ways. Evidence from 4,500 patients in naturalistic studies should provide insights that will tell us where we need more controlled trials."

Both Drs. Sachs and Ghaemi pointed out that the trial, just now getting underway, intends to serve as a start-up infrastructure and launch pad from which other researchers can design add-on clinical trials, further multiplying the knowledge base. For that matter, the STEP-BD web site (access it through the NIMH homepage and click on "clinical trials") already invites independent investigators to submit proposals consistent with the study's aims.

"We expect the original study will encourage researchers to seek further incremental funding from NIMH," Dr. Ghaemi concluded. "By the end of STEP-BD, we could have ten, maybe 20 additional trials that relate to the original investigation."

UPDATE ON THE USE OF TOPIRAMATE IN BIPOLAR DISORDER

Joseph Calabrese, MD, Director, Mood Disorders Program, University Hospitals and Professor of Psychiatry, Case Western Reserve University, Cleveland, OH

Several clinical trials have increased interest in the potential role of third-generation antiepileptic drugs such as gabapentin1, lamotrigine1, and topiramate1 for the treatment of bipolar disorder.

Dr. Joseph Calabrese reviewed and evaluated recent clinical data concerning the relative efficacy, novel characteristics, and side effects associated with the three agents.

Dr. Calabrese, who uses the term "third-generation antiepileptic drugs" (AEDs) to refer to the newest generation of these medications, said the principal features that distinguish this generation of medications are:

• increased ease of use, since screening, blood work, and therapeutic blood monitoring are not routinely required

• the agents' safety profile, particularly in overdose situations

• improved tolerability compared to traditional alternatives such as carbamazepine (Tegretol®)1 and, to a lesser extent, valproate sodium (Depacon®, Depakene®)1, which can produce side effects that result in non-compliance-notably weight gain

Unfortunately, he added, early promise seen with gabapentin when added to other mood stabilizers in an open trial with bipolar patients who were hypomanic or depressed has not been confirmed in two double-blind, placebo-controlled studies. The first, by Pande et al., compared gabapentin to placebo augmentation of lithium carbonate (Eskalith®)1 or valproate sodium; the other, by Frye et al., compared gabapentin and lamotrigine to placebo as monotherapies (both in press).

"Essentially, both researchers and their co-investigators have told the research community that this agent [is not effective] in manic phases of bipolar disorder," Dr. Calabrese said. "The hope was that the agent would be [superior to] placebo because the open trial data had shown efficacy, but as is frequently the case, the placebo-controlled information did not replicate those findings."

Conversely, three placebo-controlled studies have shown efficacy with lamotrigine in depression, he said. The first, a three-arm trial published by Dr. Calabrese and colleagues last year, involved 195 patients who were studied over a seven-week period. Patients received either placebo, lamotrigine 50 mg/d, or lamotrigine 200 mg/d. Results showed both lamotrigine arms were superior to placebo in most but not all measures, with the 200 mg arm being most effective.

The second study, by Frye et al., which compared gabapentin and lamotrigine monotherapy versus placebo, found that after six weeks of treatment followed by cross-over to the alternative treatment, lamotrigine, but not gabapentin, was more effective.

Dr. Calabrese reported that the third multicenter trial (unpublished) is a recently completed investigation showing lamotrigine's efficacy in rapid-cycling bipolar disorder. Over a six-month study period, the agent was more effective than placebo on most outcome measures, and particularly in patients with bipolar II disorder.

"Further, we have not seen this agent cause [a] switch into hypomania or mania-a common occurrence with conventional anti-depressants," Dr. Calabrese added. "In the first study we published, [a] switch from the depressed phase to hypomania or mania did not exceed that of placebo."

Because the greatest unmet need in BD therapy to date has been management of the depressed phase, lamotrigine is a welcome addition to the BD armamentarium, he added, and shows an onset of effect as fast-acting as selective serotonin reuptake inhibitors (about 21 days), with significant differences from placebo observed at three weeks.

Topiramate, another third generation AED, has been studied in 12 clinical reports (open case series rather than well-organized, multicenter trials), involving a total of 224 patients with BD. Observed results from these reports indicate a potential efficacy for topiramate when added to other medicines (typically, lithium or divalproex sodium [Depakote®]1) for the treatment of hypomanic, manic, and depressed phases of the illness, he said.

Dr. Calabrese also reviewed results of an as yet unpublished, Janssen-sponsored, 20-site, US-based, double-blind, placebo-controlled monotherapy trial comparing topiramate to placebo. Subjects (n = 97) were all acutely manic type-1 BD patients.

Powered only to inform researchers on design criteria for the next large multicenter topiramate study, 31 patients received placebo, 33 received 256 mg/day of topiramate, and 33 patients received 512 mg/day of topiramate. (Currently established monotherapy dosing ranges for topiramate are 200-400 mg/day for management of acute mania, with titration occurring between two and four days. As an add-on drug, the range is 50-400 mg/d, with titration limited to 25 mg/week.) Key findings included a positive interim analysis, showing topiramate was more effective than placebo (n = 36) when data were examined midway through the trial.

Results of the final analysis were conflicting. Based on the Young Mania Rating Scale (YMRS) scores, neither of the topiramate arms was more effective than placebo. However, the Global Assessment Scale demonstrated significant differences. Dr. Calabrese noted that Janssen also did a post-hoc analysis of the data and removed randomized patients (n = 28) who had received concurrent antidepressant treatment during the index episode of mania, prior to the study-mandated washout. Analysis of the remaining sample (n = 69) showed the high dose topiramate arm had indeed outperformed placebo throughout the trial (p = 0.020).

Investigators concluded that recent antidepressant use by some patients prior to study entry had driven up the placebo response, and based on the post-hoc findings, the evidence warranted proceeding with additional topiramate studies.

Dr. Calabrese also commented on topiramate's unique safety profile. In particular, the drug usually produces desired weight loss among obese BD patients. Evidence from the neurologic literature suggests weight loss occurs early and averages about five pounds per month in these patients, he said.

Topiramate's undesirable effects are relatively minor, he added. About 20 percent of patients experience numbness and tingling in the extremities, while eight to nine percent experience fatigue or somnolence. The most significant side effect is a cognitive deficit, he concluded, but this can usually be avoided by slow titration.

Like carbamazepine and valproate, lamotrigine and topiramate are active at the sodium channel, an action that appears common to all AEDs that are also effective in the treatment of bipolar disorder, Dr. Calabrese concluded.

THE USE OF ATYPICAL ANTIPSYCHOTIC AGENTS IN BIPOLAR DISORDER

Nassir Ghaemi, MD, Instructor in Psychiatry, Harvard Medical School; Researcher in Psychopharmacology, Cambridge Hospital, MA

Recent data, some of which were presented for the first time at the APA 2000 meeting, continue to raise interest among clinicians in the use of atypical antipsychotic agents for the treatment of bipolar disorder (BD).

According to Dr. Nassir Ghaemi, "Risperidone1 and olanzapine1 in particular now appear to have similar evidence that supports their efficacy in treating the manic phase of this disorder, though they differ in side effects."

Food and Drug Administration (FDA) approval in November of 1999 for olanzapine as a treatment for acute mania has also increased interest in atypical antipsychotics, Dr. Ghaemi said, because it has cleared the way for olanzapine's maker, Eli Lilly, to actively market the new indication.

The possibility of using atypical antipsychotics to treat BD has gathered momentum among researchers and community practitioners since the early 1990s, he added, when clozapine (Clozaril®)1 was first released for treating schizoaffective disorders and was discovered through naturalistic case series to be effective for bipolar illness.

Risperidone soon followed clozapine as a novel new option for schizophrenia and psychotic disorders, Dr. Ghaemi pointed out, and naturalistic studies also suggested it offered benefits in controlling mania in BD.

However, neither clozapine nor risperidone were formally tested in placebo-controlled trials for efficacy in acute mania for a number of years, he added. When olanzapine entered the market, it was studied in industry-sponsored, double-blind, clinical trials almost from the beginning.

"Combined, the naturalistic and clinical data suggested that these newer agents were helpful in the treatment of BD," he observed, which led researchers into a more structured, well-organized phase.

For example, Dr. Ghaemi pointed out that Dr. Mauricio Tohen and colleagues at Lilly Research Laboratories have completed two randomized, double-blind, placebo-controlled studies-one published, one in press-that show olanzapine to be effective in the treatment of acute episodes of BD (pure mania or mixed) and in patients with rapid-cycling BD.

The published study (Am J Psych, 1999) was conducted over a three-week period in patients with acute mania. Researchers defined clinical response as a decrease (50 percent in the Young Mania Rating Scale (YMRS) score from baseline to endpoint). They compared 70 patients receiving 10 mg olanzapine once daily to 69 patients receiving placebo. Results showed significantly more patients taking olanzapine (48.6 percent) achieved clinical improvement compared to the placebo group (24.2 percent). Although somnolence, dry mouth, dizziness, and weight gain occurred more often with olanzapine, no patients discontinued use due to those side effects.

In the unpublished study, Tohen et al., tested the hypothesis that olanzapine would be effective for rapid-cycling BD by conducting a secondary subgroup analysis of 44 rapid-cycling bipolar patients who had participated in the acute mania trial. Patients were randomized to either olanzapine (5 to 20 mg/day) or placebo during a three-week period. The primary assessment tool was the YMRS, with a minimum score of 20 required for randomization. Researchers defined rapid-cycling as a total of four or more manic, mixed, and depressive episodes in the past year. They randomized 25 qualified patients to placebo and 19 to olanzapine.

Compared to placebo, olanzapine showed a statistically significant reduction of the YMRS total score (-13.9 vs. -4.1, respectively, p = 0.017). Clinical response, defined here as a 30 percent improvement on YMRS total score from baseline, also occurred statistically more often with olanzapine versus placebo (84.2 percent vs. 36.0 percent, respectively, p = 0.002). Further, more rapid-cycling patients completed olanzapine treatment than those on placebo (73.7 percent vs. 34.6 percent, respectively, p = 0.035). Adverse events did not occur significantly more often with olanzapine than with placebo. The researchers concluded olanzapine was safe and effective in treating the manic symptoms of rapid-cycling bipolar patients.

Dr. Ghaemi pointed out that Janssen has sponsored two placebo-controlled risperidone studies in BD, the first published by South African researchers who compared risperidone, lithium1, and haloperidol1 for acute mania and showed all were equally effective. Although the trial was small-only 15 patients in each treatment arm-it provided the basis for a larger, multicenter, full protocol study, he added.

That trial, presented for the first time during poster sessions at APA 2000, compared the efficacy and safety of risperidone versus haloperidol or placebo as add-on treatments to either lithium or divalproex1 in 156 patients with acutely manic BD.

"Among the key findings, researchers found risperidone and haloperidol equally effective and superior to placebo, but risperidone had fewer side effects than haloperidol," Dr. Ghaemi said. "In particular, extrapyramidal side effects-perhaps the most common reason for non-compliance with standard [antipsychotics]-were clearly less common with risperidone [compared to] haloperidol."

Further, no worsening or new cases of mania were observed with risperidone, he pointed out, dispelling concerns generated by earlier case reports. Dr. Ghaemi suspects the earlier observations were investigative "noise," probably involving patients who needed, but did not receive, a mood stabilizer like lithium or divalproex.

That, in turn, raises the issue of whether atypical antipsychotics can be used solely as mood stabilizers, he added, because a true mood-stabilizing drug should be effective in treating both of two phases of BD.

"We now have double-blind studies that show risperidone and olanzapine to be effective in the treatment of acute mania," he explained, "but they were not shown effective in treating acute depression or prevention of either mania or depression. To describe these agents as true mood stabilizers, I believe we need longer-term data to establish the prophylactic properties of these drugs in the prevention of mania and depression. I suspect atypical antipsychotics do have preventive properties, but probably as adjunctive therapy with standard mood stabilizers such as lithium or divalproex, [as well as antidepressants.]"

Safety and Efficacy of Risperidone Versus Placebo as Add-on Therapy to Mood Stabilizers in the Treatment of the Manic Phase of Bipolar Disorder

Gary Sachs, MD, Director, Harvard Bipolar Research Program, Assistant Professor of Psychiatry, Harvard Medical School and Massachusetts General Hospital, Boston

Psychotropic agents like lithium1, valproate1, and carbamazepine1 remain the backbone of pharmacotherapy for bipolar disorder (BD) and have proven effective in up to 70 percent of patients during acute manic episodes. Unfortunately, they are also associated with a number of side effects that many patients find intolerable.

Encouraged by naturalistic studies, researchers in search of alternative therapies have investigated atypical antipsychotic agents such as risperidone1 as a means of providing some of the benefits of the older agents while avoiding their adverse effects.

Dr. Gary Sachs and colleagues performed the first two-stage, double-blind trial comparing the safety and efficacy of a combination of an atypical antipsychotic (risperidone) with a mood stabilizer versus a mood stabilizer alone during an acute BD episode and in the maintenance phase.

According to Dr. Sachs, preliminary results from the investigation make a stronger case for combination therapy with risperidone than therapy with a stand-alone antipsychotic.

"Safety without efficacy and efficacy without safety are valueless," he explained, "and what we are seeing in the results from this trial is a clear indication of advantage from combination treatment with risperidone and a standard antipsychotic, with significant improvement seen as early as the first week of treatment, which is where it counts.

"While some might suspect patients would fare worse on two drugs as opposed to one, we are getting exactly the opposite results in this trial. We found that up to 50 percent of patients were unable to stay with mood stabilizer treatment alone, while 75 percent of patients remained on risperidone plus lithium or divalproex1. In short, adding the risperidone to a mood stabilizer was actually better tolerated. Remember, no treatment works that patients will not take, so based on our results, I would say combination therapy has to be the way to go."

He added that Phase I of the trial involved a three-week, double-blind, parallel-group treatment in which the efficacy and safety of risperidone (1-6 mg/d) and haloperidol1 (2-12 mg/d) were compared to placebo given in combination with lithium or divalproex in acutely manic bipolar patients. In all, 158 bipolar patients were randomized into the three treatment arms.

Phase II consisted of a ten-week, open-label extension period where 85 eligible patients exiting the double-blind phase were offered open-label risperidone therapy (1-6 mg/d) and additional follow-up to gain more information regarding the efficacy, safety, and usage patterns of risperidone in the period following the acute treatment of the manic phase.

Among key preliminary results to date, Dr. Sachs pointed out, investigators found a statistically significant change in favor of risperidone versus placebo on both the Young Mania Rating Scale (YMRS) (p = 0.009) and the Cognitive Global Index (p = 0.002) at endpoint (three weeks). Placebo and risperidone groups had a similar overall incidence of adverse events, while patients receiving haloperidol experienced greater extrapyramidal symptoms (EPS).

"What we are seeing," Dr. Sachs said, "is that combination therapy using risperidone with mood stabilizers is giving patients two chances to get better in the shortest period of time-as early as one week-with no price to pay in terms of side effects. Tolerability was better with two agents than one, and it looks as if there may even be synergy between them. In short, unless you see an unacceptable price to be paid for a combination therapy that works, which we haven't, why not use it?"

SAFETY OF RISPERIDONE AS AN ADD-ON THERAPY TO MOOD STABILIZERS IN THE MAINTENANCE AND TREATMENT OF BIPOLAR DISORDER

Charles Bowden, MD, Professor and Chairman in the Department of Psychiatry, University of Texas Health Sciences Center, San Antonio

Preliminary findings of a two-phase, multicenter, placebo-controlled trial suggest that the atypical antipsychotic risperidone1 is effective as add-on therapy for the management of bipolar disorder (see report, page 8). However, a question remains as to whether or not the combination therapy is safe in manic patients following an acute episode and during the maintenance phase. According to Dr. Charles Bowden, the add-on design is indeed both efficacious and safe, particularly when patients who started on standard, first-line monotherapy (lithium1 or divalproex1) for bipolar disorder (BD), slip into a manic episode. In a sense, he added, risperidone can act as a rescue medication, an adjunctive therapy to help regain and maintain control.

"The interesting thing," Dr. Bowden added, "is that the degree of combination advantage over the lithium or divalproate monotherapy was about as great as you see in studies involving divalproex or olanzapine1 versus placebo."

Concentrating on safety aspects of the trial, Dr. Bowden demonstrated that some outcome measures included:

• efficacy parameters: changes compared with baseline at endpoint evaluation as measured on the Young Mania Rating Scale (YMRS), Clinical Global Impression (CGI), and Hamilton Depression Rating Scale (HAM-D)

• safety parameters: extrapyramidal symptom rating scale (ESRS), laboratory evaluations, vital signs, body weight, electrocardiogram, and adverse event monitoring

Preliminary results showed that patients tolerated risperidone therapy well. Dr. Bowden reported that adverse events occurred in 79 patients (92.9 percent) during Phase I, with the most common treatment emergent adverse events (TEAEs) of risperidone add-on treatment with either lithium or divalproex being somnolence, headache, dyspepsia, extrapyramidal symptoms, dizziness, constipation, and tremor. Two of 52 patients (3.8 percent) receiving risperidone add-on therapy experienced serious TEAEs, including anxiety, tachycardia, and an increase in creatinine phosphokinase. Comparatively, four of 51 patients receiving placebo (7.8 percent) and four of 53 patients (7.5 percent) receiving haloperidol add-on therapy experienced serious TEAEs. None of the 52 patients receiving risperidone experienced an induction of mania during the double-blind phase of the trial.

The investigators concluded that Phase II results also indicated risperidone was safe and effective for the treatment of BD and supported the favorable adverse-event pattern observed in the double-blind treatment period. Eleven patients (12.9 percent) reported severe adverse events, including extrapyramidal disorder, hypertonia, somnolence, pain, dyspnea, and breast enlargement. No adverse event was life threatening.

Overall, the data allowed Dr. Bowden and colleagues to conclude:

• Risperidone is well-tolerated, safe, and effective as combination therapy with mood stabilizers in the treatment of acute manic episodes of BD.

• Risperidone in combination with a mood stabilizer is associated with a lower risk of extrapyramidal symptoms and somnolence.

• The risk of breakthrough episodes of mania or depression is low during extended treatment with risperidone combination therapy.

• Further investigation of risperidone's mood-stabilizing effects is warranted for the management of bipolar-manic or mixed-episode patients.

"Although the evidence for a lower risk of breakthrough depression with the combination therapy is modest at this point," Dr. Bowden commented, "we know first generation neuroleptics tend to have a dose-dependent tendency to cause some components of what patients experience as depression. Th[is] can be a negative effect of using first-generation medicines in some patients unless you have to pull out all the stops. If the current evidence continues to hold, combination therapy with an atypical antipsychotic and a mood stabilizer could significantly heighten interest in using these newer drugs for BD, because it might allow us to get some additional benefit from lithium or divalproex."

A COMPARISON OF ATYPICAL ANTIPSYCHOTIC AGENTS AS AN ADJUNCT TO MOOD STABILIZERS IN RAPID-CYCLING BIPOLAR DISORDER

Christina Demopulos, MD, Department of Psychiatry, Massachusetts General Hospital, Boston

Dr. Christina Demopulos and colleagues conducted a retrospective pilot review study and concluded that rapid-cycling bipolar patients demonstrate an overall improvement in treatment course when the atypical antipsychotic agents risperidone1, quetiapine (Seroquel®)1, or olanzapine1 are used as adjunctive therapy with concomitant medications.

Dr. Demopulos explained that the rationale for the review grew out of the dearth of information available on management of this form of bipolar illness. "Rapid-cycling bipolar disorder (RCBD) is an extremely severe and pernicious form of this illness, so we're always looking for treatment strategies to get these patients to remit," she explained. "But when there's little out there in the literature, you have to start somewhere, so we started at step one. We began by looking into the charts to see how patients' improvement scores did from baseline to endpoint with adjunctive treatment using each of these atypical antipsychotics."

The objective, she added, was to see whether risperidone, quetiapine, and olanzapine improve overall treatment outcomes, and if so, which one worked best.

Dr. Demopulos and colleagues reviewed the charts of 25 patients with RCBD who were receiving atypical antipsychotics (AAP). Each patient's gender, age, bipolar type, history of first-rank psychotic symptoms, and concomitant medication used at initiation of AAP therapy was recorded. Clinical Global Impression (CGI) and Global Assessment of Functioning (GAF) scores were obtained at the treatment's baseline and endpoint, and changes in CGI and GAF were calculated.

Forty-four percent (n = 11) received risperidone, 24 percent (n = 6) received quetiapine, and 32 percent (n = 8) received olanzapine. Mean duration and dosing for risperidone were 23.6 ± 14.6 wks at 1.96 ± 10 mg; quetiapine, 20 ± 17.4 wks at 162.5 ± 130.5 mg; and olanzapine, 35.9 ± 27.7 wks at 14.7 ± 12.9 mg. Both the CGI and GAF improved, but improvement in the GAF score was more impressive (t-test; p = 0.10, p = 0.002, respectively). All three AAP agents were equally effective (ANOVA; ?CGI; p = 0.50; ?GAF; p = 0.42), and only 36 percent of cyclers had a history of psychosis.

Dr. Demopulos and co-investigators concluded the preliminary findings showed that rapid-cycling bipolar patients improved with AAP agents, with no apparent significant differences between agents. Consistent with the literature, they added, the study found that most rapid cyclers do not have a history of significant psychotic symptoms. A larger sample population is needed to determine the significance of these findings.

Dr. Demopulos commented that the findings provide a starting point for an expanded retrospective study that examines a larger population sample, which may lead to a prospective study in rapid-cycling BD that she is committed to conducting under the STEP-BD program. (See related story, page 3.)

Dr. Demopulos, who works with Gary Sachs' STEP-BD group, said a prospective study would involve a more intensive assessment approach using HAM-D and YMRS.

MEDICAL NONCOMPLIANCE AND THE EVOLUTION OF POLYPHARMACY IN BIPOLAR DISORDERS

Joseph Goldberg, MD, Assistant Professor of Psychiatry at the Weill Medical College of Cornell University; Director of the Biodisorders Research Program, New York Presbyterian Hospital

Pharmacotherapy noncompliance occurs in 50 percent or more of bipolar patients and significantly impacts relapse rates, yet little is known about why patients stop taking medications. Dr. Joseph Goldberg and his team wanted to understand factors related to compliance with mood stabilizers and how bipolar patients take multiple mood stabilizers.

The investigators first surveyed 31 patients about attitudes toward thymoleptic drugs and their side effects. They then assessed what made the patients either keep taking or stop taking their drugs. Results showed that approximately 25 percent of patients missed ± 3 mood stabilizer doses per month, regardless of drug type. Over 80 percent of patients rated divalproex1 as effective, as did 63 percent and 64 percent regarding lithium1 and carbamazepine1, respectively.

Patients' ranking of factors influencing their adherence to drug regimens were, in order of importance: drug effectiveness, side effects, desire to not take medications for mood, ability to take only one drug, and cost. Significant side effects were perceived as more common with lithium (41 percent) than divalproex (19 percent) or carbamazepine (0 percent, p = 0.05). Noncompliance was associated with prior treatment nonresponsiveness, psychosis when manic, and chronic polypharmacy (p = 0.05).

The investigators concluded noncompliance may arise in a significant minority of patients in an academic medical center and, for a majority of bipolar patients, mood stabilizer efficacy may supersede concerns about adverse effects or unwanted treatment consequences.

"Those findings essentially took the researchers into the second study," Dr. Goldberg said, "because we were interested in the evolution of polypharmacy in bipolar disorders. Although clinicians often prescribe polypharmaceutical regimens for bipolar patients, little empirical data exist on polypharmacy in routine treatment."

In all, researchers interviewed 37 bipolar patients from Dr. Goldberg's clinic for lifetime medication histories, which were subsequently corroborated by hospital records. Investigators compared the characteristics of patients receiving one versus two or more mood stabilizers and assessed their successive versus simultaneous use.

Results for lifetime use showed 54 percent of patients took = 2 mood stabilizers (lithium, divalproex, carbamazepine, gabapentin1, lamotrigine1, and/or topiramate1). Of those, 43 percent received their first two stabilizers simultaneously, while 57 percent had successive trials.

Patients' average time from first to second mood stabilizer was longer (55.4 months) than the time from a second to third (20.5 months) or a third to fourth agent (13.3 months) (p < 0.05).

Concomitant mood stabilizers were added less often among patients taking divalproex (48 percent) than lithium (66 percent), and fewer subsequent mood stabilizers were added after beginning divalproex than lithium (p < 0.05).

Mood stabilizers were prescribed simultaneously more often than successively in patients with histories of psychotic mania or substance abuse and longer durations of lifetime illness (p < 0.05).

"Data from these two trials," Dr. Goldberg said, "would suggest monotherapy is ideal if it works, and divalproex may be the better agent to use first. Further, it appears that if lithium isn't working, the patient is more likely to stop taking it, so at that point you would switch them to divalproex, and if that doesn't work, you go to polypharmacy sooner than later in the course of the illness, and this might well make a difference."

This early use of combination therapy is a paradigm shift in the management of bipolar disorder that is not only being proposed but already happening in clinical and academic research circles, he added.

"People are inadvertently backing into this approach," Dr. Goldberg explained. "As more drugs come along, clinicians are more inclined to try them sooner and sooner, and it actually does have a rationale, as Dr. Mark Frye's recent paper demonstrates ("Aggressive Early Intervention Polypharmacy Versus Late Salvage Polypharmacy," Journal of Clinical Psychiatry, January, 2000). He makes the point that aggressive polypharmacy is the intervention of choice-what we do up front everywhere else in medicine-so why not in psychiatry?"

Dr. Goldberg added that he and his colleagues not only concur with Dr. Frye's sentiment, they practice it. "Instead of waiting to see if a bipolar patient will get better with one agent," he explained, "and we have already seen [that] the vast majority won't and will stop taking their medication, we will add more agents in an almost ad-hoc fashion over time. In our second study, when we looked at how patients progressed over time, the duration between subsequent mood stabilizer trials [became] increasingly shorter from the time the clinician went on to a second, third, and fourth agent. Like Dr. Frye has shown in his research, we believe aggressive intervention in treating the pathology earlier on may result in a better outcome later in the course of the illness."

He added that his trial data found that more patients stayed on multiple medications than monotherapy and, in terms of overall compliance rates, it made no difference whether simultaneous or successive polypharmacy drug regimens were used so far as the likelihood of patients discontinuing their medications.

"We suspect and hope that meant the combination therapy was working," he concluded. "In our studies, compliance came down to whether the treatment was bringing the depression under control. That is what patients were most concerned about. They cared about and didn't like the side effects, but they were more likely to put up with them if the depression was responding."

Bipolar Disorder Forum Report™ is a product of Millennium Medical Communications, Inc. (“MMC, Inc.”), an independent, third-party organization providing educational information concerning current medical data and opinions presented at worldwide medical meetings. The Bipolar Disorder Forum Report™ is published in accordance with the Guidance for Industry: Industry Supported Scientific and Educational Activities, 62 Fed. Reg. 64,093, 64,096-99 (1997) adopted by the U.S. Department of Health and Human Services Food and Drug Administration. Pursuant to the foregoing standards, MMC, Inc. is solely responsible for selecting the topics discussed herein as well as the guest editor. The ideas and opinions expressed by the guest editor are those solely of the guest editor and do not necessarily reflect the opinions of Millennium Medical Communications, Inc. or any Sponsor hereto. This Bipolar Disorder Forum Report™ may contain data on products, product uses, indications, and dosages, which are not approved for use in the USA, Canada and the European Union and no endorsement is hereby made or intended by coverage of any unapproved use. The content of this report is intended for educational purposes only, and merely conveys scientific data presented at medical meetings. Approved product labeling should always be consulted for prescribing information. The Bipolar Disorder Forum Report™ is an independent and non-promotional report intended to provide accurate scientific and medical information for educational purposes. MMC, Inc. is not responsible for errors or omissions in reports. The production of this report was supported by a wholly unrestricted educational grant from Ortho-McNeil Pharmaceutical. Ortho-McNeil Pharmaceutical maintains no control, direct or indirect, over the content, substance, or distribution of this report.