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PRIORITY PRESS - 162nd Annual Meeting of the American Psychiatric Association

San Francisco, California / May 16-21, 2009

There is a strong association between serious mental illness and metabolic dysregulation. Dr. David E. Kemp, Director of the Mood and Metabolic Clinic, Case Western Reserve University School of Medicine, Cleveland, Ohio, cited studies demonstrating that the metabolic syndrome is two to four times more common in schizophrenia and bipolar disorder than in the general population. Furthermore, a study by Correll et al. (Bipolar Disord 2008;10(7):788-97) showed that the prevalence of metabolic dysregulation among bipolar patients treated with atypical antipsychotic medications exceeds 43%. “The three criteria that we see most commonly abnormal are an elevated abdominal obesity, high triglyceride levels and low HDL cholesterol levels,” stated Dr. Kemp, adding that these findings are associated not only with worsened medical outcomes, but also with more frequent and longer mood episodes, and earlier relapse.

Notwithstanding this, recent research, stimulated by the need for more effective long-term regimens than monotherapy with mood stabilizers, has suggested a wider role for atypical antipsychotics in the treatment of bipolar disorder. These new data have led to the addition of several atypical antipsychotics as recommended first-line maintenance therapy in bipolar disorder by the Canadian Network for Mood and Anxiety Treatments (CANMAT) and the International Society for Bipolar Disorders (ISBD) in the CANMAT 2009 update.

Combination Therapy for Bipolar Disorder

Speaking here at the APA, Dr. Eduard Vieta, Clinical Institute of Neuroscience Hospital Clinic, University of Barcelona, Spain, commented on the research he originally presented at the European Psychiatric Association Meeting earlier this year in Lisbon that led to the addition of one of these agents, ziprasidone, to the guidelines as a recommended first-line adjunct to the mood stabilizers lithium or divalproex.

In this study, eligible patients had a diagnosis of bipolar I disorder, with a current or recent manic or mixed episode. After at least 8 weeks of stabilization (CGI-I <u><</u>3) during a 10- to16-week initial open-label phase on a regimen of the atypical adjunctive to either lithium or divalproex, 239 patients were randomized to either continued ziprasidone or placebo. By the end of the six-month study period, 25 (19.7%) atypical-treated patients and 36 (32.4%) in the placebo group had received intervention for a mood episode (P=0.0104). The median time to intervention among those who required it was 43 days in the ziprasidone group compared to 26.5 days for those on placebo. Furthermore, significantly fewer patients discontinued the atypical compared to placebo. The combination regimen was well-tolerated; the most common adverse events in the open-label stabilization phase of the study were sedation (23%), somnolence (17%) and tremor (12.5%).

“The question that the trial was trying to answer is, once you have responded to the combination, should you stay a long period of time on the combination, or can you be treated only with lithium or valproate,” explained Dr. Vieta, “and the answer was that the patients who stayed on the combination did better than the patients who had ziprasidone withdrawn.” This group of patients also performed well on other secondary end points such as quality of life, he added. However, Dr. Vieta noted that the study did not discriminate between the types of mood event that triggered an intervention. “The study was not powered to analyze separately prevention of mania and prevention of depression,” he told delegates. The reason for this, he explained, was that the FDA did not require the separation of events in the study design.

According to Dr. Vieta, the efficacy of the atypical antipsychotic is comparable to that of other agents in the same class. However, the lack of weight gain differentiates it even from such relatively safe agents as aripiprazole, he noted, and there was also an absence of QTc effects.

Metabolic Profile

These observations were confirmed by a sub-analysis of safety data at the end of the 24-week maintenance phase from the same study discussed by Dr. Elizabeth Pappadopulos, New York, New York. She presented findings on changes in body weight and metabolic parameters (Table 1, 2).

Dr. Pappadopulos was not able to explain the weight increase seen when patients on divalproex were placed on adjunctive placebo instead of ziprasidone. One possibility is that the atypical inhibits the weight gain associated with divalproex therapy. She mentioned that a similar effect has been reported with the combination of aripiprazole and olanzapine.

The apparent safety benefits of combination therapy reinforce the utility of this approach in bipolar disorder. “It’s certainly the state of the field right now to use combination approaches for bipolar disorder in general,” remarked Dr. Pappadopulos. “Monotherapy doesn’t seem to work as well as maintenance.” Given that the bipolar population tends to have increased mortality, the enhanced safety seen with this regimen is very encouraging.

Corroboration of Metabolic Benefits in Schizophrenia

The promising safety profile seen in this study confirms results obtained in the context of schizophrenia. “The metabolic profile is very consistent with what we see in a much larger database on schizophrenia and this confirms what we are seeing here. Replication is very important,” noted Dr. Cynthia Siu, Data Power (DP) Inc., Ringoes, New Jersey. Presenting safety data from the long-term EUFEST study of antipsychotic use in first-episode schizophrenia patients, Dr. Siu noted that patients taking ziprasidone did not experience increased weight or waist circumference for one year, unlike those taking amisulpride, haloperidol, quetiapine or olanzapine. Furthermore, patients on ziprasidone, amisulpride, quetiapine and olanzapine decreased their tobacco use, unlike those on haloperidol, who actually significantly increased their usage.

The data allowed the investigators to conclude that there are significant differences in metabolic side effects and cardiovascular risks among antipsychotics in this patient population. They also found that patients who initially had one or more metabolic comorbidities suffered worse health consequences from weight gain than those without baseline comorbidities.