Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - 163rd Annual Meeting of the American Psychiatric Association

New Orleans, Louisiana / May 22-26, 2010

Despite the large body of evidence that many of the most commonly prescribed atypical antipsychotics increase the risk of dyslipidemias, hyperglycemia and diabetes mellitus, the tendency towards alternative antipsychotic therapy with a reduced propensity to generate these effects has been slow. Several symposia, workshops and new research presented here during the scientific sessions this week were devoted to exploring this phenomenon further and discussing strategies to provide better global risk management for bipolar disease and schizophrenia, the psychiatric diseases in which these agents are most often employed.

For example, in a study conducted at a tertiary medical centre, less than half of patients with hyperglycemia discharged on an antipsychotic were given one of the newer atypical agents, according to Dr. M. Jared Iqbal, Director of Psychiatry Residents, Bergen County Medical Center, Paramus, New Jersey. He and his co-investigators suggested that patients with hyperglycemia are particularly strong candidates for one of the newer agents that pose a low relative risk of weight gain and metabolic disturbances.

Reducing Metabolic Effects

In this study, 125 patients who had received a diagnosis of schizophrenia or schizoaffective disorder over a recent one-year period were randomly selected for chart review. Within this group, 25 patients had diabetes and four patients had impaired glucose tolerance. The remainder had normal blood glucose, defined as <140 mg/dL. In the group with any degree of hyperglycemia vs. those without, the body mass index (BMI) was on average significantly higher (31.0 vs. 28.6; P<0.05). At discharge, only 20.6% left the hospital on ziprasidone or aripiprazole, which were identified as the available medications less likely to induce metabolic syndrome. A slightly greater proportion was discharged on clozapine or olanzapine, which are among antipsychotics commonly associated with metabolic disturbances. More than 40% received antipsychotics with more modest but still known metabolic effects, such as risperidone, quetiapine and paliperidone.

There is an increasing array of antipsychotics that pose a lower risk of metabolic complications. In addition to ziprasidone and aripiprazole, asenapine, a newer molecule with a low propensity for weight gain and adverse metabolic effects, is now in use in the US. The relative advantages of the newer drugs that pose less risk of metabolic disturbances may become particularly important in those patients who already have comorbidities, such as diabetes, renal disease or heart disease. This was a point emphasized by Dr. John Brooks III, University of California, Los Angeles. In his presentation on management of bipolar disease in older adults, Dr. Brooks focused on the important metabolic differences between currently available agents and indicated that these cannot be ignored in a holistic concept of treatment benefit.

“Pharmacological interventions in older adults diagnosed with bipolar disorder can be very challenging because of comorbid conditions, altered metabolism and potential drug interactions,” Dr. Brooks reported. Although he noted that the anticonvulsants often employed in bipolar disease have very little effect on glucose or lipid metabolism, antipsychotics must be selected more cautiously. Some of the newer second-generation antipsychotics are particularly important for their role in expanding choice in this regard.

Second-generation Antipsychotics

As noted during the scientific sessions here this week, the three second-generation antipsychotics available in the US that are associated with a reduced risk of metabolic disturbances—ziprasidone, aripiprazole and asenapine—have all demonstrated efficacy against both schizophrenia and bipolar disease in controlled trials. Investigators report that ziprasidone, which was recently approved in the US as a maintenance therapy for bipolar disease (largely on the basis of a 240-patient study in which it was compared to lithium or placebo), has long been of interest because of its relative metabolic safety. In one example of objective difference between this agent and other atypicals, 191 patients with schizophrenia were randomized to olanzapine or ziprasidone (Brown RR, Estoup MW. Int Clin Psychopharmacol 2005;20(2):105-12). Although symptom control was similar, there were significant increases in HbA1c and total cholesterol from baseline on olanzapine that were not observed on ziprasidone.

Regarding aripiprazole, researchers here also indicated that a more clinically-driven end point study was conducted that compared this agent to olanzapine in patients with schizophrenia for development of metabolic syndrome (L’Italien et al. J Clin Psychiatry 2007;68(10):1510-6). In a pooling of data from comparator trials, the incidence rates of metabolic syndrome were 27.4% for the 212 patients who received olanzapine vs. 15.7% for the 198 patients who received aripiprazole (P=0.006). This is important for patients with increased risk of metabolic syndrome because this is a strong determinant of new-onset diabetes and coronary heart disease in the general population.

Also during the meeting, presenters noted asenapine, the newest agent, is approved in the US for the treatment of both bipolar mania and schizophrenia. One of the studies leading to regulatory approval for bipolar disorder was led by Dr. Roger S. McIntyre, Head, Mood Disorders Psychopharmacology, University Health Network, University of Toronto, Ontario. In this double-blind non-inferiority trial, asenapine was compared to olanzapine for extended control of acute mania (Bipolar Disord 2009;11(8):815-26). This study was not specifically designed to compare safety and tolerability. Although both asenapine and olanzapine appeared effective, clinically significant weight gain was observed in 19% of patients randomized to asenapine vs. 31% in the olanzapine cohort.

Expanded Choices May Be Useful in Non-compliant Patients

Noteworthy in Canada, only ziprasidone and aripiprazole are approved for use. The increasing array of second-generation agents that offer a relatively low risk of metabolic disturbances is important, according to both Dr. McIntyre and Dr. Steven G. Potkin, Director, Clinical Psychiatric Research, University of California at Irvine. Although these agents are not necessarily the first choice for all patients, particularly in younger individuals who are active and have a low risk of developing weight gain or comorbidities, they expand choices for individuals who might be at a high risk of non-compliance in the event of weight gain or who are concerned about the potential for metabolic disturbances.

“It is nice to have new compounds and options because every one of you knows that no one drug works for everybody,” Dr. Potkin told delegates. He suggested that even independent of the relative safety advantages of newer compounds, the ability to offer agents that presumably have different relative neurotransmitter receptor affinities expands the opportunities to extend symptom control to those not currently optimally managed on their current agent.

Summary

According to research presented here this week, newer antipsychotic agents with better metabolic and weight gain profiles than previous atypical compounds are providing options that have the potential to reduce the risk of long-term complications and may, therefore, improve the compliance essential for long-term symptom control. Data from controlled direct comparisons of newer agents that pose a relatively low risk of metabolic disturbances to older atypical agents suggest that the newer agents preserve efficacy against bipolar disorder and schizophrenia but may have a better safety profile.

Note: At press time, asenapine is not available in Canada.