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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.

20th Congress of the European College of Neuropsychopharmacology

Vienna, Austria / October 13-17, 2007

As discussed by Dr. Jeffrey A. Lieberman, Chair, Department of Psychiatry, College of Physicians and Surgeons, Columbia University, and Director, New York State Psychiatric Institute, New York, antipsychotic dosing is a challenging but important aspect of care for patients with schizophrenia. Clinical response to antipsychotic agents is typically linked to blood levels; although a series of published studies did not show a dose response for symptomatic improvement on the PANSS (Positive and Negative Syndrome Scale) for atypicals (including risperidone, sertindole, quetiapine, olanzapine and ziprasidone), these trials were not powered to do so. Dr. Lieberman observed that they did, however, demonstrate a dose-response relationship for specific side effects.

In a six-week, placebo-controlled study of acute treatment of schizophrenia, both ziprasidone 80 mg/day and 160 mg/day were found to be more efficacious than placebo in improving overall psychopathology (P<0.05 for 80 mg/day, P<0.001 for 160 mg/day; Daniel et al. Neuropsychopharmacology 1999; 20(5):491-505). Dr. Lieberman noted that the trial was not powered to detect differences between the two dose levels and consequently, no significant difference was observed in the PANSS between the two active arms. Importantly, study findings indicated that clinical benefit was achieved within one to three weeks at an initial dose of 80 mg without titration.

“Clinical experience with ziprasidone supports the need to dose >80 mg/day for acute treatment, and even up to 160 mg/day, but the doses required for maintenance may be lower,” Dr. Lieberman commented. He also noted that the therapeutic dose range of atypicals has not been sufficiently well defined and that phase III trials are called for to identify more precise dosing strategies.

Dose-related Side Effects

Side effects can compromise adherence, confirmed Dr. Charles Nemeroff, Professor and Chair, Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia. Patients with schizophrenia are already cognitively impaired, which makes it difficult for them to adhere to their treatment. “It may be hard for them to remember to do things that maximize the success of their therapy, such as remembering to take ziprasidone with food to improve absorption of the drug. In the CATIE [Clinical Antipsychotic Trials of Intervention Effectiveness], patients were instructed only once to take ziprasidone with meals, which may have compromised efficacy results,” Dr. Nemeroff explained. He suggested that if patients assigned to ziprasidone had taken the drug with meals, efficacy results would have been more robust.

Further support for the importance of administering ziprasidone with food to ensure optimal absorption of the compound was presented by Dr. Sheldon Preskorn, Professor and Chair, Department of Psychiatry and Behavioral Sciences, University of Kansas School of Medicine, and President and Medical Director, Psychiatric Research Institute, Wichita. His analysis, which was based on three different food effect studies in small numbers of patients, demonstrated that ziprasidone concentration increased in a dose-proportional manner when taken with a meal; fat content had no affect on its absorption; and intake of at least 500 calories enhanced its absorption and reduced variability of absorption regardless of fat content.

Dr. Nemeroff also emphasized that adherence to therapy is critical to preventing relapse in schizophrenia. With each successive relapse, further deterioration is seen, making even partial recovery an elusive goal. “Antipsychotic therapy is essential for patients with schizophrenia, but these drugs are not a ‘silver bullet.’ They have a variety of actions at different receptors and a higher side-effect burden than other classes of agents. The choice of antipsychotic should be made between the patient and the practitioner, and ideally, with the family. Informed consent is necessary, and patients and family should be aware of risks vs. benefits of treatment,” he stated.

Efficacy, First and Foremost

The first treatment consideration is effectiveness. “All atypicals are similarly effective; no antipsychotic drug has ever been shown to be more efficacious than another,” Dr. Nemeroff told delegates. He said that although the recent naturalistic CATIE trial showed that fewer schizophrenic patients discontinued olanzapine during phase I of the study compared with other agents, olanzapine was the only one given at higher than the recommended dosage, “so the finding [in favour of olanzapine] can be considered an artifact.”

Regarding side effects of atypicals, Dr. Nemeroff noted that five years ago, prolongation of QTc interval was a major concern. With experience, it has become clear that QTc prolongation is a small concern, but metabolic side effects, such as hyperlipidemia, weight gain, insulin resistance and elevated glucose leading to diabetes and coronary heart disease, have gained attention. These side effects increase mortality, especially due to cardiovascular (CV) disease, gall bladder disease and diabetes. Even without treatment, patients with schizophrenia and other mood disorders are more vulnerable to CV disease than the general population, Dr. Nemeroff commented.

Although available atypicals have equivalent efficacy, it is important to note that they are not equal in side-effect burden, Dr. Nemeroff continued. It has been well documented in the literature that clozapine and olanzapine have the highest propensity for clinically significant weight gain among the atypicals, while ziprasidone and aripiprazole are basically weight-neutral, he noted.

A one-year study by Dr. Nemeroff and colleagues analyzed the mean change from baseline weight in patients taking atypicals. In that study, ziprasidone and aripiprazole were basically weight-neutral, while olanzapine, quetiapine and risperidone were associated with greater weight gain. Dr. Nemeroff urged clinicians to inform their patients to beware of getting on the “metabolic highway,” the starting point of which is weight gain, obesity, dyslipidemia and insulin resistance. The finish line is premature death due to diabetes and CV events, representing a 20- to 30-year shorter life span, he told listeners. Patients taking atypicals should be monitored for weight gain, waist circumference and fasting triglycerides. Dr. Nemeroff remarked that in his opinion, best practice includes two tests: fasting plasma glucose and insulin measurement. When side effects emerge, options include adding other compounds to treat side effects, lowering the antipsychotic dosage, switching to a different antipsychotic or accepting the side effect because all interventions have side effects.

Optimizing Dose and Minimizing Side Effects

Atypicals are a pseudopharmacologic class because they have diverse pharmacologic effects on dopamine, serotonin, muscarinic, adrenergic and histaminic receptors, stated Dr. Allan Young, LEEF Leadership Chair in Depression Research and Associate Director, University of British Columbia Institute of Mental Health, Vancouver. “Atypicals have a variety of occupancy at different receptors and this has implications for efficacy and side effects. But we have a limited amount of pharmacologic data that allows us to extrapolate.”

Although atypicals are widely used in schizophrenia and schizoaffective disorders, a large percentage of patients discontinue treatment. CATIE showed that 74% of patients discontinued treatment during phase I, 24% due to lack of efficacy, 15% for intolerability, and 30% because of patient decision (Lieberman et al. N Engl J Med 2005;353(12):1209-23). Patients with schizophrenia commonly take other treatments, such as antidepressants, cardiac therapy, anxiolytics, anticonvulsants and analgesics, which add to the side-effect burden, Dr. Young noted.

The most well-documented side effects of antipsychotics include extrapyramidal symptoms and weight gain. Lesser-known effects include sexual and reproductive dysfunction, neuroleptic dysphoria, metabolic changes and long-term medical consequences, Dr. Young added. When any new side effect emerges during antipsychotic treatment, the clinician needs to review the medications the patient is already taking and then make a decision about how to manage the side effect.

“The strategy [for managing side effects] should be tailored to the individual patient,” Dr. Young noted. For example, he suggested that strategies for treating schizophrenia would be different between a 45-year-old patient who has diabetes, a large waist circumference, is a smoker and who has been taking multiple medications and a 19-year-old female with first-episode mania who is medication-free and concerned about weight gain. Dr. Young observed that emerging evidence suggests that patients with bipolar disorder are more sensitive to extrapyramidal symptoms, which should be factored into decision-making regarding treatment selection.

Summary

Atypical antipsychotic agents have equivalent efficacy in treating schizophrenia but differ with regard to side effects. Researchers here agreed that when metabolic or other side effects emerge, management decisions should be based on individual patient factors and side-effect profiles of available treatments.