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21st Congress of the European College of Neuropsychopharmacology

Barcelona, Spain / September 1-3, 2008

“Life expectancy of patients with schizophrenia and bipolar disorder has decreased by 20% over the past decade,” stated Dr. John L. Beyer, Director, Mood and Anxiety Disorders Clinic, Duke University, Durham, North Carolina, “and this excess mortality appears to be due more to medical causes than the usual suicides or accidents.”

Patients with schizophrenia now have more than twice the expected risk for death than the general population and a higher standardized mortality ratio (SMR), especially in cerebrovascular diseases, diabetes and epilepsy, and SMRs are even more significantly increased in patients who smoke, he noted. Individuals with bipolar disorder have a 50% greater risk of death from medical causes than the general population and SMRs for natural causes are about twice what is observed in the general population, with increased mortality being especially high for cardiovascular (CV) and respiratory death.

Dr. Beyer told delegates, “Psychiatrists are not sensitive to the fact that natural causes of death are increased in schizophrenia and are probably the reason for higher levels of mortality and shorter life expectancy. We can get so focused on making sure that patients are not psychotic that we overlook problems involving obesity or increased cholesterol or CV disease. Medical diseases and psychiatric disorders have a bi-directional relationship in which each illness exacerbates the other, and we have to realize that the very things we do that help patients also have the potential to make them worse in other areas and even shorten their life expectancy.”

Metabolic Side Effects

“Metabolic side effects can have a significant impact on patients’ quality of life in addition to serious long-term health implications,” confirmed Dr. W. Wolfgang Fleischhacker, Department of Psychiatry and Psychotherapy, Innsbruck University Clinics, Austria. “For example, antipsychotic-induced weight gain has been shown to be associated with increased body fat and serum leptin levels. High serum prolactin has been linked to sexual dysfunction, gynecomastia, amenorrhea and galactorrhea. Changes in QTc interval, which can occur with some antipsychotic treatments, may heighten the risk of arrhythmias.”

Dr. Fleischhacker characterized the mean weight gain among schizophrenic patients treated with second-generation antipsychotics as frightening. As co-investigator of the EUFEST (European First Episode Schizophrenia Trial), he reported that ziprasidone caused the least weight gain among other atypicals or haloperidol in a year (Lancet 2008 Mar 29;371(9618):1085-97).

“Beyond their damaging clinical consequences, side effects can have important implications for treatment,” he continued. Poor tolerability of a medication can lead to non-compliance, which is one of the main factors for the relatively high relapse rate among patients with schizophrenia. Antipsychotic therapy that combines good efficacy with a favourable safety and tolerability profile may lead to improved compliance.

“I would argue that the pharmacologic profile of these drugs is generally a better predictor of its safety than of its efficacy,” Dr. Fleischhacker commented. “They are hugely different with regard to actions on various receptor systems, which can usually be very well linked to safety problems and tolerability issues, whereas they look more or less similar on the efficacy spectrum.” He cited, for example, a short-term study published by Simpson et al. (Am J Psych 2005;162:1535-8). Findings demonstrated total cholesterol and LDL-C actually decreased by a mean of 1.0 mg/dL (0.03 mmol/L) and 1.0 mg/dL (0.03 mmol.L), respectively, and triglycerides by 2.0 mg/dL (0.02 mmol/L) in a group of schizophrenic or schizoaffective disorder patients treated with ziprasidone. Results indicated that total cholesterol and LDL-C increased by a mean of 19.5 mg/dL (0.50 mmol/L) and 13.0 mg/dL (0.34 mmol/L), respectively, as did triglycerides by 26.0 mg/dL (0.29 mmol/L), in the matched treatment arm receiving olanzapine. Coronary heart disease is the leading cause of death in schizophrenia and related to elevated metabolic risk factors such as obesity and dyslipidemia/cholesterol.

It is noteworthy that the primary efficacy measures in this study, improvements in the Brief Psychiatric Rating Scale and Clinical Global Impression of Severity Scale scores did not differ significantly between the study arms at either last patient visit (P=0.74) or study end point (P=0.95), demonstrating that there is no sacrifice of efficacy with metabolic advantage achieved with ziprasidone treatment. Certainly, one key factor in the management of patients with schizophrenia would appear be the selection of an antipsychotic with a low risk for physical and metabolic side effects, Dr. Fleischhacker remarked.

Titration and Compliance

“The starting dose as well as the choice of medication is critical to avoid side effects and the risk of poor compliance and relapse in the treatment of schizophrenia and bipolar disorder,” noted Dr. David C. Henderson, Director, Schizophrenia Diabetes and Weight Reduction Research Program, Harvard Medical School, Boston, Massachusetts. “Frequency and duration of treatment are critical to adherence to antipsychotic medication.”

Dr. Eduard Vieta, Hospital Clinic, University of Barcelona, Spain, stated that ziprasidone can be rapidly titrated from 80 mg/day to reach its optimal dose level of 160 mg/day in divided doses in as early as three days. He reported on his study which demonstrated that with early dosing, early partial responses to that atypical antipsychotic would predict subsequent treatment responses in patients. He suggested that a clinician’s decision to continue or switch antipsychotic agents for patients with bipolar disorder would be better informed when an early response to treatment predicted a later full response.

Dr. Vieta reported that at day 4, by which time patients were titrated to 80 to 160 mg/day, 101 of 230 (43.9%) treated patients and 38 of 80 (32.2%) placebo patients were early partial responders. “A partial response at day 4 correctly predicted a full response at the last observation carried forward [LOCF] end point in 71 of the 101 [70.3%] ziprasidone-treated patients and 23 of 38 [60.5%] placebo-treated patients. At the LOCF end point, the mean least squares [LS] mean change from baseline Mania Rating Scale [MRS] score was greater in ziprasidone-treated [-12.6±0.65] than in placebo-treated patients [-9.1±0.99; P=0.003],” he told delegates.

“A significant difference in LS mean change from baseline MRS score was also observed between patients with a partial response at day 4 [-15.7±0.98] and those without a partial response [-5.9±0.68; P<0.0001],” Dr. Vieta added. “Sensitivity, specificity and predictive power for ziprasidone were 64.4%, 76.9% and 71.0%, respectively. For placebo, those values were 66.7%, 80.0% and 76.4%.”

Partial response to active treatment at day 4 predicted a later full response at three weeks, Dr. Vieta concluded. Day 4 responders achieved a greater change in MRS scores at the LOCF end point than did day 4 non-responders. Early response to the atypical antipsychotic may allow clinicians to predict which patients with mania will benefit from extended treatment with this agent.

Dr. Henderson added that the safety and tolerability of medications have a major impact on adherence and efficacy. Adherence is a critical component of successful treatment and the newer antipsychotics have been linked to medical morbidity, including hyperglycemia, diabetes mellitus, weight gain and lipid abnormalities, as well as incorrect dosing and medication side effects, all of which increase the risk of non-adherence. Obese patients are 2.5 times as likely to stop medication as normal-weight patients—“and if you think patients do not mind being overweight, you are wrong,” Dr. Henderson stressed. Lack of satisfaction with weight correlates with non-compliance. In an anonymous survey, 47% of schizophrenic individuals with a body mass index (BMI)>30 were non-compliant with medication compared with 39% who had a BMI of 25 to 30 and 26% whose BMI was <25.

He concluded that effective interventions to improve adherence to antipsychotic treatment require a multidisciplinary approach which includes pharmacotherapy that provides the best long-term outcomes and the least adverse physical metabolic drug reactions.