Improvement in antipsychotic-related metabolic disturbances in patients with schizophrenia switched to ziprasidone

Results Significant baseline to endpoint reductions were seen in mean weight (− 5.1 kg), Body Mass Index (BMI; − 1.6 kg/m 2 ), serum glucose (− 14.0 mg/dL), total cholesterol (− 24.1 mg/dL), and triglyceride leves (− 46.2 mg/dL). Mean PANSS total score improved 13.9% after 6 months of treatment with ziprasidone. A proportion (34.3%) of patients were classified as much improved in the CGI-I. Conclusions Switching patients with schizophrenia to ziprasidone when metabolic disturbances are detected may improve these side effects and result in an improved overall outcome. Abbreviations BMI Body Mass Index CGI-S Clinical Global Impression of Severity Scale CGI-I Clinical Global Impression of Improvement Scale HDL High-Density Lipoprotein Cholesterol ITT Intention-to-Treat LDL Low-Density Lipoprotein Cholesterol LOCF Last Observation Carried Forward PANSS Positive and Negative Syndrome Scale Keywords Antipsychotics Metabolic syndrome Naturalistic Schizophrenia Ziprasidone 1 Introduction For the majority of patients with schizophrenia, this represents a recurrent chronic disorder associated with significant impaired functioning. Atypical antipsychotics have become the first-line agents in the treatment of this disorder, perhaps related to better tolerance, particularly of extrapyramidal side effects, as well as greater improvement in negative and affective symptoms ( Kane, 1996 ). On the other hand, a growing awareness of an increased risk of impaired glucose metabolism, weight gain, and dyslipidemia with these second generation agents has led to concerns about their use ( Nasrallah and Newcomer, 2004 ). According to recent reviews, the risk of developing diabetes or obesity is highest for clozapine and olanzapine, followed by quetiapine and risperidone ( Allison et al., 1999; Sernyak et al., 2002 ). Clozapine and olanzapine have also been associated with a worsening in lipid profile, while discrepant results have been reported for quetiapine and risperidone ( Kato and Goodnick, 2001 ). Although efficacy should be the primary goal of an antipsychotic agent given the morbidity and mortality risks of schizophrenia, safety and tolerability should also be taken into account for selecting adequate treatment based on the risk/benefit ratio ( Nasrallah and Newcomer, 2004 ). Since metabolic disturbances represent risks factors for developing cardiovascular diseases, they may negatively influence the outcome of patients with schizophrenia. Ziprasidone is considered a new generation antipsychotic drug with atypical characteristics. Its effectiveness and safety in the treatment of schizophrenia has been shown in several clinical trials both compared to placebo ( Daniel et al., 1999 ) and to haloperidol ( Hirsch et al., 2002 ). Moreover, ziprasidone appears to be associated with a low risk for metabolic disturbances as compared to other atypical antipsychotics ( Kato and Goodnick, 2001; Simpson et al., 2004, 2005 ). The primary objective of this study was to assess the impact upon weight, glucose and lipid metabolism of switching to ziprasidone in an outpatient population with schizophrenia and weight or metabolic disturbances related to their previous antipsychotic treatment. Other objectives of the study were to assess the global tolerability of ziprasidone and its impact upon clinical status after switching to this agent from other antipsychotics. 2 Methods 2.1 Patient population Those patients meeting DSM-IV-TR ( APA, 2000 ) criteria for schizophrenia or schizoaffective disorder, who had developed glucose intolerance, diabetes, worsening of previous diabetes, dyslipidemia or weight gain associated with their current antipsychotic medication were recruited for the study. Patients were informed about the objectives of the study, and their oral consent to participate was obtained. This was an observational study, and according to clinical practice, approval by the Ethics Committees of the participating centers and signed informed consent from patients were therefore not required before the start of the study. Patient confidentiality was maintained, since no identification data were recorded in the study documentation. 2.2 Study design This was a multicenter, observational, prospective, open-label study conducted in four outpatient centers in Spain from November 2003 to October 2004. Metabolic laboratory tests, including nonfasting glucose, total and fractionated cholesterol, and triglyceride levels were performed at baseline, after three months of ziprasidone treatment, and at endpoint. Nonfasting condition may not be optimal but this practice was similar for patients at baseline and throughout the study. Body weight was also determined at baseline, after three months of ziprasidone treatment, and at endpoint. Body Mass Index (BMI) was calculated based on height measured at baseline. Clinical status of patients was evaluated using the Clinical Global Impression of Severity (CGI-S) and Improvement (CGI-I) scales ( Guy, 1976 ) and the Positive and Negative Syndrome Scale (PANSS) ( Kay et al., 1987 ). Assessment scales of clinical status were administered by investigators at baseline and 3 and 6 months after ziprasidone was started. All adverse events spontaneously reported by patients or elicited during a physician–patient interview were recorded. 2.3 Drug administration Patients were started on flexible dosing of ziprasidone based on individual clinical criteria. Prior antipsychotic medication was discontinued in different ways depending on the investigator experience: abrupt discontinuation or slow tapering up to the fourth week of ziprasidone treatment. The only antipsychotic drug allowed for the rest of the study period was ziprasidone. Other previously prescribed psychotropic drugs were continued. 2.4 Data analysis The European Biometrics Institute performed the statistical analysis. Some analyses were made establishing two groups for comparison: one group included patients previously receiving olanzapine, and a second group included patients switched from risperidone to ziprasidone. Analyses were made on an intention-to-treat (ITT) basis, including all patients who had received at least one dose of ziprasidone and for whom at least one efficacy assessment was available. The last observation carried forward (LOCF) approach was used, i.e. every longitudinal missing value was replaced by the last value available for that variable. Changes in outcome variables were analyzed using a McNemar's test for dichotomic variables and a paired t test or a Wilcoxon's signed rank test for quantitative variables. To test the independence between the two groups (olanzapine versus risperidone) a Fisher's exact test or a Chi-square test was used for nominal data, while a t test was used for normal quantitative variables, and a Wilcoxon–Mann–Whitney test for non-normal quantitative variables. 3 Results A total of 84 patients were enrolled into the study. Of these, 67 patients received at least one dose of ziprasidone and were included in the ITT sample. Table 1 shows the demographic and baseline clinical characteristics of the 67 patients comprising the ITT population. The mean baseline CGI-S score of 4.1 in the sample population suggests that these patients had a moderately severe disease despite the antipsychotic treatment previously prescribed. Table 2 shows the reasons for switching from prior antipsychotic treatment. Most patients were switched from olanzapine ( n = 40), while 20 patients were taking risperidone before being switched to ziprasidone, three patients were switched from haloperidol, and one patient each from fluphenazine, quetiapine, amisulpride, and combined treatment with quetiapine and risperidone. The study was completed by 69.1% of the total sample population. The proportions of patients switched from olanzapine and risperidone who dropped out of the study were similar (30.6% and 34.6% respectively). Consent withdrawal was the most common reason for study discontinuation (14.3%), whereas the proportions of patients who discontinued the study because of inadequate clinical response or adverse event occurrence were only 7.3% and 5.9% respectively. Table 3 shows the initial and final ziprasidone doses received by the ITT population in the study. Mean initial ziprasidone dose was slightly higher in patients switched from olanzapine (114.0 mg/day) than in those switched from risperidone (105.0 mg/day), but this difference was not statistically significant (Mann–Whitney's U test; p = 0.08). At baseline, 19 (28.4%) patients were taking benzodiazepines, five (7.5%) were on antidepressants, five (7.5%) on mood stabilizers and three (4.5%) received anticholinergic medication. At endpoint, 12 (17.9%) patients were taking benzodiazepines, three (4.5%) were on mood stabilizers, two (3.0%) patients were on antidepressants and one (1.5%) patient received anticholinergic medication. Thus, the proportion of patients requiring concomitant psychopharmacological treatment other than ziprasidone was reduced from 46.3% at baseline to 26.9% at endpoint ( p = 0.046). 3.1 Weight and metabolic parameters Mean baseline body weight was similar ( p = 0.671) in patients switched from olanzapine (86.4 kg) and risperidone (84.9 kg). A significant decrease in mean body weight (− 5.1 kg, p < 0.0001) was seen in the ITT sample population from baseline to endpoint ( Fig. 1 ). Percent body weight reduction was significantly greater ( p = 0.01) in men (6.0%) as compared to women (5.6%). Body weight loss was also significantly greater ( p < 0.001) in patients switched to ziprasidone from olanzapine (− 7.0 kg) than in those switched from risperidone (− 2.2 kg). BMI significantly decreased from baseline to endpoint (30.3 to 28.6 kg/m 2 , p < 0.001) in the ITT group. This BMI decrease was also significantly greater in patients switched from olanzapine as compared to those switched from risperidone (− 2.1 vs − 0.8 kg/m 2 , p = 0.008), although mean baseline BMI was similar ( p = 0.2792) in both groups. At endpoint, a statistically significant decrease (112.6 to 98.5 mg/dL, p < 0.0001) in mean serum glucose levels was seen in the ITT sample ( Fig. 2 ) with the trend ( p = 0.101) for a greater reduction in the olanzapine as compared to the risperidone patients (− 18.9 vs − 10.2 mg/dL). A significant decrease (− 24.1 mg/dL, p < 0.0001) occurred in mean total cholesterol levels from baseline to endpoint ( Fig. 3 ). Mean changes were also significantly greater ( p < 0.01) in patients switched from olanzapine (− 33.0 mg/dL) than in those switched from risperidone (− 7.5 mg/dL). Mean baseline total cholesterol levels remained high ( p < 0.001) in patients previously treated with olanzapine (244.1 mg/dL) as compared to risperidone (204.4 mg/dL). Low-density lipoprotein (LDL) and high-density lipoprotein (HDL) levels were only measured in 36 patients. Mean LDL levels significantly decreased from baseline to endpoint (− 17.1 mg/dL, p = 0.004), while HDL levels remained unchanged throughout the study. There were also significant reductions (− 46.2 mg/dL, p < 0.0001) in mean triglyceride levels in the ITT population ( Fig. 4 ). This decrease in triglyceride levels was also greater in patients switched from olanzapine (− 56.7 mg/dL) than in those switched from risperidone (− 25.0 mg/dL), but the difference did not reach statistical significance. 3.2 Effectiveness Overall psychopathology improved after switching to ziprasidone as measured by PANSS and CGI scales. Mean PANSS total score significantly improved after three months of ziprasidone treatment (7.9% improvement, p < 0.0001) and at the endpoint (13.9% improvement, p < 0.0001) as compared to baseline ( Fig. 5 ). Decreases in mean PANSS total scores were similar in both patient subsets switched from olanzapine and risperidone. The proportion of patients classified as CGI-I responders (scoring lower than 3) at endpoint was of 34.3% (all these patients scored 2). Furthermore the proportion of patients classified as remitted (PANSS total score lower than 60) increased from 24.2% at baseline to 42.4% after 6 months of ziprasidone treatment. 3.3 Tolerability Only 12 patients in the ITT sample population (17.9%) experienced treatment-emergent adverse events ( Table 4 ). No adverse event was reported with a frequency higher than 3%, and most events were mild or moderate in severity. Only five patients reported the following extrapyramidal symptoms: akathisia ( n = 1), oculogyric crisis ( n = 2), tremor ( n = 1) and rigidity ( n = 2). 4 Discussion This naturalistic study was conducted in four mental health centers on a sample population that is representative of ordinary community-living patients with schizophrenia. These patients were considered to be stable, but were moderately ill despite antipsychotic treatment. In addition, weight gain and other metabolic disturbances, which may represent risk factors for cardiovascular disease, were present. In this patient sample, switching to ziprasidone was associated to metabolic improvement with no evidence of clinical impairment; in fact, some improvement was seen. The primary objective of this study was to assess changes in these antipsychotic-related metabolic disturbances after switching to ziprasidone. There were significant reductions in weight without any special interventions apart from the switch to ziprasidone. Significant improvements were also noted in glucose metabolism and lipid profile after switching to ziprasidone. It should be noted that greater metabolic improvements were found in patients switched from olanzapine, mainly because of the more marked increases in weight, glucose and lipid levels previously experienced by such patients. Similar metabolic improvements were previously reported in another six-week study on patients switched to ziprasidone ( Weiden et al., 2003 ). The six-month follow-up in our study contributed to collect relevant information about long-term changes in metabolic parameters after switching patients with schizophrenia or schizoaffective disorder to ziprasidone. The above reported short-term decrease in values of these metabolic parameters continued after three and six months of follow-up. Thus, our study agrees with and supports information available from those short-term clinical trials regarding the benign metabolic profile of ziprasidone. Overall, ziprasidone was well tolerated, and very few patients discontinued the drug for adverse events. The low incidence of extrapyramidal symptoms seen in these patients treated with ziprasidone under routine clinical conditions at higher doses than in clinical trials ( Keck et al., 1998 ) supports the low potential of ziprasidone for inducing these motor side effects. Since the occurrence of extrapyramidal symptoms may result in treatment noncompliance ( Blackwell, 1996 ), use of ziprasidone may lead to a greater adherence and maybe a decreased recurrence. However, this study was not specifically designed to assess effectiveness and the emphasis on side effects, particularly metabolic, may indeed have biased the study in favor of ziprasidone. Furthermore, patients probably received more attention than previously and items like negative symptoms may have improved merely because more time was spent with the patient. Bearing in mind these limitations, a slight beneficial effect on the clinical status of this sample of chronic patients was noted after they were switched to ziprasidone, a high proportion of whom experienced remission. Mean ziprasidone final dose was 150 mg/day (range 100–240), suggesting that doses higher than those generally used in clinical trials may increase clinical effectiveness in some groups of patients without impairing tolerability. 5 Conclusions In this outpatient sample with schizophrenia, ziprasidone administered on an open-label basis, improved metabolic disturbances associated to prior antipsychotic treatment. Although caution is required in assessing clinical improvement because of the naturalistic design of the study, switching to ziprasidone may lead to an improved overall outcome in patients with this condition. Acknowledgment This study was supported by a grant from Pfizer S.A. References Allison et al., 1999 D.B. Allison J.L. Mentore M. Heo L.P. Chandler J.C. 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