Ziprasidone versus Olanzapine in the weight gain associated with the treatment of schizophrenia: A six-month double-blind randomized parallel group study

Enric Álvarez*; Miguel Bernardo**; José Ramón Gutiérrez Casares***; Ángel L. Montejo****

* Department of Psychiatry. Hospital de la Santa Creu i Sant Pau. CIBERSAM, Universitat Autónoma de Barcelona, IBSantpau Barcelona. Spain
** Department of Psychiatry, Hospital Clinic de Barcelona, CIBERSAM, University of Barcelona, IDIBAPS, Barcelona. Spain
*** Complejo Hospitalario Universitario de Badajoz. Servicio Extremeño de Salud, Badajoz. Spain
**** Hospital Universitario de Salamanca. School of Medicine, University of Salamanca, Salamanca. Spain

Correspondence

ABSTRACT

Background and Objectives: Previous data from safety analysis indicate that olanzapine can result in substantial weight gain, while no change has been observed with ziprasidone. Obesity may be a threat to health and cause subjects to discontinue their antipsychotic medication. To further evaluate the differential effects of ziprasidone and olanzapine on weight gain, a study was carried out having body weight as the primary efficacy endpoint.
Methods: A six-month randomized, double-blind, parallel study was carried out in male and female subjects aged 18-70 years with a primary diagnosis of schizophrenia (DSM-IV-TR) and a clinical condition requiring treatment initiation with a new antipsychotic, ziprasidone or olanzapine 1:1, to assess treatment-related weight changes. Fifty patients were included. Efficacy outcomes were assessed at baseline and at weeks 1, 4, 12, 18 and 24. The primary efficacy endpoint was the percent change from baseline in body weight at week 24. Safety was also assessed.
Results: At week 24, there was a significantly greater increase in body weight (7.5%, p <0.0001) in patients treated with olanzapine than in those treated with ziprasidone and the number of subjects who had a weight gain > 7% was significantly higher in the olanzapine compared to the ziprasidone group (n = 11 [47.8%]) vs n = 3 [11.1%]; OR = 6.246, p-value = 0.0150). PANNS-N significantly decreased in both groups. Most AEs were moderate or mild in both groups.
Conclusions: Olanzapine increases body weight significantly over ziprasidone at week 24. However, treatment with either ziprasidone or olanzapine improved PANSS positive, negative and general psychopathology scores and was well tolerated.

Key words: Antipsychotic agents; Weight gain; Ziprasidone; Olanzapine; Obesity.

Introduction

Schizophrenic patients show a higher pre-valence of obesity, glucose intolerance and type 2 diabetes mellitus, with a genetic link to enzymes involved in glycolysis^1,2, and a higher rate of cardiovascular events³. Moreover, many second generation antipsychotics are associated with a higher risk for weight gain^2,4, insulin resistance, hyperglycemia and dyslipidemia⁵. The combination of these different factors, genetic susceptibility, a sedentary lifestyle and poor diet and the adverse side effects of the antipsychotic treatment, represent an important risk factor for cardiovascular disease in patients treated with atypical antipsychotics⁶. Not only is obesity a threat to health and longevity, but it may also cause subjects to discontinue their antipsychotic medication⁷.

Both ziprasidone and olanzapine are efficient atypical antipsychotics frequently used in the treatment of schizophrenia and schizoid disorders. Atypical antipsychotic drugs show better efficacy and less adverse side effects than typical antipsychotics^8,9. However, they are still prone to cause unwanted effects, including hypostatic hypotension¹⁰, somnolence¹¹, weight gain^1,2, dyslipidemia¹², hyperglycemia and diabetes mellitus⁵ and hyperprolactinaemia, which may generate fertility problems, sexual dysfunction and reduced bone mineral density^13,14.

Previous studies have shown no changes in weight or metabolism in subjects treated with ziprasidone^1,2,15, Ziprasidone shows low propensity to cause extrapyramidal side effects (EPS) or laboratory abnormalities^8,16,17, and does not negatively affect the sexual function of schizophrenic patients¹⁸. Ziprasidone has been reported to cause weight loss and reduction in serum lipid levels^19,20.

Olanzapine is one of the most frequently prescribed antipsychotic drugs, with proven efficacy for schizophrenia symptoms^21-23. However, olanzapine stands among the atypical antipsychotic drugs that induce weight gain^24,25, being also associated with substantial increases in total cholesterol, triglycerides, LDL and fasting insulin^20,26,27. In previous studies comparing ziprasidone vs. olanzapine, exclusively or combined with other treatments, olanzapine showed significantly greater increases in weight and BMI and a higher probability of rapid weight gain than any other treatment^7,20,26,27. However, all these studies had an efficacy variable as the primary variable, being weight assessment only part of the safety study.

Antipsychotic treatments are often long-term and it is necessary to consider the increased risk for metabolic alterations in patient care. Therefore, this randomized, double-blind study was designed to specifically address the issue of weight gain in the long-term (6 month), this being the primary variable. Also, considering that other factors are related to the patients disposition and compliance with treatment, this study assessed quality of life, general functioning, preferences and attitude to treatment, in order to provide more information on issues to be addressed in these long-term treatments and to discuss their relationship with the main purpose.

Methods

A six-month randomized, multi-center, parallel, double-blind study was carried out from April 2003 through February 2007 to estimate and compare the effects of ziprasidone versus olanzapine on body weight in the treatment of subjects with schizophrenia.

The study was developed in agreement with the declaration of Helsinki²⁹ and the study protocol was approved by the Ethics Committees corresponding to the centers involved and by the Medicinal Products for Human Use Department of the Medicine and Health Products Spanish Agency (AEMPS).

Subjects were included in the study 12 hours after the previous antipsychotic dose, except for subjects treated with a depot antipsychotic (see above), and were randomly allocated in a 1:1 ratio.

Treatment dosage and visit schedule

Dosage was flexible within 3 levels: Low (ziprasidone 40mg BID or olanzapine 5mg BID), Medium (ziprasidone 60mg BID or olanzapine 15mg QD) and High (ziprasidone 80mg BID or olanzapine 10mg BID). Treatment was initiated at low dose for days 1-7 and from day 3 onwards, the dose could be adjusted.

The treatment phase (6 months) included 6 visits: Day 1 (Week 0), Week 1, Week 4, Week 12, Week 18 and Week 24. Follow-up visit (Week 48) performed six months after treatment completion. Study medication was reported from visit 1 through 6. Subjects who showed insufficient response at any time during the study, as indicated by a Clinical Global Impression of Improvement (CGI-I) score of ≥ 6, were withdrawn.

Efficacy and safety assessments

The efficacy outcomes measured were weight, BMI and waist circumference (WC); blood pressure and pulse; the positive and negative syndrome scale (PANSS)³⁰; the Clinical Global Impression (CGI) scale³¹ and another for improvement (CGI-I); patient's physical activity; the patient preference scale (PPS), to measure patient's satisfaction with medication; the Spanish version of the Health Utilities Index-Mark 3 (HUI-3)^32,22. Appetite was measured by a visual analogue scale (VAS), a subjective quantification method. The patient marks his/her appetite level since the last visit on a horizontal line marked 0 (no appetite) left and 10 (extremely hungry) on the right. The distance from 0 is then measured in cm and appetite level quantified.

All efficacy outcomes were assessed at visit 1 (baseline values) and additionally: CGI-S, CGI-I and PANSS from visit 2 to 7, appetite and patient's physical activity from visit 3 to 6, PPS and HUI-3 at visits 4 and 6

Safety evaluations included clinical monitoring, electrocardiograms, vital signs, adverse events (AEs), and safety laboratory tests. Safety assessments were reported according to Worldwide Safety Standards (WSS) Version 3 requirements.

All analyses were performed on the intent-to-treat (ITT) population, using the SAS^® version 8.2 or higher. Statistical tests were 2 tailed and p-values of 0.05 or smaller were considered statistically significant. Treatment was fitted as a categorical. 95% confidence intervals (CI) were constructed around all estimated treatment differences. All changes were analyzed by analysis of covariance (ANCOVA) including effects for treatment group and baseline value (if applicable). Descriptive statistics were used to summarize all safety assessments. Adverse events were coded according to the Medical Dictionary for Regulatory Activities (MedDRA). No formal statistical testing was performed on safety parameters.

Results

Subject disposition and drug dose

Although the study was initially intended for 112 patients, in the study period only 58 subjects were screened. Finally, 50 ITT patients were included: 27 to ziprasidone and 23 to olanzapine. During the study period a total of 29 subjects discontinued their treatment (19 in the ziprasidone group and 10 in the olanzapine). Although most discontinuations were not related to the study drug, 2 (one in each group) were due to lack of efficacy and 7 (5 in the ziprasidone and 2 in the olanzapine) were due to drug-related adverse events. Median duration of treatment was lower for the ziprasidone (52.5 days [1-175 days]) than for the olanzapine group (164 days [2-181 days]; 32% of subjects in the ziprasidone group and 58% in the olanzapine completed the study.

During the treatment phase, patients on ziprasidone received a mean dose of 107.4 ± 27.3 mg/day and patients on olanzapine received a mean dose of 15 ± 3.3 mg/day.

Baseline characteristics

Demographic characteristics were homogeneous between both groups showing no significant differences. ITT patients were aged 19-63 years, being the majority in between 18-44 years. Detailed demographic data are provided in table 1. Similar numbers of subjects in both treatment groups received concomitant drug treatments during the study (26 in the ziprasidone and 21 in the olanzapine group). The most frequently taken (by ≥ 5 subjects in either treatment group) in both treatment groups were lorazepam, lormeta-zepam, and risperidone.

Effects on Weight Gain

Body weight was stable at week 24 in the ziprasidone group, showing no significant difference with basal weight (-0.1% percent decrease; n.s.) while there was a statistically significant increase from baseline in the olanzapine group (7.4% percent increase in body weight from baseline, p < 0.0001) (Table 2). The difference between treatment groups in body weight change from baseline was statistically significant at all time points and olanzapine-treated patients showed significant weight increase from baseline in all visits (Table 2). The number of subjects who had a weight gain ≥ 7% at week 24 was significantly lower in the ziprasidone (n = 3 [11.1%]) than in the olanzapine group (n = 11 [47.8%]) (OR = 6.246; p = 0.0150). The difference between treatment groups was also evident at weeks 12 (p = 0.0266) and 18 (p = 0.0261) (data not shown).

The secondary endpoints at week 24 are summarized in Table 3. Ziprasidone treated patients did not experience any significant change in WC and BMI at 24 weeks, while olanzapine treated patients suffered a significant increase in both parameters, resulting in a significant difference in the 24-week LSM (least square means) of either value between groups.

Efficacy Results

Ziprasidone treatment resulted in a significant decrease (i. e. improvement) of PANNS-N and olanzapine in a significant decrease of all PANNS subscales. All decreases were significantly larger in the olanzapine than in the ziprasidone group. However, there was no significant difference in the number of patients that experienced improvement of schizophrenia symptoms between groups, as assessed by PANNS (7 [26.9%]) ziprasidone vs. 11 [47.8%] olanzapine; p = 0.1385). On the CGI-S scale, 19 patients in the ziprasidone group and 16 in the olanzapine were moderately to markedly ill at baseline; at 24 weeks, there were 19 and 12 patients, respectively (data not shown). On the CGI-I scale, 5 patients in the ziprasidone group and 4 in the olanzapine were "much improved" and 1 in the ziprasidone and 4 in the olanzapine "very much improved" at 24 weeks (data not shown). Subjects treated with olanzapine had better ratings for symptom exacerbation (CGI-S) (OR: 3.321, p = 0.0286) and improvement (CGI-I) (OR: 3.512, p = 0.0307) at week 24 than those treated with ziprasidone. However, and similarly to PANNS results, there were no significant differences in the number of patients that showed improvement in CGI-S (4 [14.8%] on ziprasidone vs. 7 [30.4%] on olanzapine; p = 0.2379) and CGI-I (6 [25.0%] on ziprasidone vs. 8 [42.1%] on olanzapine; p = 0.2823) between groups. Better satisfaction with medication, as measured in PPS, was observed in the ziprasidone group than in the olanzapine group (p = 0.0161). As shown in Table 4, appetite also decreased significantly in ziprasidone-treated patients, while it increased slightly in the olanzapine group. Although appetite increase in the latter did not reach statistical significance, the change was statistically different between treatment groups. There were no significant differences between treatment groups' blood pressure and heart rate.

Safety Results

No deaths were reported during this study. Adverse effects during this study and laboratory tests have been summarized in Table 5. Half the AE events in each group were treatment-related (ziprasidone: sedation, anxiety, restlessness, schizophrenia and hypersomnia; olanzapine: schizophrenia, restlessness). Twenty-one treatment-related AEs were experienced by 15 subjects (53.6%) in the ziprasidone group and 11 by 8 subjects (33.3%) in the olanzapine group.

Discussion

According to the study protocol, 78 patients (39 in each group) should have been evaluated for a statistical power of 80% to detect a difference of 5 kg, estimating an SD = 7.7. However, the final ITT population included was 50 patients. Although this could have represented a limitation, the difference in body weight between groups at 24 weeks was 7.5% (SD = 4.5). Power was 99% and the result was better than initially planned.

In agreement with previous studies, body weight was stable in the ziprasidone group while there was a statistically significant increase from baseline in the olanzapine group at every time point^6,7. Accordingly, ziprasidone-treated patients did not experience any significant change in WC and BMI, while olanzapine-treated patients suffered a significant increase in both parameters and weight. In a previous study³⁴, the percentage of olanzapine-treated patients with ≥ 7% weight gain was even higher: 60% of patients at 3 months which rose to 80% after 1 year of olanzapine treatment. The olanzapine dosage of the mentioned study was similar or lower than that of our study. This fact is not surprising, since dose has not been related to olanzapine weight gain, but related to therapeutic response²⁵. Patients with maximal olanzapine benefit on symptoms are also those at a highest risk of significant weight gain.

Variations in food intake have been proposed as a possible cause for these effects on weight. In this study, appetite decreased significantly in ziprasidone treated patients while no significant change in olanzapine treated patients was reported. Appetite stimulation is strongly correlated with antipsychotic drug affinity for H1 and alpha1 adrenergic receptors³⁵ and appetite decrease in ziprasidone treated patients is probably associated to the drug's low affinity for H1 receptor. The olanzapine treated patients did not show a significant increase in appetite, but still showed a significant increase in body weight, suggesting that other mechanisms may be involved in olanzapine-induced weight gain. Tschoner et al. found higher fasting glucose and an increased score in an insulin resistance model in patients treated with olanzapine, while this effect could not be observed in ziprasidone treated patients, indicating the involvement of this effect in olanzapine-induced weight gain⁶. Animal studies have shown that olanzapine, but not ziprasidone, stimulates the consumption of fat³⁶ and that chronic treatment with olanzapine impairs lipolysis by adipocytes³⁷. Also, previous studies have found cholesterol, triglycerides and LDL-cholesterol increase in olanzapine treated patients, and not in ziprasidone treated individuals^6,38. Physical activity is significantly reduced in olanzapine treated patients^39,40, but the OR of physical exercise in this study significantly favors olanzapine over ziprasidone treated patients and hence, does not explain the difference in weight gain.

Olanzapine-treated patients showed significantly better outcomes in PANNS subscales than those under ziprasidone treatment, confirming results of a previous study²⁰. Participants in that study had discontinued a previous treatment due to intolerance, making difficult the comparison with our present study. The dose of ziprasidone was similar but olanzapine dose was higher. Olanzapine shows increasing dose-response curves for schizophrenia symptoms^21,41, which might explain the greater improvement in PANNS compared to ziprasidone in the study with higher olanzapine dose. However, olanzapine doses higher than 20 mg/day have been described to present greater risks of important side effects^42,43.

In contrast, two other studies found no difference in efficacy between treatments. The study carried out by Lieberman et al.⁷ showed no significant differences in PANNS total score change from baseline nor between olanzapine and ziprasidone. Likewise, the study by Simpson et al. showed no differences in PANNS score improvement between groups^26,27. These studies used similar flexible doses as the ones we used found the same efficacy with either olanzapine or ziprasidone treatment. A plausible explanation might be that although ziprasidone is indicated for the treatment of schizophrenia at a dose range of 40-160 mg/day, the optimal dose is closer to 120 mg/day⁴⁴ and the mean dose of our study, slightly lower than the mean doses of the other two studies, might not have been optimal. Furthermore, the bioavailable dose might have been even lower. Although ziprasidone plasma level shows a significant positive correlation with receptor occupancy, the dose does not predict plasma level⁴⁴, since food can interfere on ziprasidone absorption⁴⁵, affects may depend on medication timing.

There were 1.6 times more treatment discontinuations in the ziprasidone than in the olanzapine group, showing a higher fold difference between both treatments than in other studies^7,20. Most AEs were mild or moderate in both groups and included adverse events usually observed with these drugs^20,34. PPS scale indicates that patients preferred ziprasidone over olanzapine.

This study shows a significantly greater increase in body weight at week 24 in patients treated with olanzapine compared to those treated with ziprasidone. The progressive appetite reduction reported may have contributed to the slight decrease in body weight observed in ziprasidone-treated patients. On the other hand, patients on olanzapine indicated some increase in their appetite, but changes in this group were not significant and did not show the progressive increase in variation that ziprasidone patients reported. The visual analogue scale is a subjective method for measuring appetite, and although differences in appetite were significant and results seemed consisted during the study, slightly increased appetite or lack of exercise do not appear responsible for the weight gain experienced by olanzapine-treated patients, suggesting other mechanisms. Fat food preference and metabolic dysregulation may play a role in the underlying cause. Both ziprasidone and olanzapine groups were well tolerated and showed a decrease in PANSS scores at week 24. Although the decrease was significantly greater for all scores in the olanzapine group, the possibility of reduced ziprasidone bioavailability cannot be ruled out.

In those patients for whom weight gain during the treatment of schizophrenia may be a problem, treatment with ziprasidone should be tried, because of its good safety profile in this field.

Acknowledgements

Medical writing support was provided by Medical Statistics Consulting and was funded by Pfizer.

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Correspondence:
Enric Alvarez
Department of Psychiatry ]]> Hospital de la Sta. Creu and St. Pau, Barcelona, Spain
C/ Sant Antoni Maria Claret, 167
08025 Barcelona
Phone: (+34) 932 91 90 00
E-mail: ealvarezm@santpau.cat

Received: 22 November 2011
Revised: 31 May 2012
Accepted: 4 June 2012