Ziprasidone as an adjuvant for clozapine- or olanzapine-associated medical morbidity in chronic schizophrenia

Hum. Psychopharmacol Clin Exp (2009)Published online in Wiley InterScience(www.interscience.wiley.com) DOI: 10.1002/hup.1012 Ziprasidone as an adjuvant for clozapine- or olanzapine-associatedmedical morbidity in chronic schizophrenia David C. Henderson1,2*, Xiaoduo Fan1,2, Paul M. Copeland2, Bikash Sharma1, Christina P. Borba1,Sharon I. Forstbauer1, Kate Miley1, Ryan Boxill1, Oliver Freudenreich1,2, Corrine Cather1,2,Anne E. Evins1,2 and Donald C. Goff1,2 1Schizophrenia Program, Massachusetts General Hospital, Boston, Massachusetts, USA2Harvard Medical School, Boston, Massachusetts, USA This study sought to examine the effect of ziprasidone on olanzapine or clozapine-associated medical morbidity such as insulin resistance, diabetes mellitus (DM) and impaired fasting glucose, obesity, and hyperlipidemia in patients with schizophrenia or schizoaffectivedisorder.
Method This was a 6-week, open label trial of ziprasidone 160 mg/day added to a stable dose of olanzapine or clozapine in 21 schizophrenia or schizoaffective patients with DM, impaired fasting glucose, or insulin resistance.
Results Ten olanzapine-treated subjects and 11 clozapine-treated subjects were enrolled in the study. There were no significant differences between the two groups at baseline for age, gender, education, ethnicity, BMI, cholesterol levels, or fasting glucose. At week 6, there were nosignificant changes in weight, BMI, cholesterol levels, or fasting glucose. There was no significant difference in psychotic, negative, ordepressive symptoms. QTc significantly increased at week 2 but not at week 6.
Conclusions The addition of 160 mg/day of ziprasidone was well tolerated but did not produce significant improvement in fasting glucose, insulin resistance, hyperlipidemia or lead to weight loss in olanzapine- or clozapine-treated subjects with schizophrenia or schizoaffectivedisorder. Copyright # 2009 John Wiley & Sons, Ltd.
key words — clozapine; olanzapine; ziprasidone; weight; lipids; insulin resistance; schizophrenia as an adjunctive agent. In this open trial, significantimprovements in ratings of positive, negative, and Clozapine, an atypical antipsychotic agent, remains the depressive symptoms were found. Furthermore, a more most effective psychopharmaceutical agent for treat- recent study found significant improvement in the ment-resistant schizophrenia. Unfortunately, the side disorganized thought subscale of the Positive and effects of clozapine are often difficult for patients to Negative Syndrome Scale (PANSS) (Freudenreich tolerate, particularly sedation and weight gain.
et al., 2007). However, the metabolic sequelae of Although some clozapine patients are able to remain combination therapy have not been fully investigated, out of the hospital, they continue to have significant though elevations of the combination lead to significant psychiatric symptoms despite adequate doses of elevations in prolactin compared to treatment with clozapine. In other symptomatic patients, the clozapine clozapine alone (Henderson et al., 2001).
dose is limited by significant side effects. Treatment Numerous reports of clozapine- and olanzapine- options for patients who do not fully respond to associated insulin resistance, hyperglycemia diabetic clozapine have not been fully elucidated. Several years ketoacidosis associated with clozapine and olanzapine ago, Henderson and Goff (1996) reported that chronic have emerged (Ananth et al., 2002; Baptista et al., schizophrenia patients demonstrated an improved 2002; Caro et al., 2002; Colli et al., 1999; Gian- response to clozapine when risperidone was utilized francesco et al., 2002; Hagg et al., 1998; Hendersonet al., 2000b, 2005, 2006a; Kato and Goodnick, 2001;Koller and Doraiswamy, 2002; Koller et al., 2001; * Correspondence to: D. C. Henderson, Freedom Trail Clinic, 25 Staniford Newcomer et al., 2002). By increasing a patient’s risk Street, Boston, MA 02114, USA. Tel: (617) 912-7853. Fax: (617) 723-3919.
E-mail: dchenderson@partners.org of obesity, antipsychotic agents may be placing Copyright # 2009 John Wiley & Sons, Ltd.
patients at risk for associated morbidity and mortality (Daniel and Copeland, 2000). Ziprasidone also acts as (Pi-Sunyer, 1993). Patients who gain greater than 10% an agonist of the 5-HT1A receptor and moderately of their total body weight are at risk for developing inhibits the re-uptake of serotonin and norepinephrine.
weight associated conditions such as hypertension and The low liability of ziprasidone with respect to weight type 2 diabetes mellitus (DM). Henderson et al.
gain may have significance for patients even beyond (2000a) found a high rate of diabetes in this cohort as the cardiovascular and other health effects (Alao et al., 30 of 82 patients (36.6%) treated with clozapine 2002; Allison et al., 1999; Cohen et al., 2003; Spivak developed DM over a 60-month period. Olanzapine has et al., 2002; Wetterling, 2001). The distressing side also been associated with significant weight gain (>7% effect of weight gain frequently leads to patient-driven total body weight), insulin resistance, hyperlipidemia, decisions to switch or discontinue medications.
and new onset DM (Cohen et al., 2003; Melkersson Ziprasidone was chosen as its side effect profile et al., 2000; Opp and Hildebrandt, 2002; Seaburg et al., greatly differs from both clozapine and olanzapine and 2001; Wilson et al., 2003). While switching to an agent there was already pilot data examining aripiprazole associated with less weight gain (such as ziprasidone or (Henderson et al., 2006b). Different receptor affinities aripiprazole) offers the greatest opportunity for may play a role in weight gain and the development of resolution of clozapine- or olanzapine-associated DM in patients on antipsychotic medication. Aripi- DM, many clinicians and patients are reluctant to prazole may have partial agonist properties at 5-HT1A, do so. Because clozapine is reserved for treatment- 5-HT2A, and 5-HT2C serotonin receptors (Shapiro resistant schizophrenia patients, switching to another et al., 2003), whereas ziprasidone is a D2 and 5-HT2A antipsychotic agent may not be feasible. The best antagonist, and an agonist at 5-HT1A receptors.
intervention for clozapine patients may be to add an Clozapine and olanzapine, which offer the greatest agent associated with less weight gain and eventually risk of weight gain, are structurally similar and both lower the dose of clozapine. In this setting, weight loss have binding capacities for serotonin 5-HT2C, hista- and improvements in glucose metabolism may occur.
mine H1, and muscarinic M1 receptors (Bymaster Additionally, when switching patients treated with et al., 1996; Millan et al., 1998). A study by Kroeze antipsychotic agents, many times clinicians make the et al. (2003) found that affinities for histamine H1, switch rapidly and provide little time for overlap.
alpha(1A) adrenergic, 5-HT2C, and 5-HT6 receptors Patients treated in this manner may have a higher risk were most strongly correlated with weight gain when of relapse that is often considered a drug trial failure, screening 17 typical antipsychotics. While neither but in fact it may be that the second agent did not have aripiprazole nor ziprasidone has high affinities for the time to take hold. Determining whether combination histamine H1 receptors, the affinity of ziprasidone is antipsychotic agents therapy results in an improvement lower than that of aripiprazole (Kroeze et al., 2003).
in metabolic parameters and psychopathology would be This discrepancy may be a factor in each drug’s ability helpful to clinicians in their decision-making regarding to counteract clozapine and olanzapine-associated pharmacotherapy. The results of this study may provide clinicians and patients with a potentially effective Additionally, 5-HT2C receptors have been implicated intervention to counteract the weight and metabolic in the control of appetite (Vickers et al., 1999) and a effects of clozapine and olanzapine, while also showing variant of the 5-HT2C receptor gene (-759C/T) was the benefits of continued or improved efficacy. It may associated with less weight gain in a study of first also allow clinicians and patients to be more comfortable episode schizophrenia patients (Reynolds et al., 2003).
with a much slower and safer switch to ziprasidone as the Therefore, it is conceivable that the minimal weight medical morbidity benefits may begin as soon as the drug gain associated with aripiprazole may be due to its is started. If a patient experiences early medical benefits moderate binding affinity at 5-HT2C receptors. Ziprasi- from ziprasidone, the speed of switching can be much done does not share this capacity for 5-HT2C receptors.
slower while also significantly reducing the risk of Accordingly, effects on clozapine and olanzapine- associated weight gain were not demonstrated with the Ziprasidone is an atypical antipsychotic agent with addition of ziprasidone comparable to aripiprazole.
high affinity for dopamine D2 and 5-HT2A receptors In the present pilot study, we investigated the bene- where it acts as an antagonist. Clinical trials indicate fits for metabolic response, weight loss, and efficacy that ziprasidone is effective against positive, negative, for positive and negative symptoms of ziprasidone and affective symptoms in schizophrenia and schi- 160 mg/day added to a stable dose of clozapine- or zoaffective disorder with minimal motor, cognitive, olanzapine-treated subjects with schizophrenia or weight, prolactin related, or anticholinergic side effects schizoaffective disorder over a 6-week period.
Copyright # 2009 John Wiley & Sons, Ltd.
ziprasidone for clozapine/olanzapine side effects consented but were lost to follow-up, and one subjectwithdrew consent after receiving one dose of zipra- We investigated the efficacy of ziprasidone for weight sidone. The target for this pilot study was to have 20 loss in clozapine- or olanzapine-treated schizophrenia subjects complete 6 weeks of the study (10 clozapine subjects during a 6-week open label trial. Based on our previous study with aripiprazole, 6 weeks was deter- Subjects were treated with open label ziprasidone mined to be adequate to see significant weight loss and 40 mg twice daily for the first 2 weeks. After 2 weeks, reduction in lipids (Henderson et al., 2006b). The ziprasidone was increased to 80 mg twice daily as hypotheses were that the addition of ziprasidone tolerated. Clozapine or olanzapine doses remained 160 mg/day to stable clozapine- and olanzapine-treated unchanged throughout the study. Patients that chose to schizophrenia or schizoaffective disorder subjects with remain on ziprasidone after the completion of the DM, impaired fasting glucose, or insulin resistance 6-week trial were assessed at week 10.
would result in significant weight loss and improve-ments in glucose and lipid metabolism over a 6-weekperiod.
Fasting blood samples were assayed for a complete blood count and concentrations of plasma glucose, This 6-week open label trial was conducted in the adult cholesterol (total, HDL and LDL), and triglycerides at outpatient clinic of an urban community mental health baseline, week 4 and week 6 using standard laboratory center. The Institutional Review Board of the procedures. Insulin immunometric assays were per- Massachusetts Department of Mental Health approved formed using an Immulite Analyzer (Diagnostic the study. After providing written informed consent, all Product Corporation, Los Angeles, CA, USA) with participants underwent a diagnostic evaluation by a an intra-assay coefficient of variation of 4.2–7.6%.
research psychiatrist using the Structured Clinical HOMA-IR was calculated from fasting glucose and Interview for DSM-IV (SCID) (Spitzer et al., 1992).
insulin values at baseline and week 6 (Kissebah et al., Subjects on clozapine or olanzapine were recruited 1982). The same assays were completed at week 10 for for the study if they met the following criteria: diag- all subjects who chose to remain on Ziprasidone.
nosis of schizophrenia or schizoaffective disorder, age Subjects were assessed with a battery of symptom 18–65 years, capable of providing informed consent, rating scales at baseline, weeks 2, 4, and 6. The treatment with clozapine or olanzapine for at least assessment battery included the Positive and Negative 1 year and with a stable dose being administered for at Syndrome Scale (PANSS) (Kay et al., 1987), Scale for least 1 month. Subjects were required to have a history Assessment of Negative Symptoms (SANS), Hamilton of DM, impaired fasting glucose, or insulin resistance Depression Rating Scale (HAM-D), Fatigue Scale to participate in the study. Impaired fasting glucose was Inventory (FSI) (Hann et al., 2000), the Quality of Life defined as a fasting glucose of greater than or equal to Scale (QOL), the Simpson–Angus Scale, Barnes 100 mg/dl and less than 126 mg/dl. Insulin resistance Akathisia Scale, and the Abnormal Involuntary Move- was defined as fasting insulin greater or equal to ment Scale (AIMS). A single rater performed all 15 mU/L or a Homeostasis Model Assessment- Insulin assessments throughout the trial. A physical examin- Resistance (HOMA-IR) units, greater or equal to 2.
ation and medical history was performed at baseline Subjects were excluded from the study if they were and measurement of vital signs, weight, and waist/hip unable to provide informed consent, had a significant circumference at each visit. Diet and exercise unstable medical illness such as unstable cardiac interventions were not performed during the trial.
disease, a current substance abuse problem, treatmentwith medications that significantly prolonged QTc or history of prolongation of QTc interval (>450 ms) onelectrocardiogram (EKG), clinically significant EKG Two-tailed paired samples t-tests were conducted to abnormalities, hepatic or renal impairment, cancer, compare baseline and week 6 values for body weight, poorly controlled seizure disorder, previous treatment BMI, fasting lipids, fasting glucose, fasting insulin, with ziprasidone, or treatment with more than one HOMA-IR, fasting lipids, and clinical symptoms. Scores antipsychotic agent. Thirty patients were screened and from week 4 (last observation carried forward (LOCF) 24 consented for the study. Of the six subjects that did method) were used for two subjects with missing end not give consent, three did not meet the BMI criteria point measurements. Separate analyses were performed and three decided not to participate. Two subjects for the clozapine group and the olanzapine group.
Copyright # 2009 John Wiley & Sons, Ltd.
Additionally, analysis of subjects with DM and subjects ficantly between the clozapine-treated group and the without DM was performed. For all analysis, p-values of olanzapine-treated group at baseline. Within the less than 0.05 were considered significant.
clozapine-treated group, nine subjects (82%) weresmokers, compared to four subjects (40%) in theolanzapine-treated group ( p ¼ 0.049). Eight subjects (38%) were treated for type 2 DM at the time of Twenty-four subjects consented to participate in the study. Two subjects were lost to follow-up prior to Table 2 shows anthropometric changes from baseline starting the study medication; and one subject discon- to week 6 for each group and the entire sample.
tinued the medication after one dose. The remaining Comparing baseline to week 6, there was no significant 21 subjects completed the 6-week trial and are included difference in weight, BMI, waist circumference, or in all analyses. Eleven patients (52%) were receiving waist/hip ratio. The mean weight for the entire sample clozapine and 10 patients (48%) were receiving was 230 Æ 35 lbs at baseline, and 229 Æ 35 lbs at week 6 ( p ¼ 0.73). There were no significant changes The demographic data are summarized in Table 1.
in total cholesterol, triglycerides, HDL-cholesterol, or The mean age of the subjects was 49 Æ 8 years and 17 LDL-cholesterol. For the entire sample, the mean total (81%) were male. Fifteen subjects (71%) were Cauca- cholesterol was 186 Æ 40 mg/dl at baseline and 185 Æ sian, four (19%) were Black, and one (5%) was 34 mg/dl at week 6 ( p ¼ 0.929). Triglyceride levels Hispanic. There were no significant differences among decreased from 256 Æ 159 mg/dl and 231 Æ 34 mg/dl the clozapine and olanzapine-treated groups for race, but was not statistically significant ( p ¼ 0.24). There marital status, employment status, or family history of was no significant difference in any of the above hypertension or diabetes. Weight, BMI, cholesterol, outcome measures comparing baseline to week 6 when and waist and hip measurements did not differ signi- analyzing subgroups for clozapine or olanzapine alone.
Demographic and clinical characteristics of 21 schizophrenia patients treated with clozapine or olanzapine Values are expressed as means Æ SD unless otherwise indicated.
Copyright # 2009 John Wiley & Sons, Ltd.
ziprasidone for clozapine/olanzapine side effects Anthropometric and metabolic measures over 6-week treatment of ziprasidone as an adjuvant for clozapine- or olanzapine-treated patients with Values are expressed as means Æ SD unless otherwise indicated, and waist circumference is taken from iliac waist measures.
BMI, body mass index; HOMA-IR, homeostasis model of assessment of insulin resistance.
In the clozapine-treated group, fasting plasma glucose decreased from 4.2 Æ 2.2 at baseline to 3.9 Æ 3.4 at and fasting serum insulin did not change significantly week 6 but was not significant ( p ¼ 0.695).
(Table 2). The mean fasting plasma glucose changed In addition, ziprasidone produced no significant from 125 Æ 43 mg/dl at baseline to 130 Æ 46 mg/dl at differences between baseline and week 6 on the PANSS week 6 ( p ¼ 0.719) in the clozapine-treated group. For total scores and subscale scores, the SANS, or the non-diabetic subjects receiving either olanzapine or HAM-D (Ps > 0.129) (Table 3). There were no serious clozapine, there were similarly no significant changes adverse events as a result of treatment with ziprasi- in fasting plasma glucose from 104 Æ 13 mg/dl at done. Four subjects (18%) experienced constipation, baseline to 102 Æ 18 mg/dl at week 6 ( p ¼ 0.577), or two subjects (9%) experienced diarrhea, and two fasting insulin 16.3 Æ 8.4 vs. 15.2 Æ 11.06 ( p ¼ 0.654).
subjects (9%) experienced tremors while on ziprasi- Furthermore, in non-diabetic subjects, HOMA-IR done. From baseline to week 2, the mean QTc Copyright # 2009 John Wiley & Sons, Ltd.
Psychopathology measures over a 6-week treatment of ziprasidone supplemented to clozapine- or olanzapine-treated subjects with schizophrenia Values are expressed as means Æ SD.
HAM-D: Hamilton Depression Rating Scale; PANSS, Positive and Negative Syndrome Scale, including positive, negative, and general subscales; SANS: Scalefor the Assessment of Negative Symptoms.
increased from 417 Æ 15 to 430 Æ 16 ms ( p ¼ 0.002); ( p ¼ 0.004), total cholesterol ( p ¼ 0.002), total trigly- however, the change in mean QTc from 417 Æ 15 at cerides ( p ¼ 0.040), and HDL-cholesterol ( p ¼ 0.020) baseline to 420 Æ 21 ms at week 6 was not statistically The sample size in this study may not have been adequate to demonstrate the effectiveness of ziprasi-done as an adjuvant to clozapine or olanzapine and resulted in a type II error. It is also plausible that the In this open label trial, the addition of ziprasidone to a receptor-binding profile of ziprasidone does not steady dose of olanzapine or clozapine resulted in no significantly counteract the mechanisms of weight significant benefit in weight loss or other metabolic gain and other metabolic disturbances associated with parameters in patients with schizophrenia or schizoaf- fective disorder. Previous research has demonstrated In the present study, ziprasidone did not worsen the efficacy of ziprasidone to significantly improve extrapyramidal side effects or psychotic symptoms. It weight and plasma lipids when switching treatment also did not result in any significant adverse events or from another atypical antipsychotic medication. A increases in resting heart rate or blood pressure. There study by Weiden et al. (2007) estimated weight loss of was a non-clinically relevant increase in QTc from 10.3% of mean initial weight and total cholesterol baseline to week 2 which was not evident at week 6.
decrease of 9.2% over 58 weeks for patients whenswitched from olanzapine to ziprasidone. However, the lack of similar effects when used in combination withclozapine and olanzapine suggests that ziprasidone is The addition of 160 mg/day of ziprasidone was well ineffectual as an adjuvant therapy for weight and tolerated but did not produce significant improvement in fasting glucose, insulin resistance, hyperlipidemia or These results differ from a previous study, where the lead to weight loss in olanzapine- or clozapine-treated addition of aripiprazole to clozapine treatment resulted subjects with schizophrenia or schizoaffective disorder.
in significant decreases in weight ( p ¼ 0.003), BMI This combination may not be of benefit to combat the Copyright # 2009 John Wiley & Sons, Ltd.
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Prevalence of diabetes and impaired glucose tolerance in patients treated supported by a research grant from Solvay, Takeda and is with clozapine compared with patients treated with conventional depot a recipient of honorariums from Bristol-Myers Squibb, neuroleptic medications. J Clin Psychiatry 59: 294–299.
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from Xenoport, Dainippon Sumitomo, Solvay/Wyeth, Henderson DC, Cagliero E, Gray C, et al. (2000a) Clozapine, diabetes Bristol Meyer Squibb, Organon, Proteus, Genactics, Forest mellitus, weight. gain, and lipid abnormalities: a five-year naturalistic Laboratories, Xytis, MedReviews, LLC, and Vanda Phar- study. Am J Psychiatry 157: 975–981.
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Merck, Takeda, Sanofi-Aventis. The research of Dr Xiadou Henderson DC, Goff DC, Connolly CE, Borba CP, Hayden D. 2001.
Fan is supported by Eli Lilly and he is a recipient of Risperidone added to clozapine: impact on serum prolactin levels.
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honorarium from Eli Lilly. The research of Dr Oliver Henderson DC, Cagliero E, Copeland PM, et al. 2005. Glucose metabolism Freudenreich is supported by Cephalon and he is a recipient in patients with schizophrenia treated with atypical antipsychotic agents: of honorariums from Primedia, Reed Medical Education.
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