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The introduction of the novel atypical antipsychotics (NAPs) has unequivocally advanced the pharmacotherapy of psychotic disorders. Compared with older agents, NAPs offer enhanced efficacy against positive and negative symptoms, improve cognitive function and quality of life, and demonstrate a diminished risk for acute extrapyramidal symptoms (EPS) and long-term tardive dyskinesia. NAPs are not, however, without adverse events. Sedation, sexual dysfunction, prolactin elevation, weight gain, and metabolic disturbances have been variably observed with the available NAPs (1,2). Weight gain is a disquieting adverse event that significantly contributes to nonadherence, which portends relapse of illness (3,4). Moreover, excess weight gain will presage obesity- related morbidity, negatively affect self-esteem, and increase risk for a myriad medical disorders (that is, hypertension and diabetes mellitus) (5). The body mass index (BMI; BMI = body weight in kilograms/ [height in metres]2) distribution in schizophrenia and bipolar disorder patients overlaps and exceeds estimates from the general population (6). Further, persons with schizophrenia are at higher risk for various obesity-related disorders (7). A large metaanalysis of 81 treatment trials (8) suggested that a spectrum of weight-gain liability exists with NAP treatments, with clozapine imparting the most weight gain and ziprasidone the least. Although quetiapine (QUE) was not included in this analysis, other lines of data have suggested that this agent also imparts significant weight gain in short- term trials (9–13). In aggregate, data from largely short-term controlled studies with the commercially available NAPs have convincingly shown some weight gain with most agents. There remains, however, a paucity of comparative, prospective, naturalistic data estimating and comparing weight-gain accrual among these agents. NAPs are recommended as first-line strategies in the contemporary treatment of schizophrenia (14). The objective of this investigation was to determine the relative risk of treatment- emergent weight gain among commercially available NAP treatments in persons with schizophrenia and in those with related psychotic disorders, who were followed prospectively in a naturalistic setting. MethodsThe Canadian National Outcomes Measurement Study in Schizophrenia (CNOMSS) is an ongoing, prospective, naturalistic study. The overarching objectives of the CNOMSS study were to estimate and compare the global effectiveness, tolerability, and safety parameters of the commercially available NAPs under conditions of routine practice. CNOMSS included 32 university and community sites across Canada. A Scientific Advisory Committee (Appendix) selected the sites. This selection was based on known information about the respective sites’ case mix and prior research participation. This study was approved by the Western Institutional Review Board (WIRB) and, where applicable, by local internal review boards. Consecutive outpatients who were capable of providing consent were enrolled at each site if they had been diagnosed with schizophrenia, schizophreniform disorder, schizoaffective disorder, or psychosis not otherwise specified (NOS) according to DSM-IV criteria (15). Patients over age 16 years who manifested both single- and multiple-episode chronic disorders were enrolled. All patients were capable and willing to provide informed consent or had a legal guardian or designate who could provide consent on their behalf. All participants at the time of study entry were receiving an antipsychotic agent. Use of any concomitant psychotropic medications was permitted as clinically indicated. Patients with a comorbid diagnosis were permitted to enter the study, whereas patients with a primary diagnosis other than schizophrenia and schizoaffective disorder or psychosis NOS were excluded. The primary efficacy parameters were the Brief Psychiatric Rating Scale (BPRS) and the Clinical Global Impression (CGI) Improvement and Severity Scales (CGI-I and CGI-S) (9,16). Functional and humanistic outcomes were measured with the Social and Occupational Functional Assessment Scale (SOFAS) and the Medical Outcomes Study Short-Form 36 (MOS–SF36) (10). All treatment-emergent adverse events were identified and coded according to the Medical Dictionary for Regulatory Activities (MedDRA). Patients were weighed at baseline and every 3 months by their treating physician during regularly scheduled follow-up visits. (Fasting blood glucose and lipid determination were obtained at the baseline visit and repeatedly throughout the study, with the results analyzed and reported in a companion paper.) Patient height was also assessed, permitting a BMI computation. To be defined as overweight or obese, patients had a BMI of over 25 and 30, respectively (11). This report presents the weight-change data with the NAP treatments. Other outcomes harvested from this study will be reported in separate companion papers. Medication assignment was determined clinically between the treatment provider and the patient. The study did not a priori specify treatments with particular agents or emphasize a requisite number of persons receiving any respective treatment. Antipsychotic manipulation throughout patient tenure in the study was determined as clinically indicated. Concomitant medications were permitted. A total of 457 patients were consecutively enrolled between June 1999 and November 2000. For the analysis, 2 groups of patients were selected from the total CNOMSS cohort and separately analyzed. The first group comprised patients who were treated with NAP (that is, no adjuvant antipsychotic agent) at enrollment into CNOMSS (n = 243). The second group included patients who initiated NAP after the baseline visit (n = 38). Both continuous and categorical weight analyses were conducted. Odds ratios (ORs) were calculated for the 243 patients receiving risperidone (RIS), olanzapine (OLZ), or quetiapine (QUE) as their sole antipsychotic agent, adjusted for demographic and disease-specific factors using a logistic regression model (all tests used a = 0.05). Patients were removed from the statistical analysis if a second antipsychotic agent was added (conventional or atypical), if the medication was changed (conventional or atypical), or if the original agent was discontinued. Patients had an estimated mean treatment duration of 10 months. A logistic regression model was used to derive ORs adjusted for drug, age, sex, diagnosis, disease characteristics (for example, positive or negative symptoms), baseline and endpoint total BPRS, hospitalizations in the past 2 years, and the estimated treatment duration with current medication or current dosage of medication. Because RIS was the most frequently prescribed antipsychotic in Canada at the time of the analysis, all ORs were calculated relative to RIS. ResultsTable 1 presents the baseline demographics for each drug cohort. Men represented a higher proportion of the OLZ patients (78%), compared with RIS (59.5%) (P = 0.003), and had lived with their illness longer than either RIS or QUE patients (P < 0.001). Of patients, 76% and 77% (n = 142) were overweight and obese, respectively, at both baseline and at the last follow-up visit. Likewise, 9.5% of patients gained enough body weight to move from the overweight to obese classification by their last follow-up visit (OLZ 11%, QUE 8.7%, and RIS 8.1%). Concomitant medication use was comparable among the drugs at baseline, although mood stabilizers were used significantly more often by OLZ patients at their last visit (P = 0.03) (Table 2).
Analysis of the first cohort (that is, persons who received and [or] initiated NAP at baseline) indicated disparity in the absolute weight gain among the 3 treatments. The spectrum of weight gain was as follows: QUE (n = 23, mean 7.55 kg, SD 9.20), OLZ (n = 109, mean 3.72 kg, SD 8.56), and RIS (n = 111, mean 1.62 kg, SD 7.72). Categorically defined significant weight gain (7% or more of baseline) was observed in 55.6% of QUE patients, 24.1% of OLZ patients, and 23.7% of RIS patients (Figure 1). The percentage of patients who gained 10% or more of their baseline weight was 38.9% in QUE patients, 18.5% in OLZ patients, and 13.2% in RIS patients. Adjusted for confounding factors, QUE patients had greater odds of gaining 7% or more (OR 3.62; 95%CI, 1.02 to 12.83; P = 0.05) and 10% or more (OR 3.91; 95%CI, 1.02 to 15.08; P = 0.05) of their baseline weight, compared with RIS patients. No statistical difference was detected between OLZ patients and RIS patients for 7% or more weight gain (OR 1.54; 95%CI, 0.63 to 3.75; P = 0.12) or 10% or more weight gain (OR 1.44; 95%CI, 0.50 to 4.13; P = 0.58). Figure 1 Unadjusted percent weight gain from baseline
Weight gain was also assessed in a second group of patients who were placed on atypical monotherapy at a postbaseline visit (Table 1). Weight gain was noted with OLZ (n = 32; mean 4.1 kg, SD 11.88; P = 0.05) and QUE (n = 11; mean 4.1 kg, SD 12.77; P = 0.29), while RIS was weight neutral in this cohort (n = 18; mean –1.1 kg, SD 3.87; P = 0.21). The duration of treatment did not differ significantly for the 3 treatment groups in this second analysis (mean duration of 8.1 months). Owing to sample size limitations, further analyses , comparing patient clinical characteristics and outcome with weight gain liability were not conducted. DiscussionResults from this analysis suggest that NAPs are associated with clinically significant and differential weight gain in naturalistic settings. The weight gain that we described with QUE was significantly greater than the weight gain observed in RIS- and OLZ-treated patients. Although weight gain with RIS and OLZ has been well described, there are fewer studies with QUE. Borison and colleagues reported that 25% of patients who take QUE gained 7% or more of their baseline weight (placebo 4%) (12), whereas in a study comparing QUE with chlorpromazine, 27% of QUE patients gained 7% or more of their baseline weight (13). Further, a review by Gunasekara and Spencer reported that average weight gain at 6 weeks was 2.1 kg, rising to 5.6 kg at 1 year in QUE-treated patients (17). Contrary to these observations, data from Brecher and colleagues suggested that QUE had only a minimal effect on weight gain after 1 year of treatment (18). A secondary finding in this analysis was that a spectrum of weight -gain liability exists with the available NAPs. Although the relative liability between RIS and QUE was convergent with the existing literature, the observation that RIS and OLZ had imparted similar weight gain was incompatible with most available data. This disagreement with other studies may be due, in part, to the limitations inherent in an observational study. Most important, CNOMSS could not control for the duration or type of antipsychotic treatment that was received prior to prospective data collection, because precise estimates of the treatment duration could not be obtained at baseline for most patients in our study. This may be critical: available data suggest that antipsychotic-associated weight gain may be duration-dependent (19). For example, for most individuals with schizophrenia, the rate of OLZ-induced weight gain has plateaued after about 30 to 52 weeks of treatment (1). Other limitations included a diagnostically heterogeneous sample (that is, many possible diagnoses and disease histories) reflective of routine clinical practice, the inclusion of patients receiving concomitant medications, no control of attempts to manage weight gain, and no reliable collection of smoking status for each patient in the study. Finally, this comparative analysis had a significantly smaller sample of QUE patients, making it difficult to model more complex relations between weight gain and the NAPs. It is possible that a larger sample size may realize a different outcome. Introducing NAPs has permitted physicians to employ an alternative in managing schizophrenia. Compared with conventional antipsychotics, the NAPs offer an improved neurological profile but appear to impart a greater weight-gain liability. Weight gain in the range of 5% to 10% of the baseline weight significantly increases the risk for a myriad medical disorders already occuring at an increased prevalence in some psychiatric populations (20). In this investigation, over 75% of NAP-treated patients were statistically overweight or obese, and all NAPs imparted weight gain. Research that attempts to identify biological mechanisms and clinical variables associated with NAP-induced weight gain, as well as appropriate management strategies, is underway. Clinicians are reminded to inform all patients of the capacity for weight gain with each agent. Moreover, anthropometric indices (for example, weight and BMI) and metabolic parameters (for example, fasting glucose and lipid fractionation) should be routinely monitored in treated persons.
Funding and SupportThis study was supported by Janssen-Ortho Canada. References1. Blin O, Micallef J. Antipsychotic-associated weight gain and clinical outcome parameters. J Clin Psychiatry 2001;62(Suppl 7):11–21. 2. Brown CS, Markowitz JS, Moore TR, Parker NG. Atypical antipsychotics: Part II: adverse effects, drug interactions, and costs. Ann Pharmacother 1999;33:210–7. 3. Buis W. Patients’ opinions concerning side effects of depot neuroleptics. Am J Psychiatry 1992;149:844–5. 4. Fleischhacker W, Meise U, Gunther V, Kurz M. Compliance with antipsychotic drug treatment: influence of side effects. Acta Psychiatr Scand Suppl 1994;382:11–5. 5. Allison DB, Casey DE. Antipsychotic-induced weight gain: a review of the literature. J Clin Psychiatry 2001;62(Suppl 7):22–31. 6. Elmslie JL, Mann JI, Silverstone JT, Williams SM, Romans SE. Determinants of overweight and obesity in patients with bipolar disorder. J Clin Psychiatry 2001;62:486–93. 7. Dixon L, Weiden P, Delahanty J, Goldberg R, Postrado L, Lucksted A, and others. Prevalence and correlates of diabetes in national schizophrenia samples. Schizophr Bull 2000;26:903–12. 8. Allison DB, Mentore JL, Heo M, Chandler LP, Cappelleri JC, Infante MC, and others. Antipsychotic-induced weight gain: a comprehensive research synthesis. Am J Psychiatry 1999;156:1686–96. 9. Overall JE, Beller SA. The Brief Psychiatric Rating Scale (BPRS) in geropsychiatric research: I. Factor structure on an inpatient unit. J Gerontol 1984;39:187–93. 10. Ware JE Jr, Sherbourne CD. The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Med Care 1992;30:473–83. 11. WHO. Physical status: the use and interpretation of anthropometry. Report of a WHO Expert Committee. Technical Report Series 854. Geneva: WHO; 1995. 12. Borison RL, Arvanitis LA, Miller BG. ICI 204,636, an atypical antipsychotic: efficacy and safety in a multicenter, placebo-controlled trial in patients with schizophrenia. US SEROQUEL Study Group. J Clin Psychopharmacol 1996;16:158–69. 13. Peuskens J, Link CG. A comparison of quetiapine and chlorpromazine in the treatment of schizophrenia. Acta Psychiatr Scand 1997;96:265–73. 14. Remington G, Chong SA. Conventional versus novel antipsychotics: changing concepts and clinical implications. J Psychiatry Neurosci 1999;24:431–41. 15. American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 4th ed. Text revision. Washington (DC): American Psychiatric Association; 1994. 16. Beller SA, Overall JE. The Brief Psychiatric Rating Scale (BPRS) in geropsychiatric research: II. Representative profile patterns. J Gerontol 1984;39:194–200. 17. Gunasekara N, Spencer C. Quetiapine: a review of its use in schizophrenia. CNS Drugs 1998;9:325–40. 18. Brecher M, Rak I, Melvin K, Jones A. The long-term effect of quetiapine (SeroquelTM) monotherapy on weight in patients with schizophrenia. Int J Psychiatry Clin Pract 2000;4:287– 91. 19. Wirshing DA, Spellberg BJ, Erhart SM, Marder SR, Wirshing WC. Novel antipsychotics and new onset diabetes. Biol Psychiatry 1998;44:778–83. 20. Pi-Sunyer FX. Comorbidities of overweight and obesity: current evidence and research issues. Med Sci Sports Exerc 1999;31(Suppl 11):S602–S6008. Author(s)Manuscript received September 2002, revised, and accepted May 2003. 1. Head, Mood Disorders Psychopharmacology Clinic, University Health Network; Assistant Professor of Psychiatry, Department of Psychiatry, University of Toronto, Toronto, Ontario. 2. Manager, Health Economics and Outcomes Research, Janssen-Ortho Inc, Toronto, Ontario. 3. Biostatistician, Syreon Corporation, Vancouver, British Columbia. 4. Senior Biostatistician, Syreon Corporation, Vancouver, British Columbia. 5. Associate Director of Health Economics and Outcomes Research, Janssen-Ortho Inc, Toronto, Ontario. 6. Director, Health Economics and Outcomes Research, Janssen-Ortho, Inc., Toronto, Ontario. Address for correspondence: Dr RS McIntyre, Department of Psychiatry, University of Toronto, University Health Network, Toronto Western Hospital, 399 Bathurst Street, Toronto, ON M5T2S8 e-mail: rmcintyr@uhnres.utoronto.ca
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