The Metabolic Syndrome and Schizophrenia: Clinical Research UpdatePublished on Psychiatric Times(http://www.psychiatrictimes.com)

The Metabolic Syndrome and Schizophrenia: Clinical ResearchUpdateFebruary 01, 2007 | Bipolar Disorder [1], Schizoaffective [2], Schizophrenia [3], Comorbidity InPsychiatry [4], Schizophrenia Psychotic Features [5], Alcohol Abuse [6]By Jonathan M. Meyer, MD [7]

The Metabolic Syndrome and Schizophrenia: Clinical Research Update

February 2007, Vol. XXIV, No. 2

Death as a result of cardiovascular (CV) complications represents the leading natural cause of excessmortality in patients with schizophrenia.1 While lifestyle variables such as high rates of smoking,poor dietary habits, and inactivity contribute to CV disease, research has also focused on a cluster ofabnormalities that define metabolic syndrome (Table 1). Although considerable debate exists aboutwhether a diagnosis of metabolic syndrome confers added CV risk compared with that attributable tothe individual criteria, there is little doubt that the syndrome captures a group of individuals at riskfor both CV disease and type 2 diabetes mellitus.2The clinical usefulness of the metabolic syndrome concept is its ability to focus attention on a clusterof abnormalities that in isolation may not attract much clinical interest. Underlying the developmentof metabolic syndrome (also referred to as syndrome X or the dysmetabolic syndrome) is the findingthat compensatory hyperinsulinemia, in certain abdominally obese persons, is associated withdyslipidemia, hypertension, and inflammatory markers.3 Those features distinguish patients withmetabolic syndrome from overweight or obese individuals in whom hyperinsulinemia develops in thepresence of decreased peripheral insulin sensitivity but without the other dysmetabolic components.Increased diabetes mellitus prevalence has been noted in patients with schizophrenia in manycountries,4 but the greater public health concern is the prevention of diabetes and preservation ofb-cell function in patients who are prediabetic.5 For that reason, recent studies of patients withschizophrenia have increasingly focused on the prevalence of prediabetic states such as themetabolic syndrome. Issues in the literature revolve around the prevalence of the syndrome as awhole and that of the individual criteria, how these prevalence data compare with those in matchedindividuals from the general population, and the role of antipsychotic medications.The purpose of this article is to review some of the newer findings that probe the link betweenmetabolic syndrome and schizophrenia and to investigate whether compelling data exist todemonstrate medication-independent risk for metabolic disease in patients with schizophrenia.Recent consensus recommendations for monitoring and preventing metabolic dysfunction will bediscussed, along with studies outlining comparative therapeutic options for those who meetmetabolic syndrome criteria.Prevalence data, disease, and medication effectsThe diagnostic criteria used in many studies are based on those elaborated by the NationalCholesterol Education Program (NCEP) in 20016 and subsequently updated by lowering the fastingglucose threshold to 100 mg/dL to match that established by the American Diabetes Association(ADA) for prediabetes7 (Table 1). Although abdominal obesity is considered a core feature of thesyndrome, the NCEP definition allowed the diagnosis to be established by meeting any 3 of the 5criteria, prompting the International Diabetes Federation (IDF) to create a newer definition thatmandates abdominal obesity as a necessary criterion, combined with any 2 of the 4 remainingcomponents.Regardless of the definition, the past 2 years have seen the publication of multiple articles on theprevalence of metabolic syndrome, predominantly using North American or Western Europeansamples, including several large studies that compared prevalences in patients with schizophreniawith those in matched comparison controls from the general population (Table 2). 8-10 Among therecent studies, 2 recruited patients with schizophrenia or schizoaffective disorder on the basis ofobesity11,12 and have limited generalizability.The first large published estimate is from a study of 240 Canadian patients with schizophrenia orschizoaffective disorder (65% male, mean age 43.3 years). The investigators found a prevalence of

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The Metabolic Syndrome and Schizophrenia: Clinical Research UpdatePublished on Psychiatric Times(http://www.psychiatrictimes.com)

42.6% for men and 48.5% for women, using the NCEP criteria8; these rates are 2-fold greater thancomparable published estimates in the United States. In their study using a cohort born in 1966 innorthern Finland, Saari and colleagues10 found a 4-fold increased risk for NCEP-defined metabolicsyndrome in the 31 patients with schizophrenia compared with their 5500 demographically identicalpeers. The largest non-US data set is an analysis of 430 Belgian patients with schizophrenia that,using NCEP criteria, showed a prevalence of 28.4% for metabolic syndrome (32.3% with the updatedNCEP definition and 36.0% using the IDF definition). Again, this prevalence for metabolic syndromewas at least twice as high as that of an age-adjusted community sample in Belgium.13

The most comprehensive and largest comparative analysis of metabolic syndrome prevalenceemerged from the baseline sample in the National Institute of Mental Health–funded ClinicalAntipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia trial.9 The data-densefindings from multiple analyses of metabolic syndrome and prevalence criteria on the basis of age,sex, and race/ethnicity were compared with a demographically matched sample from the ThirdNational Health and Nutrition Examination Survey (NHANES III).There were several important findings of CATIE worth highlighting, including the fact that increasedmetabolic syndrome prevalence (compared with NHANES III) was seen across nearly all individualmetabolic syndrome criteria for men and women (Table 3). The discrepancy in prevalence was foundin patients with schizophrenia as young as those aged 20 through 30 and was always greatest forwomen. A sex difference in metabolic syndrome prevalence was found in the general population(approximately 25% greater in women),14 but this difference was magnified to 42% within theschizophrenia population. Adding further clinical concern were the low rates of treatment formetabolic syndrome components evaluated as part of CATIE.15

Another finding that emerged from the CATIE baseline analysis was the association betweenmetabolic syndrome and poor perceived health.16 After adjustment for demographic variables, thosewith metabolic syndrome rated themselves significantly lower on physical health and scored higheron somatic preoccupation (P = .03). This echoes earlier data from the Patient Outcomes ResearchTeam study that documented an association between poor physical and mental health in patientswith schizophrenia.17

What the various data from treated patients who have schizophrenia cannot answer is the extent towhich the disease itself presents a risk for metabolic dysfunction independent of antipsychoticexposure. Some small early studies from a group in Ireland seemed to suggest that increasedvisceral adiposity and glycemic abnormalities could be found in untreated and neuroleptic-naivepatients with schizophrenia,18,19 but these findings have not been replicated. A larger and morerigorous study from China found no pretreatment differences in visceral fat or other metabolicparameters between patients with schizophrenia and matched controls,20 but marked differencesemerged immediately after antipsychotic exposure.Similarly, a Spanish study that compared 50 neuroleptic-naive subjects with schizophrenia with 50nonadherent patients with schizophrenia and 50 control subjects found no differences in metabolicmeasures between the neuroleptic-naive cohort and the control subjects, arguing against a uniquepredisposition toward glycemic dysfunction in patients with schizophrenia.21 The nonadherentpatients with schizophrenia, antipsychotic-free at the time of analysis, showed significantly increasedmarkers of insulin resistance compared with patients who were antipsychotic-naive and the controlcohort, indicating the effects of earlier treatment as an important causative factor in the highprevalence of metabolic dysfunction seen in treated cohorts with schizophrenia.While the debate over disease effects awaits more studies of neuroleptic-naive patients withschizophrenia, the relative contribution of various antipsychotics has become firmly established.Following early expert opinion that olanzapine and clozapine are the antipsychotic agents with thehighest risk for metabolic dysfunction,22 the large CATIE schizophrenia trial (n = 1460) providedsound confirmation of this conclusion while noting that ziprasidone appears to be metabolicallyneutral.23-25 Aripiprazole was not included in the first 2 phases of CATIE, but data from long-termprospective studies (26 and 52 weeks) also indicate a benign metabolic profile comparable to thatfor ziprasidone.26

Obesity increases risk for metabolic dysfunction, but reports of type 2 diabetes mellitus andketoacidosis occurring in patients with schizophrenia without marked weight gain raised the issue ofweight-independent drug effects on glucose/insulin homeostasis.27 Aside from clinical data providedby these case reports, compelling biologic findings have emerged from animal28 and humanstudies,29 which indicate that olanzapine not only increases weight but appears to preferentiallyinduce increases in visceral adiposity.Moreover, exposure to single doses of clozapine and olanzapine is associated with decreased

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The Metabolic Syndrome and Schizophrenia: Clinical Research UpdatePublished on Psychiatric Times(http://www.psychiatrictimes.com)

peripheral insulin sensitivity in a dose-dependent manner in laboratory animals.30 Insulin normallyacts to suppress hepatic gluconeogenesis, but clozapine and olanzapine appear to interfere with thisprocess immediately after exposure, resulting in abnormal hepatic glucose output from the liver.This presents the most compelling argument for weight-independent effects of these medications onmetabolic function, although confirmation of this effect in human studies with larger samples isrequired.Monitoring and treatmentIn response to the obvious public health impact of the high prevalence of metabolic syndrome,several expert and consensus panels have convened in the United States,22,31 Canada, andBelgium32-34 to support aggressive monitoring of metabolic parameters in all patients exposed toantipsychotics. At the minimum, those prescribing antipsychotics should obtain baseline and annualmeasures of all variables that encompass metabolic syndrome criteria—including waistcircumference—with more frequent monitoring suggested for weight (typically at each visit), lipids,and glucose related to aggregate risk from the antipsychotic agent itself (Table 4).In addition, patient variables including age, personal or family history, and ethnicity should berecorded. The ADA consensus panel did not provide clear guidelines for treatment of allantipsychotic-related metabolic problems, but the parameters that define the metabolic syndromeprovide useful markers for determining when to intervene. The sole exception is weight gain, forwhich the ADA consensus panel recommended intervention when the patient experiences a 5%weight gain,22 since most individuals have difficulty in losing more than 5% on their own.Once abnormalities have been identified, both the ADA consensus panel22 and NCEP suggest a trialof lifestyle modification for up to 3 months.6 The clinical difficulty rests in the fact that theseprograms are not widely available to patients with schizophrenia, and even those targeted for weightreduction in this population often fail to achieve clinical goals.35Nonetheless, when available theyshould be offered, but the interventions must be reassessed for effectiveness after 3 months. If noprogress toward metabolic goals has occurred, other strategies must be pursued, includingpharmacotherapy for hyperlipidemia, hypertension, or mild type 2 diabetes or switching frommetabolically offending antipsychotic medications.The conundrum facing many practitioners is whether to treat metabolic problems as they arise, orattempt to switch patients from metabolically offending medications and thus obviate the need forreferral and additional medications. For patients with refractory schizophrenia who are being treatedwith clozapine, the absence of other viable medication choices precludes switching, but extensivedata from industry switch studies,12,36,37 other switch data,38 and the CATIE schizophrenia trial23

demonstrate that many patients can be switched to metabolically more benign antipsychoticswithout loss of effectiveness. A reanalysis of the CATIE phase 1 data showed that the patients whowere randomized to the same antipsychotic medication taken at study entry (in essence,nonswitchers) continued to take their medication longer than those who were switched to a newmedication, arguing for attempts at behavioral or other management of metabolic problems as thefirst step before medication changes.39

For those patients for whom switching is not feasible or initially preferred, establishment ofrelationships with primary care providers is paramount to ensure that the patient receivesappropriate follow-up and treatment. Further research will help clarify the risks and benefits ofswitching for metabolic purposes and elucidate the biologic mechanisms for drug-related metaboliceffects (and disease-related effects if they exist), but minimization of CV risk remains a major clinicalgoal during antipsychotic therapy of schizophrenia.Dr Meyer is attending psychiatrist at the Veterans Affairs San Diego Healthcare System in La Jolla,Calif, and assistant professor of psychiatry at the University of California, San Diego School ofMedicine. Dr Meyer discloses that he has received a research grant from Bristol-Myers Squibb andPfizer; he is on the Speakers Bureau at Bristol-Myers Squibb, Pfizer, and Janssen; and he is aconsultant for Bristol-Myers Squibb, Pfizer, Janssen, Wyeth, Sanofi, AstraZeneca, and AbbottLaboratories.

Drugs Mentioned in This ArticleAripiprazole (Abilify)Clozapine (Clozaril)Olanzapine (Zyprexa)Topiramate (Topamax)Ziprasidone (Geodon)References

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The Metabolic Syndrome and Schizophrenia: Clinical Research UpdatePublished on Psychiatric Times(http://www.psychiatrictimes.com)

1. Osby U, Correia N, Brandt L, et al. Mortality and causes of death in schizophrenia in StockholmCounty, Sweden. Schizophr Res. 2000;45:21-28.2. Wannamethee SG, Shaper AG, Lennon L, Morris RW. Metabolic syndrome vs Framingham riskscore for prediction of coronary heart disease, stroke, and type 2 diabetes mellitus. Arch Intern Med.2005;165:2644-2650.3. Reaven GM. Compensatory hyperinsulinemia and the development of an atherogenic lipoproteinprofile: the price paid to maintain glucose homeostasis in insulin-resistant individuals. EndocrinolMetab Clin North Am. 2005;34:49-62.4. Bushe C, Holt R. Prevalence of diabetes and glucose intolerance in patients with schizophrenia. BrJ Psychiatry. 2004;184(suppl 47):67-71.5. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes withlifestyle intervention or metformin. N Engl J Med. 2002;346:393-403.6. Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults.Executive summary of the third report of the national cholesterol education program (NCEP) expertpanel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatmentpanel III). JAMA. 2001;285:2486-2497.7. Grundy SM, Brewer B, Cleeman JI, et al. Definition of metabolic syndrome: report of the NationalHeart, Lung, and Blood Institute/American Heart Association conference on scientific issues relatedto definition. Circulation. 2004;109:433-438.8. Cohn T, Prud'homme D, Streiner D, et al. Characterizing coronary heart disease risk in chronicschizophrenia: high prevalence of the metabolic syndrome. Can J Psychiatry. 2004;49:753-760.9. McEvoy JP, Meyer JM, Nasrallah HA, et al. Prevalence of the metabolic syndrome in patients withschizophrenia: baseline results from the clinical antipsychotic trials of intervention effectiveness(CATIE) schizophrenia trial and comparison with national estimates from NHANES III. Schizophr Res.2005;80:19-32.10. Saari KM, Lindeman SM, Viilo KM, et al. A 4-fold risk of metabolic syndrome in patients withschizophrenia: the Northern Finland 1966 birth cohort study. J Clin Psychiatry. 2005;66:559-563.11. Basu R, Brar JS, Chengappa KN, et al. The prevalence of the metabolic syndrome in patients withschizoaffective disorder—bipolar subtype. Bipolar Disord. 2004;6: 314-318.12. Meyer JM, Pandina G, Bossie CA, et al. Impact of an open-label switch from olanzapine torisperidone on the prevalence of the metabolic syndrome in overweight or obese patients withschizophrenia or schizoaffective disorder. Clin Ther. 2005;27:1930-1941.13. De Hert MA, van Winkel R, van Eyck D, et al. Prevalence of the metabolic syndrome in patientswith schizophrenia treated with antipsychotic medication. Schizophr Res. 2006;83:87-93.14. Ford ES, Giles WH, Mokdad AH. Increasing prevalence of the metabolic syndrome among USadults. Diabetes Care. 2004;27:2444-2449.15. Nasrallah HA, Meyer JM, Goff DC, et al. Low rates of treatment for hypertension, dyslipidemiaand diabetes in schizophrenia: data from the CATIE Schizophrenia Trial sample at baseline. SchizophrRes. 2006;86:15-22.16. Meyer JM, Nasrallah HA, McEvoy JP, et al. The clinical antipsychotic trials of interventioneffectiveness (CATIE) schizophrenia trial: clinical comparison of subgroups with and without themetabolic syndrome. Schizophr Res. 2005;80:9-18.17. Dixon L, Postrado L, Delahanty J, et al. The association of medical comorbidity in schizophreniawith poor physical and mental health. J Nerv Ment Dis. 1999;187: 496-502.18. Thakore JH, Mann JN, Vlahos I, et al. Increased visceral fat distribution in drug-naive anddrug-free patients with schizophrenia. J Int Assoc Study Obesity. 2002;26: 137-141.19. Ryan MC, Flanagan S, Kinsella U, et al. The effects of atypical antipsychotics on visceral fatdistribution in first episode, drug-naive patients with schizophrenia. Life Sci. 2004;74:1999-2008.20. Zhang ZJ, Yao ZJ, Liu W, et al. Effects of antipsychotics on fat deposition and changes in leptinand insulin levels: magnetic resonance imaging study of previously untreated people withschizophrenia. Br J Psychiatry. 2004;184:58-62.21. Arranz B, Rosel P, Ramirez N, et al. Insulin resistance and increased leptin concentrations innoncompliant schizophrenia patients but not in antipsychotic-naive first-episode schizophreniapatients. J Clin Psychiatry. 2004;65:1335-1342.22. American Diabetes Association, American Psychiatric Association, American Association ofClinical Endocrinologists, North American Association for the Study of Obesity. Consensusdevelopment conference on antipsychotic drugs and obesity and diabetes. J Clin Psychiatry.2004;65:267-272.23. Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness of antipsychotic drugs in patients with

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The Metabolic Syndrome and Schizophrenia: Clinical Research UpdatePublished on Psychiatric Times(http://www.psychiatrictimes.com)

chronic schizophrenia. N Engl J Med. 2005;353:1209-1223.24. McEvoy JP, Lieberman JA, Stroup TS, et al. Effectiveness of clozapine versus olanzapine,quetiapine, and risperidone in patients with chronic schizophrenia who did not respond to prioratypical antipsychotic treatment. Am J Psychiatry. 2006;163:600-610.25. Stroup TS, Lieberman JA, McEvoy JP, et al. Effectiveness of olanzapine, quetiapine, risperidone,and ziprasidone in patients with chronic schizophrenia following discontinuation of a previousatypical antipsychotic. Am J Psychiatry. 2006;163:611-622.26. Newcomer JW. Second-generation (atypical) antipsychotics and metabolic effects: acomprehensive literature review. CNS Drugs. 2005;19(suppl 1):1-95.27. Jin H, Meyer JM, Jeste DV. Phenomenology of and risk factors for new-onset diabetes mellitus anddiabetic ketoacidosis associated with atypical antipsychotics: an analysis of 45 published cases. AnnClin Psychiatry. 2002;14:59-64.28. Ader M, Kim SP, Catalano KJ, et al. Metabolic dysregulation with atypical antipsychotics occurs inthe absence of underlying disease: a placebo-controlled study of olanzapine and risperidone in dogs.Diabetes. 2005; 54:862-871.29. Graham KA, Perkins DO, Edwards LJ, et al. Effect of olanzapine on body composition and energyexpenditure in adults with first-episode psychosis. Am J Psychiatry. 2005;162:118-123.30. Houseknecht KL, Robertson AS, Zavadoski W, et al. Acute effects of atypical antipsychotics onwhole-body insulin resistance in rats: implications for adverse metabolic effects.Neuropsychopharmacology. 2006 Oct 11; [Epub ahead of print].31. Marder SR, Essock SM, Miller AL, et al. Physical health monitoring of patients with schizophrenia.Am J Psychiatry. 2004;161:1334-1349.32. De Nayer A, De Hert M, Scheen A, et al. Conference report: Belgian consensus on metabolicproblems associated with second-generation antipsychotics. Int J Psychiatry Clin Pract.2005;9:130-137.33. Poulin MJ, Cortese L, Williams R, et al. Atypical antipsychotics in psychiatric practice: practicalimplications for clinical monitoring. Can J Psychiatry. 2005;50:555-562.34. De Hert M, van Eyck D, De Nayer A. Metabolic abnormalities associated with second generationantipsychotics: fact or fiction? Development of guidelines for screening and monitoring. Int ClinPsychopharmacol. 2006;21(suppl 2):S11-S15.35. Loh C, Meyer JM, Leckband SG. A comprehensive review of behavioral interventions for weightmanagement in schizophrenia. Ann Clin Psychiatry. 2006;18:23-31.36. Casey DE, Carson WH, Saha AR, et al. Switching patients to aripiprazole from other antipsychoticagents: a multicenter randomized study. Psychopharmacology. 2003;166:391-399.37. Weiden PJ, Loebel A, Yang R, Lebovitz H. Course of weight and metabolic benefits 1 year afterswitching to ziprasidone. Presented at: American Psychiatric Association Annual Meeting; May 5,2004; New York. Abstract.38. Gupta S, Masand PS, Virk S, et al. Weight decline in patients switching from olanzapine toquetiapine. Schizophr Res. 2004;70:57-62.39. Essock SM, Covell NH, Davis SM, et al. Effectiveness of switching antipsychotic medications. Am JPsychiatry. 2006;163:2090-2095.40. International Diabetes Federation. The IDF Consensus Worldwide Definition of the MetabolicSyndrome, Brussels. Available at: http://www.idf.org/webdata/docs/MetSyndrome_FINAL.pdf.Accessed on December 27, 2006.41. Meyer JM, Loh C, Leckband SG, et al. Prevalence of the metabolic syndrome in veterans withschizophrenia. J Psychiatr Pract. 2006;12:5-10.42. Correll CU, Frederickson AM, Kane JM, Manu P. Metabolic syndrome and the risk of coronaryheart disease in 367 patients treated with second-generation antipsychotic drugs. J Clin Psychiatry.2006;67:575-583.43. Hagg S, Lindblow Y, Mjorndal T, Adolfsson R. High prevalence of the metabolic syndrome amonga Swedish cohort of patients with schizophrenia. Int Clin Psychopharmacol. 2006;21:93-98.Evidence-Based References

Houseknecht KL, Robertson AS, Zavadoski W, et al. Acute effects of atypical antipsychoticson whole-body insulin resistance in rats: implications for adverse metabolic effects.Neuropsychopharmacology. 2006 Oct 11; [Epub ahead of print].McEvoy JP, Meyer JM, Nasrallah HA, et al. Prevalence of the metabolic syndrome in patientswith schizophrenia: baseline results from the clinical antipsychotic trials of intervention

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The Metabolic Syndrome and Schizophrenia: Clinical Research UpdatePublished on Psychiatric Times(http://www.psychiatrictimes.com)

effectiveness (CATIE) schizophrenia trial and comparison with national estimates fromNHANES III. Schizophr Res. 2005;80:19-32.

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