Marc De Hert, M.D. Ph.D., Professor Psychiatry, UPC KU Leuven, Campus Kortenberg, Leuvense Steenweg 517, B-3070 Kortenberg, Belgium

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1 METABOLIC SYNDROME IN PEOPLE WITH SEVERE MENTAL ILLNESS Introduction Marc De Hert, M.D. Ph.D., Professor Psychiatry, UPC KU Leuven, Campus Kortenberg, Leuvense Steenweg 517, B-3070 Kortenberg, Belgium People with severe mental illnesses (SMI), such as schizophrenia or bipolar disorder, have a reduced life expectancy compared to the general population [1-7]. They have a 2-3 fold increased risk of dying and that the mortality gap associated with mental illness compared to the general population has widened in recent decades [7]. People with severe mental illness have nearly twice the normal risk of dying from cardiovascular disease (CVD) [1-7]. In the psychiatric community this has lead in recent years to an increased interest in physical illnesses in people with SMI, specifically with regard to CVD risk. Cardio-metabolic Risk in SMI People with SMI are more likely to be overweight, to smoke, and to have hyperglycemia/diabetes, hypertension, and dyslipidemia [8-15] (Table1). In part these cardiometabolic risk factors are attributable to an unhealthy lifestyle, including poor diet and sedentary behavior. But over recent years it has become apparent that antipsychotic agents (AP) can have a negative impact on some of the modifiable risk factors [8-15] (Table 2). Part of this negative impact can be explained by the liability of some antipsychotics to induce significant weight gain [16-18]. A recent study indicates that these metabolic changes are dose independent [19]. Metabolic syndrome (MetS) brings together a series of abnormal clinical and metabolic findings which are predictive of CV risk, though there is continuing debate around the use of the term [20-29]. The concept has found its way into the psychiatric literature helping psychiatric clinicians to focus more on CVD risk in patients treated with AP [30-37]. To date 40 different studies have yielded consistent results showing elevated rates of MetS in both patients with schizophrenia and bipolar disorder [32]. In the largest study, the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study, approximately one third of patients in CATIE met National Cholesterol Education Program (NCEP) criteria for metabolic syndrome at baseline [33-34]. A troubling finding was that 88% of patients with dyslipidemia were not receiving treatment, as were 62% of the hypertensive patients and 38% of those with diabetes [35]. Some antipsychotic agents were associated with more significant adverse effects on weight, lipids, and glucose metabolism than others [34]. A large Belgian study found similar rates of MetS, which were 2 to 3 fold higher than in an age-adjusted population sample [32,36]. The prevalence of diabetes per age-band was 4-5 times higher in schizophrenia patients than in the general population. In a recent study of metabolic syndrome in patients diagnosed with schizophrenia from compared to , those started on second generation antipsychotics (SGA) had over twice the rate of new incident cases of metabolic syndrome after three years, compared to those treated with first generation antipsychotic agents (27.8% versus 9.8%) [37]. In patients

2 without metabolic syndrome at baseline, the risk of developing this combination of metabolic abnormalities was significantly greater in patients started on SGA (odds ratio 3.6) [37]. The majority of evidence is in patients with schizophrenia who are taking antipsychotic medication. There is, however, emerging evidence that there is an increase of modifiable CV risk factors, such as diabetes, in patients with bipolar disorder and in those with a history of depression and/or taking drugs to treat depression [38-40]. We recently reported on elevated rates of MetS in bipolar patients [41]. In another study we found that psychiatric diagnosis independent of medication and other confounding factors independently influenced the risk for MetS, with people with schizoaffective disorder having higher risk than people with schizophrenia or bipolar disorder [42]. Until recently there was no data on the safety and efficacy of statins in patients also exposed to antipsychotics. In patients with schizophrenia statins were an effective and safe treatment for severe dyslipidemia but they did not succeed in reversing MetS [43-44]. Growing evidence suggests that children and adolescents who take antipsychotic medication are at higher risk of weight gain and metabolic effects than adults who use the same drugs [45-48]. Guidelines for Screening and Monitoring Prevention should be of key importance. Clinicians should take into account both the present CVD risk as well as the metabolic risk profile of the antipsychotic chosen. Diet and lifestyle interventions should be started early after treatment initiation. Despite the risks many patients with SMI have limited access to general healthcare with less opportunity for cardiovascular risk screening and prevention than would be expected in a non-psychiatric population [3,49]. There is a lack of consensus over who should take responsibility for the general healthcare needs of mental health patients which has resulted in a continuing failure to provide appropriate services. General health care needs in this population were commonly neglected and psychiatrists mainly focus on efficacy of treatment of psychotic symptoms [3,5,14-15]. Over recent years both national and international groups have developed screening and monitoring guidelines [9,50-56] but these have not made their way to routine clinical care for patients [57-58]. If a patient develops metabolic abnormalities (e.g. weight gain, increased blood pressure, glucose, or lipid levels) following initiation of antipsychotic therapy, consideration should be given to switching the patients to an SGA which has not been associated with significant weight gain or diabetes. Initiation of appropriate blood pressure, glucose, or lipid lowering therapy should also be considered, in consultation with the patient s GP when that is possible, or with a specialist physician when this is considered appropriate [3,54]. A European current update of screening and monitoring guidance is being written by the EPA in collaboration with ESAD and ESC [59,60]. Conclusions Mets and other CVD risk factors are highly prevalent in people with SMI. The psychiatrist needs to be aware of the potential metabolic side-effects of antipsychotic medication and to include them in the risk/benefit assessment when choosing a specific antipsychotic. He should also be

3 responsible for the implementation of the necessary screening assessments and referral for treatment of any physical illness. Multidisciplinary assessment of psychiatric and medical conditions is needed. The somatic treatments offered to people with severe and enduring mental illness should be at par with general health care in the non-psychiatrically ill population [3,49]. References 1. Angst F, Stassen HH, Clayton PJ, Angst J Mortality of patients with mood disorders: follow-up over years. J Affect Disord 68(2-3): Brown S Excess mortality of schizophrenia. A meta-analysis. Br J Psychiatry 171: Fleischhacker WW, Cetkovich-Bakmas M, De Hert M, et al Cormorbid somatic illnesses in patients with severe mental disorders: clinical, policy and research challenges. J Clin Psych 69: Hennekens CH, Hennekens AR, Hollar D, Casey DE Schizophrenia and increased risks of cardiovascular disease. Am Heart J 150: Leucht S, Burkard T, Henderson J, Maj M, Sartorius N Physical illness and schizophrenia: a review of the literature. Acta Psychiatr Scand 116: Ösby U, Correia N, Brandt L, et al Mortality and causes of death in schizophrenia in Stockholm county, Sweden. Schizophr Res 45(1-2): Saha S, Chant D, McGrath J A systematic review of mortality in schizophrenia. Arch Gen Psychiatry 64: Correll CU Balancing efficacy and safety in the treatment with antipsychotics. CNS Spectrums 12(Suppl.17): Consensus Development Conference on Antipsychotic Drugs and Obesity and Diabetes Diabetes Care 27: De Hert M, van Winkel R, van Eyck D, et al Prevalence of the metabolic syndrome in patients with schizophrenia treated with antipsychotic medication. Schizophr Res 83: Newcomer JW Second-generation (atypical) antipsychotics and metabolic effects a comprehensive literature review. CNS Drugs 19(Suppl.1): Scheen AJ, De Hert MA Abnormal glucose metabolism in patients treated with antipsychotics. Diabetes Metab 33: Tschoner A, Engl J, Laimer M, et al Metabolic side effects of antipsychotic medication. Int J Clin Pract 61(8): Meyer JM, Nasrallah HA Medical illness and schizophrenia. Washington, DC: American Psychiatric Publishing. 15. Voruganti LP, Punthakee Z, Van Lieshout RJ, et al Dysglycemia in a community sample of people treated for schizophrenia: the Diabetes in Schizophrenia in Central-South Ontario (DiSCO) study. Schizophr Res 96: Allison DB, Mentore JL, Heo M, et al Antipsychotic-induced weight gain: a comprehensive research synthesis. Am J Psychiatry 156(11): Citrome L Risk-benefit analysis of available treatments for schizophrenia. Psychiatric Times Suppl 1: Kinon BJ, Kaiser CJ, Ahmed S, et al Association between early and rapid weight gain and change in weight over one year of olanzapine therapy in patients with schizophrenia and related disorders. J Clin Psychopharmacol 25(3): Simon V, van Winkel R, De Hert M Are weight gain and metabolic side-effects of atypical antipsychotics dose-dependent? A literature review. J Clin Psychiatry In press. 20. Alberti KGMM, Zimmet P, Shaw J Metabolic syndrome a new world-wide definition. A consensus statement from the International Diabetes Federation. Diabetic Med 23:

4 21. Byrne CD, Wild SH The global burden of the metabolic syndrome and its consequences for diabetes and cardiovascular disease. In: Byrne CD, Wild SH, eds. The metabolic syndrome. West Sussex, MD: John Wiley & Sons, Ford ES, Giles WH, Mokdad AH Increasing prevalence of the metabolic syndrome among US adults. Diabetes Care 27(10): Grundy SM, Cleeman JI, Daniels SR, et al Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation 112: 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) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 285: Grundy SM, Brewer HB, Cleeman JI, Smith SC, Lenfant D, for the Conference Participants Definition of metabolic syndrome: report of the National, Heart, Lung, and Blood Institute/American Heart Association conference on scientific issues related to definition. Circulation 109: Grundy SM The changing face of cardiovascular risk. JACC 46: Isomaa B, Almgren P, Tuomi T, et al Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care 24(4): Kahn R, Buse J, Ferranninni E, Stern M The metabolic syndrome: time for a critical appraisal. Joint statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 28: Lorenzo C, Hunt KJ, Williams K, Haffner SM The National Cholesterol Education Program Adult Treatment Panel III, International Diabetes Federation, and World Health Organization definitions of the metabolic syndrome as predictors of incident cardiovascular disease and diabetes. Diabetes Care 30: Arango C, Bobes J, Aranda P, Carmena R, Garcia-Garcia M, Rejas J; on behalf of the CLAMORS Study Collaborative Group A comparison of schizophrenia outpatients treated with antipsychotics with and without metabolic syndrome: findings from the CLAMORS study. Schizophr Res Jul 5. [Epub ahead of print]. 31. Bobes J, Arango C, Aranda P, Carmena R, Garcia-Garcia M, Rejas J; CLAMORS Study Collaborative Group Cardiovascular and metabolic risk in outpatients with schizophrenia treated with antipsychotics: results of the CLAMORS Study. Schizophr Res 90(1-3): De Hert M, van Winkel R The metabolic syndrome in patients treated with antipsychotic medication. World Psychiatry Submitted. 33. Goff DC, Sullivan LM, McEvoy JP, et al A comparison of ten-year cardiac risk estimates in schizophrenia patients from the CATIE study and matched controls. Schizophr Res 80(1): Meyer JM, Davis VG, Goff DC, et al Change in metabolic syndrome parameters with antipsychotic treatment in the CATIE Schizophrenia Trial: prospective data from phase 1 Schizophr Res 101(1-3): Nasrallah HA, Meyer JM, Goff DC, et al Low rates of treatment for hypertension, dyslipidemia and diabetes in schizophrenia: data from the CATIE schizophrenia trial sample at baseline. Schizophr Res 86(1-3): De Hert M, van Winkel R, Van Eyck D, et al Prevalence of diabetes, metabolic syndrome and metabolic abnormalities in schizophrenia over the course of the illness: a cross-sectional study. Clin Pract Epidemiol Ment Health 2: De Hert M, Schreurs V, Sweers K, et al Typical and atypical antipsychotics differentially affect long-term incidence rates of the metabolic syndrome in first-episode patients with schizophrenia: a retrospective chart review. Schizophr Res 101(1-3):

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7 Table 1: Estimated Prevalence and RR of Modifiable Cardiovascular Disease Risk Factors in Schizophrenia and Bipolar Disorder Compared to the General Population [8] Estimated Prevalence and Relative Risk Modifiable Risk Factors Schizophrenia Bipolar Disorder Obesity 45%-55% RR: %-49% RR: 1-2 Smoking 50%-80% RR: %-68% RR: 2-3 Diabetes 10%-15% RR: 2 8%-17% RR: Hypertension 19%-58% RR: %-61% RR: 2-3 Dyslipidemia 25%-69% RR: 5 23%-38% RR: 3 Metabolic Syndrome 37%-63% RR: %-49% RR: RR=relative risk.

8 Table 2: Second generation antipsychotic agents and metabolic abnormalities [9,13,54] Antipsychotic Weight gain Risk for diabetes Worsening lipid profile Clozapine Olanzapine Risperidone ++?? Quetiapine ++?? Aripiprazole + No report No report Ziprasidone + No report No report Amisulpride + No report No report * Cases of diabetes have now been reported with all the SGAs, but the difference in relative risk remains the same; no report: at moment of publication no cases reported, since then cases of diabetes have been reported with all SGA