1. Alex J Mitchell www.psycho-oncology.info University of Leicester (UK) Acknowledgements Davy Vancampfort, Belgium Marc De Hert, Belgium Weight Gain, Diabetes and Metabolic Problems in Patients prescribed Atypical Antipsychotics Online Information Oct 2011. Only use these slides for personal use and/or with credit to the author

2. I. Background

3. What are Severe Mental Health problems? These usually include Schizophrenia and related disorders Bipolar Affective Disorder (prev known as manic-depression) Severe depression These conditions are sometimes collectively called SMI and tend to be the ones where are antipsychotic is prescribed

4. Is there Accelerated mortality in SMI? Yes, there is premature mortality by 20 years on average This mortality gap has been increasing, as shown over….

5. Schizophrenia –Standardized Mortality Ratio Pooled estimate=2.50 (95% CI=2.18-2.83) > > > > Saha Arch Gen Psychiatry. 2007 Oct;64(10):1123-31.

6. *Controlling for age at first diagnosis and years of follow-up **Standardised by the sex and age distribution of the patients Data from Osby et al 2000 Mortality trends in Stockholm County 1976–79 to 1990–95, cardiovascular causes of death 0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1976–791980–851986–891990–95 Deaths/100,000 1976–79 period of reference Patients with schizophrenia* General population**

7. Cardiovascular disease is primary cause of death in persons with mental illness* *Average data from 1996–2000 Percentage of deaths 50 40 20 10 0 30 Heart diseaseCancerCerebrovascularChronic respiratory DiabetesInfluenza/pneumoniaAccidentsSuicide MOOKRITXUTVA Data From Colton & Manderscheid 2006

8. What is the Concern Re Obesity in the Popn? In 1950 25% US adults were overweight (BMI > 25) In 2005 25% were obese (BMI > 30) In 1998 25% of children were overweight By 2012 Only 25% of the US population will not be overweight BMI = weight / height squared

11. Obesity increases the risk of disease Willet et al. Guidelines for Healthy Weight (1999) NEJM 341, 427 - 433

12. Which Risk Factors Are Important? For cardiovascular disease and general mortality… Blood pressure (BP) Smoking Inactivity (fitness) Weight / obesity Cholesterol / lipids

13. Ranking of selected risk factors: 6 leading causes of death by income group, estimates for 2004 Percentage of total (total: 1.53 billion) World Health Organization. http://www.who.int/healthinfo/global_burden_disease/global_health_risks/en/index.htm

14. The following are important for diabetes IFG BP WaistHDL TG 102 cm or 40 inches (m) 88 cm or 36 inches(f) 150 mg/dl < 40 mg/dL (m) < 50 mg/dL (f) 130/85 mmHg 6.1 mmol/L (110 mg/dl). TG = triglycerides; IFG = impaired fasting glucose; HDL = high density lipids Collectively known as metabolic syndrome (when 3x are present)

15. How Many Antipsychotics are prescribed? About 6million prescriptions in the UK per year Perhaps to 0.5 million people in the UK annually (estimated) Globally they generate about 20billion per year for the pharmaceutical industry They are prescribed for several mental health conditions About 15% are given to the under 18s

16. Source: IMS; Robert Rosenheck MD Global Antipsychotic Market Sales (MAT Q1 by Yr)

17. Most common uses of atypical antipsychotics Off label use accounts for ~ 1/3 of prescriptions

19. II. Weight, diabetes complications of Atypicals The following are of high concern in SMI (next slide)

20. IFG BP Waist HDL TG 102 cm or 40 inches (m) 88 cm or 36 inches(f) 150 mg/dl < 40 mg/dL (m) < 50 mg/dL (f) – 130/85 mmHg 6.1 mmol/L (110 mg/dl). Diab Smoking

21. Prevalence of diabetes in schizophrenia compared to general population 8.6% diabetes; n=415 Slide thanks to De Hert et al 2006 15 Age group (years) General populationPatients 15–2525–3535–4545–55 55–65 0 5 10 20 25 30 0.4 2.0 0.91.1 6.1 25.0 5.8 Prevalence of diabetes (%) 3.2 2.4 12.7

22. Bipolar comparison study – prevalence of metabolic disturbances 72.3 59.8 71.6 17.0 29.3 22.1 10.7 10.9 6.4 0 10 20 30 40 50 60 70 80 90 100 Bipolar (n=112) Schizoaffective (n=92) Schizophrenia (n=503) Prevalence of metabolic disturbances (%) Normal glucose values (n=496)Pre-diabetes (n=157)Diabetes (n=54) van Winkel et al 2008

23. BMI change after 52 weeks of olanzapine in bipolar patients Image Credit: Hennen (2004)

24. Antipsychotic-induced diabetes mellitus..warning in 2003 l October 20, 2003 l FDA warns diabetes and antipsychotic medications l FDA to require diabetes warning on antipsychotics l In a series of letters delivered in mid-September, the US FDA disclosed to makers of atypical antipsychotic medications that it will require each drug maker to re-label its product to include warnings regarding risk of hyperglycaemia and diabetes mellitus

25. About the CATIE Study of Atypicals….. Non-industry sponsored. 1493 patients. 18 month double blind. Olanzapine, quetiapine, risperidone, ziprasidone & perphenazine 74% discontinued before 18 months, median 4.6 months. Olanzapine 9.2 months Metabolic problems much greater versus general population Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, Keefe RS, Davis SM, Davis CE, Lebowitz BD, Severe J, Hsiao JK: Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005; 353:1209–1223

26. 26 Comparison of Metabolic Syndrome and Individual Criterion Prevalence: Fasting CATIE vs Matched NHANES III Subjects MenWomen CATIE (%) (N=509) NHANES (%) (N=509) P CATIE (%) (N=180) NHANES III (%) (N=180) P Metabolic syndrome prevalence 36.019.7.000151.625.1.0001 Waist circumference criterion 35.524.8.000176.357.0.0001 Triglyceride criterion50.732.1.000142.219.6.0001 HDL criterion48.931.9.000163.336.3.0001 BP criterion47.231.1.000146.926.8.0001 Glucose criterion14.114.2.963521.711.2.0075 CATIE = Clinical Antipsychotic Trials of Intervention Effectiveness; NHANES = National Health and Nutrition Examination Survey. McEvoy JP et al. Schizophr Res. 2005;80:19-32.

27. CATIE: rates of pharmacological interventions for abnormal blood pressure, lipids and glucose Nasrallah et al 2006 n=1488n=685n=690 Patients (%) n=481n=300n=75n=34n=471n=421 33.2 10.9 68.3 62.4 45.3 89.4 0 20 40 60 80 100 HypertensionDiabetesDyslipidaemia PrevalenceLack of medical intervention

28. But not everyone gains weight….

29. 20% do not gain weight over 2yrs of Olanzapine Treatment Data from Basson, Kinon JCP

30. Weight gain begins early, typically plateaus

31. Weight Gain 3yrs of Olanzapine (n=573) vs Haloperidol (n=103) Treatment Data from Kinon (2001) J Clin Psychiatry 62:92-100; Image Credit: JCP / Physicians Press 7kg

32. Weight Gain During 3yrs of Olanzapine (n=573) by baseline weight 9.5kg 7kg 3kg Data from Kinon (2001) J Clin Psychiatry 62:92-100; Image Credit: JCP / Physicians Press

33. Weight gain seen in bipolar disorder too

34. Weight Gain During 32 weeks of Olanzapine (n=948) by baseline weight in bipolar disorder 8kg Lipkovich Early Predictors of Substantial Weight Gain in Bipolar Patients Treated with Olanzapine. J Clin Psychopharm 2006;26:316-320 6kg 4.5kg

35. Weight gain highest in drug-naive patients

36. 36 2-Year Weight Gain in First-Episode Schizophrenia: Effect of Type of Analysis Zipursky RB et al. Br J Psychiatry. 2005;187:537-543. OLZ = olanzapine HAL = Haloperidol 18 16 14 12 10 8 6 4 2 0 0 10 20 30 40 50 60 70 80 90 100 110 OLZ( Yr 1): n=35 OLZ (Yr 2): n=13 HAL (Yr 1): n=47 HAL (Yr 2): n=28 15.4 kg 7.5 kg Week of Therapy

37. HaloperidolAmisulprideOlanzapine QuetiapineZiprasidone 0 10 20 30 40 50 60 70 80 90 Weight gain >7% from baseline (%) p=0.053* 53 63 86% 65 37 0 2 4 6 8 10 12 14 16 7.3 9.7 13.9 4.8 10.5 p<0.0001* Weight change from baseline (kg) EUFEST – randomised controlled 12-month trial (n=498) Kahn RS et al. Effectiveness of antipsychotic drugs in first-episode schizophrenia and schizophreniform disorder: an open randomised clinical trial. Lancet. 2008 Mar 29 ; 371(9618):1085-97

38. CAFE study – weight and related measures in first-episode schizophrenia McEvoy et al 2007 5.7 Weight change * * 7.0 11.0 3.7 4.0 6.6 0 2 4 6 8 10 12 Week 12Week 52 Least squares mean change (kg) Risperidone (n=133)Quetiapine (n=134)Olanzapine (n=133) 0 20 40 60 80 100 Week 12Week 52 Percentage of patients ** 80.0 50.0 58.0 60.0 29.0 32.0 Weight gain 7% #

39. Summary of Metabolic Complications We have summarized all existing data of studies measuring metabolic problems in three groups: Established schizophrenia Vs early (first epsiode schizophrenia) Vs unmedicated patients with schizophrenia

41. ….and against general population rates?

43. …are patients monitored for these problems? Mitchell AJ, Delaffon V, Vancampfort D, Correll CU, De Hert M. Guideline concordant monitoring of metabolic risk in people treated with antipsychotic medication: systematic review and meta-analysis of screening practices. Psychol Med. 2011 Aug 10:1-23. [Epub ahead of print]

45. Can metabolic complications be avoided? Yes by…. By switching to a weight sparing antipsychotic By giving lifestyle advice and assistance By adding in weight loss medication (early or late) By avoiding weight gaining antipsychotics (only a few exist)

46. Estimated Weight Change (lb) After Switch to Ziprasidone Repeated measures analysis Improvement Presented at APA 2004, New York, NY

47. Alvarez-Jiménez– lifestyle in Unmedicated 1st Episode (10-14 sessions over 3mo) Alvarez-Jiménez M J Clin Psychiatry. 2006 Aug;67(8):1253-60. Attenuation of antipsychotic-induced weight gain with early behavioral intervention in drug-naive first-episode psychosis patients: A randomized controlled trial.

48. Chen – Metformin after 3mo of Olanzapine Rx Chen et al (2008) Metformin for metabolic dysregulation in schizophrenic patients treated with olanzapine. Progress in Neuro-Psychopharmacology & Biological Psychiatry 32 (2008) 925–931

49. Metformin Coprescription at start of Olanzapine Wu et al Metformin Addition Attenuates Olanzapine-Induced Weight Gain in Drug-Naive First-Episode Schizophrenia Patients: Am J Psychiatry 2008; 165:352–358

50. Metformin in patients on antipsychotic drugs: a systematic review and meta-analysis Bjorkhem-Bergman Journal of Psychopharmacology 2010; 25(3) 299–305

51. Alex J Mitchell www.psycho-oncology.infowww.psycho-oncology.info University of Leicester (UK) Acknowledgements Davy Vancampfort, Belgium Marc De Hert, Belgium Weight Gain, Diabetes and Metabolic Problems in Patients prescribed Atypical Antipsychotics Online Information Oct 2011