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Alex J Mitchell www.psycho-oncology.info University of Leicester (UK) Acknowledgements Dav

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

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Alex J Mitchell www.psycho-oncology.info University of Leicester (UK) Acknowledgements Dav

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  1. Weight Gain, Diabetes and Metabolic Problems in Patients prescribed Atypical Antipsychotics Alex J Mitchell www.psycho-oncology.info University of Leicester (UK) Acknowledgements • Davy Vancampfort, Belgium • Marc De Hert, Belgium 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. Mortality trends in Stockholm County 1976–79 to 1990–95, cardiovascular causes of death 1.4 Patients with schizophrenia* 1.2 1.0 0.8 Deaths/100,000 1976–79 period of reference 0.6 General population** 0.4 0.2 0 1976–79 1980–85 1986–89 1990–95 *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

  7. Cardiovascular disease is primary cause of death in persons with mental illness* 50 40 30 Percentage of deaths 20 10 0 MO OK RI TX UT VA Heart disease Cancer Cerebrovascular Chronic respiratory Accidents Diabetes Influenza/pneumonia Suicide Data From Colton & Manderscheid 2006 *Average data from 1996–2000

  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

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

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

  11. 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

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

  13. 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 18’s

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

  15. Most common uses of atypical antipsychoticsOff label use accounts for ~ 1/3 of prescriptions

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

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

  18. Prevalence of diabetes in schizophrenia compared to general population 30 General population Patients 25.0 25 20 Prevalence of diabetes (%) 15 12.7 10 6.1 5.8 5 3.2 2.4 2.0 0.9 1.1 0.4 0 55–65 15–25 25–35 35–45 45–55 Age group (years) 8.6% diabetes; n=415 Slide thanks to De Hert et al 2006

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

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

  21. Antipsychotic-induced diabetes mellitus..warning in 2003 • October 20, 2003 • FDA warns diabetes and antipsychotic medications • FDA to require diabetes warning on antipsychotics • 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

  22. 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

  23. Comparison of Metabolic Syndrome and Individual Criterion Prevalence: Fasting CATIE vs Matched NHANES III Subjects CATIE = Clinical Antipsychotic Trials of Intervention Effectiveness; NHANES = National Health and Nutrition Examination Survey. McEvoy JP et al. Schizophr Res. 2005;80:19-32. 26

  24. CATIE: rates of pharmacological interventions for abnormal blood pressure, lipids and glucose n=1488 n=685 n=690 100 89.4 80 68.3 62.4 60 Patients (%) 45.3 40 33.2 20 10.9 0 n=481 n=300 n=75 n=34 n=471 n=421 Hypertension Diabetes Dyslipidaemia Prevalence Lack of medical intervention Nasrallah et al2006

  25. But not everyone gains weight….

  26. 20% do not gain weight over 2yrs of Olanzapine Treatment Data from Basson, Kinon JCP

  27. Weight gain begins early, typically plateaus

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

  29. 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

  30. Weight gain seen in bipolar disorder too

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

  32. Weight gain highest in drug-naive patients

  33. 2-YearWeight Gain in First-Episode Schizophrenia: Effect of Type of Analysis OLZ( Yr 1): n=35 OLZ (Yr 2): n=13 18 16 14 12 10 8 6 4 2 0 15.4 kg HAL (Yr 1): n=47 HAL (Yr 2): n=28 7.5 kg 0 10 20 30 40 50 60 70 80 90 100 110 Week of Therapy Zipursky RB et al. Br J Psychiatry. 2005;187:537-543. OLZ = olanzapine HAL = Haloperidol 36

  34. p=0.053* 86% p<0.0001* 90 16 13.9 80 14 65 70 63 12 10.5 60 53 9.7 Weight gain >7% from baseline (%) 10 50 Weight change from baseline (kg) 7.3 8 37 40 6 4.8 30 4 20 2 10 0 0 Haloperidol Amisulpride Olanzapine Quetiapine Ziprasidone 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

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

  36. 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

  37. ….and against general population rates?

  38. …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]

  39. Psychol Med. 2011 Aug 10:1-23. [Epub ahead of print]

  40. 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)

  41. Weeks 19 27 58 14 32 49 53 6 23 36 40 45 10 5 0 * *** -5 ** LS Mean Change, lb -10 *** ** -15 *P<0.05 **P<0.001 ***P<0.0001 -20 *** -25 Switched from Conventionals Olanzapine Risperidone Estimated Weight Change (lb) After Switch to Ziprasidone† Improvement †Repeated measures analysis Presented at APA 2004, New York, NY

  42. 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.

  43. 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

  44. 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

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

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