1. Schizophrenia Update: Treatment Options and Side Effects Jonathan M. Meyer, M.D Assistant Professor Department of Psychiatry University of California San Diego Jonathan M. Meyer, M.D Assistant Professor Department of Psychiatry University of California San Diego

2. Outline  Recent Data from the NIMH Sponsored CATIE Schizophrenia Study  Medical Issues in Schizophrenia  Side Effect Concerns With Antipsychotics  What’s New?

3. Timeline of Major Antipsychotic Therapies Ziprasidone 19501960197019801990 2001 2003 2007 ECT, etc. Chlorpromazine Fluphenazine Thioridazine Haloperidol Clozapine Risperidone Olanzapine Quetiapine Aripiprazole Consta Paliperidone Consta = Long-acting injectable risperidone

4. The CATIE Schizophrenia Trial

6. CATIE Study Phase 1: Time to Discontinuation for Any Cause Lieberman JA et al. N Engl J Med. 2005;353:1209-1223. Olanzapine (N=330)Risperidone (N=333) Ziprasidone (N=183) Quetiapine (N=329)Perphenazine (N=257) 0.8 0.9 0.7 0.6 0.4 0.3 0.1 0.5 0.2 0.0 0369121518 1.0 Time to Discontinuation for Any Cause (months) Proportion of Patients Continuing Treatment

7. Stroup TS et al. Am J Psychiatry. 2006; 163:611-622. Proportion of Patients Continuing Treatment Time to Phase 2 Discontinuation (months) 1.0 0.8 0.6 0.4 0.2 0369121518 Olanzapine (N=66)Quetiapine (N=63)Risperidone (N=69)Ziprasidone (N=135) CATIE Study Phase 2T: Time to Discontinuation for Any Cause

8. Average Monthly Symptom Scores Rosenheck R et al. Cost Effectiveness of Second-Generation Antipsychotics and Perphenazine in a Randomized Trial of Treatment for Chronic Schizophrenia Am J Psychiatry 2006; 163:2080-89

9. Medical and Safety Issues During Antipsychotic Treatment

10. Recent Multi-State Study Mortality Data: Years of Potential Life Lost Compared with the general population, persons with major mental illness typically lose more than 25 years of normal life span Colton CW, Manderscheid RW. Preventing Chronic Disease. Apr 2006;3:1-14 Miller BJ, et al. Psych Services Oct 2006; 57: 1482-87 YearAZMOOKRITXUTOH 199726.325.128.5 199827.325.128.829.3 199932.226.826.329.326.9 200031.827.924.9 1998 - 2002 32.0

11. FactorPrevalence in Schizophrenia Prevalence in BipolarPrevalence in General Population Smoking75%43-75%25% Obesity50%58%33% Diabetes Mellitus13-14%9.9-26%7% HIV3%?0.3% Hepatitis C20%?1.8% Other: -inactivity, poor nutrition -substance use Medical Issues in Schizophrenia and Bipolar Disorder Meyer JM and Nasrallah H eds. Medical Illness and Schizophrenia. APPI 2003 Regenold WT, et al. Increased prevalence of type 2 diabetes mellitus among psychiatric inpatients with bipolar I affective and schizoaffective disorders independent of psychotropic drug use. Journal of Affective Disorders. 2002 Jun;70(1):19-26

12. Undertreatment of Common Disorders in the CATIE Schizophrenia Trial at Enrollment Nasrallah HA, Meyer JM et al. Schiz Res 2006.

13. Side Effects of Atypical Antipsychotics CLOZ = clozapine; RIS = risperidone; OLZ = olanzapine; QUET = quetiapine; ZIP = ziprasidone; ARIP = aripiprazole; Adapted from: Nasrallah HA, Mulvihill T. Ann Clin Psychiatry. 2001(Dec);13(4):215-227 00++++++ Blood sugar 00++++++ Lipids -/+ +++++++ Weight gain 00++++++/-+++ Sedation 0+/000/++/++0 Tremors, stiffness, endocrine problems 000+/++0+++ Dry mouth, constipation 0/+ +++/0++++ Low Blood Pressure INVEGA/ CLOZARIL RISPERDAL ZYPREXA SEROQUEL GEODON ABILIFY

14. Past Areas of Concern Current Medical Realities Shift in Risk Perception of Antipsychotics Sedation Weight Gain Insulin Resistance CHD Hyper- lipidemia Weight Gain Diabetes Prolactin Insulin Resistance Sedation Hyperlipidemia Coronary Heart Disease Tardive Dyskinesia TD Prolactin

15. DrugWeight GainRisk for Diabetes Worsening Lipid Profile Clozapine (Clozaril)+++++ Olanzapine (Zyprexa)+++++ Risperidone (Risperdal) Paliperidone (Invega) +++/- Quetiapine (Seroquel)+++/-+ Aripiprazole* (Abilify)+/--- Ziprasidone* (Geodon)+/--- ADA/APA Consensus Conference on Antipsychotic Drugs and Obesity and Diabetes Summary + = increase effect; - = no effect; D = discrepant results. *Newer drugs with limited long-term data.

16. Inquiry Personal or family history: Personal or family history: – Diabetes – Hypertension – CHD (MI or Stroke) – Cigarette smoking – Diet – Physical Activity Measure Height Height Weight Weight Waist circumference Waist circumference Blood Pressure Blood PressureLab Fasting Glucose Fasting Glucose Fasting Lipids Fasting Lipids What We Should Be Doing And - trying to use medications which have fewer metabolic side effects!

17. Equipment

18. Clinical Issues Lack of access to medical care for patients with severe mental illnessesLack of access to medical care for patients with severe mental illnesses Switching to more metabolically neutral medications may reverse many problems, but requires careful attention by the psychiatrist and motivation by the clientSwitching to more metabolically neutral medications may reverse many problems, but requires careful attention by the psychiatrist and motivation by the client

19. Change in Body Weight Following Switch to Aripiprazole-8 Wk Study * † *p<0.001; † p=0.077 LOCF analysis. Casey, et al. Int J Neuropsychopharmacol. 2002;5(suppl 1):S187. n =16910614 Prior antipsychotic

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

21. What’s New?

22. Newer Antipsychotics Paliperidone (Invega®) - Risperdal metabolite –Very similar side effect profile to Risperdal –Very similar effectiveness to Risperdal Bifeprunox - similar in mechanism to Abilify –More nausea than Abilify -> Long titration (8 days) - not for acute use –Questions about effectiveness - awaiting FDA decision Asenapine - another atypical antipsychotic –No major efficacy or safety benefits - awaiting FDA decision Iloperidone - another atypical antipsychotic –No major efficacy benefits, QTc concerns - awaiting FDA decision Long-Acting Injectables (Not Yet Approved) –Olanzapine Pamoate: 2-4 wks, effective, major safety concerns –Paliperidone Palmitate: 4 wks, not yet filed with FDA (?2009)

23. On the Horizon Some features of schizophrenia may be due to decreased levels of activity at a certain type of receptor (NMDA glutamate receptors) Glycine can stimulate those receptors and might prove useful as a treatment for schizophrenia Glycine Transport Inhibitors (GlyT1 Blockers) –The GlyT1 transporter is localized to important areas of the brain –Interesting data in animal models of psychosis induced by PCP

24. How A Reuptake Inhibitor Works Glycine Reuptake Pump Postsynaptic Neuron Presynaptic Nerve Ending NMDA Receptors Synaptic vesicles with Glycine Glycine

25. Conclusions Except for clozapine, most of the currently available agents, and those on the horizon, are more alike than different in terms of effectiveness Safety and avoidance of metabolic side effects are major reasons to choose certain medications Providers have a duty to monitor weight, blood pressure, blood sugar and cholesterol (lipids) Long-acting injectable medications are useful, will have more options in the next few years Ongoing research may help identify newer classes of medications