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Schizophrenia Update: Treatment Options and Side Effects

Schizophrenia Update: Treatment Options and Side Effects. Jonathan M. Meyer, M.D Assistant Professor Department of Psychiatry University of California San Diego. Outline. Recent Data from the NIMH Sponsored CATIE Schizophrenia Study Medical Issues in Schizophrenia

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Schizophrenia Update: Treatment Options and Side Effects

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  1. Schizophrenia Update:Treatment Options and Side Effects 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 Paliperidone ECT, etc. Olanzapine Quetiapine Aripiprazole Consta Chlorpromazine Fluphenazine Risperidone Thioridazine Ziprasidone Haloperidol Clozapine 1950 1960 1970 1980 1990 2001 2003 2007 Consta = Long-acting injectable risperidone

  4. The CATIE Schizophrenia Trial

  5. CATIE Study Phase 1: Time to Discontinuation for Any Cause Olanzapine (N=330) Risperidone (N=333) Perphenazine (N=257) Quetiapine (N=329) 1.0 Ziprasidone (N=183) 0.9 0.8 0.7 Proportion of Patients Continuing Treatment 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 3 6 9 12 15 18 Time to Discontinuation for Any Cause (months) Lieberman JA et al. N Engl J Med. 2005;353:1209-1223.

  6. CATIE Study Phase 2T: Time to Discontinuation for Any Cause 1.0 0.8 Proportion of Patients Continuing Treatment 0.6 0.4 0.2 0 3 6 9 12 15 18 Time to Phase 2 Discontinuation (months) Olanzapine (N=66) Quetiapine (N=63) Risperidone (N=69) Ziprasidone (N=135) Stroup TS et al. Am J Psychiatry. 2006; 163:611-622.

  7. 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

  8. Medical and Safety Issues During Antipsychotic Treatment

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

  10. 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

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

  12. Side Effects of Atypical Antipsychotics INVEGA/ CLOZARIL RISPERDAL ZYPREXA SEROQUEL GEODON ABILIFY Low Blood Pressure +++ + +/0 ++ 0/+ 0/+ Dry mouth, constipation +++ 0 +/++ 0 0 0 Tremors, stiffness, endocrine problems 0 +/++ 0/+ 0 +/0 0 Sedation +++ +/- ++ +++ 0 0 Weight gain ++++ + ++++ ++ -/+ -/+ Lipids +++ + +++ ++ 0 0 Blood sugar +++ + +++ ++ 0 0 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

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

  14. 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.

  15. What We Should Be Doing And - trying to use medications which have fewer metabolic side effects!

  16. Equipment

  17. Clinical Issues • Lack 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 client

  18. Change in Body Weight Following Switch to Aripiprazole-8 Wk Study † * n = 169 106 14 Prior antipsychotic *p<0.001; †p=0.077 LOCF analysis. Casey, et al. Int J Neuropsychopharmacol. 2002;5(suppl 1):S187.

  19. 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

  20. What’s New?

  21. 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) Newer Antipsychotics

  22. 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 On the Horizon

  23. How A Reuptake Inhibitor Works Synaptic vesicles with Glycine PresynapticNerve Ending Glycine Reuptake Pump Glycine PostsynapticNeuron NMDA Receptors

  24. 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

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