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Schizophrenia treatment – The past 10 years 10 th Annual Schizophrenia Education Day November 10, 2012 Oliver Freudenreich, MD Associate Professor of Psychiatry Harvard Medical School Medical Director, MGH Schizophrenia Program Massachusetts General Hospital
Disclosures I have the following relevant financial relationship to disclose (2011 – 2012): – Pfizer – Research grant – Psychogenics – Research grant – MGH Psychiatry Academy – Honoraria – General Medical Education – Honoraria – Oakstone Medical Education – Honoraria – Beacon Health Strategies – Consultant – Transcept – Consultant – Optimal Medicine – Consultant
Learning Objectives After participation in this educational seminar series, participants will be able to Outline the four stages of schizophrenia Describe differences between first- and second-generation antipsychotics List clinical reasons for the use of clozapine Erich Lindemann Mental Health Center
Where were we in 2002? Sports – Patriots miss 2002 post-season; QB Brady Politics – President George W. Bush – Mitt Romney elected Governor Culture – Best picture: Chicago – Best-selling album: The Eminem Show Personal
CATIE design Funding: NIMH Study design of this SWITCH STUDY – Double-blind, randomized, flexible-dose – Long duration: 18-month trial – Large N: almost 1500 schizophrenia patients – Representative sample – Several phases including a clozapine arm – Novel outcome: all-cause-discontinuation CATIE=Clinical Antipsychotic Trials of Intervention Effectiveness Lieberman et al. NEJM 2005
CATIE main results Most striking – High rate of treatment discontinuation (up to 74%) – Short median time to discontinuation (about 6 months) Most controversial – No effectiveness difference between SGA and perphenazine Lieberman et al. NEJM 2005 CATIE=Clinical Antipsychotic Trials of Intervention Effectiveness
CATIE clinical summary Main findings – Olanzapine more effective than risperidone, quetiapine, ziprasidone and perphenazine – Perphenazine relatively well-tolerated and effective – No cognitive benefit with 2nd generation agents 1 – Disadvantage to switching 2 – Substantial metabolic complications with olanzapine Lieberman JA and Stroup TS. Am J Psychiatry 2011;168: Arch Gen Psychiatry 2007;64: Am J Psychiatry 2006;163:2090.
Antipsychotic summary Antipsychotics are not effective for all patients and rarely effective for all symptom domains SGAs are not a homogeneous class 1 Clozapine remains the gold standard for refractory psychosis 2 – Also FDA approved for suicidality in schizophrenia – Might have survival benefit The distinction between FGA and SGA should be abandoned. (But: no better nomenclature…) 1 Leucht at al. Lancet 2009;373:31. 2 Hill and Freudenreich. Clin Schizophr Rel Psychoses (in press).
Early course schizophrenia Prodromal PeriodPost-Psychotic Period Initiation of Antipsychotic Psychosis Positive Sx Negative Sx Depression Based on Häfner, ABC Schizophreniestudie 5 years1-2 years* *DUP Psychosis Threshold
Prodromal schizophrenia Pre-psychotic phase 1 – Premorbid phase = CLINICALLY SILENT – Prodromal period Change in thinking and feeling – Unspecific anxiety, depression; attenuated psychotic symptoms (late) Social withdrawal Impaired function Problem – Prodrome can only be diagnosed in retrospect – Transition risk for ARMS not 100% 2 18% after 6 months 22% after 1 year 29% after 2 years 36% after 3 years 1 Klosterkoetter et al. Dtsch Arztebl Int 2008;105: Fusar-Poli P. Arch Gen Psychiatry 2012;69:220.
SOHO – Remission Lambert et al., Acta 2008 N=392 never-treated patients SOHO = Schizophrenia Outpatient Health Outcomes
Clinical staging STAGEDEFINITION 0Increased risk, no symptoms 1aMild/unspecific symptoms 1bModerate but subthreshold symptoms 2First episode of illness 3aIncomplete remission 3bRecurrence 3cMultiple relapses 4Unremitting illness McGorry 2006, McGorry 2009
DSM-V Attenuated Psychosis Syndrome (Draft Criteria for section III) A.Characteristic symptoms Attenuated positive symptoms with insight B.Frequency/currency Once per week in past month C.Progression D.Distress/disability/treatment seeking E.Symptoms not better explained by Depression, mania, substance use, ADD, … F.Never had frank psychosis Carpenter WT and van Os J. Am J Psychiatry 2011;168:460. Fleischhacker WW and DeLisi L. Curr Opin Psychiatry 2012;25:327. DSM-IV
Indicated prevention trial Amminger GP et al. Arch Gen Psychiatry 2010;67:146. 5% 28% ω-3 FA Placebo 12 weeks 700 mg EPA 480 mg DHA
Duration of Untreated Psychosis (DUP) Prolonged DUP 1,2 – Poorer response – Worse outcome. – DUP can be reduced 3 – Clinical advantage at baseline, 2-year 3 and 5- year f/u 4 – Sustained information campaign is key 5 – Focus on outliers 6 Social toxicity – Stigmatization – Loss of job – Interrupted schooling – Loss of friendships – Loss of family support – Criminal record – Accidental death – Accidental homicide Shame and demoralization 1 Perkins et al. 2005, 2 Marshall et al Melle et al. 2004, 2008; 4 Larsen et al Joa et al Lloyd-Evans et al., Br J Psychiatry 2011;198:256.
Early use of clozapine Agid O et al. J Clin Psychiatry 2011;72: st and 2 nd antipsychotic: Risperidone Olanzapine 3 rd antipsychotic: Clozapine
Lifestyle intervention and metformin for antipsychotic-induced weight gain N = 128 Wu RR, et al. JAMA 2008;299: week placebo-controlled trial, metformin 750 mg/day Change from Baseline
New Antipsychotics Aripiprazole (ABILIFY); Nov Risperidone LAI (RISPERDAL CONSTA); Oct Paliperidone (INVEGA); Dec Iloperidone (FANAPT); May 6 Paliperidone LAI (INVEGA SUSTENNA); Jul 31 Asenapine (SAPHRIS); Aug 13 Olanzapine LAI (ZYPREXA RELPREVV); Dec Lurasidone (LATUDA); Oct LAI = Long-acting injectable Paliperidone = 9-hydroxy-risperidone
Seige cycle The first reports sounded in every respect extremely favorable; but before long it became clear that [these drugs] did not satisfy the traditional conditions of cito, tuto et jucunde [quickly, safely, and pleasantly]—at least, that even in small doses they caused all kinds of unpleasant or detrimental side effects. Finally most of them found a small, limited, special territory within which the conscientious physician uses them. Max Seige, 1912 Snelders S et al. Bull Hist Med 2006;80:95.
Sequential antipsychotic trials Select – Lowest-risk choice – Patient factors – Early ancillary treatments Behavioral prevention 1,2 Adjunctive metformin 2,3 Monitor – Clinical response – Follow guidelines (e.g., ADA, Mt. Sinai, MGH) 4 Adjust – Switch antipsychotics – Add behavioral treatment 5 – Treat medical morbidities “However beautiful the strategy, you should occasionally look at the results.” -Sir Winston Churchill 1 Wu et al., JAMA 2008, 2 Wu et al., Am J Psych 2008, 3 Wang M et al. Schizophr Res 2012 (in press) 4 ADA 2004, Marder et al., Am J Psych 2004, Goff et al, J Clin Psych 2005; 5 Dixon et al., Schiz Bull 2010
Phase-specific treatment GOALSKEY DECISIONS ProdromeDelay psychosis Prevent schizophrenia? Treat with antipsychotic? Acute Psychosis Keep DUP short Achieve initial response and early positive symptoms remission Which antipsychotic? Problems: early non-response (positive Sx) Engagement Post-psychotic Phase Achieve sustained remission Recovery and QOL Prevent medical morbidity Treat for how long? Problems: early relapse and residual Sx (adherence); risk- benefit
Did we make progress? No new breakthrough medications No cure Incremental progress – Medications are only tools – New is not better – Clozapine is unique – Real choice New (re-discovered) prevention paradigm – Early intervention – Illness staging Clarification of goals – Remission and recovery – Mens sana in corpore sano Insel TR. Nature 2010;468:187. A decade of refinement, Not revolution. Pincus HA and Naber D. Curr Opin Psychiatry 2012;25:513.
John Umstead Hospital, Butner, NC, ca Those were the days...
MCQ – FGA vs. SGA In general, all second-generation antipsychotics are: A.Causing similar weight gain. B.Essentially interchangeable. C.Less likely to cause tardive dyskinesia compared to haloperidol. D.More effective than first-generation antipsychotics.
MCQ – Clozapine Clozapine is a good antipsychotic for patients with schizophrenia who are: A.Against regular blood work. B.Experiencing suicidal ideation. C.In their first episode of psychosis. D.Obese.