Presentation on theme: "Www.mghcme.org Schizophrenia treatment – The past 10 years 10 th Annual Schizophrenia Education Day November 10, 2012 Oliver Freudenreich, MD Associate."— Presentation transcript:
www.mghcme.org 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
www.mghcme.org 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
www.mghcme.org 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
www.mghcme.org 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
www.mghcme.org 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
www.mghcme.org 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
www.mghcme.org 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;168:770. 1 Arch Gen Psychiatry 2007;64:633. 2 Am J Psychiatry 2006;163:2090.
www.mghcme.org 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).
www.mghcme.org 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
www.mghcme.org 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;105:532. 2 Fusar-Poli P. Arch Gen Psychiatry 2012;69:220.
www.mghcme.org SOHO – Remission Lambert et al., Acta 2008 N=392 never-treated patients SOHO = Schizophrenia Outpatient Health Outcomes
www.mghcme.org 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
www.mghcme.org 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 www.dsm5.org 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
www.mghcme.org 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
www.mghcme.org 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. 2005 3 Melle et al. 2004, 2008; 4 Larsen et al. 2011 5 Joa et al. 2008 6 Lloyd-Evans et al., Br J Psychiatry 2011;198:256.
www.mghcme.org Early use of clozapine Agid O et al. J Clin Psychiatry 2011;72:1439. 1 st and 2 nd antipsychotic: Risperidone Olanzapine 3 rd antipsychotic: Clozapine
www.mghcme.org Lifestyle intervention and metformin for antipsychotic-induced weight gain N = 128 Wu RR, et al. JAMA 2008;299:185-193. 12-week placebo-controlled trial, metformin 750 mg/day Change from Baseline
www.mghcme.org New Antipsychotics 2002-2012 2002Aripiprazole (ABILIFY); Nov 15 2003Risperidone LAI (RISPERDAL CONSTA); Oct 29 2004 2005 2006Paliperidone (INVEGA); Dec 19 2007 2008 2009Iloperidone (FANAPT); May 6 Paliperidone LAI (INVEGA SUSTENNA); Jul 31 Asenapine (SAPHRIS); Aug 13 Olanzapine LAI (ZYPREXA RELPREVV); Dec 11 2010Lurasidone (LATUDA); Oct 28 2011 2012 LAI = Long-acting injectable Paliperidone = 9-hydroxy-risperidone
www.mghcme.org 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.
www.mghcme.org 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
www.mghcme.org 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
www.mghcme.org 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.
www.mghcme.org John Umstead Hospital, Butner, NC, ca. 1995 Those were the days...
www.mghcme.org 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.
www.mghcme.org 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.