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Schizophrenia treatment – The past 10 years

10th Annual Schizophrenia Education DayNovember 10, 2012

Oliver Freudenreich, MDAssociate Professor of Psychiatry

Harvard Medical SchoolMedical Director, MGH Schizophrenia Program

Massachusetts General Hospital

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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

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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

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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

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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

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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 2005CATIE=Clinical Antipsychotic Trials of Intervention Effectiveness

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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 agents1

– Disadvantage to switching2

– Substantial metabolic complications with olanzapine

Lieberman JA and Stroup TS. Am J Psychiatry 2011;168:770.1Arch Gen Psychiatry 2007;64:633.2Am J Psychiatry 2006;163:2090.

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SGA – Side effect propensity

Sedation Metabolic EPS Prolactin Other

Perphenazine ++ + ++ +

Clozapine ++++ ++++ 0 0

Olanzapine +++ ++++ + +

Quetiapine +++ +++ +/- 0

Risperidone ++ ++ ++ ++++

Paliperidone ++ ++ ++ ++++

Aripiprazole + + ++ decrease

Ziprasidone +/- + + +/- QTc

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Antipsychotic summary

• Antipsychotics are not effective for all patients and rarely effective for all symptom domains

• SGAs are not a homogeneous class1

• Clozapine remains the gold standard for refractory psychosis2

– Also FDA approved for suicidality in schizophrenia– Might have survival benefit

• The distinction between FGA and SGA should be abandoned. (But: no better nomenclature…)

1Leucht at al. Lancet 2009;373:31.2Hill and Freudenreich. Clin Schizophr Rel Psychoses (in press).

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EARLY INTERVENTION

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Early course schizophrenia

Prodromal Period Post-Psychotic Period

Initiation of Antipsychotic

Psychosis

Positive Sx

Negative SxDepression

Based on Häfner, ABC Schizophreniestudie

5 years 1-2 years*

*DUP

PsychosisThreshold

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Prodromal schizophrenia

• Pre-psychotic phase1

– 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 1Klosterkoetter et al. Dtsch Arztebl Int 2008;105:532.

2Fusar-Poli P. Arch Gen Psychiatry 2012;69:220.

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SOHO – Remission

60.3

45.4

57

28.1

0 10 20 30 40 50 60 70

Symptoms

Function

Subjective Well-being

Combinedremission

Percent

Lambert et al., Acta 2008

N=392 never-treated patients

SOHO = Schizophrenia Outpatient Health Outcomes

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Clinical staging

STAGE DEFINITION0 Increased risk, no symptoms1a Mild/unspecific symptoms1b Moderate but subthreshold symptoms2 First episode of illness3a Incomplete remission3b Recurrence3c Multiple relapses4 Unremitting illness

McGorry 2006, McGorry 2009

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DSM-V Attenuated Psychosis Syndrome (Draft Criteria for section III)

A. Characteristic symptomsAttenuated positive symptoms with insight

B. Frequency/currencyOnce per week in past month

C. ProgressionD. Distress/disability/treatment seekingE. 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

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Prevention

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Indicated prevention trial

Amminger GP et al. Arch Gen Psychiatry 2010;67:146.

5%

28%

ω-3 FA

Placebo12 weeks

700 mg EPA480 mg DHA

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Duration of Untreated Psychosis (DUP)

• Prolonged DUP1,2

– Poorer response– Worse outcome

• .– DUP can be reduced3

– Clinical advantage at baseline, 2-year3 and 5-year f/u4

– Sustained information campaign is key5

– Focus on outliers6

• Social toxicity– Stigmatization– Loss of job– Interrupted schooling– Loss of friendships– Loss of family support– Criminal record– Accidental death– Accidental homicide

Shame and demoralization1Perkins et al. 2005, 2Marshall et al. 20053Melle et al. 2004, 2008; 4Larsen et al. 20115Joa et al. 20086Lloyd-Evans et al., Br J Psychiatry 2011;198:256.

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Early use of clozapine

75.4

16.7

75

0

10

20

30

40

50

60

70

80

1st 2nd 3rd

Response in %

Agid O et al. J Clin Psychiatry 2011;72:1439.

1st and 2nd antipsychotic:

RisperidoneOlanzapine

3rd antipsychotic:

Clozapine

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Lifestyle intervention and metformin forantipsychotic-induced weight gain

N = 128Wu RR, et al. JAMA 2008;299:185-193.

12-week placebo-controlled trial, metformin 750 mg/day

Cha

nge

from

Bas

elin

e

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MGH resident call room

wwwc.mentalfloss.com/.../07/the-end-is-near.jpg

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New Antipsychotics 2002-2012• 2002 Aripiprazole (ABILIFY); Nov 15• 2003 Risperidone LAI (RISPERDAL CONSTA); Oct 29• 2004• 2005• 2006 Paliperidone (INVEGA); Dec 19• 2007• 2008• 2009 Iloperidone (FANAPT); May 6

Paliperidone LAI (INVEGA SUSTENNA); Jul 31Asenapine (SAPHRIS); Aug 13Olanzapine LAI (ZYPREXA RELPREVV); Dec 11

• 2010 Lurasidone (LATUDA); Oct 28• 2011• 2012

LAI = Long-acting injectablePaliperidone = 9-hydroxy-risperidone

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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.

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Sequential antipsychotic trials

• Select– Lowest-risk choice– Patient factors– Early ancillary treatments

• Behavioral prevention1,2

• Adjunctive metformin2,3

• Monitor– Clinical response– Follow guidelines (e.g., ADA,

Mt. Sinai, MGH)4

• Adjust– Switch antipsychotics– Add behavioral treatment5

– Treat medical morbidities

“However beautiful the strategy, you should occasionally look at the results.”

-Sir Winston Churchill

1Wu et al., JAMA 2008, 2Wu et al., Am J Psych 2008, 3Wang M et al. Schizophr Res 2012 (in press) 4ADA 2004, Marder et al., Am J Psych 2004, Goff et al, J Clin Psych 2005; 5Dixon et al., Schiz Bull 2010

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Phase-specific treatment

GOALS KEY DECISIONS

Prodrome Delay psychosisPrevent schizophrenia?

Treat with antipsychotic?

AcutePsychosis

Keep DUP shortAchieve initial response and early positive symptoms remission

Which antipsychotic?Problems: early non-response (positive Sx)Engagement

Post-psychoticPhase

Achieve sustained remissionRecovery and QOLPrevent medical morbidity

Treat for how long?Problems: early relapse and residual Sx (adherence); risk-benefit

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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.orgJohn Umstead Hospital, Butner, NC, ca. 1995

Those were the days...

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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.

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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.