Transcript Document

Schizophrenia treatment –
The past 10 years
10th 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
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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
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
CATIE=Clinical Antipsychotic Trials of Intervention
Effectiveness
Lieberman et al. NEJM 2005
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 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.
www.mghcme.org
SGA – Side effect propensity
Sedation
Metabolic
EPS
Prolactin
++
+
++
+
++++
++++
0
0
Olanzapine
+++
++++
+
+
Quetiapine
+++
+++
+/-
0
Risperidone
++
++
++
++++
Paliperidone
++
++
++
++++
Aripiprazole
+
+
++
decrease
Ziprasidone
+/-
+
+
+/-
Perphenazine
Clozapine
Other
QTc
www.mghcme.org
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).
www.mghcme.org
EARLY INTERVENTION
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Early course schizophrenia
Initiation of Antipsychotic
5 years
1-2 years*
Positive Sx
Negative Sx
Depression
Psychosis
Threshold
*DUP
Prodromal Period
Psychosis
Post-Psychotic Period
Based on Häfner, ABC Schizophreniestudie
www.mghcme.org
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.
www.mghcme.org
SOHO – Remission
SOHO = Schizophrenia Outpatient Health Outcomes
Combined
remission
28.1
Subjective Wellbeing
57
Function
45.4
Symptoms
60.3
0
10
N=392 never-treated patients
20
30
40
50
60
70
Percent
Lambert et al., Acta 2008
www.mghcme.org
Clinical staging
STAGE
0
1a
1b
2
3a
3b
3c
4
DEFINITION
Increased risk, no symptoms
Mild/unspecific symptoms
Moderate but subthreshold symptoms
First episode of illness
Incomplete remission
Recurrence
Multiple relapses
Unremitting 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.
D.
E.
Progression
Distress/disability/treatment seeking
Symptoms not better explained by
DSM-IV
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.
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Prevention
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Indicated prevention trial
ω-3 FA
5%
12 weeks
Placebo
28%
700 mg EPA
480 mg DHA
Amminger GP et al. Arch Gen Psychiatry 2010;67:146.
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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 5year 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 demoralization
1Perkins
et al. 2005, 2Marshall et al. 2005
3Melle et al. 2004, 2008; 4Larsen et al. 2011
5Joa et al. 2008
6Lloyd-Evans et al., Br J Psychiatry 2011;198:256.
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Early use of clozapine
80
75.4
75
1st and 2nd antipsychotic:
70
60
Risperidone
Olanzapine
50
3rd antipsychotic:
Clozapine
40
Response in %
30
16.7
20
10
0
1st
2nd
3rd
Agid O et al. J Clin Psychiatry 2011;72:1439.
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Lifestyle intervention and metformin for
antipsychotic-induced weight gain
Change from Baseline
12-week placebo-controlled trial, metformin 750 mg/day
N = 128
Wu RR, et al. JAMA 2008;299:185-193.
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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 31
Asenapine (SAPHRIS); Aug 13
Olanzapine LAI (ZYPREXA RELPREVV); Dec 11
• 2010 Lurasidone (LATUDA); Oct 28
• 2011
• 2012
LAI = Long-acting injectable
Paliperidone = 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.
www.mghcme.org
Sequential antipsychotic trials
• Select
“However beautiful the
strategy, you should
occasionally look at the
results.”
-Sir Winston Churchill
– 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
1Wu
et al., JAMA 2008, 2Wu et al., Am J Psych 2008, 3Wang M et al. Schizophr Res 2012 (in press)
www.mghcme.org
4ADA 2004, Marder et al., Am J Psych 2004, Goff et al, J Clin Psych 2005; 5Dixon et al., Schiz Bull 2010
Phase-specific treatment
GOALS
KEY DECISIONS
Prodrome
Delay 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); riskbenefit
www.mghcme.org
Did we make progress?
• No new breakthrough
medications
• No cure
A decade of refinement,
Not revolution.
Pincus HA and Naber D. Curr Opin Psychiatry 2012;25:513.
• 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.
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Those were the days...
John Umstead Hospital, Butner, NC, ca. 1995
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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.
www.mghcme.org
MCQ – Clozapine
Clozapine is a good antipsychotic for patients
with schizophrenia who are:
A.
B.
C.
D.
Against regular blood work.
Experiencing suicidal ideation.
In their first episode of psychosis.
Obese.
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