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Schizophrenia: Moving Backward Toward Mechanism and Prevention T.H. McGlashan, M.D. Schizophrenia days Stavanger, Norway November 5, 2008

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Title: Schizophrenia: Moving Backward Toward Mechanism and Prevention T.H. McGlashan, M.D. Schizophrenia days Stavanger, Norway November 5, 2008


1
Schizophrenia Moving Backward Toward
Mechanismand PreventionT.H. McGlashan,
M.D.Schizophrenia daysStavanger,
NorwayNovember 5, 2008
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With (my patients at Chestnut Lodge) I came upon
the scene too late most of the damage was
already done. I remain convinced that with
schizophrenia in its moderate to severe form, our
current treatment efforts amount to palliation
and damage control. There is no doubt that our
efforts make a difference, but they effect little
if any restitution of what has been lost. For
many vulnerable to schizophrenia, the ultimate
answer lies in early detection and preventive
intervention. Thomas McGlashan. Editors
Introduction Early detection and intervention in
schizophrenia, Schizophrenia Bulletin, 1996,
22(2)197-9
6
Clinical Course of Schizophrenia
Premorbid
Progressive
Residual
Prodromal
Onset of Psychosis
Behavioral Adaptation
Psychotic Symptoms
B 15 20
25 40.
7
Early Intervention Is Key
Premorbid
Progressive
Residual
Prodromal
First Episode Treatment
Behavioral Adaptation
Psychotic Symptoms
B 15 20
25 40.
8
TYPES OF PREVENTION
  • Primary
  • Secondary
  • Tertiary

9
Primary Prevention
  • Reducing incidence of disorder
  • Universal target population
  • Prevention strategies treat the etiology
  • - Fluoridation and dental caries
  • - Seat belts and automobile deaths

10
Secondary (Indicated) Prevention
  • Reducing prevalence or severity of disorder
  • - Delaying onset
  • - Improving prognosis and long-term course
  • High risk target populations
  • - Family history of breast cancer
  • - High cholesterol risk for cardiovascular
    disease
  • Prevention strategies treat the risk
  • - Prophylactic mastectomy
  • - Cholesterol lowering agents and exercise

11
Tertiary Prevention
  • Reducing acuity and destructiveness of disorder
  • - Reducing time actively ill
  • - Reducing collateral damage (e.g., involuntary
    hospitalization)
  • Clinically ill target population meeting
    diagnostic criteria
  • Prevention strategies treat the disorder earlier
    and/or more aggressively
  • - Early identification after onset
  • Increasing awareness of disorder (e.g., education
    campaigns)
  • Improving access to services
  • - Early treatment
  • - Continuous treatment if necessary

12
Early Intervention Is Key
Premorbid
Progressive
Residual
Prodromal
First Episode Treatment
Behavioral Adaptation
Psychotic Symptoms
B 15 20
25 40.
13
Early Detection Research in theFirst Psychotic
Episode
  • The basic observation Long duration of
  • untreated psychosis is correlated with
  • poorer clinical course and outcome
  • Highly replicated correlation, but
  • The causal direction of the association
  • between long DUP and poor outcome
  • is not at all clear

14
The Central Research Question Does long
DUP cause chronicity or does a
vulnerability for chronic disorder cause a long
DUP? The optimal research design for
addressing the question is unethical. The
next-best research approach is a
quasi-experimental service-systems design where
one population of patients gets earlier treatment
and their outcome is compared to another
population of patients not receiving earlier
treatment.
15
TIPS Project
  • The aim is to test in a multicenter trial
    whether reducing DUP in one healthcare sector
    will improve the prognosis/long-term course and
    outcome of first-episode, nonaffective,
    functional psychosis compared to healthcare
    sectors without a program for reducing DUP

16
Design
  • Expected number of included patients with
    first-onset psychosis over 4 years 300

17
TIPS TEAM
PI Thomas McGlashan, Yale
University Co-PIs Svein Friis, University
of Oslo Per Vaglum, University of
Oslo Investigators Rogaland (Stavanger)
Health Care District, Norway Jan Olav
Johannessen, Tor Kjetl Larsen, Inge Joa, Wenche
ten Velden Hegelstad, Hans
Langeveld Investigators Ulleval (Oslo)
Health Care District, Norway Ingrid Melle,
Stein Opjordsmoen, Bjorn Rund, Jan Ivar
Rossberg, Julie Evensen Investigators
Roskilde Health Care District, Denmark Erik
Simonsen, Ulrik Haahr
18
Overall Design
  • First-episode, nonaffective psychosis
  • Age 15-65
  • Follow-up at 5 years
  • A 2-year treatment program at all sites
  • Individual supportive psychotherapy
  • Medication algorithm starting withnovel
    antipsychotics
  • Multifamily groups

19
TIPS Early Detection Strategies in Rogaland
County
  • Educational and informational campaigns
  • Low threshold detection teams

20
The Parallel Control Study
  • Comparison between detection as usual
  • sample, Oslo/Roskilde 1997-2000, and
  • early detection sample, Rogaland County
  • 1997-2000
  • ED Early Detection
  • No-ED Detection as usual

21
Duration of Untreated Psychosisand Age at Intake
ED (N141)
p-Value
No ED (N140)
22
Symptoms at Start of Treatment
No ED(N140)
ED (N141)
p-Value
PANSS
21.7 (5.6)
18.8 (4.9)
Positive
lt.01
16.6 (7.5)
13.9 (5.7)
Negative
lt.01
38.4 (10.4)
31.6 (7.6)
General
lt.01
27.1 (6.9)
31.0 (6.4)
GAF s
lt.01
28.8 (9.7)
33.6 (10.0)
GAF f
lt.01
23
Summary
  • The ED program succeeded in identifying patients
    earlier in the course of illness!
  • Family and schools used the ED Detection Teams

24
OTHER TIPS BASELINE FINDINGS
Baseline ED vs No ED Differences - Less
suicidality with ED - Less involuntary
hospitalization with ED
25
Two Year Outcome
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  • Conclusion
  • No difference in positive symptoms and
  • excitation
  • Lower levels of cognitive, depressive,
  • and negative symptoms in ED area
  • Difference in symptom levels not
  • explained by confounders
  • Early detection and intervention may
  • have achieved secondary prevention
  • of negative symptom psychopathologies

31
  • TIPS Current Status
  • Five year follow-up results ready
  • Ten year follow-up underway as of
  • January 1, 2008

32
Early Intervention Is Key
Premorbid
Progressive
Residual
Prodromal
First Episode Treatment
Behavioral Adaptation
Psychotic Symptoms
B 15 20
25 40.
33
Schizophrenia Prodrome
  • The period preceding the onset of the first
    florid psychotic episode, with increasing
    symptomatic presentation and functional
    deterioration
  • Cognitive impairments
  • Behavioral disturbances
  • Anxiety, depression, hostility
  • Attenuated psychotic symptoms

34
Early Interest in the Sz Prodrome
The psychiatrist sees too many end states and
deals professionally with too few of the
pre-psychotic states With this in mind, it
would seem as if we should lay great stress on
the prompt investigation of failing adjustment,
rather than, as is so often the case, wait and
see what happens I feel certain that many
incipient cases might be arrested before the
efficient contact with reality is completely
suspended, and a long stay in institutions made
necessary.
Sullivan, H.S., 1927. The onset of schizophrenia.
Am. J. Psychiatry, 6, pp. 105134.
35
Modern Prospective Diagnostic Criteria
  • At-Risk Mental States
  • Attenuated Psychotic Symptoms
  • Genetic Risk (Family Hx, SPD) Functional
    Deterioration
  • Brief Limited Intermittent Psychotic Episodes

Yung, A., Phillips, L. J., McGorry, P. D., et al
(2001) Comprehensive Assessment of At-Risk Mental
States (CAARMS). PACE Clinic University of
Melbourne.
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SCALE OF PRODROMAL SYMPTOMS 5 POSITIVE ITEMS
1) Unusual Thought Content /
Delusional Ideas 2) Suspiciousness /
Persecutory Ideas 3) Grandiose Ideas 4)
Perceptual Abnormalities / Hallucinations 5)
Conceptual Disorganization
38
SIPS Interview Probes Attenuated Psychotic
Phenomena
PANSS Delusions
7
6
5
SIPS Unusual Thought Content/Delusional Ideas
4
6
3
5
4
2
Psychosis Threshold
3
2
1
0
1
39
  • Why study prodromal
  • syndromes and symptoms?
  • To test treatments that might prevent or
    delay onset of psychosis

40
  Randomized Controlled Trial of Interventions
Designed to Reduce the Risk of Progression to
First-Episode Psychosis in a Clinical Sample With
Subthreshold Symptoms       Patrick D. McGorry,
PhD, FRANZCP Alison R. Yung, FRANZCP Lisa J.
Phillips, MPsych Hok Pan Yuen, MSci Shona
Francey, MPsych Elizabeth M. Cosgrave, MA
Dominic Germano, MPsych(Clinical) Jenny Bravin,
MPsych(Neuro) Tony McDonald, MPsych Alison
Blair, MRCPsych Stephen Adlard, FRANZCP Henry
Jackson, PhD
Arch Gen Psychiatry. 200259921-928
41
Randomized Groups
  • Needs based
  • Support
  • Antidepressant if needed
  • No CBT
  • No antipsychotic
  • 36 conversion in 6 months (10/28)
  • Specific Preventive
  • Support
  • Antidepressant if needed
  • Cognitive behavior therapy
  • Risperidone 1-2 mg/d
  • 10 conversion in 6 months (3/31)

42
PRIME STUDYPrevention Through Risk
IdentificationManagement and Education
  • Drafted 1997
  • Funded 1998-2003 by Eli Lilly Co. and NIMH
    (Senior K Award)
  • Launched 1998
  • New Haven alone for 11/2 years, then added
  • Toronto Robert Zipursky
  • Chapel Hill Diana Perkins
  • Calgary Jean Addington
  • Finished Major report May 2006 in AJP

43
PRIME PRODROMAL CLINICAL TRIAL
PI Thomas McGlashan Co-PI Alan Breier
New Haven, CT Calgary, Alberta Scott
Woods Jean Addington Ralph Hoffman Don
Addington Tandy Miller Keith Hawkins Chapel
Hill, NC Adrian Preda Diana
Perkins Toronto, Ontario Eli Lilly
Co. Robert Zipursky Mauricio Tohen Irvin
Epstein Stacy Lindborg Quynh Trzaskoma
44
Results Conversion Patients Converting to
Psychosis in Year 1 (n16)
p0.08
of Patients
37.9
16.1
26.7 of the total sample (N60) converted to
psychosis in one year
45
SOPS Positive Symptoms Mean Change from Baseline
N30
olanzapine
placebo
-1
p-value lt 0.1 from MMRM model p-value lt
0.05 from MMRM model
n16
n13
n12
-3
Mean Change
n21
n20
n10
-5
n16
n8
n14

n9

n12




n10
-7
0
10
20
30
40
50
VISIT WEEK
46
Vital Signs and WeightMean Change from Baseline
to Endpoint (LOCF)
Treatment Year
No-Treatment Year
Within-group p-value is from a paired t-test on
mean change.
47
CURRENT STATE OF PREVENTION IN
SCHIZOPHRENIAandTREATMENT IMPLICATIONST.
McGlashan
48
TIPS Early Detection in First Episode
Schizophrenia Summary of Results
  • Duration of Untreated Psychosis can be
    significantly reduced with education and easier
    access to care
  • Early detection brings patients to treatment
    when they are younger and less severely ill
  • Early detection appears to reduce the
    frequency of
  • illness associated suicidal behavior and
    involuntary
  • treatment at intake
  • Early detection is associated with less
    severe negative
  • symptoms at one and two years, and less
    depression and better cognition at two years

49
TIPS Early Detection in First Episode
Schizophrenia Are We Seeing Prevention?
Primary Not demonstrated Secondary Appears
to have been achieved and demonstrated for
the first time, needs replication Tertiary
Definitely, in terms of reduced illness
severity and collateral damage
50
Second Generation Pharmacotherapyof the Prodrome
Summary of Results
  • Onset may be delayed with medication
  • Positive prodromal symptom severity
    significantly
  • reduced with medication
  • Weight gain that is significant

51
Second Generation Pharmacotherapy of the
Prodrome
Are We Seeing Prevention?
  • Primary Not demonstrated but remotely possible

Secondary Reduced prevalence can be achieved
52
Second Generation Pharmacotherapy of the
Prodrome
Are We Seeing Prevention?
  • Tertiary Reduced acuity and collateral damage
    can be achieved
  • - PRIME Clinic experience with persons who
    converted (became a first-episode psychosis
    patient)
  • - No hospitalization
  • - No loss of time and school or work
  • - Treatment adherent
  • - Treatment alliance with patient and family
    already
  • in place

53
Prodromal Research and Treatment Implications
  • Positive benefit to risk ratio
  • Supports continuing research
  • Further data needed to reach treatment guideline
    status
  • Currently, clinical strategies should include
    frequent, careful follow-along evaluations with
    psychoeducation and support over the course of
    the prodrome to its resolution either in
    remission or in the development of a treatable
    syndrome
  • (APA Treatment Guidelines for Schizophrenia,
    2004)

54
  • Why study prodromal
  • syndromes and symptoms?
  • To study prospectively the onset,
  • clinical course, and pathophysiology
  • of schizophrenia

55
The Psychosis ProdromeUpdates from the North
American ProdromeLongitudinal Study
  • Thomas H. McGlashan, M.D.
  • Yale University School of Medicine
  • PRIME Research Clinic

56
NAPLS Investigators
Diana Perkins MD University of North Carolina
Larry Seidman PhD Harvard University Ming
Tsuang MD Harvard University/UCSD Elaine Walker
PhD Emory University Scott Woods MD Yale
University
Jean Addington PhD University of Toronto Kristin
Cadenhead MD UCSD Tyrone Cannon PhD UCLA Barbara
Cornblatt PhD Hillside Hospital Thomas McGlashan
MD Yale University
Robert Heinssen, Ph.D. NIMH
57
NAPLS Subject Groups
N860
58
NAPLS Psychosis Outcomes
59
Comparative 2.5-Year Incidence Rates
1AESOP Study Kirkbride et al. Arch Gen
Psychiatry 200663250-258.
60
Diagnostic Efficiency Parameters
Disorder
  • Base rate (AC)/(ABCD)
  • Sensitivity A/(AC) probability of symptom
    given the disorder
  • Specificity D/(BD) probability of not having
    symptom, given
  • absence of disorder
  • Positive predictive power A/(AB) probability
    of disorder, given
  • symptom or combination of symptoms
  • Negative predictive power D/(CD) probability
    of not having disorder,
  • given absence of symptom or combination of
    symptoms

61
Improving PredictionSingle-Variable Prediction
Algorithms
Cannon, et al. Arch Gen Psychiatry, 2008
62
Best Performing Three-Variable Prediction
Algorithms
Note. Four and five-variable algorithms do not
improve prediction.
63
Sensitivity vs PPV
  • Low baserate predictors yield high PPV but kill
    sensitivity
  • Allowing for non-coincident combinations of risk
    factors (A or B instead of A and B) results in
    excellent sensitivity, but PPV drops to that of
    single variable models
  • Sensitivity could potentially be improved by
    adding variables presumably closer to the
    underlying etiology with possibly better
    distributional properties, such as assays of
    brain structure and function and other bioassays

64
Normal Development Possible Paths to
Schizophrenia Psychosis Threshold
of Cortical Synapses
10 15 20 25
Age
McGlashan and Hoffman
65
UCLA-Melbourne Collaboration 12-Month Follow-Up
Study (Frank Sun)
Mean Surface Retraction in UHR-Non-Converted
Mean Surface Retraction in UHR-Converted
Significantly Greater Retraction in UHR-Converted
Significantly Greater Expansion in UHR-Converted
66
Genetic Risk, Cognitive Impairment, and Clinical
Symptoms as Predictors of First Episode
Psychosis NAPLS Results and Clinical Implications
  • Larry J. Seidman, Barbara A. Cornblatt, Ming T.
    Tsuang, Jean Addington, Kristen S. Cadenhead,
    Tyrone D. Cannon, Thomas H. McGlashan, Diana O.
    Perkins, Elaine F. Walker, Scott W. Woods,
    Robert Heinssen
  • Statistical and Data Management Anthony
    Giuliano, Ph.D., Eric Meyer, Ph.D. (Harvard),
    Jennifer Johnson (UCLA), Diane Kirsopp (Toronto),
    and Roy Money (Yale) and the entire NAPLS
    collaborative team

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Risk of Mania in Persons atHeightened Risk for
PsychosisDiana Perkins, M.D. et al
  • Individuals meetings SIPS criteria may be
    at-risk for Bipolar Disorder with or without
    psychosis
  • Sample N included 194 SIPS subjects and 67
    help-seeking comparison (HSC) subjects
    (treatment seeking but not SIPS)
  • At follow-up, 12 of SIPS and 24 of HSC met
    DSM-IV mania criteria
  • Of those meeting mania criteria (N39), only 5
    (13) had psychotic symptoms

70
Risk of Mania, Continued
  • Among PRODROMALS, symptoms predicting mania
    included
  • - Social anhedonia
  • - Avolition
  • - Impaired occupational functioning
  • - Dysphoric mood (irritability, depression,
    etc.)
  • Among HELP-SEEKING CONTROLS, symptoms
    predicting
  • mania included
  • - Suspiciousness
  • - Decreased focus and attention
  • - sleep disturbance
  • - Intolerance to stress
  • - Dysphoric mood (irritability, depression)

71
Risk of Mania, Continued
  • Most subjects developing DSM-IV mania (20/23
    SIPS and 16/16 HSC) had depression at baseline
  • Mania was more common among persons referred
    for prodromal evaluation who failed to meet
    prodromal syndromal criteria

72
Cannabis Misuse and Risk for Psychosis in a
Prodromal SampleKristin Cadenhead et al
  • Prodromal sample N236
  • Hx of cannabis abuse/dependence N57 (249)
  • Among converters to psychosis (N60), 33 had
    positive cannabis history and 22 did not (p lt
    .05)
  • Cannabis appears to be an important risk
    factor for conversion in prodromals

73
Naturalistic Study of Antipsychotic (AP) and
Antidepressant (SSRI) Use in Prodromal
SubjectsElaine Walker et al
  • Data on medication use at baseline and 6
    months for
  • N252 SIPS patients
  • Baseline
  • - Patients on AP had higher disorganized and
    general
  • symptoms than those not on APs. Patients on
    SSRI had
  • higher general symptoms than those not on
    SSRIs
  • Longitudinal Course
  • - Patients on AP had more reduction of positive
    and
  • disorganized symptoms than those not on APs
  • - Being on SSRI was unrelated to symptoms
    severity over time

74
Naturalistic Study of Antipsychotic (AP) and
Antidepressant (SSRI) Use in Prodromal
SubjectsElaine Walker et al
  • Impressions
  • - Antipsychotic medication appears to work
  • - Antidepressant medication appears not to
    work
  • - Both findings validate that the SIPS prodrome
    is a prodrome primarily for psychosis, not
    affective disorder
  • - Findings are consistent with the Perkins
    finding that the
  • highest rate of conversion to mania in the
    NAPLS sample is
  • among the SIPS negative
    help-seeking controls

75
State of the Prodrome 2008
  • At high risk for getting worse
  • Currently symptomatic
  • Currently functionally impaired
  • Currently cognitively impaired
  • Reliably and validly diagnosable
  • DSM-V codification ?
  • FDA Indication ?

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STEPSpecialized Treatment for Early Psychosis
  • Begun May 2006 at CMHC
  • First randomized study of integrated treatment in
    US
  • Ages 16 - 45
  • lt 8 weeks lifetime antipsychotic

78
STEPSpecialized Treatment for Early Psychosis
  • 48 patients enrolled as of June 2008
  • 23 insured patients randomized
  • 13 to STEP
  • 10 to usual care
  • 25 CMHC eligible assigned to STEP

79
Treatment Received
80
STEP Randomized Outcomes at 6 Months
81
RAISE RFPRecovery After Initial Schizophrenic
Episode
  • Solicitation Released by NIMH
  • June 12, 2008
  • Due Date August 4, 2008

82
STEP to RAISE
Person Centered Care, Health Behavior Change,
Adolescent Development, Cultural Competence
83
Phase 3 Aims
  • December 2010 to December 2014
  • Implement integrated treatment at 20 sites
  • Assess program effectiveness
  • Assess program costs

84
Phase 3
N1200
85
Team RAISE USA
Scott Woods, Vinod Srihari, Tom McGlashan, John
Krystal, Peter Salovey, Leslie Hyman, Selby
Jacobs, Larry Davidson, Bruce Wexler, Morris
Bell, Sandy Resnick, Mary Schwab Stone, Andres
Martin, Larry Scahill, John Saksa, Nick
Breitborde, David Roberts, Cenk Tek, Lydia
Chwastiak, David Paltiel, Jody Sindelar, Susan
Busch, Max Birchwood, , Bill McFarlane, Joe
Parks, Bob Glover, Noel Mazade, David Shern, John
Davis, Herb Meltzer, Alan Breier, Gene Laska,
Steven Potkin, Dan Javitt, Bob Freedman, John
Csernansky, Steve Taylor, Peter Weiden, Tom
Kosten, Tom Patterson, Carole Siegel, Alex
Rothman, Elaine Walker, Kristin Cadenhead, Sophia
Vinogradov, Sally Jacobs, Anirban Basu, John
Mullahy, Steven Madonick, Joe Friedman, Rachel
Loewy, Dan Mathalon, Andrew Goddard, Steve Batki,
Jonathan Meyer, Dost Ongur, Adrienne Lahti,
Allison Brabban, Mike Jackson, Peter Roy-Byrne,
Ron Diamond, Jessica Pollard
86
External Advisors
Merete Nordentoft, Shitij Kapur, Ashok Malla,
Shôn Lewis, Bob Zipursky, Raimo Salokangas,
Ingrid Melle, Svein Friis, Per Vaglum, Ole
Andreasson, Paul Roy, Ira Glick, Matti Isohani,
Til Wykes, Gretchen Haas NAMI-CT CMHC Advisory
Board Consumer, Youth, and Family Advisory
Council Connecticut Transformation Network
Consumer, Youth, and Family Continuous Quality
Improvement Collaborative Connecticut Consumer
Research and Evaluation Network
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