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Schizophrenia: Moving Backward Toward Mechanismand PreventionT.H. McGlashan, M.D.Schizophrenia daysStavanger, NorwayNovember 5, 2008


“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. Editor’s Introduction:

Early detection and intervention in schizophrenia,

Schizophrenia Bulletin, 1996, 22(2):197-9

clinical course of schizophrenia
Clinical Course of Schizophrenia





Onset of Psychosis

Behavioral Adaptation

Psychotic Symptoms

B 15 20 25 40….

early intervention is key
Early Intervention Is Key





First Episode Treatment

Behavioral Adaptation

Psychotic Symptoms

B 15 20 25 40….

types of prevention




primary prevention
Primary Prevention
  • Reducing incidence of disorder
  • Universal target population
  • Prevention strategies treat the etiology

- Fluoridation and dental caries

- Seat belts and automobile deaths

secondary indicated prevention
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

tertiary prevention
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

early intervention is key12
Early Intervention Is Key





First Episode Treatment

Behavioral Adaptation

Psychotic Symptoms

B 15 20 25 40….

early detection research in the first psychotic episode
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


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.

tips project
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



Early detection



and Roskilde

Detection as usual


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


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

overall design
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
tips early detection strategies in rogaland county
TIPS Early Detection Strategies in Rogaland County
  • Educational and informational campaigns
  • Low threshold detection teams
the parallel control study
The Parallel Control Study
  • Comparison between “detection as usual”

sample, Oslo/Roskilde 1997-2000, and

“early detection” sample, Rogaland County


  • ED = Early Detection
  • No-ED = Detection as usual
duration of untreated psychosis and age at intake

DUP weeks


median 16

range 0-966

31.1 (10.5)

median 5

range 0-1196

26.2 (7.6)



Duration of Untreated Psychosisand Age at Intake






symptoms at start of treatment
Symptoms at Start of Treatment

No ED(N=140)






21.7 (5.6)

18.8 (4.9)



16.6 (7.5)

13.9 (5.7)



38.4 (10.4)

31.6 (7.6)



27.1 (6.9)

31.0 (6.4)



28.8 (9.7)

33.6 (10.0)


  • The ED program succeeded in identifying patients earlier in the course of illness!
  • Family and schools used the ED Detection Teams



Baseline ED vs No ED Differences

- Less suicidality with ED

- Less involuntary hospitalization with ED



  • 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

TIPS: Current Status

  • Five year follow-up results ready
  • Ten year follow-up underway as of
  • January 1, 2008
early intervention is key32
Early Intervention Is Key





First Episode Treatment

Behavioral Adaptation

Psychotic Symptoms

B 15 20 25 40….

schizophrenia prodrome
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
early interest in the sz prodrome
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. 105–134.

modern prospective diagnostic criteria
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.




1) Unusual Thought Content /

Delusional Ideas

2) Suspiciousness / Persecutory Ideas

3) Grandiose Ideas

4) Perceptual Abnormalities / Hallucinations

5) Conceptual Disorganization


SIPS Interview Probes Attenuated Psychotic Phenomena

PANSS Delusions




SIPS Unusual Thought Content/Delusional Ideas







Psychosis Threshold







Why study prodromal

  • syndromes and symptoms?
  • To test treatments that might prevent or delay onset of psychosis

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. 2002;59:921-928

randomized groups
Specific Preventive


Antidepressant if needed

Cognitive behavior therapy

Risperidone 1-2 mg/d

10% conversion in 6 months (3/31)

Needs based


Antidepressant if needed


No antipsychotic

36% conversion in 6 months (10/28)

Randomized Groups
prime study prevention through risk identification management and education
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



PI: Thomas McGlashan

Co-PI: Alan Breier

New Haven, CTCalgary, Alberta

Scott Woods Jean Addington

Ralph Hoffman Don Addington

Tandy Miller

Keith Hawkins Chapel Hill, NC

Adrian Preda Diana Perkins

Toronto, OntarioEli Lilly Co.

Robert Zipursky Mauricio Tohen

Irvin Epstein Stacy Lindborg

Quynh Trzaskoma

results conversion patients converting to psychosis in year 1 n 16
Results: ConversionPatients Converting to Psychosis in Year 1 (n=16)*


% of Patients



*26.7% of the total sample (N=60) converted to psychosis in one year

sops positive symptoms mean change from baseline
SOPS Positive Symptoms Mean Change from Baseline





† p-value < 0.1; from MMRM model

* p-value < 0.05; from MMRM model





Mean Change

























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.


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

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


second generation pharmacotherapy of the prodrome
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
second generation pharmacotherapy of the prodrome51
Second Generation Pharmacotherapy of the Prodrome

Are We Seeing Prevention?

Primary: Not demonstrated but remotely possible

Secondary: Reduced prevalence can be achieved

second generation pharmacotherapy of the prodrome52
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

prodromal research and treatment implications
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)


Why study prodromal

  • syndromes and symptoms?
  • To study prospectively the onset,
    • clinical course, and pathophysiology
    • of schizophrenia
the psychosis prodrome updates from the north american prodrome longitudinal study

The Psychosis Prodrome:Updates from the North American ProdromeLongitudinal Study

Thomas H. McGlashan, M.D.

Yale University School of Medicine

PRIME Research Clinic

napls investigators
NAPLS Investigators

Jean Addington PhD

University of Toronto

Kristin Cadenhead MD


Tyrone Cannon PhD


Barbara Cornblatt PhD

Hillside Hospital

Thomas McGlashan MD

Yale University

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

Robert Heinssen, Ph.D.


comparative 2 5 year incidence rates
Comparative 2.5-Year Incidence Rates

1AESOP Study: Kirkbride et al. Arch Gen Psychiatry 2006;63:250-258.


Diagnostic Efficiency Parameters


  • Base rate = (A+C)/(A+B+C+D)
  • Sensitivity = A/(A+C) probability of symptom given the disorder
  • Specificity = D/(B+D) probability of not having symptom, given
  • absence of disorder
  • Positive predictive power = A/(A+B) probability of disorder, given
  • symptom or combination of symptoms
  • Negative predictive power = D/(C+D) probability of not having disorder,
  • given absence of symptom or combination of symptoms
improving prediction single variable prediction algorithms
Improving PredictionSingle-Variable Prediction Algorithms

Cannon, et al. Arch Gen Psychiatry, 2008

best performing three variable prediction algorithms
Best Performing Three-Variable Prediction Algorithms

Note. Four and five-variable algorithms do not improve prediction.

sensitivity vs ppv
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

Normal Development

Possible Paths to Schizophrenia

Psychosis Threshold

# of



10 15 20 25


McGlashan and Hoffman


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


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

risk of mania in persons at heightened risk for psychosis diana perkins m d et al

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 (N=39), only 5 (13%) had psychotic symptoms

risk of mania continued

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)

risk of mania continued71

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

cannabis misuse and risk for psychosis in a prodromal sample kristin cadenhead et al

Cannabis Misuse and Risk for Psychosis in a Prodromal SampleKristin Cadenhead et al

Prodromal sample N=236

Hx of cannabis abuse/dependence N=57 (249)

Among converters to psychosis (N=60), 33% had positive cannabis history and 22% did not (p < .05)

Cannabis appears to be an important risk factor for conversion in prodromals


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

N=252 SIPS+ patients


- 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


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
state of the prodrome 2008
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 ?
step specialized treatment for early psychosis
STEPSpecialized Treatment for Early Psychosis
  • Begun May 2006 at CMHC
  • First randomized study of integrated treatment in US
  • Ages 16 - 45
  • < 8 weeks lifetime antipsychotic
step specialized treatment for early psychosis78
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
raise rfp recovery after initial schizophrenic episode

RAISERFPRecovery After Initial Schizophrenic Episode

Solicitation Released by NIMH

June 12, 2008

Due Date August 4, 2008

step to raise

Person Centered Care, Health Behavior Change, Adolescent Development, Cultural Competence

phase 3 aims
Phase 3 Aims
  • December 2010 to December 2014
  • Implement integrated treatment at 20 sites
  • Assess program effectiveness
  • Assess program costs
phase 3
Phase 3


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…

external advisors
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