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Schizophrenia: Moving Backward Toward Mechanism and Prevention T.H. McGlashan, M.D . Schizophrenia days Stavanger, Norw

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

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Schizophrenia: Moving Backward Toward Mechanism and Prevention T.H. McGlashan, M.D . Schizophrenia days Stavanger, Norw

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

  2. “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

  3. Clinical Course of Schizophrenia Premorbid Prodromal Progressive Residual Onset of Psychosis Behavioral Adaptation Psychotic Symptoms B 15 20 25 40….

  4. Early Intervention Is Key Premorbid Prodromal Progressive Residual First Episode Treatment Behavioral Adaptation Psychotic Symptoms B 15 20 25 40….

  5. TYPES OF PREVENTION Primary Secondary Tertiary

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

  7. 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

  8. 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

  9. Early Intervention Is Key Premorbid Prodromal Progressive Residual First Episode Treatment Behavioral Adaptation Psychotic Symptoms B 15 20 25 40….

  10. 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

  11. 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.

  12. 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

  13. Rogaland Early detection N=320,000 Oslo and Roskilde Detection as usual N=285,000 Design • Expected number of included patients with first-onset psychosis over 4 years: 300

  14. 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

  15. 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

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

  17. 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

  18. DUP weeks Age median 16 range 0-966 31.1 (10.5) median 5 range 0-1196 26.2 (7.6) <.05 <.01 Duration of Untreated Psychosisand Age at Intake ED (N=141) p-Value No ED (N=140)

  19. Symptoms at Start of Treatment No ED(N=140) ED (N=141) p-Value PANSS Positive 21.7 (5.6) 18.8 (4.9) <.01 Negative 16.6 (7.5) 13.9 (5.7) <.01 General 38.4 (10.4) 31.6 (7.6) <.01 GAF s 27.1 (6.9) 31.0 (6.4) <.01 GAF f 28.8 (9.7) 33.6 (10.0) <.01

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

  21. OTHER TIPS BASELINE FINDINGS Baseline ED vs No ED Differences - Less suicidality with ED - Less involuntary hospitalization with ED

  22. Two Year Outcome

  23. 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

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

  25. Early Intervention Is Key Premorbid Prodromal Progressive Residual First Episode Treatment Behavioral Adaptation Psychotic Symptoms B 15 20 25 40….

  26. 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

  27. 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.

  28. 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.

  29. 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

  30. SIPS Interview Probes Attenuated Psychotic Phenomena PANSS Delusions 7 6 5 SIPS Unusual Thought Content/Delusional Ideas 4 3 6 5 4 2 Psychosis Threshold 3 2 1 1 0

  31. Why study prodromal • syndromes and symptoms? • To test treatments that might prevent or delay onset of psychosis

  32. 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

  33. Specific Preventive Support Antidepressant if needed Cognitive behavior therapy Risperidone 1-2 mg/d 10% conversion in 6 months (3/31) Needs based Support Antidepressant if needed No CBT No antipsychotic 36% conversion in 6 months (10/28) Randomized Groups

  34. 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

  35. PRIME PRODROMAL CLINICAL TRIAL 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

  36. Results: ConversionPatients Converting to Psychosis in Year 1 (n=16)* p=0.08 % of Patients 37.9% 16.1% *26.7% of the total sample (N=60) converted to psychosis in one year

  37. SOPS Positive Symptoms Mean Change from Baseline N=30 olanzapine placebo -1 † p-value < 0.1; from MMRM model * p-value < 0.05; from MMRM model n=16 n=13 n=12 -3 Mean Change n=21 n=20 n=10 -5 n=16 n=8 n=14 * n=9 † n=12 * * * * n=10 -7 0 10 20 30 40 50 VISIT WEEK

  38. 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.

  39. CURRENT STATE OF PREVENTION IN SCHIZOPHRENIAandTREATMENT IMPLICATIONST. McGlashan

  40. 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

  41. 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

  42. 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

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