Predicting psychosis using neurobiology: Where are we now?

1. Predicting psychosis using neurobiology: Where are we now? Stephen Wood

2. Acknowledgements… • NHMRC (Australia) • NARSAD • Prof Chris Pantelis • Prof Pat McGorry • Dr Dennis Velakoulis • Prof Alison Yung • A/Prof Murat Yücel

3. The Psychiatrist - Jose Perez

4. Prediction of Schizophrenia • Imagine that the year is 2006. . . . . . As the new century dawns, a youthful, callow invitee, intent on publishing rather than perishing, is asked to review the early studies on risk-for-schizophrenia research for the Intergalactic Institute of Mental Health. He sets out to trace early longitudinal investigations, surveys the now definitive follow-up data, assigns the children now grown to middle age into disordered and adaptive groups, and comes to the inescapable conclusion that efficiency of predictions, based on their biologic and psychologic statuses, is depressingly low (Garmezy, 1978).

5. Clinical (‘Ultra’) high-risk • Around 23 different studies currently in existence • Provide high transition rates in a short time (1-2 years) • However… • Major methodological and conceptual differences • State effects present at baseline • Not representative of all who develop psychosis

6. UHR Criteria • Differs from genetic high-risk studies because participants are help-seeking and functionally impaired • About half have a mental disorder at intake Yung et al., (2004) Schizophrenia Research

7. Transition to psychosis • 35% of UHR patients developed psychosis over 12 months • About half have a diagnosis of schizophrenia • Not becoming psychotic does not mean ‘well’ Yung et al., (2004) Schizophrenia Research

8. METHODOLOGY - VOLUME MEASURES Hippocampal volume estimation Posterior- greatest length of fornix Superior border -superior border of hippocampus Medial border - open end of hippocampal fissure posteriorly, uncal fissure in body of hippocampus, medial aspect of gyrus ambiens anteriorly Lateral - temporal horn Inferior border - nearest white matter Anterior border - alveus b/n hippocampus and amygdala (Cook et al 1992) The hippocampus was traced manually, using the above criteria, by DV (intrarater reliability=0.85).

9. Brain regions implicated in schizophrenia: Global vs Focal ? Dorsolateral Prefrontal Cortex Anterior Cingulate Hippocampus Orbital Prefrontal Cortex

10. Velakoulis et al, 2006

11. Influence of family history of psychosis Boos et al, 2007

12. Wood et al Schizophr Res (2005)

13. Automated analysis - UHR-psychotic vs nonpsychotic Pantelis et al, 2003 Borgwardt et al, 2007

14. Pituitary volume in Psychosis

15. Survival Analysis of Time to Psychosis Below Above Risk for Psychosis Below median: 32% P and 59% NP (Risk=0.55) Above median: 68% P and 41% NP (Risk=1.64) Relative Risk=3.0 P=0.014 Garner et al, 2005

17. Verbal memory Ozgurdal et al 2009 Seidman et al 2010

18. Visual & Verbal Memory Brewer et al 2005

21. * * P<0.05 SMELL IDENTIFICATION PRE-PSYCHOSIS ONSET * Brewer et al, Am J Psychiatr, 2003

22. More adventures in hippocampal volume UHR-P UHR-P UHR-NP UHR-NP UHR-P UHR-NP Buehlmann et al 2010 Wittman et al 2010 Wood et al 2010

23. NAA Cho Cr mI Glx Lac Adventures beyond volume - MRS NAA – N-acetylaspartate Cr – Creatine & Phospho-creatine Cho – Choline-containing compounds mI – myo-inositol Glx – Glutamate/glutamine Lac - Lactate

24. Medial temporal lobe No significant differences for any ratio Wood et al, Schizophr Bull, 2003

25. Adventures beyond volume

27. T2 relaxometry • Non-specific but highly sensitive measure of brain pathology • Longer T2 associated with gliosis and oedema • E.g. hippocampal sclerosis • ? neurodevelopmental lesions • Shorter T2 associated with reduced water content and iron deposition • E.g. Alzheimer’s disease • T2 in schizophrenia may be • Longer in frontal grey & caudate (Andreasen, 1991) • Longer in temporal lobe & hippocampus (Williamson, 1992)

28. 29 ms TE 231 ms

29. 66 ultra high-risk patients Mean age 19.2 38% male 29 controls Mean age 21.1 38% male Regions-of-interest traced on maps blind to diagnosis Hippocampus Superior temporal gyrus Participants & Methods

30. Hippocampal head (L) & body (R)

31. Results Side x group x region; p=0.003

32. A brief pilot study… • Lithium is thought to be neuroprotective at therapeutic doses • 4 weeks of lithium produced a significant increase in NAA in medication-free bipolar subjects and healthy controls (Moore et al 2000) • Lithium acts to stimulate production of mitochondrial bcl-2 • This study aims to determine whether chronic, low-dose lithium exerts neurotrophic effects in the hippocampi of those at ultra-high risk of developing psychosis

33. Participants • Consecutive referrals to the Personal Assessment and Crisis Evaluation (PACE) Clinic • Aged between 14 and 30 • At risk for psychosis according to definied criteria • Offered entry into the comparison or intervention group according to referral number • Referral numbers ending 0 or 5 offered lithium first • Lithium group took 450 mg of slow-release lithium carbonate each night for the length of the interval between scans

35. Results Time x group; p=0.018

36. Follow up * Transition status available on 411 subjects

37. Transition rate - Survival curve

38. PACE 400 Follow-up Study 1994 – 2006 N = 416 Psychopathology Assessment (+CAARMS)‏ Functional Outcome Neurocognitive Assessment Neuroimaging Genetics Other: schizotypy, family history, drug use Later participants at PACE 2000 – 2006 n = 218 Later participants at PACE 2000 – 2006 n = 218 Later participants at PACE 2000 – 2006 n = 218 Early participants at PACE 1994 – 2000 n = 198

39. Transition to psychosis 42% Visual memory Odds ratio = 0.94, 95% CI = 0.90 – 0.98, p = 0.001

42. Face to face assessment n = 120 (61%)‏ 198 individuals at UHR of psychotic disorder (1994 - 2000)‏ Face to face assessment n = 120 (61%)‏ Brief telephone assessment n = 18 (9%)‏ Could not be located n = 26 (13%)‏ Refused n = 26 (13%)‏ Deceased n = 8 (4%)‏

43. Where are they now? Completed Year 12 53% Work/study/home duties full-time 63% Mean GAF score 63 Living independently 75% Married or in a relationship 48% Transitioned to psychosis 42%

44. Global assessment of functioning (GAF) scores at follow-up Number of participants 31 -40 41 - 50 61 - 70 71 - 80 81 - 90 91 - 100 ≤ 30 GAF score Transitioned to psychosis Never transitioned to psychosis

45. Poor functioning group Full-time work/study Living independently 16% 48% Completed Yr 12 Married or in relationship 32% GAF score 16% 40 Diagnosis of schizophrenia Ever psychotic 63% 37%

46. Poor verbal memory – stories Lower mania scores Higher BPRS scores Higher SANS scores Poor verbal memory – stories Odds ratio = 0.70 95% CI = 0.55 – 0.90 p = .005 Poor functioning group

47. Verbal Memory Index ≥ 1 s.d. below the mean Verbal IQ ≥ 1 s.d. below the mean Odds for poor functioning Odds ratio = 14.00, p = 0.001 Odds ratio = 6.30, p = .007

49. Psychotic symptoms Psychotic threshold Impairment in Functioning

50. Return of the hippocampus