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Predicting psychosis using neurobiology:Where are we now?
Stephen Wood
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Acknowledgements…
• NHMRC (Australia)• NARSAD• Prof Chris Pantelis• Prof Pat McGorry• Dr Dennis Velakoulis• Prof Alison Yung• A/Prof Murat Yücel
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The Psychiatrist - Jose Perez
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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).
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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
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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
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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
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METHODOLOGY - VOLUME MEASURES
Posterior - greatest length of fornixSuperior border - superior border of hippocampusMedial border - open end of hippocampal fissure
posteriorly, uncal fissure in body of hippocampus, medial aspect of gyrus ambiens anteriorlyLateral - temporal hornInferior border - nearest white matterAnterior 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).
Hippocampal volume estimation
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Brain regions implicated in schizophrenia: Global vs Focal ?
Anterior Anterior CingulateCingulate
DorsolateDorsolateral ral
Prefrontal Prefrontal CortexCortex
Orbital Orbital Prefrontal Prefrontal
CortexCortex
HippocampuHippocampuss
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Velakoulis et al, 2006
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Influence of family history of psychosis
Boos et al, 2007
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Wood et al Schizophr Res (2005)
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Automated analysis - UHR-psychotic vs nonpsychotic
Borgwardt et al, 2007Pantelis et al, 2003
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Pituitary volume in Psychosis
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Survival Analysis of Time to Psychosis
Below
Above
Time From Scan to Psychosis or to Follow-Up (Years)
43210
Cum
ulat
ive
Surv
ival
1.0
.8
.6
.4
.2
0.0
Risk for PsychosisBelow median: 32% P and 59% NP (Risk=0.55)Above median: 68% P and 41% NP (Risk=1.64)
Relative Risk=3.0P=0.014
Garner et al, 2005
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Verbal memory
Seidman et al 2010
Ozgurdal et al 2009
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Visual & Verbal Memory
-0.8
-0.7
-0.6
-0.5
-0.4
-0.3
-0.2
-0.1
0Designs Story recall Verbal pairs
Effec
t size
UHR-PUHR-NP
Brewer et al 2005
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SMELL IDENTIFICATION PRE-
PSYCHOSIS ONSET
Brewer et al, Am J Psychiatr, 2003
*
* P<0.05
*
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More adventures in hippocampal volume
-14
-12
-10
-8
-6
-4
-2
0
2
4
6
Perc
ent d
iffer
ence
from
con
trols
LeftRight
UH
R-P
UH
R-P
UH
R-P
UH
R-N
P
UH
R-N
P
UH
R-N
P
Wood et al 2010
Buehlmann et al 2010
Wittman et al 2010
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Adventures beyond volume - MRS
NAA
mICho Cr
Glx
Lac
NAA – N-acetylaspartate
Cr – Creatine & Phospho-creatine
Cho – Choline-containing compounds
mI – myo-inositol
Glx – Glutamate/glutamine
Lac - Lactate
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No significant differences for any ratio
.0
.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
NAA/Cr Cho/Cr NAA/Cho
FEUHRCtrl
Medial temporal lobe
Wood et al, Schizophr Bull, 2003
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Adventures beyond volume
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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)
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29 ms
231 ms
TE
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Participants & Methods
• 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
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Hippocampal head (L) & body (R)
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Results
90
92
94
96
98
100
102
104
106
108
Head BodyRIGHT
ControlUHR-PUHR-NP
90
92
94
96
98
100
102
104
106
108
Head BodyLEFT
T2 re
laxa
tion
time
(mse
c)
Side x group x region; p=0.003
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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
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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
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Results
93
94
95
96
97
98
99
100
101
Control Lithium
BaselineFollow-up
Time x group; p=0.018
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Follow up
Count Percent
Interview completed 311 74.8
Interview refused 49 11.8
Cannot be found 47 11.3
Dead 9 2.2
Total 416* 100.0
* Transition status available on 411 subjects
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Transition rate - Survival curve
0 500 1000 1500 2000 2500 3000 3500 4000 4500 5000 55000
0.2
0.4
0.6
0.8
1
Number of days from entry
Est
imat
ed tr
ansi
tion
rate
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PACE 400 Follow-up Study
1994 – 2006
N = 416
Early participants at PACE
1994 – 2000
n = 198
Later participants at PACE
2000 – 2006
n = 218
Later participants at PACE
2000 – 2006
n = 218
Later participants at PACE
2000 – 2006
n = 218
Psychopathology Assessment (+CAARMS)Functional Outcome
Neurocognitive AssessmentNeuroimaging
GeneticsOther: schizotypy, family history, drug use
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Transition to psychosis
Visual memoryOdds ratio = 0.94, 95% CI = 0.90 – 0.98, p = 0.001
42%
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198 individuals at UHR of psychotic disorder
(1994 - 2000)
Deceased n = 8 (4%)
Face to face assessment n = 120 (61%)
Brief telephone assessment n = 18 (9%)
Refused n = 26 (13%)
Could not be located n = 26 (13%)
Face to face assessment
n = 120
(61%)
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Where are they now?
Mean GAF score63
Work/study/home duties full-time
63%
Completed Year 12 53%
Living independently
75%Married or in a relationship
48%
Transitioned to psychosis
42%
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0
2
4
6
8
10
12
14
16
18
≤ 30 61 - 70 71 - 80 81 - 90 91 - 10041 - 5031 -40
Transitioned to psychosis Never transitioned to psychosis
Global assessment of functioning (GAF) scores at follow-upN
umbe
r of p
artic
ipan
ts
GAF score
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Poor functioning groupFull-time
work/study
GAF score
Completed Yr 12
Married or in relationship
Living independently
Diagnosis of schizophrenia
Ever psychotic
16%
37%63%
16%
48%
32%
40
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Poor functioning
group
Poor verbal memory –
storiesOdds ratio = 0.70
95% CI = 0.55 – 0.90
p = .005
Poor verbal memory –
storiesLower mania
scoresHigher BPRS
scoresHigher SANS
scores
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Odds for poor functioning
Verbal IQ
≥ 1 s.d. below the mean
Odds ratio = 6.30, p = .007 Odds ratio = 14.00, p = 0.001
Verbal Memory Index
≥ 1 s.d. below the mean
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Psy
chot
ic s
ympt
oms
Impairment in Functioning
Psychotic threshold
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Return of the hippocampus
2400
2500
2600
2700
2800
2900
3000
3100
3200
3300
UHR-P UHR-NP
Hipp
ocam
pal v
olum
e
Good outcomeAverage outcomePoor outcome
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Conclusion• Hippocampal volume probably not specific• Not enough data on hippocampal memory
function• Non-volumetric imaging data looks
interesting• Important to know what we are trying to
predict
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