Predicting psychosis
using neurobiology:
Where are we now?
Stephen Wood
Acknowledgements…
•
•
•
•
•
•
•
NHMRC (Australia)
NARSAD
Prof Chris Pantelis
Prof Pat McGorry
Dr Dennis Velakoulis
Prof Alison Yung
A/Prof Murat Yücel
The Psychiatrist - Jose Perez
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).
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
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
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
METHODOLOGY - VOLUME MEASURES
Hippocampal volume estimation
Posterior Superior border Medial border -
greatest length of fornix
superior border of hippocampus
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).
Brain regions implicated in schizophrenia:
Global vs Focal ?
Dorsolatera
l Prefrontal
Cortex
Anterior
Cingulate
Hippocampus
Orbital
Prefrontal
Cortex
Velakoulis et al, 2006
Influence of family history of
psychosis
Boos et al, 2007
Wood et al Schizophr Res (2005)
Automated analysis - UHR-psychotic vs
nonpsychotic
Pantelis et al, 2003
Borgwardt et al, 2007
Pituitary volume in Psychosis
Survival Analysis of Time to Psychosis
1.0
Below
.8
Above
.6
Risk for Psychosis
Below median: 32%
P and 59% NP
(Risk=0.55)
Above median: 68%
P and 41% NP
(Risk=1.64)
.4
.2
0.0
0
1
2
3
4 Relative Risk=3.0
P=0.014
Time From Scan to Psychosis or to Follow-Up (Years)
Garner et al, 2005
Verbal memory
Ozgurdal et al 2009
Seidman et al 2010
Visual & Verbal Memory
Designs
Story recall
Verbal pairs
0
-0.1
-0.2
Effect size
-0.3
-0.4
UHR-P
UHR-NP
-0.5
-0.6
-0.7
-0.8
Brewer et al 2005
SMELL
IDENTIFICATION PREPSYCHOSIS ONSET
*
* P<0.05
*
Brewer et al, Am J Psychiatr,
2003
Percent difference from controls
UHR-NP
UHR-P
UHR-NP
UHR-P
4
UHR-NP
6
UHR-P
More adventures in hippocampal volume
2
0
-2
Left
Right
-4
-6
-8
-10
-12
-14
Buehlmann et al
2010
Wittman et al 2010
Wood et al
2010
Adventures beyond volume - MRS
NAA – Nacetylaspartate
NAA
Cr – Creatine &
Phospho-creatine
mI
Cho
Cho – Cholinecontaining compounds
Cr
Glx
mI – myo-inositol
Lac
Glx –
Glutamate/glutamine
Lac - Lactate
Medial temporal lobe
4.0
FE
UHR
Ctrl
3.5
3.0
No significant
differences for
any ratio
2.5
2.0
1.5
1.0
.5
.0
NAA/Cr
Cho/Cr
NAA/Cho
Wood et al, Schizophr Bull, 2003
Adventures beyond volume
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)
29
ms
TE
231
ms
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
Hippocampal head (L) & body
(R)
T2 relaxation time (msec)
Results
108
108
106
106
104
104
102
102
100
100
98
98
96
96
94
Control
UHR-P
UHR-NP
94
92
92
90
Head
90
Head
LEFT
Body
Body
RIGHT
Side x group x region; p=0.003
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
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
Results
101
100
99
98
Baseline
Follow-up
97
96
95
94
93
Control
Lithium
Time x group; p=0.018
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
Transition rate - Survival curve
Estimated transition rate
1
0.8
0.6
0.4
0.2
0
0
500 1000 1500 2000 2500 3000 3500 4000 4500 5000 5500
Number of days from entry
PACE 400 Follow-up Study
1994 – 2006
N = 416
Psychopathology Assessment (+CAARMS)
Functional Outcome
Neurocognitive Assessment
Neuroimaging
Genetics
Other: schizotypy, family history, drug use
Early participants at PACE
Later participants at PACE
1994 – 2000
2000 – 2006
n = 198
n = 218
Transition to psychosis
42%
Visual memory
Odds ratio = 0.94, 95% CI = 0.90 – 0.98, p = 0.001
Face to face assessment
n = 120 (61%)
198
individuals
at UHR of
psychotic
disorder
(1994 - 2000)
Brief telephone assessment
n = 18to(9%)
Face
face
assessment
Could not be located
120
n =n
26=(13%)
Refused(61%)
n = 26 (13%)
Deceased
n = 8 (4%)
Where are they now?
Work/study/home
duties full-time
63%
Completed Year 12
53%
Living
independently
75%
Married or in a
relationship
48%
Transitioned
to psychosis
42%
Mean GAF
score
63
Global assessment of functioning (GAF) scores at follow-up
18
Number of participants
16
14
12
10
8
6
4
2
0
≤ 30
31 -40
41 - 50
61 - 70
71 - 80
81 - 90
91 - 100
GAF score
Transitioned to psychosis
Never transitioned to psychosis
Poor functioning group
Full-time
work/study
16%
Married or in
relationship
16%
Completed
Yr 12
32%
Ever psychotic
63%
Living
independently
48%
GAF score
40
Diagnosis of
schizophrenia
37%
Poor verbal
memory –
Poor verbal
stories
memory –
Lower mania
stories
scores
Odds ratio = 0.70
Higher BPRS
95% CI = 0.55 – 0.90
scores
p = .005
Higher
SANS
scores
Poor
functioning
group
Verbal IQ
≥ 1 s.d. below the
mean
Odds ratio = 6.30, p = .007
Verbal Memory Index
≥ 1 s.d. below the
mean
Odds ratio = 14.00, p = 0.001
Odds for poor functioning
Psychotic symptoms
Psychotic threshold
Impairment in Functioning
Return of the hippocampus
3300
3200
Hippocampal volume
3100
3000
2900
Good outcome
Average outcome
Poor outcome
2800
2700
2600
2500
2400
UHR-P
UHR-NP
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