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

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

Brain regions implicated in schizophrenia: Global vs Focal ?

Anterior Anterior CingulateCingulate

DorsolateDorsolateral ral

Prefrontal Prefrontal CortexCortex

Orbital Orbital Prefrontal Prefrontal

CortexCortex

HippocampuHippocampuss

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

Borgwardt et al, 2007Pantelis et al, 2003

Pituitary volume in Psychosis

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

Verbal memory

Seidman et al 2010

Ozgurdal et al 2009

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

SMELL IDENTIFICATION PRE-

PSYCHOSIS ONSET

Brewer et al, Am J Psychiatr, 2003

*

* P<0.05

*

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

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

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

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

231 ms

TE

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)

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

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

93

94

95

96

97

98

99

100

101

Control Lithium

BaselineFollow-up

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

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

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

Transition to psychosis

Visual memoryOdds ratio = 0.94, 95% CI = 0.90 – 0.98, p = 0.001

42%

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%)

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%

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

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

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

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

Psy

chot

ic s

ympt

oms

Impairment in Functioning

Psychotic threshold

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

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