Transcript THE ELEMENTS OF EARLY PSYCHOSIS

Prediction and prevention of
psychotic disorders?
Ultra High Risk research:
background and recent developments
Associate Professor Alison Yung
ORYGEN Research Centre
University of Melbourne, Australia
People involved
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Alison Yung
Barnaby Nelson
Gregor Berger
Lisa Phillips
Elizabeth Cosgrave
Cathy Greenwood Smith
Magenta Simmons
Chris Pantelis
Danny Kelly
Lisa O’Dwyer
George Patton
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Patrick McGorry
Hok Pan Yuen
Paul Amminger
Shona Francey
Ilona Di Bella
John Koutsogiannis
Denis Velakoulis
Carrie Stanford
Susanne Jones
Natalie Kobilek
Henry Jackson
Any many more………
“The best hope now for the prevention of
schizophrenia lies with indicated preventive
interventions targeted at individuals manifesting
precursor signs and symptoms who have not yet
met full criteria for diagnosis. The identification of
individuals at this early stage, coupled with the
introduction of pharmacological and psychosocial
interventions, may prevent the development of the
full-blown disorder”
– Mrazek and Haggerty (1994)
Can we predict and prevent
psychotic disorder?
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We know that psychotic disorders, such as
schizophrenia, are almost always preceded
by a prodromal phase
sys
treatment
psychosis
DUP
prodrome
time
Characteristics of the initial
psychotic prodrome
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1993 literature review and retrospective
study of patients with first episode
psychosis
Prodromal symptoms
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Non -specific symptoms eg depressed mood,
anxiety, sleep disturbance
Subthreshold or attenuated psychotic symptoms more proximal to psychosis onset
Behavioural changes eg social withdrawal,
deterioration in role functioning - could be the
result of a number of underlying causes eg
depression, other prodromal phenomena or frank
psychosis
Prodromal symptoms
About 25 % of individuals experienced
suicidal thoughts, self harm and forensic
behaviour
 Period of psychosocial decline and of health
damaging behaviours
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Subthreshold psychotic symptoms, distress
and serious functional decline occur before
frank psychosis
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Need for care ≠ threshold psychotic
disorder
Recognising the ‘prodrome’
prospectively
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A “prodrome” is difficult to recognise
prospectively because of its non-specific
symptoms
sys
Threshold for diagnosis of psychosis
?
time
True Positive
sys
Threshold for diagnosis of psychosis
psychosis
prodrome
time
False positive
sys
Threshold for diagnosis of psychosis
resolving symptoms
time
False false positive
sys
Threshold for diagnosis of psychosis
symptoms resolved with intervention
time
How do we identify those
truly experiencing a prodrome?
Prodrome is a retrospective concept
 Definitive “diagnosis” only after psychosis
onset
 Prospectively can only use the term At Risk
Mental State (ARMS)
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At Risk Mental State
sys
Threshold for diagnosis of psychosis
?
time
“We want to know… what to ask to split clearly
between the people who are having trouble in
living and the people who are in grave risk of
serious psychosis”
– Harry Stack Sullivan (1938)
How do we identify those
truly experiencing a prodrome?
Combine risk factors
 And/or use those symptoms which seem to
be more specific or more proximal to the
time of psychosis onset
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Combining risk factors
(‘close-in strategy’)
Age 14 - 30 (age range at highest risk for
onset of a psychotic disorder)
 plus ARMS with one (or more) of the
following features
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Group 1
Attenuated psychotic features
 Overvalued ideas, perceptual distortions
 Duration - at least one week, not longer than
5 years
 Frequency - at least twice per week
 Recency - in the last year
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Group 2
BLIPS: Brief Limited Intermittent Psychotic
Symptoms
 Frank psychotic features
 Either resolve spontaneously within 7 days
 Or occur very infrequently - less than twice
per week
 Recency - in the last year
 Can be drug induced
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Group 3
Family history of psychotic disorder in a
first degree relative
 Or schizotypal PD
 PLUS non-specific ARMS symptoms
 Duration - at least one month, not longer
than 5 years
 Associated with significant decline in
functioning
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Setting
PACE Clinic established
 Youth friendly and easily accessible health
service
 Located at Highpoint Shopping Centre and
previously Centre for Adolescent Health
 “Personal Assessment and Crisis
Evaluation”
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PACE referrals March 1995 January 1999
Total referrals
681
Excluded by telephone
248
Did not attend initial
appointment
Assessed but did not
meet criteria
Met criteria but refused
research
Participated in research
97
175
57
104
Results - transition to psychosis
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29 of the 104 (28%) subjects had developed by 6
month follow up point psychosis.
By 12 months 36 (34.6 %) subjects had developed
psychosis
5 subjects developed psychosis after 12, 15, 18, 25
and 28 months
Total developing psychosis thus far: 41 subjects
(39.4% of sample)
Survival curve of proportion
remaining non-psychotic
Transition to full blown
psychosis - by centre
Service
PACE Melbourne
PRIME Yale
TOPP Norway
CARE San Diego
EDIE Manchester
PAS Newcastle, NSW
PIER Portland
RAP NYC
Total populn
104
14
14
25
23
74
47
34
Psychotic
36 (34.6%)
7 (50%)
6 (43%)
4 (16%)
5 (22%)
37 (50%)
11 (23.4%)
9 (26.5%)
UHR criteria in different
populations
UHR criteria applied to a help-seeking
sample of people aged 14 - 25 presenting to
a mental health service for young people
 Assessed by Triage service as not psychotic
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UHR in general adolescent
sample
From April - October 2003
 207 individuals presented
 149 agreed to research assessment (72%
response rate)
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UHR in general adolescent
sample
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Of these 149, 43 met UHR criteria at
baseline, 106 did not
UHR in general adolescent
sample
UHR
status at
baseline
Psychotic Not
Total
at 6 month psychotic
follow up at 6 month
follow up
UHR+
5
38
43
UHR-
1
105
106
Total
6
143
149
UHR in general adolescent
sample - 6 month follow up
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Transition rate = 11.6%.
UHR+ status:
PPV 0.116
Sensitivity 0.833
Specificity 0.734
NPV 0.991
UHR+ status at baseline was significantly
associated with psychosis at 6 month follow up
(Fisher’s exact two tailed p= 0.008).
UHR in general adolescent
sample - 2 year follow up
2 more developed psychotic disorder
 1 was UHR positive at baseline, 1 UHR
negative
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UHR in general adolescent
sample
UHR
status at
baseline
Psychotic Not
Total
at 2 year psychotic
follow up at 2 year
follow up
UHR+
6
37
43
UHR-
2
104
106
Total
8
141
149
UHR in general adolescent
sample - 2 year follow up
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Transition rate = 14%.
UHR+ status:
PPV 0.14
Sensitivity 0.75
Specificity 0.738
NPV 0.981
UHR+ status at baseline was significantly
associated with psychosis at 2 year follow up
(Fisher’s exact two tailed p= 0.008).
So…?
UHR criteria still predict onset of psychosis
within short time frame
 Transition rate much lower than in the
previous PACE group, and most other UHR
centres
 (only 11% at 6 months, 14% at 2 yrs)
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More alarmingly…
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Transition rate in
PACE also seems to
have declined recently
Reduction in transition rate
Year
Kaplan-Meier estimate
1995
0.50
1996
0.33
1997
0.32
1998
0.29
1999
0.21
2000
0.12
Reduction in transition rate
Estimated 95% CI
hazard ratio
Year
0.80
(continuous
variable)
(0.66,
0.98)
P-value
0.027
Effect of year on transition rate
after adjusting for:
GAF score
0.019
BPRS Total
0.016
BPRS Psychotic
subscales
Depression
0.043
SANS
0.027
Duration of symptoms
0.143
0.012
So year is still a significant predictor of
transition even after adjusting for symptoms
and functioning
 However it was no longer significant after
adjusting for duration of symptoms prior to
coming to PACE.
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1500
560 (776)
525 (817)
1000
367 (411)
205 (290)
500
115 (211)
46 (97)
0
1995
1996
1997
1998
1999
2000
Schizophrenia
Frank psychotic symptoms
Psychotic-like experiences associated with distress
help-seeking, decreased functioning, comorbidity
Psychiatric disorders with “incidental” PLEs
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But there’s more ….
Psychotic experiences
are actually quite
common in the
community
Community studies
Van Os et al: 17.5% of people in the
NEMESIS study reported “psychotic-like
experiences” at some time in their lives
 Eaton et al ECA
 Poulton et al: 14.7% of children aged 11
 Hanssen 83 of 4067 (2%) developed new
psychotic experiences over the course of 2
years
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Schizophrenia
Frank psychotic symptoms
Psychotic-like experiences associated with distress
help-seeking, decreased functioning, comorbidity
Psychiatric disorders with “incidental” PLEs
Non-distressing PLEs
No psychiatric symptoms
Thus there are many people with attenuated or
isolated psychotic symptoms who apparently do
not have a need for care
 A subgroup do have a need for care
 A subgroup are at high risk of developing full
blown psychotic disorder within a brief period
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Predictive power of UHR criteria is related
to the sample they are applied in
The “Dutchness” test
Tall + ride a bike = Dutch
 In Holland, these criteria work very well
 In Europe less predictive
 In Australia not predictive at all
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The story so far
UHR criteria predictive of onset of
psychotic disorder in clinical samples
 PPV depends on sample
 Not justified to apply UHR criteria to
general population
 Need additional predictive factors
 Need to think about appropriate
interventions
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Predictive factors within UHR
groups - Negative symptoms
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Impaired concentration and attention, subjectively
abnormal emotional experiences, blunted affect,
impaired energy and impaired tolerance to stress (Yung
et al 2005)
Marked impairment in role functioning, anhedonia,
asociality blunted affect (Mason et al 2004)
Social withdrawal (Haroun et al 2006)
Predictive factors within UHR
groups - Basic symptoms
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Subtle thought, language, perception or motor
disturbances
The Cologne Early Recognition (CER) project
Klosterkotter et al 2001 studied the predictive capacity
of the basic symptoms in a cohort of non-psychotic
patients attending a tertiary referral psychiatric setting
and who were suspected as being ‘susceptible to
schizophrenia’ on the basis of their psychopathology.
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Subjects were followed up on average eight years after
initial assessment
Over 50% developed schizophrenia.
Certain basic symptoms - disturbances of receptive
speech, blocking of thoughts, visual perceptual
disturbances, olfactory, gustatory and other sensory
disturbances - were found significantly more often in the
group which developed schizophrenia compared to the
group which did not,
Predictive factors within UHR
groups - depression, distress
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Depression has found to be a significant predictor of
psychosis (Yung et al, 2003)
Also in the EHRS (Johnstone et al, 2005)
Community samples: individuals who experience
distress or depression related to their psychotic-like
experiences are more likely to seek help compared to
their counterparts without such accompanying
symptoms (Hanssen et al, 2005; Krabbendam et al
2005).
Predictive factors within UHR
groups - poor functioning
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Poor functioning at intake predicted onset of psychosis
in UHR cohorts (Yung et al, 2003; Mason et al 2004).
This may indicate that a deterioration process, and
actual onset of psychotic disorder, has already begun.
However, the process may be more dynamic than this.
Those with poor functioning may be less able to cope
with psychotic experiences, more susceptible to
depression and distress, more likely to use substances
Vicious cycle may develop
Predictive factors within UHR
groups - cannabis
History of substance abuse was present in
significantly more subjects who developed
psychosis in the Haroun et al, 2006
 Cannabis use not predictive in PACE sample
(Phillips et al, 2002)
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Predictive factors within UHR
groups - stress
Subjectively reported impaired tolerance to
stress a significant predictor in PACE group
(Yung et al, 2005)
 PACE study, subjects who developed psychosis
had larger pituitary volumes at baseline
compared to UHR individuals who did not
develop psychosis (Garner et al 2005).
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Predictive factors within UHR
groups - structural brain
abnormalities
Smaller volumes of grey matter at baseline
in:
 Right prefrontal cortex
 Right temporal cortex
 Right basal ganglia
 Right and left cingulate cortex
 In those who became psychotic compared to
those who did not (Pantelis et al, 2003)
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Predictive factors within UHR
groups - neurocognitive
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Findings to date indicate that those who go on to
develop psychosis have abnormalities of logical
memory and visual reproduction compared to
those who don’t develop psychosis and normal
controls (Wood et al, 2007)
Olfactory identification deficits have also been found to
occur prior to psychosis onset, and have been shown to
be worse in patients later diagnosed with schizophrenia
(Brewer et al, 2001)
So is it possible to focus on a subgroup
within the UHR group?
 May risk sacrificing sensitivity for
specificity
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Old weather forecaster saying:
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If there's a 50-50 chance that a
forecast will go wrong, 9 times out of
10 it will.
PACE response
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We have now added the criterion of reduced
functioning to all categories of UHR
30% reduction in SOFAS score, sustained for at
least 1 month, within last 12 months OR
SOFAS of 50 or below, for past 12 months or
longer
Attempt to get around the problem of many people
in the general population who have psychotic
experiences but who apparently have no need for
intervention
Has this worked?
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Collecting and analysing data
Don’t go where the path leads,
Rather, go where there is no path
and leave a trail
Don’t go where the path leads,
Rather, go where there is no path
and leave a trial
Intervention Study -Phase 1
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Randomized Controlled Trial of
Prepsychotic Intervention in Early
Psychosis
Intervention Strategies
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Nonspecific intervention
 Supportive
psychotherapy
 Regular monitoring
 Needs-based case
management
 SSRI if indicated
 Family support
SSRI = selective serotonin reuptake inhibitor.

Specific intervention
 Risperidone 1-2 mg/d
for 6 months
 Cognitive therapy
for 6 months
 Needs-based case
management
 SSRI if indicated
 Family support
Study Flow and Drop-Out
Referral to PACE
n = 522
Met study criteria
n = 135
Agreed to research
participation
n = 92
Refused all research
participation
n = 43
Randomized
n = 59
Refused randomization,
agreed to research
assessment and follow-up
n = 33
Nonspecific intervention
n = 28
Specific intervention
n = 31
Protocol adherent
(full drug adherence)
n = 14
Protocol nonadherent
(partial/poor adherence)
n = 17
Sample Characteristics
Nonspecific
Intervention
(NSI)
Specific
Intervention
(SI)
Sample size
28
31
Mean age, y
20.4
20.1
P = 0.76
50
64
P = 0.26
% Male
NSI vs SI
Baseline Characteristics
NSI
(n = 28)
No.
%
SI
(n = 31)
No. %
Male
14
50
20
65
0.26
34
58
14
42
0.16
Australian-born
25
89
28
90
0.90
53
90
31
94
0.50
Live with family
17
61
12
39
0.09
29
49
16
49
0.95
c2-test
P-value
NSI+SI
(n = 59)
No. %
Refusers
(n = 33)
No. %
c2-test
P-value
Baseline Characteristics
NSI
(n = 28)
Mean SD
Age
20
3
Time-contact
320
359
Time-PACE
369
Anx
SI
(n = 31)
Mean SD
523 1086
0.33
344 490
296 382
0.61
373
572 1110
0.34
398 533
385 453
0.91
16.8
9.0
16.1 7.0
0.76
16.5 7.9
11.6 6.8
<0.005
BPRS
20.9
9.3
20.1 7.2
0.73
20.5 8.2
16.1 7.8
0.02
BPRSP
4.6
2.6
4.7
2.7
0.92
4.6
3.3
0.03
DEP
20.4
10.2
19.4 7.0
0.67
19.9 8.7
12.3 7.4
Mania
3.4
3.6
4.2
4.9
0.45
3.7
4.3
QLS
66.1
23.5
69.2 19.2
0.58
68.3 21.2
84.2 19.2
<0.005
SANS
21.2
14.3
18.0 11.2
0.35
19.5 12.8
10.9 10.5
<0.005
59
14
12
0.24
61
4
2.6
4.2
13
20
69
4
t-test
P-value
20
63
4
Refusers
(n = 33)
Mean SD
0.76
GAF
20
t-test
P-value
NSI+SI
(n = 59)
Mean SD
2.8
4.6
13
0.54
<0.001
0.49
0.01
Time-contact: Time between symptom onset and first contact in pathway to psychiatric service (days).
Time-PACE: Time between symptom onset and first PACE contact (days).
BPRSP: BPRS Psychotic subscale.
Influence of Treatment on
Transition
to Psychosis
100
80
P = 0.026
% Psychotic
by 6 Months
60
40
35.7
20
9.7
0
NSI
SI
n = 28
n = 31
PACE RCT Treatment Phase
1.0
SI
0.8
NSI
Proportion 0.6
not Psychotic
P = 0.027
0.4
n = 59
0.2
0
50
100
150
Days From Entry
200
250
Rate of Transition to Psychosis
40
35
30
25
Percentage 20
Psychotic 15
10
5
0
N=
*, †
‡, §
35.7
35.7
§
29.4
‡
19.4
*
9.7
NSI
SI
28
31
†
11.8
†
§
7.1
SI-NP SI-F
17
14
At end of treatment phase
7.1
NSI
SI
28
31
SI-NP SI-F
17
14
At follow-up
*NSI vs SI: P = 0.026; †NSI vs SI-NP vs SI-F: P = 0.072;
‡NSI
vs SI: P = 0.24; §NSI vs SI-NP vs SI-F: P = 0.14.
NSI = nonspecific intervention; SI = specific intervention; SI-NP = specific intervention, no or
partial adherence; SI-F = Specific intervention, full adherence
Survival Curves
1.0
SI, full adherence, n = 14
0.8
SI, n = 31
Proportion 0.6
not Psychotic
SI, no or partial
adherence, n = 17
0.4
NSI, n = 28
0.2
0
200
400
600
800
No. of Days From Entry
NSI = nonspecific intervention; SI = specific intervention.
SI vs NSI: P = 0.087
SI, full adherence vs NSI: P = 0.032.
P-values are from log-rank test.
1000
Final (12-Month Follow-up) Diagnoses of
Psychotic Subgroups
Diagnosis
Psychotic subjects
Schizophrenia/schizophreniform
Major depressive disorder with psychotic features
Bipolar disorder (with psychotic features)
Brief psychotic disorder
Psychotic disorder NOS
Substance-induced psychotic disorder
N
16
7
3
3
1
1
1
Final (12-Month Follow-up) Diagnoses of
Nonpsychotic Subgroups
Nonpsychotic subjects
Nil
Major depressive disorder
Generalized anxiety disorder
Panic disorder
Obsessive compulsive disorder
Social phobia
Dysthymia
Eating disorder
43
26
4
1
2
2
3
4
1
Number Needed to Treat:
a worked example
Response to active treatment:
Response to placebo:
35%
10%
Absolute Risk Reduction (in response rates)
= 35% - 10% = 25%
NNT = 100/risk reduction = 100/25 = 4
How Potent Is Risk Reduction in
PACE Study?
Absolute risk reduction: 0.357 (comparison)
- 0.097 (specific) = 0.26
 Number needed to treat (NNT): 1/0.26 = 3.8
 NNT = 3.8 (CI = 2.1 - 18.3)
 NNT for moderate hypertension = 13
 NNT for mild hypertension = 160

Conclusions from this study
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First-episode psychosis can be deferred in proportion of cases with
psychosocial treatment and novel antipsychotic at least during
treatment phase
This constitutes prevalence reduction
Even if first-episode psychosis does occur, DUP is minimized and
comorbidity reduced in PACE model
Some cases may be averted (reduced incidence) but further followup required
Caveats and Issues
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RCT design was “real world” and did not involve
double blind
Frank psychosis was target for prevention, not
“schizophrenia”
Combined drug and cognitive therapy compared with
more basic psychosocial intervention
Need for longer follow-up, more complex designs,
and multiple replications
Ethical Issues

Labeling people as “At Risk”
Self-stigmatization
Depression, anxiety as reactions
Social stigma
Implications for work and health insurance
Ethical Issues

Providing a service to UHR individuals


Asymptomatic versus symptomatic
Help seeking

Need to offer treatment for manifest syndromes and problems
Could offer intervention for potential syndromes and subthreshold
symptoms
Informed consent required for both aims

Economic issues


Ethical Issues

Treating false positives


“Damned if you do, damned if you don’t”
Need to do no harm vs potential benefits—same
with first-episode psychosis and later phases

How long do you treat for?
PRIME study
McGlashan et al, Am J Psychiatry 2006
 Double blind placebo controlled study of
olanzapine in UHR “prodromal” patients
 12 month treatment phase, 12 month follow
up

PRIME study
Transition to psychosis: whole sample 21
out of 60 (35%)
 Treatment group: 16.1% transition (5 of 31)
 Control group: 37.9% (11 of 29), p = 0.08
 All 5 conversions in olanzapine group
occurred within then first 4 weeks

EDIE study
Morrison et al, Br J Psychiatry 2004
 Compared cognitive therapy with treatment
as usual in 58 patients at ultra-high risk of
psychosis
 6 month therapy, 6 month no treatment

EDIE study
60 patients randomised, 37 to CT, 23 to
monitoring
 Transition to psychosis - whole sample 7 of
60 (11.7%)
 CT group: 2 of 37 (6%)
 Monitoring group: 5 of 23 (22%)

FETZ study
FETZ Germany
 Bechdolf et al
 Open labelled study of amisulpride versus
psychosocial treatment

FETZ study
Needs focused intervention (NFI):
psychoeducation, family counselling,
assistance with education or work-related
difficulties (n = 59).
 Specific intervention: (n = 65) combined
NFI with the second generation neuroleptic
amisulpride.

FETZ study

Initial analysis of the first twelve weeks of
intervention revealed superior treatment
effects of the combination regarding basic
symptoms, attenuated and full-blown
psychotic symptoms, negative and affective
symptoms and global functioning
Fish oil: PACE Vienna
Amminger et al
 RCT comparing of eicosapentoic acid
(EPA) (fish oil) with placebo
 N = 38 in both groups

Fish oil: PACE Vienna

At 3-month follow-up, 2.6% (1 of 38)
individuals in the EPA group and 21.1% (8
of 38) in the placebo group developed
psychotic disorder (chi-square exact
p=0.028).
Fish oil: PACE Vienna
At 6-month follow-up, 11 (28.9%) of 38
individuals developed psychotic disorder in
the placebo group (ie 3 more)
 No further transitions occurred in the EPA
group (chi-square exact p=0.002)

Intervention study - Phase 2
Commenced September 2000
 Design: Double blind randomised control
trial
 3 cells:
Risperidone + CBT
Placebo + CBT
Placebo + Supportive therapy
 120 subjects randomised

Hot new data
12 month transition rates
 Risperidone + CBT: 14%
 Placebo + CBT : 10%
 Placebo + Supportive therapy: 22%
 No statistically significant difference

Taking into account:




Lower transition rate
Evidence of effectiveness of “benign”
interventions, such as cognitive therapy and fish
oil
Possible changed sample - ie we may be seeing
more “generally distressed” young people
High levels of psychotic experiences in people
who apparently have no need for intervention…..
Need for new generation of
studies?
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Staged approach
Benign interventions initially
Anti-psychotics may be justified if people fail to
respond to these
Other treatments to be investigated
?
mood stabilisers
 ? anti-depressants
 ? vitamins eg folate, Vitamins D, E……
 ? supportive psychotherapy