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Is Schizofrenie een Progressieve Ziekte?
VJC, 09-04-2014
Progressive Reduction in Plasticity?
% no response after each
relapse
Wiersma et al, Schiz Bull, 1998; Hegarty et al, 1994
15-year follow-up
15- year follow-up of first episodes;
2 out of 3 had relapse
Good outcome Poor outcome 0% 50% 100%
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
Van Os & Kapur, Lancet, 2009
Recovery: Less Than 15%?
Nomothetic: Group-level
Level
Symptom A
Level Symptom B
N=250
Idiographic: Within-Person
Level
Symptom A
Level Symptom B
Cognitieve symptomen
Manie
Depressie
Psychose
Cognitieve symptomen
Manie Motivationele beperkingen
Depressie
Psychose
Schizofrenie
Cognitieve symptomen
Manie
Depressie
Psychose
Bipolaire stoornis
Schizoaffectieve stoornis
Motivationele beperkingen
Motivationele beperkingen
The Longterm AP Story
The Longterm AP Story
Wunderink et al, 2013, JAMA Psychiatr
The Longterm AP Story
Wunderink et al, 2013, JAMA Psychiatr
The Longterm AP Story
Wunderink et al, 2013, JAMA Psychiatr
But: Better functioning
at 7-year FU
Cognition Impacts Outcome?
Neurocognition
Functional Outcome
Millan et al, Nat Rev Drug Disc, 2012
Cognitive Alterations as a Dimension
Impact Social Factors on Cognition
Mani et al, Science, 2013
Cannabis Impacts Outcome?
Cannabis Use
Functional Outcome
GROUP in preparation
Diagnosis according to CASH or SCAN
GROUP in preparation
45% 60% 58%
GROUP 3-year GAF-d outcome
3-yr AP dose
> ½ SD Reduction
B=0.38, p=0.87
3-yr AP dose
> ½ SD Increase
B=-0.62, p=0.72
GROUP 3-year GAF-d outcome
Baseline Poly -
Polypharmacy start
B=-9.4, p=0.036
N=10/331
Baseline Poly +
Polypharmacy stop
B=16.2, p=0.039
N=47/51
GROUP 3-year GAF-d outcome
Baseline THC
B=-5.5, p=0.009
Baseline IQ
B=-0.32, p<0.001
Schizophrenia is an outcome itself!
Psychotic Disorder
Risk State
Transition 1 Year
Symptoms impacting on each other in relational Network or Interactome
S1 S2
S3 S4
S5 S6
S7 S8
Correlated symptoms clustering in dimensions
S1 S2
S3 S4
S5 S6
S7 S8
Clustering people into diagnostic categories
Things Happen for a Reason in a Sequence
Hartmann et al. Br J Psychiartry, 2013; Freeman et al. J Psychiatr Res 2010;44:1021–1026
Stress
Insomnia
Low
Stress
Insomnia
Hypomanic
Stress
Insomnia
Paranoid
Clinical Mechanisms?
Thought
Percep-tion
Mood
GENES CANNABIS
Crucial Connection in the Psychosis Network
Hallucinatory Experience
Delusional Meaning
Genes Environment
Dynamic Interactions: Delusions and Hallucinations
Subthreshold Delusions and Hallucinations
78 (3.1)
Combined Hallucinations and delusions
observed
25 (1.0)
Combined Hallucinations and delusions
expected
Smeets et al, Schiz Bull, 2010 & Acta Psychiatr Scan, 2012
General Population Samples (NL, TUR, GER)
Hallucinatory-Delusional States: Outcome
None Hal Del Hal+Del
Depression 8.2% 24.7% 25.8% 39.7%
Negative Sx 11.7% 15.4% 16.6% 21.5%
10-yr persistence 0.0% 14.2% 6.5% 33.1%
Dysfunction -- 32.3% 35.8% 57.9%
“Caseness” 1.2% 3.1% 7.0% 20.7%
Help-seeking 0.1% 7.7% 8.7% 35.5%
Smeets et al, Schiz Bull, 2010 & Acta Psychiatr Scan, 2012
Parents, n=919
Siblings, n=1057 Patients, n=1120 Controls, n=590
Dutch G.R.O.U.P. Study
Ontogenesis Psychosis
Hallucinatory
anomaly
Smeets, Janssen & GROUP, in press
0
10
20
30
40
50
60
70
Cannabis + Cannabis -Delusional
Meaning
Risk 0-100%
Ontogenesis Psychosis
Smeets, Janssen & GROUP, in press
0
10
20
30
40
50
60
Family history+ Family history -
Hallucinatory
anomaly
Delusional
Meaning
Risk 0-100%
Ontogenesis Psychosis
Smeets, Janssen & GROUP, in press
0
5
10
15
20
25
30
35
40
Trauma + Trauma -
Hallucinatory
anomaly
Delusional
Meaning
Risk 0-100%
Transition from Health to Psychotic Disorder
n=810 siblings
n=462 controls
1.1%
0.4%
3-year
transition rate RR=2.2
THC: Transition from Health to Psychotic Disorder
THC Exposure
Transitions (n=11) 73%
Non-Transitions (n=1261) 37%
OR=4.1, p<0.001
PAF=57%
Trauma: Transition from Health to Psychotic Disorder
Trauma Exposure
Transitions (n=11) 89%
Non-Transitions (n=1261) 21%
OR=34.4, p<0.001
PAF=86%
Clinical Mechanisms?
Thought
Percep-tion
Mood
Psychosis as a Trans-Diagnostic Dimension
SCHIZ SzAFF DEPR ANX POP
Psychosis
Mood Disorder and Psychosis
Psychotic disorder
Common mental disorder
General population
Delusions & Hallucinations:
80%
Delusions & Hallucinations:
30%
Delusions & Hallucinations:
8%
EDSP Sample n=3021 / NEMESIS samples n=13.767
Cross-dimensional Impact in MD
Arch Gen Psychiatry, 2010
Subclinical Mania Subclinical Psychosis
NO IMPACT OUTCOME POOR OUTCOME
Psychotherapy and Sub-Psychosis in MD
Subclinical Psychosis and Mania and
Outcome of Depression (n=120)
Association
with BDI SD
improvement
from baseline
to FU
Wigman et al, Psychol Med, 2013
Week
8
Week
16
Week
26
Week
52
Week
104
-0.1
-0.2
-0.3
0.1
Sub-Psychosis
Sub-Mania
* * *
Slower
response Faster
relapse
Mechanism E at Symptom Level
CMD
+ Psychosis
CMD
+ Psychosis
E + E ‒ Excess relative risk
Wouda et al, 2014
EDSP=3021, interviewed 4 times over 10 years
Mechanism Cannabis Symptom Level
CMD
Psychosis
CMD
Psychosis
Cannabis + Cannabis ‒ Cannabis excess
relative risk: 2.19
Wouda et al, 2014
EDSP=3021, interviewed 4 times over 10 years
Mechanism Trauma Symptom Level
CMD
+ Psychosis
CMD
+ Psychosis
Trauma + Trauma ‒ Trauma excess
relative risk: 1.74
Wouda et al, 2014
EDSP=3021, interviewed 4 times over 10 years
Clinical Mechanisms?
Thought
Percep-tion
Mood
GENES ENVIRONMENT
Fin
Cannabis or Spice or….?
700 different psychoactive substances available?
179 PIA/phenethylamines/MDMA-like drugs; amphet-type substances (fluoroamphetamine, PMA, 2C-T, 2C-B etc);
14 PIA derivatives: „fly‟; NBOMe; indanes; benzofurans (5; 6-APB/APDB); „BenzoFury‟
220 synthetic cannabimimetics; incl: AM-2201; AM-2233; AKB-48F
30 synthetic cathinones; incl: mephedrone; methedrone; methylone; etc
A few synthetic opiate/opioids, such as 4-fluorbutyrfentanyl; AH-7921; IC-26; MT-45; nortilidine; W15; W18
3 synthetic cocaine substitutes: RTI 111; RTI 121; RTI 126
64 tryptamine classical derivatives and 5 tryptamine derivatives such as 5-Meo-DALT; AMT; 5-Meo-AMT etc
126 psychedelic phenethylamines/stimulants from the Shulgin Index (2011); about 1,300 molecules being
covered; including DMAA; related deaths reported in the UK
3 GHB-like drugs: GHB; GBL; 1,4-BD
7 PCP-like drugs: PCP; ketamine; methoxetamine; PCE; 3-MeO-PCP; ethylketamine; 3-HO-PCP etc
2 piperazines: BZP; TFMPP
12 Herbs/plants/fungi/animals: Salvia divinorum; Mytragina speciosa/kratom; Tabernanthe iboga/ibogaine; Kava
Kava; Psychotria viridis/Ayahuasca; hydrangea; Rhodiola rosea; Datura stramonium; psychedelic mushrooms; bufo;
sponges; flies; etc
11 medicinal products: tramadol, oxycodone, and remaining opiates/opiods; anticonvulsants (gabapentin and
pregabalin); antiseptics (benzydamine); DXM; benzodiazepines/sedatives (phenazepam „Zinnie‟; methaqualone);
stimulants (ethylphenidate; camfetamine); antiparkinsonian /anticholinergics: selegiline; tropicamide); chloroquine;
anitretrovirals/‟whoonga‟; xylazine
6 PIEDs: minikikke/super strength caffeine tablets; DNP; testosterone booster concoctions such as Tribulus terrestris-
containing products; cognitive enhancers (aniracetam; piracetam)
Slide: Fabrizio Schifano
3%
15%
Clinical Phenotype: MH services
Extended Phenotype: Correlated Liabilities General population
Help
seeking
Social
conflict
Reduced social
competence
positive (hal/del)
affective motivation
cognitive
Van Os et al,
Nature, 2010
SZ BP
Mechanism Urbanicity Symptom Level
CMD
+ Psychosis
CMD
+ Psychosis
Urban + Urban ‒ Urban excess
relative risk: 1.86
Wouda et al, 2014
EDSP=3021, interviewed 4 times over 10 years
Ontogenesis Psychosis
Smeets, Janssen & GROUP, in press
0
10
20
30
40
50
Urban + Urban -
Hallucinatory
anomaly
Delusional
Meaning
Risk 0-100%
Alvarez-Jimenez?
Transition from Health to Psychotic Disorder
Exposed to both G & E
Transitions (n=11) 82%
Non-Transitions (n=1261) 43%
E=Cannabis use, Minority status, Urban birth, Trauma
G=high-risk sibling status
p=0.03
Genetic Sensitivity to Cannabis
Cannabis impact on risk
SIS-R psychosis
n=1096 sibs
n=590 controls
GROUP, Arch. Gen. Psychiatry, 2010
Controls Sibs
Cannabis Lifts Familial Psychosis Correlation
Level of
psychosis
relative 1
Level of psychosis
relative 2
Rel.1 Non-exposed
Rel.1 Exposed
Cannabis Lifts Familial Psychosis Correlation
Sibling SIS-
R psychosis
score
Patient CAPE psychosis score
978 pairs;
1723 observations
Van Winkel &
GROUP, submitted
P=0.0014
Cannabis Lifts Familial Psychosis Correlation
Sibling SIS-
R psychosis
score
Parent SIS-R psychosis score
669 pairs;
1222 observations
Van Winkel &
GROUP, submitted
P=0.0017
Stereotyping Psychosis
Prediabetes Diabetes Severe Diabetes
Stereotyping Psychosis
Prediabetes Diabetes Severe Diabetes
Psychotic
experiences
Psychosis-
spectrum
Severe
Psychosis
Onwetenschappelijke tweedeling
Ahn, 2009
Héél ernstig
Biologisch
“Fysische”
behandeling
Mild
Sociaal
“Psychische”
behandeling
De Belofte van Kennis
“Schizophrenia is a
devastating, highly
heritable brain disorder”
Science, 2009
….De essentie van herstel is
de psychiatrische diagnose te
boven komen…..
Herstel
Wilma Boevink, 2002
Cognition and Expectation
Am J Psychiatry, 2014
Are we asking the right questions?
What Patients Want………
“I want to be able to do things that other people
do, like have a boyfriend and a job …”
“I want to have friends”
“I want to be able to cook and eat when I want”
“I want to live in my own place not a hostel”
“I want to be a person, not a diagnosis”
Vocational functioning
Social functioning
Life skills
Independent living
Personal recovery
Patiënt wordt behandeld;
toont meer of minder
therapietrouw
DSM diagnose
Evidence-based richtlijnen
Adaptatie en
zelfmanagement
Persoonlijke crisis
Constructie eigen verhaal
KWANTITATIEVE BENADERING KWALITATIEVE BENADERING
Worstelen met ervaringen
Leven met ervaringen
Ervaringen zijn op de
achtergrond
Overweldigd worden door
ervaringen
Vroege expressie
kwetsbaarheid
Transition from Health to Psychotic Disorder
Environmental Exposure
Transitions (n=11) 100%
Non-Transitions (n=1261) 65%
Cannabis use, Minority status, Urban birth, Trauma
OR=∞, p=0.014
Voorwaardelijk of
Oorzakelijk?
Is de “hardware” het probleem
De zoektocht naar hersenschade
Of is het een software probleem?
Psychische problemen kunnen ook door “verkeerd leren” ontstaan
Psychopathology
Consequences for Patient
Weak relation between diagnosis and
Psychopathology
Care Needs
Prognosis
Multiple diagnoses; Change of diagnosis
Did UHR make it into the DSM?
APS?
How Many Transitions?
Anxiety
“light”
Anxiety
disorder
Depression
“light”
Major
depression
Mania
“light”
Bipolar
disorder
Schiz
“light”
Schizo-
phrenia
Psychotic Experience and Clinical Outcome
Psychotic & Non-Psychotic
0.6%
90% TRANSIENT EXPERIENCE
Extended Transition Function
No strong symptom Strong symptom
Werbeloff et al, Arch Gen Psychiatry, 2012
Psychosis is a Trans-Diagnostic Dimension
Mood Disorder and Psychosis
Psychotic disorder
Common mental disorder
General population
Delusions & Hallucinations:
80%
Delusions & Hallucinations:
30%
Delusions & Hallucinations:
8%
EDSP Sample n=3021 / NEMESIS samples n=13.767
Cross-dimensional Impact in MD
Arch Gen Psychiatry, 2010
Subclinical Mania Subclinical Psychosis
NO IMPACT OUTCOME POOR OUTCOME
Psychotherapy and Sub-Psychosis in MD
Subclinical Psychosis and Mania and
Outcome of Depression (n=120)
Association
with BDI SD
improvement
from baseline
to FU
Wigman et al, Psychol Med, 2013
Week
8
Week
16
Week
26
Week
52
Week
104
-0.1
-0.2
-0.3
0.1
Sub-Psychosis
Sub-Mania
* * *
Slower
response Faster
relapse
Psychosis as a Trans-Diagnostic Dimension
SCHIZ SzAFF DEPR ANX POP
Psychosis
Stage 0 asymptomatic
Stage 1a distress disorder
Stage 1b distress disorder +
sub-threshold specificity
Stage 2 first treated
episode
Stage 3 recurrence or persistence
Stage 4 treatment resistance
Incre
asin
g s
ym
pto
m s
pecific
ity
and d
isability
schizophrenia
bipolar disorder
depressive disorder
substance misuse
anxiety disorder
early intervention focus
McGorry & Van Os, submitted
Specific High-risk versus Non-Specific Public Health Perspective
Non-
helpseeking
Help-
seeking
Treatment Paradigms
Psychotropics Passive
Active Training
The Plasticity Argument
% R
esponse
aft
er
each r
ela
pse
15-year follow-up
Early Intervention
The Psychosis Interactome?
Thought
Percep-tion
Mood
Things Happen for a Reason in a Sequence
Hartmann et al. Br J Psychiartry, 2013; Freeman et al. J Psychiatr Res 2010;44:1021–1026
Stress
Insomnia
Low
Stress
Insomnia
Hypomanic
Stress
Insomnia
Paranoid
Munich EDSP Study Young People
T0
T3
± 3000
± 2200
10 yr T2
Age 13-24 yrs
Lieb, Isensee, Von Sydow & Wittchen, Eur. Add. Res., 2000
HAL / DEL
HAL / DEL
HAL / DEL
Company
Activity
Negative affect
Paranoia
DAY 5
DAY 6
DAY 3
DAY 4
DAY 1
DAY 2
Experience Sampling Method (ESM)
Stress Positive affect
Beep 2
Beep 3
Beep 4
Beep 5
Beep 6
Beep 7
Beep 8
Beep 9
Beep 10
Beep 1
(day 4 in detail)
Wigman et al, PLos ONE, 2013
Macro-level Symptoms and Micro-level Momentary Persistence
Non-Persistence: REPORTS NO SYMPTOM
Level of
paranoia
moment 1 moment 2 moment 3 moment 4 moment 5 moment 6 moment 7
Level of
paranoia
moment 1 moment 2 moment 3 moment 4 moment 5 moment 6 moment 7
Persistence: SYMPTOM HELPSEEKING
PLoS ONE 2013
Momentary Transfer Dynamics
Dynamics underlying Psychotic Symptoms
Paranoid state
negative affect
negative context A
Paranoid state momentary transfer +
30 min 60 min 90 min t-1 t
positive affect
positive context B
Non-paranoid state Paranoid state momentary transfer ‒
30 min 60 min 90 min t-1 t
Persistence Non-transfer
30 min 60 min 90 min t-1 t 30 min 60 min 90 min t-1 t
Wigman et al, PLoS ONE, 2013
Positive
event
Low
Paranoia
Irritable
+ event
Van Os et al, World Psychiatry, 2013
Precision Diagnosis “HUB”
Mechanism Trauma Symptom Level
CMD
Psychosis
CMD
Psychosis
Trauma + Trauma ‒ Trauma excess
relative risk: 1.74
Wouda et al, 2014
EDSP=3021, interviewed 4 times over 10 years
Mechanism Urbanicity Symptom Level
CMD
Psychosis
CMD
Psychosis
Urban + Urban ‒ Urban excess
relative risk: 1.86
Wouda et al, 2014
EDSP=3021, interviewed 4 times over 10 years
Mechanism Cannabis Symptom Level
CMD
Psychosis
CMD
Psychosis
Cannabis + Cannabis ‒ Cannabis excess
relative risk: 2.19
Wouda et al, 2014
EDSP=3021, interviewed 4 times over 10 years
Symptoms impacting on each other in relational Network or Interactome
S1 S2
S3 S4
S5 S6
S7 S8
Correlated symptoms clustering in dimensions
S1 S2
S3 S4
S5 S6
S7 S8
Clustering people into diagnostic categories
Episodic variation
Years
Symptom variation
Weeks
Momentary variation
Hours
Nomothetic
disorder
Personal
Vulnerability
Prediction of Clinical Transition
Mood
AR(1)
30 days
Van de Leemput et al, PNAS, 2014
Parents, n=919
Siblings, n=1057 Patients, n=1120 Controls, n=590
G x E Risk: GROUP Study
CASH interview psychosis
3-year follow-up: TRANSITION
Environmental exposures
Psychosis is a Trans-Diagnostic Dimension
SCHIZ SzAFF DEPR ANX POP
Cognition
Psychosis
Affective dysregulation
UHR UHR ?
What is an UHR Transition?
Anxiety /
depression
4
3
2
1
psychosis
Anxiety /
depression
4
3
2
1
psychosis
Fusar-Poli & Van Os, 2012
1-year transition
rate: 20%
Blood pressure is part of functional Network
Hyper-tension
Kid-ney
Metabolic
CNS
Heart
Representation
social world
Actual Environment: bottom-up sensory input
“Expectation”
“Facts”
Affectively
meaningful
Interaction
Motivation
Learned Environment: Top-down cortical processing
Learning
Needs & Treatments: Not Specific
Treatment needs Treatments
Suicidality
Work
Hallucinations
Child care
Substance use
Dysphoria
Anti-depressants
Motivational interviewing
CBT
Antipsychotics
Psychoeducation
Family intervention
Transition from Health to Psychotic Disorder
n=810 siblings 1.1%
n=462 controls 0.4%
3-year transition rate
RR=2.2 100% related to environmental
exposure
Van Nierop, Janssens & GROUP, PLoS One, 2013
Transition from Health to Psychotic Disorder
Environmental Exposure
Transitions (n=11) 100%
Non-Transitions (n=1261) 65%
Cannabis use, Minority status, Urban birth, Trauma
OR=∞, p=0.014
Trauma: Transition from Health to Psychotic Disorder
Trauma Exposure
Transitions (n=11) 89%
Non-Transitions (n=1261) 21%
OR=34.4, p<0.001
PAF=86%
THC: Transition from Health to Psychotic Disorder
THC Exposure
Transitions (n=11) 73%
Non-Transitions (n=1261) 37%
OR=4.1, p<0.001
PAF=57%
Symptoms not specific for disease
psychosis negative cognitive depression
Patient
Non-
patient “sub-symptoms”
Ontogenesis Psychosis
Hallucinatory Experience
Delusional Meaning
Genes Environment
Ontogenesis Psychosis
Hallucinatory
anomaly
Smeets, Janssen & GROUP, in press
0
10
20
30
40
50
60
70
Cannabis + Cannabis -Delusional
Meaning
Risk 0-100%
Ontogenesis Psychosis
Smeets, Janssen & GROUP, in press
0
5
10
15
20
25
30
35
40
Trauma + Trauma -
Hallucinatory
anomaly
Delusional
Meaning
Risk 0-100%
Ontogenesis Psychosis
Smeets, Janssen & GROUP, in press
0
10
20
30
40
50
Urban + Urban -
Hallucinatory
anomaly
Delusional
Meaning
Risk 0-100%
Ontogenesis Psychosis
Smeets, Janssen & GROUP, in press
0
10
20
30
40
50
60
Family history+ Family history -
Hallucinatory
anomaly
Delusional
Meaning
Risk 0-100%
Back to Basics: Delusions and Hallucinations
78 (3.1)
Combined Hallucinations and delusions
observed
25 (1.0)
Combined Hallucinations and delusions
expected
Smeets et al, Schiz Bull, 2010 & Acta Psychiatr Scan, 2012
Experiment 1
Van Os et al, Nature, 2010
Fluctuating mental responses to environment
1 week
Momentary Psychopathology
Psychotic Intensity: Delusions and Hallucinations
H D
D H
D H Aetiological
loading
Clinical
severity
Smeets et al, Schiz Bull, 2010 + Acta Psychiatr Scan, 2012 + Binbay et al, Schiz Bull, 2012
FU 6 months
FU 12 months
MindMaastricht RCT: PA = Paranoia
Sample: 130 participants with mood disorders.
6 days Experience Sampling
6 days Experience Sampling
Mindfulness Training
Control
Geschwind et al, J. Consulting & Clinical Psychology, 2011
Flow of Daily Life
Para
no
ia
Reduction in Paranoia
Collip et al, 2013
The TURKSCH study of Psychosis Continuum
Binbay et al, submitted
N=4011 representative sample interviewed with CIDI + clinical
reinterview; impairment based on level of frequency, duration,
help-seeking, severity and psychosocial impairment
Psychosis & Impairment ++++
Psychosis & Impairment +++
Psychosis & Impairment ++
Psychosis & Impairment +
No psychosis
5
4
3
2
1
Disorganisation
Negative ss
HAL+DEL
Fam. History SMI
Cannabis use
Continuity / discontinuity underlying apparent continuum
Level of predictor variable
Position on
psychosis
spectrum
Binbay et al, submitted
Continuity / discontinuity underlying apparent continuum
Level of predictor variable
Position on
psychosis
spectrum
Binbay et al, submitted
Trauma
Continuity / discontinuity underlying apparent continuum
Level of predictor variable
Position on
psychosis
spectrum
Binbay et al, submitted
Affective symptoms
Impairment: Symptom Associations
ONSET IMPAIRMENT
37%*
51%*
Van Rossum et al, Schizophr Bull, 2010
Controlling for negative symptoms; similar results manic symptoms
P<0.01
POS only POS + DEP T2
T3
Munich EDSP Study Young People
T0
T3
± 3000
± 2200
10 yr T2
Age 13-24 yrs Neg / Pos
Neg / Pos
Neg / Pos
“indifferent &
without clear
emotions”
Hallucinations &
Delusions “Flat Affect”
“Empty speech” “Lack goal-
directed
activities” 12% 17%
Lieb, Isensee, Von Sydow & Wittchen, Eur. Add. Res., 2000
General Population (n=4727):
Predictors 3-yr TRUE PsychosisTransition
Type of predictor
Subclinical Psychosis (n=105)
No Subclinical Psychosis (n=4627)
9.5%
0.3%
Hanssen et al, Br J Clin Psychology, 2005
Risk Clinical Transition
False-positive = 90.5%!
Do Positive & Negative have Natural Association?
T0
T3
T2 NEG POS
NEG POS
OR=1.3*
OR=1.7*
Controlling for depression
Dominguez et al, Am J Psychiatry, 2010
Do Positive & Negative have Natural Association?
T0
T3
T2 NEG POS
NEG POS
OR=2.4 *
Controlling for depression
Dominguez et al, Am J Psychiatry, 2010
Impairment: Symptom Associations
Clinical Transition
37%*
54%*
Dominguez, et al, Am J Psych, 2010
Controlling for depressive symptoms
P<0.01
POS only POS + NEG T2
T3
5 yrs
Israeli Transition Study (n=4548)
Cohort: 13 item False Beliefs and
Perceptions scale of the PERI (25%)
Follow-up National Case Register: NAP=22
Werbeloff et al, Arch Gen Psychiatry, 2012
Up to 25 yr FU
Transition is Contingent on Neg-Pos Synergism
Werbelof et al, in preparation
Type of Symptoms Risk hospitalization
No symptoms 1
Positive only 0.74
Negative only 0.78
Both 9.12 P interaction < 0.05
Where There Is No Data……
Onset Death
RCT Rest of Life
Recovery: Illness plasticity (illness changeability in response to treatment)
% R
esponse
aft
er
each r
ela
pse
Graphic summary-free after Wiersma D et al. Schiz Bull,1998;24:75-85.
15-year follow-up
15-year follow-up of first episodes 2 out of 3 had relapse
18 Main syndromes
o Neurodevelopmental Syndrome
o Psychotic Syndrome
o Bipolar Syndrome
o Depressive Syndrome
o Anxiety Syndrome
o Obsessive-Compulsive Syndrome
o Trauma-and Stressor-Related Syndrome
o Dissociative Syndrome
o Somatic Symptom Syndrome
o Feeding / Eating Syndrome
o Elimination Syndrome
o Sleep-Wake Syndrome
o Sexual Dysfunctions
o Impulse Control / Conduct Syndrome
o Addiction Syndrome
o Neurocognitive Syndrome
o Personality Syndrome
o Other Syndrome
400 DSM/ICD Diagnoses
DSM / ICD: It Never Quite Fits…
DSM-1 Disorder A
DSM-1 Disorder B
DSM-2
Disorder A
DSM-2
Disorder B
DSM-2
Disorder C
DSM / ICD: It Never Quite Fits
DSM-3
Disorder A
DSM-3
Disorder B
DSM-3
Disorder C
DSM-3
Disorder D
DSM / ICD: It Never Quite Fits…
DSM-4
Disorder A
DSM-4
Disorder B
DSM-4
Disorder C
DSM-4
Disorder
D
DSM-4
Disorder
E
DSM-4
Disorder F
DSM-4
Disorder
G
DSM / ICD: It Never Quite Fits…
Course of Cognition in Schizophrenia
Premorbid Onset Post-onset
UHR Literature: Risk
UHR literature
30% Transition in 2 years
80% “Schizo”-conversion
Almost all in 6 months
Elusive UHR sampling practice
North American MC: “Each site
recruited potential subjects through
clinical referrals as stimulated by
talks to school counselors and
mental health professionals in
community settings”
What is an UHR Transition?
Anxiety /
depression
4
3
2
1
psychosis
Anxiety /
depression
4
3
2
1
psychosis
Fusar-Poli & Van Os, 2012
Is Transition Relevant?
To date, this is the longest follow-up study of an UHR sample. Poor
functional outcome was associated with specific neurocognitive
decrements, regardless of transition to psychosis.
Psychopathology asTrans-Diagnostic Dimensions
SCHIZ SzAFF DEPR ANX POP
Cognition
Psychosis
Affective dysregulation
UHR UHR ?
Mental Disorders
Medical Disorder
Pharmacological
intervention
Personal
Vulnerability
Adaptation and
self-management
Anxiety
Syndrome Mood
Syndrome
Psychosis
Syndrome
Stage of non-specific
mental distress
Stage of specific
mental syndrome
Early
treatment
STRESS
ANERGIA
WORRY
LOW
GUILT
LOW
ANXIOUS
ANXIOUS
AVOIDANCE
PANIC
SLOW
ANERGIA
ANERGIA
WORRY
AVOLITION
DYSPHORIA
ABERRANT SALIENCE
HALLUCINATIONS
DELUSIONS
Van Os, Am J Psychiatry, 2013
You will transition to
Schizo-diagnosis
Media
Beelden
What is UHR Transition?
Fusar-Poli & Van Os, 2012