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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