“Is het gebruik van cannabis een risicofactor voor schizofrenie?

Biologische grondslagen en klinische implicaties”

Ruud van Winkel Rebecca Kuepper

Maastricht University

Bunnik Symposium 8 maart 2013

Disclosure Ruud van Winkel

•Speaker fees received from: AstraZeneca, Eli Lilly, Lundbeck

•Positions held on Advisory Boards: None

•Grants and sponsoring: AstraZeneca, Eli Lilly, Janssen-Cilag

Disclosure Rebecca Kuepper

• Speaker fees received from: Lundbeck

• Positions held on Advisory Boards: none

• Grants and sponsoring: none

Moore et al, Lancet

2007

OR 1.41

Moore et al, Lancet 2007 OR 2.09

PSYCHOSIS

t0 t1

Psychotic sym ptom sPsychotic sym ptom s

t3t2

Psychotic sym ptom sPsychotic sym ptom s

German EDSP study (Early Developmental Stages of Psychopathology) Lieb et al., 2000; Wittchen et al., 1998

Kuepper et al., BMJ 2012

Does cannabis cause

persistence?

Het is bewezen, cannabis is een causale factor in de ontwikkeling van psychose.

Individuals differ in sensitivity

Genetic (e.g. familial

liability) and non-genetic

factors

time

response ‘Sensitization’

-severe -enduring

van Winkel et al, Schizophrenia Bulletin, 2008

Collip et al, Schizophrenia Bulletin, 2008

NEMESIS

Association between trauma and later cannabis use:

OR = 1.57 (1.33-1.86), p < 0.001 Konings et al., Psych Med, 2012

Causality over the life course

Phenotype

Early causes Late causes

Vulnerability Neuroendocrine

Behavioural deviance

Cognitive set

Developmental programming

Decoster et al, 2012

0 250 500 750 N(risk variants)

Frequency in

population

0 250 500 750 N(risk variants)

Frequency in

population

Distribution of psychotic symptoms in the general population?

85% no symptoms

14% symptoms

5% true psychotic symptoms

1% schizophrenia

Number of

genetic risk

variants

Psychosis

expression

Number of

genetic risk

variants

Psychosis

expression

“Liability-threshold model”

Liability

Psychosis

expression

Liability

Psychosis

expression

Parents, n=919

Siblings, n=1057 Patients, n=1120 Controls, n=590

Genetic Risk and Outcome in Psychosis Study

(GROUP)

Parents, n=919

Siblings, n=1057 Patients, n=1120 Controls, n=590

Genetic Risk and Outcome in Psychosis Study

(GROUP)

Cross-sib, cross-trait: no evidence for rGE

Caspi et al, 2005

COMT Val158Met

Decoster et al, Curr Pharm Des, 2012

Which genes?

Association with schizophrenia: RGS4, NRG1, DTNBP1, PIP5K2A, G72/DAOA, DISC1, HT2A, AKT1,

LRRTM1, FGF2, FGFR1, GPM6A, PRODH, GRM3, GABRA6, GAD1,

NOS1, RGS2, ROBO1, CHRM3, TBX1

Important for dopaminergic neurotransmission COMT, ANKK1, DRD1, DRD2, DRD3, SLC6A3, PPP1R1B, SLC18A2

Directly related to cannabinoid signaling CNR1

Responsivity to environmental stress ADRA2C, FKBP5

Adaptive neuronal survival BDNF, P2RX7, NPY, NQO1, GST-1, GST-2

Epigenetic regulation of environmental influences MTHFR, MTR, MTRR, DNMT3B, EHMT1, EHMT2, PRDM2

van Winkel et al, Arch Gen Psychiatry, 2011

van Winkel, R. et al. Arch Gen Psychiatry 2011

Significant SNP x Cannabis Interactions (at P<.05) in 740 Unaffected Siblings

van Winkel, R. et al. Arch Gen Psychiatry 2011.

Siblings

Patients

Di Forti, Biol Psychiatry 2012

RRR

P= .13

AKT1 follow-up: case-only analysis of the UPC Catholic

University Leuven sample N=533

van Winkel & GROUP, submitted

time

response ‘Sensitization’

-severe -enduring

van Winkel et al, Schizophrenia Bulletin, 2008

Collip et al, Schizophrenia Bulletin, 2008

Nina B.L. Urban , Mark Slifstein , Judy L. Thompson , Xiaoyan Xu , Ragy R. Girgis , Sonia Raheja , Margaret Haney...

Dopamine Release in Chronic Cannabis Users: A [11C]Raclopride Positron Emission Tomography Study

Biological Psychiatry Volume 71, Issue 8 2012 677 - 683

Figure 1. Total striatal [11C]-raelopride BPND values for volunteers with a history of cannabis

use compared to control volunteers.

Stokes P R et al. J Psychopharmacol 2011;26:144-149

Copyright © by British Association for Psychopharmacology

D2

dopamine

AKT1

D2

dopamine

AKT1

dopaminesignaal

CB1

Percentages of voxels with significant (sig. threshold of t > 2.4) THC-induced ligand displacement

0

10

20

30

40

Patients Population

% cannabis

users

Why do patients with schizophrenia use cannabis??

e.g. Mueser et al., Schiz Bull, 1992; Regier et al., JAMA, 1990

Acute effecten

Hal

luci

nat

ies

Stem

min

g “Ik voel me opgewekt...”

“Ik hoor stemmen...”

Henquet et al., British Journal of Psychiatry, 2010

Sub-acuut

Acuut

Effecten van Cannabis

“Ik voel me ontspannen...”

“Ik hoor stemmen...”

Henquet et al., British Journal of Psychiatry, 2010

Patienten zijn verhoogd gevoelig voor cannabis

0

0,05

0,1

0,15

0,2

0,25

0,3

E

ffe

ct

Siz

e

(TH

C)

Controles

Patienten

Henquet et al., British Journal of Psychiatry, 2010

Acute reacties als voorspeller

0

20

40

60

No treatment Other psychoticdisorder

Bipolar Sz spectrumdisorder

% o

f case

s a

t fo

llo

w-u

p

Baseline cannabis psychosis

n = 535 incident cases

3-5 year follow-up

Arendt at al., British Journal of Psychiatry, 2005

But Are There Changes in

Schizophrenia Incidence?

Incidence Schizophrenia South-East London, 1965-1997

1

1,2

1,4

1,6

1,8

2

2,2

1965 1997

Rela

tive I

ncid

en

ce

Boydell, van Os, et al., British Journal of Psychiatry, 2003

Incidence Changes?

• Sensitivity of assessment • DSM-IV definitions

• Other risk factors

TREATMENT???

Minder angst / stress

Meer stemmen

Stress

Als ik drink Ben ik meer relaxed word ik leuk gevonden Als ik cannabis gebruik Ben ik minder angstig Heb ik minder last van stemmen

Behandeling:

• Cognitieve gedragstherapie ?

• Motiverende gespreksvoering ?

• Terugvalpreventie ?

Verwachtingen van gebruik

X

• Adapted from substance use field (Miller and Rollnick, 2001)

• Substance use is not identified by the therapist as being problematic

• Emphasis on helping client to identify the consequences of their substance use (positive or negative)

MOTIVATIONAL INTERVIEWING

Ik weet het niet. Ik zou

wel willen stoppen met

blowen, maar ik denk dat ik

het erg zal gaan missen.

Ja.

Nee, het brengt me niets.

Maar het helpt me wel met mijn

angstige gevoelens. Het

kalmeert me.

Ja. Ik durf dan nog

steeds niet goed naar

buiten, maar voel me

thuis wel rustiger.

Ja, ik wil wel graag

stoppen, maar ik ben

bang dat ik niet zonder

kan.

Ik voelde me minder

achterdochtig toen ik niet

gebruikte. Maar nu ben ik

soms zo paranoide dat ik

moet blowen om te

kunnen slapen. Maar dan

als ik ‘s ochtends wakker

wordt….

The ‘spirit’ of Motivational Interviewing Motivational Interviewing can be described as forming a partnership with the client or patient, within which one’s style is quiet, accepting, attentive, respectfully curious, and directive rather than overtly persuasive. Motivation to change is elicited.

“It’s dancing; not wrestling.” (Jeff Allison)

MOTIVATIONAL INTERVIEWING

M.I. and Motivation

“ M.I. is more than a set of techniques for doing counselling. It is a way of being with clients.”

“ Lack of motivation is not a fault for which to blame your clients: It’s a challenge for your therapeutic skills”

Miller & Rollnick, 1991

Barrowclough et al., Am J Psychiatry, 2001:

• N = 36 patient-caregiver (parents/partners) pairs

• Gender: majority patients were male

• Mean age: 31.1 years

• Mean illness duration: 8.4 years

• Study design: • Randomized to either TAU or integrated therapy (CBT +

MI, family intervention)

• Baseline to 12 months follow-up

EVIDENCE SO FAR…

PRIMARY OUTCOME: GAF score

46

48

50

52

54

56

58

60

62

0m 9m 12m 18m

CBT

N=15

Control

N=14

Global Assessment Functioning at 0, 9, 12, and 18 month p = 0.001

Barrowclough et al., Am J Psychiatry, 2001

Positive symptoms

12

13

14

15

16

17

18

0m 9m 12m 18m

CBT

N=15

Control

N=14

Mean PANSS positive score at 0, 9, 12, and 18 month p > 0.5, n.s

Barrowclough et al., Am J Psychiatry, 2001

10

11

12

13

14

15

16

17

0m 9m 12m 18m

CBT

N=15

Control

N=14

Negative symptoms

Mean PANSS negative score at 0, 9, 12, and 18 month p = 0.028

Barrowclough et al., Am J Psychiatry, 2001

28

29

30

31

32

33

34

0m 9m 12m 18m

CBT

N=15

Control

N=14

Mean PANSS general score at 0, 9, 12, and 18 month p > 0.05, n.s.

General symptoms

Barrowclough et al., Am J Psychiatry, 2001

A first conclusion…

CBT + MI superior to TAU

Treatment needs to be extended or boosters delivered

Barrowclough et al., Am J Psychiatry, 2001

Het is van groot belang om cannabis gebruik onder patiënten met

psychose te behandelen, omdat dit een positief effect heeft op het

ziekteverloop en de klinische outcome significant verbetert.

Further evidence?

Barrowclough et al., BMJ, 2010

N = 327 patients with psychosis and comorbid substance use

Dr. Rebecca Küpper (Maastricht University)

Dr. Monique Konings (GGzEindhoven)

Drs. Maurice Smits (Mondriaan)

Dr. Cécile Henquet (Mondriaan)

Prof. dr. Inez Germeys (Maastricht University)

Prof. dr. Jim van Os (Maastricht University)

Maastrichtse Behandelstudie naar de effecten van M.I. in combinatie met CGT

Study Design

Behandelfase: 24 sessies van 45-60 min over 40 weken (eerste fase MI, tweede fase in combinatie met CGT)

2 booster sessies 5 en 10 weken na afronding van de behandeling

Assessment (incl. GAF, PANSS, BPRS, craving): Meting 1: baseline

Meting 2 en 3: na 12 en na 24 behandelsessies

Meting 4 en 5: 6 maanden na afronding en 12 maanden na afronding

Deelnemers: Patiënten met dubbel diagnose psychose en cannabis gebruik

Gerandomiseerd naar MI+CGT versus TAU (treatment as usual)

Preliminary Results

0

10

20

30

40

50

60

1 2 3 4 5

MI+CBT

TAU

GAF

Preliminary Results

PANSS – Negative syndrome scale

1

1,1

1,2

1,3

1,4

1,5

1,6

1,7

1 2 3 4 5

MI+CBT

TAU

1

1,1

1,2

1,3

1,4

1,5

1,6

1,7

1,8

1,9

1 2 3 4 5

MI+CBT

TAU

Preliminary Results

PANSS – Positive syndrome scale

Results: Frequency & amount of cannabis use

Craving for cannabis

No difference in GAF

Psychological Medicine, 2012

A second conclusion…

CBT + MI + family intervention superior to TAU

But: effects rather on substance use, and not on clinical or functional outcome variables

Cannabis gebruik is schadelijk voor de mentale gezondheid,

ongeacht iemands leeftijd of andere risicofactoren. Daarom is het

ook sterk aan te raden om het gebruik van cannabis in de hele

populatie te verminderen.

Thank you for your attention!

Ruud van Winkel, PhD ruud.vanwinkel@maastrichtuniversity.nl Rebecca Kuepper, PhD r.kuepper@maastrichtuniversity.nl

Maastricht University, Department Psychiatry & Psychology, School for

Mental Health and Neuroscience (MHeNS), Maastricht, The

Netherlands