Is het gebruik van cannabis een risicofactor voor

“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
OR 1.41
Moore et al, Lancet
2007
OR 2.09
Moore et al, Lancet 2007
PSYCHOSIS
Does cannabis cause
persistence?
German EDSP study (Early Developmental Stages of Psychopathology)
Lieb et al., 2000; Wittchen et al., 1998
t0
t1
t2
Psych otic sym p tom s
Kuepper et al., BMJ 2012
t3
Psych otic sym p tom s
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
‘Sensitization’
response
-severe
-enduring
time
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
Vulnerability
Neuroendocrine
Behavioural deviance
Cognitive set
Developmental programming
Phenotype
Early causes
Late causes
Decoster et al, 2012
Frequency in
population
0
250
500
750
N(risk variants)
Frequency in
population
0
250
500
750
N(risk variants)
Distribution of psychotic symptoms in the general population?
85% no symptoms
14% symptoms
5% true psychotic symptoms
1% schizophrenia
Psychosis
expression
Number of
genetic risk
variants
Psychosis
expression
“Liability-threshold model”
Number of
genetic risk
variants
Psychosis
expression
Liability
Psychosis
expression
Liability
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)
Parents, n=919
Siblings, n=1057
Patients, n=1120
Controls, n=590
Cross-sib, cross-trait: no evidence for rGE
COMT Val158Met
Caspi et al, 2005
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
Significant SNP x Cannabis Interactions (at P<.05) in 740 Unaffected Siblings
van Winkel, R. et al. Arch Gen Psychiatry 2011
Siblings
Patients
van Winkel, R. et al. Arch Gen Psychiatry 2011.
Di Forti, Biol Psychiatry 2012
AKT1 follow-up: case-only analysis of the UPC Catholic
University Leuven sample
N=533
RRR
P= .13
van Winkel & GROUP, submitted
‘Sensitization’
response
-severe
-enduring
time
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
dopamine
CB1
D2
AKT1
dopaminesignaal

Percentages of voxels with significant (sig. threshold of t > 2.4) THCinduced ligand displacement
Why do patients with schizophrenia
use cannabis??
40
30
% cannabis
users
20
10
0
Patients
Population
e.g. Mueser et al., Schiz Bull, 1992; Regier et al., JAMA, 1990
“Ik voel me opgewekt...”
“Ik hoor stemmen...”
Hallucinaties
Stemming
Acute effecten
Henquet et al., British Journal of Psychiatry, 2010
Effecten van Cannabis
Acuut
“Ik voel me ontspannen...”
Sub-acuut
“Ik hoor stemmen...”
Henquet et al., British Journal of Psychiatry, 2010
Patienten zijn verhoogd gevoelig
voor cannabis
0,3
Effect Size
(THC)
0,25
0,2
Controles
Patienten
0,15
0,1
0,05
0
Henquet et al., British Journal of Psychiatry, 2010
Acute reacties als voorspeller
% of cases at follow-up
Baseline cannabis psychosis
60
n = 535 incident cases
3-5 year follow-up
40
20
0
No treatment
Other psychotic
disorder
Bipolar
Sz spectrum
disorder
Arendt at al., British Journal of Psychiatry, 2005
But Are There
Changes in
Schizophrenia
Incidence?
Incidence Schizophrenia South-East London, 19651997
Relative Incidence
2,2
2
1,8
1,6
1,4
1,2
1
1965
1997
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
MOTIVATIONAL INTERVIEWING
• 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)
 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….
MOTIVATIONAL INTERVIEWING
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)
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
EVIDENCE SO FAR…
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
PRIMARY OUTCOME: GAF score
Global Assessment Functioning at 0, 9, 12, and 18 month
p = 0.001
62
60
58
56
CBT
N=15
54
52
Control
N=14
50
48
46
0m
9m
12m
18m
Barrowclough et al., Am J Psychiatry, 2001
Positive symptoms
Mean PANSS positive score at 0, 9, 12, and 18 month
p > 0.5, n.s
18
17
16
15
CBT
N=15
14
Control
N=14
13
12
0m
9m
12m
18m
Barrowclough et al., Am J Psychiatry, 2001
Negative symptoms
Mean PANSS negative score at 0, 9, 12, and 18 month
p = 0.028
17
16
15
14
CBT
N=15
13
Control
N=14
12
11
10
0m
9m
12m
18m
Barrowclough et al., Am J Psychiatry, 2001
General symptoms
Mean PANSS general score at 0, 9, 12, and 18 month
p > 0.05, n.s.
34
33
32
31
CBT
N=15
30
Control
N=14
29
28
0m
9m
12m
18m
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?
N = 327 patients
with psychosis
and comorbid
substance use
Barrowclough et al., BMJ, 2010
Maastrichtse Behandelstudie naar de
effecten van M.I. in combinatie met CGT
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)
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
GAF
60
50
40
MI+CBT
30
TAU
20
10
0
1
2
3
4
5
Preliminary Results
PANSS – Negative syndrome scale
1,7
1,6
1,5
1,4
MI+CBT
1,3
TAU
1,2
1,1
1
1
2
3
4
5
Preliminary Results
PANSS – Positive syndrome scale
1,9
1,8
1,7
1,6
1,5
MI+CBT
1,4
TAU
1,3
1,2
1,1
1
1
2
3
4
5
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