Cannabis; het endocannabinoide systeem en psychose

Drs. Rebecca Kuepper, Maastricht University,Psychiatry and Neuropsychology, The Netherlands

r.kuepper@sp.unimaas.nl

StellingStelling

“Het gebruik van Cannabis is een

RISICO FACTOR voor schizofrenie !

The dual images of Cannabis

Murray et al, Nature Reviews Neuroscience, 2007

Murray et al, Nature Reviews Neuroscience, 2007

01020304050607080

% cannabis users

Patients Population

Cannabis and SchizophreniaCannabis and SchizophreniaCannabis and SchizophreniaCannabis and Schizophrenia

• Hasj• Weed

• decreases:- negative symptoms (Compton, 2004;

Peralta and Cuesta, 1992)

- affective symptoms (Dixon, 1991)

• enhances: - positive affect - coping with negative affect - social functioning (Addington and Duchak,

1997; Spencer, 2002)

In Patients…..

-1

0,5

2

3,5

Odd

s R

atio

's

0 < 1 permaand

3-4 permaand

1-2 perweek

> 3 perweek

Andreasson et al. Lancet, 1987

Association between frequency of cannabis use and later psychosis

15-year follow-up cohort study in N = 45.570

Causaliteit ?Causaliteit ?

PSYCHOSISPSYCHOSIS

Psychosis phenotypePsychosis phenotype

Psychotic Psychotic symptoms (5%)symptoms (5%)

Psychotic Psychotic experiences experiences

(15%)(15%)

Schizophrenia Schizophrenia (1%)(1%)

Are subclinical symptoms a marker of genetic liability?

Are subclinical symptoms a marker of genetic liability?

1. Associated with risk factors for psychosis

2. Show continuity with illness

3. Cluster within families(twin studies)

(RR=10)1st degree schizophrenic relative

Risk factors and effect in schizophrenia

RR 1 5 10

(Van Os et al 1998)

50% discordance

• prenatal exposure to influenza

• obstetric complications

• childhood trauma

• members of some immigrant populations

• urbanicity

• life events

• substance use

Todo lo que ocurre en el cerebro es biología y todo lo que ocurre en la mente ocurre a través del cerebro.

Joseph le Doux, 1999

Todo lo que ocurre en el cerebro es biología y todo lo que ocurre en la mente ocurre a través del cerebro.

Joseph le Doux, 1999

MAOAMAOA

NOTCH4NOTCH4

SYN3SYN3

L1CAML1CAM

RELNRELN

G72/G30G72/G30

DAAODAAO

PRODHPRODH GRM3GRM3

DysbindinDysbindin

RGS4RGS4

NTRK1NTRK1BDNFBDNF

NRG1NRG1IL-1BIL-1B

DRD2DRD2COMTCOMT

SLC6A4SLC6A4

DRD3DRD3

DRD4DRD4

SLC6A3SLC6A3

HTR2AHTR2A

DISC1DISC1

Major gene?

Rare and inconsistent

• zelf-medicatie?• symptomen of ziekte?• waarom niet iedereen?• waarom blijven patiënten gebruiken?

DEBAT

EDSPEDSP (EEarly DDevelopmental SStages of PPsychopathology)

Prospective-longitudinal study on substance use and mental disorders

N = 3,021N = 3,021 (aged 14-24, birth cohorts 1970-1981)Follow-up at t1 (+2 years, only subsample)

t2t2 (+4 years, whole sample)t3t3 (+8 years, whole sample)

Substance use and clinical status were assessed using the CIDI (Composite International Diagnostic Interview)CIDI (Composite International Diagnostic Interview)

Lieb et al., 2000, Wittchen et al., 1998

CannabisCannabis & PsychosisPsychosis

t0 t1

PsychPsych

PsychPsych

OR = 1.88, 95% CI: 1.11-3.17, OR = 1.88, 95% CI: 1.11-3.17, pp = 0.018 = 0.018

t3t2

Adjusted forAdjusted for age gender socio-economic status use of other drugs childhood trauma urbanicity

Kuepper et al., submitted

IsIs cannabiscannabis useuse associated with true true incidenceincidence of psychotic symptomspsychotic symptoms??

t0 t1

PsychPsych

OR = 0.89, 95% CI: 0.67-1.19, OR = 0.89, 95% CI: 0.67-1.19, pp = 0.45 = 0.45

t3t2

Adjusted forAdjusted for age gender socio-economic status use of other drugs childhood trauma urbanicity

Kuepper et al., submitted

SELFMEDICATION?SELFMEDICATION?

t0 t1

PsychPsych

t3t2

Kuepper et al., submitted

IsIs cannabiscannabis useuse associated with persistencepersistence of psychotic symptomspsychotic symptoms??

PsychPsych

Kuepper et al., submitted

Is continued cannabis usecannabis use associated with greater risk of persistencepersistence of

psychotic symptomspsychotic symptoms??Risk of persistence* of psychotic

symptoms [OR (95%CI; p-value)]

Level of exposure unadjusted adjusted

no use 1 1

1.95 (1.22-3.11; 0.005) 1.63 (1.01-2.64; 0.045)

2.68 (1.53-4.72; 0.001) 2.21 (1.17-4.19; 0.015)

use at t1 or t2

use at t1 and t2*Persistence = psychotic symptoms at t2 AND at t3

Is continued c cannabis useannabis use associated with greater risk of persistencepersistence of

psychotic symptomspsychotic symptoms??

Cannabis effectsCannabis effects

+ No psychosis

???

Age of first use:(Arseneault et al, 2002)

N=472 (12 – 23 jr)

Cann use before 14th

Cann use after 14th

CAPECommunity

Assessment of Psychic

Experiences

CAPECommunity

Assessment of Psychic

Experiences

The CAPE-42 is based on the PDI-21 and PDI-40 developed by Emmanuelle Peters et al (2001)

(van Os, Verdoux, Hanssen)

• Positive dimension psychosis

Age of first use:

Onset before age 14 yrs

Onset after age 14 yrs

Ris

ik o

f p

sy

cho

tic

sy

mp

tom

s

Cannabis +Cannabis -

N=472 (12 – 23 jr)

Konings et al., Acta Psychiatr Scand, 2008.

Cannabis

No sign of psychosis liability

Subclinical symptoms (SCL-

90)

Psychotic symptoms

Start:

4 years later:

EDSP;n=2436

THC * vulnerability interaction

% psychotic symptoms

risk difference

No predisposition

Baseline predisposition

15%

21%6%

25%26%

51%

Henquet et al., BMJ 2006

-

+

+

-

THC * vulnerability interaction

Adjusted RD: 5.6% and 23.8% (for age, sex, SES, urbanicity, trauma, predisposition at follow-up)

Genetische kwetsbaarheid ?Genetische kwetsbaarheid ?

• Dopamine: COMT-gene

Dopamine breakdown

psychosiscognition

COMT

• Endophenotype• D’Souza et al, 2005

Val

Val

Val

Met

Met

Met

Val158Met:

Het dagelijks leven van patiHet dagelijks leven van patiëntenëntenHet dagelijks leven van patiHet dagelijks leven van patiëntenënten

Cannabis

Stemming

Hallucinaties

60 observaties:

PATRONEN VAN GEBRUIK EN SYMPTOMEN

0

0,15

0,3

0,45

0,6

0,75

Eff

ect

Siz

e A

H

Met/MetVal/Met

Val/Val

COMT x Cannabis: ESM Hallucinations

‘hearing voices’ ‘seeing things’

Henquet et al., Neuropsychopharm, 2006.Henquet et al., Acta Psych Scan, 2009.

40 controls, 40 psychotic patients

Gene-environment interplayGene-environment interplay

Psychosis

Henquet et al., Schizophrenia Bull, 2009.

Beyond GEI…Beyond GEI…Beyond GEI…Beyond GEI…

Cannabis

No Childhoodtrauma

Childhoodtrauma

Psychotic symptoms (CAPE)

Assessed at age 7:

Assessed at age 19:

The Greek Birth Cohort study; N= 3500

Bakoula, Stefanis et al

Beyond GEI…Beyond GEI…Beyond GEI…Beyond GEI…

0

0,2

0,4

0,6

0,8

1

1,2

1,4

No childhoodtrauma

Childhood trauma

No childhood trauma

Childhood trauma B= 0.20 (0.02-0.38),

p= 0.027

Eff

ect

Siz

e c

ann

ab

is o

n C

AP

E s

core

Konings et al., in preparationKonings et al., in preparation

B= 1.36 (0.67-1.59), p= 0.000

Growing up in rural environment

Growing up in urban environment

Psychotic symptoms

T2:

T3:

EDSP studyEDSP study (age 14-24)EDSP studyEDSP study (age 14-24)

EDSP;(Wittchen,

LIeb, 1998)

n=2436

Cannabis

Cannabis X urbanicity

% psychotic symptoms risk difference*

- 8% -1.0%95%CI: -0.7-0.05, p = 0.758

+ 6%

- 7%7.0%

95%CI: 0.01-0.12, p =0.019 + 15%

*Adjusted for age, gender, socio-economic status, use of other drugs, childhood trauma

rural

urban

Kuepper et al., submitted

Cross-sensitization stress X THC

Kuepper et al., Schiz Res 2010

• Hasj• Weed

9-tetrahydrocannabinol (THC)8-THC Cannabidiol (CBD) Cannabinol (CBN) Cannabigerol Cannabichromene

How THC might cause psychosis

(Mechoulam, 1960’s)

Endocannabinoids act to modulate e.g. GABA and glutamate

Neurobiology: THC and dopamine

• In rodents – THC facilitates DA transmission in several brain

regions including PFC and striatum (Chen et al., 1990; Jentsch et al., 1997, 1998; Tanda et al., 1997)

• In humans– THC might increase DA release in striatum

(Voruganti et al., 2001, Bossong et al., 2008)

biological pathway to psychosis?

DA in schizophrenia

Mesocortical DA hypohypo-

activity

Mesolimbic DA hyperhyper-activity

DA D1 receptors

DA D2 receptors

Negative and cognitive symptoms

Positive and disorganized symptoms

Cognitive tasks Imaging

Dopamine release can be inferred from displacement of IBZM or [18F]Fallypride

Rebecca Kuepper; Prof. Koen van Laere

LR

Striatum

Baseline

Following THC

PET study

[18F]Fallypride

Baseline

Burst firing of DA neurones in the ventral tegmental area (VTA) signifies the appearance of novel or salient stimuli.

Abnormal or dysregulated bursting in dopaminergic neurones may lead to the attachment of aberrant salience to otherwise mundane percepts and concepts and a delusional-style of thinking.

“…In this way, an unexpected sound, the comments of a TV news reader or eye contact with a stranger are transformed from trivial everyday occurrences into highly salient events of great personal meaning to the psychotic individual”.

Hyland, B. I.,(2002) Firing modes of midbrain dopamine cells in the freely moving rat. Neuroscience 114, 475-492

Kapur, S et al (2005) Schizophr Res 79, 59-68

Murray RM et al (2007) Nat. Rev Neurosci (2007).

Dopamine and Aberrant Salience

01020304050607080

% cannabis users

Patients Population

Why do patients with schizophrenia use cannabis??

Why do patients with schizophrenia use cannabis??

Acute effecten Acute effecten Acute effecten Acute effecten

geen THC

Ha

lluci

na

ties

na T

HC

Ste

mm

ing

geen THC

na THC

“Ik voel me opgewekt...”

“Ik hoor stemmen...”

Henquet et al., BJP 2010.

Sub-acuut

Acuut

Effecten van Cannabis Effecten van Cannabis Effecten van Cannabis Effecten van Cannabis

“Ik voel me ontspannen...”

“Ik hoor stemmen...”

Henquet et al., BJP 2010.

Patienten zijn verhoogd gevoelig Patienten zijn verhoogd gevoelig voor cannabisvoor cannabis

Patienten zijn verhoogd gevoelig Patienten zijn verhoogd gevoelig voor cannabisvoor cannabis

0

0,05

0,1

0,15

0,2

0,25

0,3

Eff

ec

t S

ize

(TH

C)

Stemming

Hallucinatio

ns

Controles

Patienten

TREATMENT???

Minder angst / stress

Meer stemmen

Stress

Geautomatiseerde

overtuigingen

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

Behandeling:• Cognitieve gedrags therapie• Motiverende gespreksvoering• Terugvalpreventie

Gedurende 1 jaarVoor- en Nameting van symptomen en middelengebruik

X

Verwachtingen van gebruik

Maastricht: Leuven:Dr. Cecile Henquet Prof.dr. Koen van LaereMonique Konings (GGzEindhoven)Maurice Smits (Mondriaan)Dr. Inez GermeysDr. Marinus van Kroonenburgh (azM)Prof.dr. Jim van Os

Grants:Zon-MW NWO (Veni-grant)

Questions?

r.kuepper@sp.unimaas.nl