The relevance of D2-AKT1 signalling for the pathophysiology of cannabis-induced psychosis Edinburgh, 14 April 2016 Dr Marco Colizzi marco.v.colizzi@kcl.ac.uk
Developmental cascade towards psychosis Family history of mental illness disorders Birth events -Prenatal and perinatal events -Genes:** NRG1, DTNBP1, COMT, DISC1, DRD2, RM3, ZNF, CNVs Chronic social adversity in childhood Subtle motor, cognitive and social deficits HPA-axis dysfunction Adulthood adversity Migration Urbanicity Social anxiety, Quasi-psychotic ideas, depression -Drug abuse e.g. cannabis, stimulants Dopamine dysregulation Neurotransmiters genes: e.g. **COMT; AKT1 P S Y C H O S I S
An integrated model of schizophrenia Howes & Murray, Lancet 2014
Cannabis and psychosis Questions Does cannabis trigger an earlier onset of psychosis in predisposed people? Does cannabis use worsen the psychotic symptoms generally? Does the cannabis use worsen the outcome and progress of the illness? Is there a causal link?
Cannabis plant A complex plant with over 60 compounds and 400 chemicals. There are 4 major compounds: THC (Gul et al., 2008) Delta-9-tetrahydrocannabinol (THC) * Cannabidiol (CBD) Delta-8-tetrahydrocannabinol * Cannabinol * CBD (Gul et al., 2008) *= has psychotogenic effect
Cannabis and endocannabinoid system Tetrahydrocannabinol (THC) Name Part of plant THC % Marijuana Leaves, small stems 1.0-3-0 Sinsemilla Sterile female flowers 3.0-6.0 Ganja Compressed sterile f.f. 4.0-8.0 Hashish Cannabis resin 10.0-15-0 Skunk Flowers (grown) 5.0-20.0 Cannabis oil Alcoholic extract of resin 20.0-60.0 Cannabidiol (CBD) No psychotomimetic effects in man Anti-epileptic, anti-anxiety and anti-psychotic effects in men and animals No significant side-effects. Even large doses have been tolerated Hollister, 1975; Zuardi et al., 1982; Pellow et al., 1985; Agurell et al, 1986; Zuardi & Guimaraes, 1997; Crippa et al., 2004 Sinsemilla potency comparison 1996/8 v 2005 UK (Potter et al., 2008) Potency levels signifantly higher in 2005 (p<0.001) Endocannabinoid system 1988: A specific cannabinoid receptor was found in the rat brain (Devane-Howlett, 1988) 1990: The discovery of a complementary DNA encoding for the first G protein-coupled cannabinoid receptor, now known as CB1 (Matsuda et al., 1990) 1992: The discovery of the neurotransmitter, a brain molecule called anandamide was identified (Devane-Mechoulam, 1992) 1993: The discovery of the second neurotransmitter, arachidonoyglycerol (2-AG, Munro et al., 1993)
Existing evidence Studies Epidemiological studies Clinical studies Biochemical studies Genetic studies Imaging studies
Epidemiological studies - A causal link: Swedish study (1969) of 50,000 Swedish conscripts followed up for 15 years showed an increased risk amongst those who smoked cannabis; 1. those who were heavy users at age 18 were 6 times more likely to develop schizophrenia over the next 15 years; 2. increased risk in those who have genetic vulnerability (i.e.; someone else in family suffers from severe mental illness (Andreasson et al., 1987). - The reanalysis of the Swedish study showed that there is an associated risk of developing schizophrenia consistent with a causal relation. This association is not explained by use of other drugs or personality traits (Zammit et al., 2002). - A Dutch study: 7500 people followed for 3 years. Regular consumers were more likely to develop schizophrenia (Van Os et al., 2002). - The Prospective Dunedin (New Zealand) Multidisciplinary Health and Development Study: 1037 individuals followed up from birth in New Zealand (Arseneault et al., 2002) 1. At age 11: information on psychotic symptoms 2. At ages 15, 18: their drug use assessed 3. At age 26: their psychotic symptoms assessed The study found that people who used cannabis by the age of 15 were four times as likely to show an increase in SCZ symptoms at the age of 26.
Epidemiological studies Systematic review of studies, cannabis use and psychosis risk (Moore et al., 2007) Systematic review of evidence related to cannabis use and occurrence of mental health outcomes Longitudinal and population based studies Cannabis use increases the risk of development of a psychotic illness in a dose dependent manner No strong evidence as yet that earlier cannabis use is particularly harmful Systematic meta-analysis, cannabis use and earlier onset of psychosis (Large et al., 2011) 443 articles: 83 studies met the inclusion criteria, involving: 1. 8167 substance-using patients 2. 14352 non-substance-using patients Meta-analysis of age at onset of psychosis revealed that the age at onset was 2.70 years earlier among samples of cannabis users (p<.001) A further meta-analysis of other confounding factors (Large et al., 2012) Possible confounding factors including: - Tobacco use - Diagnosis - Male gender - Study quality The association between cannabis use and earlier onset of psychosis is robust It is not the result of tobacco smoking by cannabis using patients or the other potentially confounding factors
Clinical studies Review of clinical studies (Atakan et al., 2008) Cannabis use in those with serious mental illness has been associated with: Poor social functioning Increased rates of violence Increased rates of suicide Increased rates of victimization Homelessness Criminal behaviour Poorer physical health Heavy burden on health services Early psychotic breakdown Exacerbation or precipitation of symptoms Poor adherence to treatment Increased rates of hospitalization Increased duration of hospitalization Increased duration of psychotic episode
The adverse effect of cannabis use on outcome of First Episode Psychosis is mediated by poor medication adherence Colizzi et al., 2015 Schizophrenia Research
Biochemical studies - The main psychotomimetic compound of the cannabis plant, delta-9-thc has an agonist/partial agonist effect on CB1 receptors (Pertwee, 2008) - Endocannabinoid and dopaminergic systems are co-localized in the CNS - Dopamine alterations have been reported in patients with schizophrenia (Laurelle, 1998) - Delta-9-THC increases dopamine release in the human striatum (Murray et al., 2014) - CBD reduces anxiety and has a profile similar to atypical antipsychotics (Atakan, 2008) Genetic studies Gene environment interaction studies have mainly focussed on genetic variants involved in the regulation of the dopaminergic system: - COMT (Caspi et al., 2005) - AKT1 (van Winkel et al., 2011; Di Forti et al., 2012) - DAT1 (Bhattacharyya et al., 2012) - BDNF Val66Met (Decoster et al., 2011) - CNR1 and NRG1 (Pelayo-Teran et al., 2012) Some genes seem to explain susceptibility to cannabis related psychosis Imaging studies - Long-term heavy cannabis users: reduction in bilateral hippocampal and amygdala volumes (Yucel et al., 2008) - First Episode Psychosis (FEP) cannabis users: decrease in GM density in the right posterior cingulate cortex, when compared with FEP with no cannabis use (Bangalore et al., 2008) - CNR1 rs2023239 by cannabis use interaction on bilateral hippocampus volumes (Schacht et al., 2012) Cannabis use alters the brain structure
Not every cannabis user develops psychosis.. Atakan et al., 2012
Cannabis and psychosis: the role of DRD2 gene DRD2 gene (11q22-q23 ) D2L D2S
Interaction between functional genetic variation of DRD2 and cannabis use on risk of psychosis and on schizotypy and working memory Interaction between DRD2 rs1076560 and cannabis use on healthy subjects Working Memory Test (2-back) accuracy Interaction between DRD2 rs1076560 and cannabis use on healthy subjects Schizotypy (SPQ questionnaire) N = 252 N = 252 Interaction between DRD2 rs1076560 and cannabis use (lifetime and frequency of use) on psychosis risk N = 506 N = 439 *Adjusted for gender, age, ethnicity, alcohol, stimulants and tobacco use Colizzi et al., 2015 Schizophrenia Bulletin
Dopamine-related behaviors Beyond camp: the regulation of AKT and GSK3 by dopamine receptors The effect of given genotype(s) on the risk of a disease can change in magnitude and direction (qualitative interaction) depending on the degree of environmental exposure
Interaction between DRD2 and AKT1 genetic variation on risk of psychosis in cannabis users Interaction between DRD2 rs1076560/akt1 rs2494732 and cannabis use (lifetime and frequency of use) on psychosis risk N = 450 N = 402 Colizzi et al., 2015 Nature Schizophrenia
Questions What do we know now? Does cannabis trigger an earlier onset of psychosis in predisposed people? Yes Does cannabis exacerbate the psychotic symptoms generally? Yes Does the cannabis use worsen the outcome and progress of the illness? Yes Is there a causal link? Yes, but only in those with a predisposition to psychosis
Cannabis and psychosis: is it just dopamine? To summarize.. Involvement of presynaptic dopamine dysfunction in psychosis is compelling (Howes & Murray, Lancet 2014) Vulnerability to the psychotogenic effects of cannabis use involves genes that control dopamine signalling postsynaptically (Colizzi et al., 2015) What about direct effect of THC on dopamine? Little evidence to suggest that cannabis use affected acute striatal dopamine release or chronic dopamine receptor status in humans (Sami et al., 2015)
Cannabis and psychosis: the role of CNR1 gene CNR1 gene (6q14-q15 ) Endogenous ligands Cannabis
Functional genetic variation of the CNR1 and cannabis use interact on prefrontal connectivity and related working memory behavior Association between CNR1 rs1406977 and postmortem CNR1 prefrontal mrna expression Interaction between CNR1 rs1406977 and cannabis use on healthy subjects Working Memory Test (2-back) accuracy N = 208 Interaction between CNR1 rs1406977 and cannabis use on Left VLPFC during Working Memory Test (2-back) N = 208 Colizzi et al., 2014 Neuropsychopharmacology
Cannabis and glutamate -> it is thought that cannabis or Δ9-THC may not act on dopamine firing directly but indirectly by altering glutamate neurotransmission. Limited research carried out in humans tends to support the evidence that chronic cannabis use reduces levels of glutamate-derived metabolites in both cortical and subcortical brain areas. Research in animals tends to consistently suggest that 1. Δ9-THC depresses glutamate synaptic transmission via CB1 receptor activation, 2. disrupting glutamate synaptic plasticity after prolonged exposure, affecting glutamate release, inhibiting 3. receptors and 4. transporters function, 5. reducing enzyme activity
Hypotheses under investigation 1. is to employ a placebocontrolled acute pharmacological challenge design to test the hypothesis that relative to placebo acute 9 -THC administration will be associated with a reduction in glutamate levels as indexed by proton magnetic resonance spectroscopy (1H-MRS) in the hippocampus and striatum Hypofunction in glutamate neurotransmission: primary deficit determining the dopamine abnormalities consistently reported in schizophrenia (Howes et al., 2015)
Hypotheses under investigation 2. acute administration of 9 -THC will be associated with the induction of transient psychotic symptoms in these healthy volunteers and that these effects on symptoms will be directly related to the changes in glutamate in the proposed brain areas induced by it
Hypotheses under investigation 3. effect of acute 9 -THC on hippocampal activity while performing a verbal paired associate learning task, and test for a mediating effect of altered glutamate neurotransmission in the association between acute cannabis exposure and hippocampal dysfunction during verbal memory processing 9 -THC and memory 9 -THC reduces hippocampal neuron activation, relevant to memory formation Brain imaging studies show regular 9 -THC users have a smaller hippocampus 9 -THC affects memory in healthy subjects
Conclusions The present results support the theory that some individuals carry genetic vulnerability to the psychotogenic effect of cannabis. The character of this vulnerability is likely to be a polygenic gene-environment interaction. Identifying those genes and organizing them into genetic pathways will facilitate understanding the mechanisms that modulate the relationship between cannabis exposure and psychosis.
Acknowledgments Prof. Alessandro Bertolino Group of Neuroscience, Bari Prof. Sir Robin M Murray Dr. Marta Di Forti GAP study, London Dr Sagnik Bhattacharyya Prof. Philip McGuire