Biological mechanisms underlying the onset and outcome of cannabis-associated psychosis.

Schizophrenia and related psychoses are an important cause of morbidity and mortality, with an annual cost in England of about £12 billion. Prospective studies have consistently shown that heavy cannabis use increases risk of the subsequent development of schizophrenia and other psychotic disorders. Cannabis use in the UK is among the highest in Europe, and its use has been variously estimated to account for between 10% and 18% of all new cases of schizophrenia: it is a major clinical problem both in provoking onset of psychosis, and in precipitating relapse. The Schizophrenia Commission (2012) recommended that particular emphasis should be placed on research into, and public education about, the hazards of heavy cannabis use as this is the most preventable of risk factors for psychosis.
I work one day per week as a Consultant Psychiatrist treating young people suffering from psychosis, often following heavy cannabis use, and I see the suffering that this avoidable illness causes them and their families. As an Academic Psychiatrist, I am interested in the causes of psychosis, and I wish to establish those patterns of cannabis use which especially increase risk of psychosis. I am one of the organisers of the London site of a large European epidemiological study. Through this collaboration, I have detailed data on history of cannabis use (e.g. age at first use, duration/frequency of use, and use of high potency cannabis), on 1200 patients suffering their first episode of psychosis and 1200 healthy controls from the same populations, plus a further 800 of each from other studies I am coordinating. My analysis of these data will enable me to a) determine the relative frequency of cannabis-associated psychosis across 5 EU countries, and b) establish the patterns of cannabis use that best identify those at greatest risk of developing psychotic disorder.
Of course, most cannabis users do not develop psychosis, suggesting that individual susceptibility must also play a role. We took blood samples from the above 2000 patients with psychosis and 2000 controls, from which DNA was extracted. I will use genetic data to produce a summary score of genetic vulnerability to psychosis, for each of my cases and controls. Then I will analyse how differences in genetic vulnerability influence the individual's risk to develop a psychotic disorder following cannabis use.
On subsets of the whole sample, I will examine epigenetic and RNA expression data across the genome. Epigenetic data indicate how exposure to an environmental risk factor (e.g. cannabis use), can affect the way the DNA structure is expressed into RNA and then into proteins that impact on biological functions. My research will be the first to conduct such an integrated approach to establishing a) the biological changes which cannabis exposure induces, and b) if changes in epigenetics and RNA expression can be used as biological markers of why certain cannabis users have developed psychotic illness.
My London sample will be followed up at an average of 5 years from onset of illness to a) assess outcome, and b) repeat the measures of epigenetics and RNA expression. Thus I will be able to a) identify how cannabis use and genetic vulnerability interact in causing poor outcome; b) what biological markers predict the greatest cannabis-associated decline; and c) if such biological changes are reversible when cannabis use ceases.

The aetiology of schizophrenia involves both genetic vulnerability and several environmental risk factors, of which the most preventable is cannabis use. It is therefore important to establish a) the patterns of exposure to cannabis that are especially likely to provoke psychosis, and b) who is especially vulnerable. My study will build on a large epidemiological EU-FP7 study of first onset psychosis for which I designed the interview regarding drug use. I will examine: a) GWAS and cannabis use data from 2,000 cases and 2,000 controls; b) baseline peripheral blood EWAS data from a subset of cases and controls (N=800) with additional genome-wide RNA data (N=600). The London participants will be followed up at a mean of 5 years and re-sampled for longitudinal EWAS (N=600) and RNA(N=400)profiling analyses.
My aims are to:
1. Develop a simple method of assessing patterns of cannabis use which best predict the development of a cannabis-associated psychosis, and so enable identification of those individuals most at risk of a) psychosis onset and b) poor outcome.
2. Establish the proportion of psychosis cases attributable to cannabis use in 5 European countries.
3. Using the GWAs data, to determine the effectiveness of combining Schizophrenia Polygenic Risk scores, including Pathway-informed ones, with information on cannabis use in order to predict a)risk of developing a psychotic disorder; b)clinical and functional outcome 5 years following onset of psychosis.
4. Carry out longitudinal-multidimensional GWAS-guided analyses of a)EWAS and b)genome-wide RNA expression data to identify pathways involved in cannabis-associated psychosis.
My work will establish a)those patterns of cannabis use which best predict psychosis, b)easily accessible biological markers of susceptibility to the effect of cannabis in provoking the onset and persistence of psychosis. It will be useful in developing better tailored preventative strategies and may indicate new drug targets.

Alongside the academic and clinical aspects previously described, findings from my proposed studies have the potential to impact on a number of other fields. Firstly, at a general population level, my study will provide information on the patterns of cannabis use which carry the highest risk for psychosis. This will be useful for: a) Primary Care: developing a simple set of questions to use in the general practice setting to identify those cannabis users at most at risk to develop psychosis. This could then lead naturally on to advice being given to high risk individuals regarding life style changes as part of primary prevention; b) Public Education: developing clearer and better tailored public health campaigns educating young people on the risks to mental health of the frequent use of high potency cannabis. This would be best done in collaboration with the Media. I have already worked successfully with the Science Media Centre in translating to the wider public, the findings from my previous work; this attracted a lot of interest from Newspapers, radio and TV c) Governmental agencies e.g. Departments of health and Justice so that the policies and websites (e.g, Talk to Frank) they develop concerning cannabis are guided by the most up-to-date scientific evidence.
Importantly, my work should make a contribution to improving the detection and understanding of patients who have developed schizophrenia or other psychosis following cannabis use, and should aid their families and the services involved in their care. The recent Schizophrenia Commission Report (2012) pointed out that drug abuse, especially cannabis use, is a huge problem among patients with psychosis, and that in theory (but not yet in practise) this is a preventable/remediable problem. Sadly, the care such patients receive usually falls unhappily between general adult psychiatry and addiction services, and patients rarely get optimum treatment for both aspects of their illness. My ambition would be not only to contribute to further knowledge in this area, but also to train other general psychiatrists/mental health workers in the understanding, and assessment, of cannabis use among psychotic patients, encouraging collaboration with addiction clinicians. The evidence concerning prediction of outcome could have a significant impact on improving the course of this patient group, who when continuing to use cannabis, are more likely to poorly respond to treatment, suffer relapses and re-admission with great cost to their families and to Mental Health services. Moreover, my work investigating cannabis associated epigenetic and RNA expression changes markers of acquired susceptibility to develop psychotic disorders represents a step forward towards identifying potential blood biomarkers for: a) acquired risk of schizophrenia and other psychosis in cannabis users; b) outcome prediction of cannabis-associated psychosis.
Finally, I hope that the novelty of my proposed integrated genetic-epigenetic-RNA expression approach in the context of a specific environmental exposure, cannabis use, will lead to 1) wider scientific collaborations within the schizophrenia research community and beyond to replicate my findings and develop them further; 2) inform Pharma companies of potential new drug targets. In the long run, this could have significant impact on the treatment of cannabis associated-psychosis disorders and on psychosis in general, where all patients with psychosis have been treated with essentially the same type of medication, antipsychotics, which rely on a single target: the D2 dopamine receptor. For example, my mentor is already involved in a trial of the cannabis constituent, cannabidiol (CBD), in the treatment of psychosis; such trials could usefully be combined with measures of epigenetics and RNA expression which my study will develop.