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      AKT1 genotype moderates the acute psychotomimetic effects of naturalistically smoked cannabis in young cannabis smokers

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          Abstract

          Smoking cannabis daily doubles an individual's risk of developing a psychotic disorder, yet indicators of specific vulnerability have proved largely elusive. Genetic variation is one potential risk modifier. Single-nucleotide polymorphisms in the AKT1 and catechol-O-methyltransferase (COMT) genes have been implicated in the interaction between cannabis, psychosis and cognition, but no studies have examined their impact on an individual's acute response to smoked cannabis. A total 442 healthy young cannabis users were tested while intoxicated with their own cannabis—which was analysed for delta-9-tetrahydrocannbinol (THC) and cannabidiol content—and also ±7 days apart when drug-free. Psychotomimetic symptoms and working memory were assessed on both the sessions. Variation at the rs2494732 locus of the AKT1 gene predicted acute psychotic response to cannabis along with dependence on the drug and baseline schizotypal symptoms. Working memory following cannabis acutely was worse in females, with some suggestion of an impact of COMT polymorphism on working memory when drug-free. These findings are the first to demonstrate that AKT1 mediates the acute response to cannabis in otherwise healthy individuals and implicate the AKT1 pathway as a possible target for prevention and treatment of cannabis psychosis.

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          Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia.

          M Egan, T Goldberg, B. S. Kolachana … (2001)
          Abnormalities of prefrontal cortical function are prominent features of schizophrenia and have been associated with genetic risk, suggesting that susceptibility genes for schizophrenia may impact on the molecular mechanisms of prefrontal function. A potential susceptibility mechanism involves regulation of prefrontal dopamine, which modulates the response of prefrontal neurons during working memory. We examined the relationship of a common functional polymorphism (Val(108/158) Met) in the catechol-O-methyltransferase (COMT) gene, which accounts for a 4-fold variation in enzyme activity and dopamine catabolism, with both prefrontally mediated cognition and prefrontal cortical physiology. In 175 patients with schizophrenia, 219 unaffected siblings, and 55 controls, COMT genotype was related in allele dosage fashion to performance on the Wisconsin Card Sorting Test of executive cognition and explained 4% of variance (P = 0.001) in frequency of perseverative errors. Consistent with other evidence that dopamine enhances prefrontal neuronal function, the load of the low-activity Met allele predicted enhanced cognitive performance. We then examined the effect of COMT genotype on prefrontal physiology during a working memory task in three separate subgroups (n = 11-16) assayed with functional MRI. Met allele load consistently predicted a more efficient physiological response in prefrontal cortex. Finally, in a family-based association analysis of 104 trios, we found a significant increase in transmission of the Val allele to the schizophrenic offspring. These data suggest that the COMT Val allele, because it increases prefrontal dopamine catabolism, impairs prefrontal cognition and physiology, and by this mechanism slightly increases risk for schizophrenia.
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            Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review.

            Theresa H M Moore, Stanley Zammit, Anne Lingford-Hughes … (2007)
            Whether cannabis can cause psychotic or affective symptoms that persist beyond transient intoxication is unclear. We systematically reviewed the evidence pertaining to cannabis use and occurrence of psychotic or affective mental health outcomes. We searched Medline, Embase, CINAHL, PsycINFO, ISI Web of Knowledge, ISI Proceedings, ZETOC, BIOSIS, LILACS, and MEDCARIB from their inception to September, 2006, searched reference lists of studies selected for inclusion, and contacted experts. Studies were included if longitudinal and population based. 35 studies from 4804 references were included. Data extraction and quality assessment were done independently and in duplicate. There was an increased risk of any psychotic outcome in individuals who had ever used cannabis (pooled adjusted odds ratio=1.41, 95% CI 1.20-1.65). Findings were consistent with a dose-response effect, with greater risk in people who used cannabis most frequently (2.09, 1.54-2.84). Results of analyses restricted to studies of more clinically relevant psychotic disorders were similar. Depression, suicidal thoughts, and anxiety outcomes were examined separately. Findings for these outcomes were less consistent, and fewer attempts were made to address non-causal explanations, than for psychosis. A substantial confounding effect was present for both psychotic and affective outcomes. The evidence is consistent with the view that cannabis increases risk of psychotic outcomes independently of confounding and transient intoxication effects, although evidence for affective outcomes is less strong. The uncertainty about whether cannabis causes psychosis is unlikely to be resolved by further longitudinal studies such as those reviewed here. However, we conclude that there is now sufficient evidence to warn young people that using cannabis could increase their risk of developing a psychotic illness later in life.
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              The SPQ: a scale for the assessment of schizotypal personality based on DSM-III-R criteria.

              A Raine (1990)
              Existing self-report measures of schizotypal personality assess only one to three of the nine traits of schizotypal personality disorder. This study describes the development of the Schizotypal Personality Questionnaire (SPQ), a self-report scale modeled on DSM-III-R criteria for schizotypal personality disorder and containing subscales for all nine schizotypal traits. Two samples of normal subjects (n = 302 and n = 195) were used to test replicability of findings. The SPQ was found to have high sampling validity, high internal reliability (0.91), test-retest reliability (0.82), convergent validity (0.59 to 0.81), discriminant validity, and criterion validity (0.63, 0.68), findings which were replicated across samples. Fifty-five percent of subjects scoring in the top 10 percent of SPQ scores had a clinical diagnosis of schizotypal personality disorder. Thus, the SPQ may be useful in screening for schizotypal personality disorder in the general population and also in researching the correlates of individual schizotypal traits.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Transl Psychiatry
                Journal ID (iso-abbrev): Transl Psychiatry
                Title: Translational Psychiatry
                Publisher: Nature Publishing Group
                ISSN (Electronic): 2158-3188
                Publication date (Print): February 2016
                Publication date (Electronic): 16 February 2016
                Publication date PMC-release: 1 February 2016
                Volume: 6
                Issue: 2
                Page: e738
                Affiliations
                [1 ]Clinical Psychopharmacology Unit, University College London , London, UK
                [2 ]Psychopharmacology and Addiction Research Centre, University of Exeter , Exeter, UK
                [3 ]Basic and Clinical Neurosciences, Institute of Psychiatry, Kings College London , London, UK
                Author notes
                [* ]Psychopharmacology and Addiction Research Centre, Washington Singer Laboratories, Department of Psychology , University of Exeter, Perry Road, Exeter EX4 4QG, UK. E-mail: celia.morgan@ 123456exeter.ac.uk
                Article
                Publisher Item ID: tp2015219
                DOI: 10.1038/tp.2015.219
                PMC ID: 4872423
                PubMed ID: 26882038
                SO-VID: a691ecc8-54c7-4068-960f-ab043daa676a
                Copyright © Copyright © 2016 Macmillan Publishers Limited
                License:

                This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

                History
                Date received : 23 July 2015
                Date revision received : 20 October 2015
                Date accepted : 09 November 2015
                Categories
                Subject: Original Article

                ScienceOpen disciplines: Clinical Psychology & Psychiatry
                Data availability:
                ScienceOpen disciplines: Clinical Psychology & Psychiatry

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