Abstract
Genetic variation in AKT1 may be associated with sensitivity to the psychotomimetic effects of cannabis as well as with increased risk for psychotic disorder following cannabis use. Investigation of the effect of this interaction on relevant intermediate phenotypes for psychosis, such as cognition, may help to clarify the underlying mechanism. Thus, verbal memory (visually presented Word Learning Task), sustained attention (Continuous Performance Test, CPT), AKT1 rs2494732 genotype, and cannabis use were examined in a large cohort of patients with psychotic disorder. No evidence was found for AKT1 × cannabis interaction on verbal memory. Cannabis use preceding onset of psychotic disorder did interact significantly with AKT1 rs2494732 genotype to affect CPT reaction time (β=8.0, SE 3.9, p=0.037) and CPT accuracy (β=−1.2, SE 0.4, p=0.003). Cannabis-using patients with the a priori vulnerability C/C genotype were slower and less accurate on the CPT, whereas cannabis-using patients with the T/T genotype had similar or better performance than non-using patients with psychotic disorder. The interaction was also apparent in patients with psychotic disorder who had not used cannabis in the 12 months preceding assessment, but was absent in the unaffected siblings of these patients and in healthy controls. In conclusion, cannabis use before onset of psychosis may have long-lasting effects on measures of sustained attention, even in the absence of current use, contingent on AKT1 rs2494732 genotype. The results suggest that long-term changes in cognition may mediate the risk-increasing effect of the AKT1 × cannabis interaction on psychotic disorder.
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Acknowledgements
The infrastructure for the GROUP study is funded by the Geestkracht program of the Dutch Health Research Council (ZON-MW, Grant number 10-000-1002) and matching funds from participating universities and mental health care organizations (Site Amsterdam: Academic Psychiatric Centre AMC, Ingeest, Arkin, Dijk en Duin, Rivierduinen, Erasmus MC, GGZ Noord Holland Noord; Site Utrecht: University Medical Centre Utrecht, Altrecht, Symfora, Meerkanten, Riagg Amersfoort, Delta; Site Groningen: University Medical Center Groningen, Lentis, GGZ Friesland, GGZ Drenthe, Dimence, Mediant, GGZ De Grote Rivieren and Parnassia Bavo Groep; Site Maastricht: Maastricht University Medical Center, GGZ Eindhoven, GGZ Midden-Brabant, GGZ Oost-Brabant, GGZ Noord- Midden Limburg, Mondriaan Zorggroep, Prins Clauscentrum Sittard, RIAGG Roermond, Universitair Centrum Sint-Jozef Kortenberg, CAPRI University of Antwerp, PC Ziekeren Sint-Truiden, PZ Sancta Maria Sint-Truiden, GGZ Overpelt, OPZ Rekem). We are grateful for the generosity of time and effort by the families who make this GROUP project possible. The research leading to these results has received funding from the European Community′s Seventh Framework Program under grant agreement No. HEALTH-F2-2009-241909 (Project EU-GEI). The analyses were supported by unrestricted grants from Jansen-Cilag, Eli Lilly and Company, Astra-Zeneca, and Lundbeck.
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Dr van Winkel has been an unrestricted grant holder with AstraZeneca and Eli Lilly. Dr van Beveren has been an unrestricted grant holder with PsyNova Neurotech Cambridge. Professor De Haan has received research funding from Eli Lilly and honoraria from Eli Lilly, Janssen-Cilag, BMS, and AstraZeneca. Professor van Os is/has been an unrestricted research grant holder with, or has received financial compensation as an independent symposium speaker from Eli Lilly, BMS, Lundbeck, Organon, Janssen-Cilag, GSK, AstraZeneca, Pfizer, and Servier. Dr Cahn is/has been an unrestricted research grant holder with, or has received financial compensation as an independent symposium speaker or as a consultant from Eli Lilly, BMS, Lundbeck, Sanofi-Aventis, Janssen-Cilag, AstraZeneca, and Schering-Plough. Professor Myin-Germeys has received financial compensation as an independent symposium speaker from BMS and Janssen-Cilag. Professor Kahn is/has been an unrestricted research grant holder with, or has received financial compensation as an independent symposium speaker or as a consultant from AstraZeneca, Eli Lilly, Janssen-Cilag, Otsuka, Sinovion, Roche, and Envivo. All other authors declare no conflict of interest.
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GROUP investigators: René S Kahn1, Don H Linszen2, Jim van Os3,4, Durk Wiersma5, Richard Bruggeman5, Wiepke Cahn1, Lieuwe de Haan2, Lydia Krabbendam3, Inez Myin-Germeys3. 1Department of Psychiatry, University Medical Center Utrecht, Rudolf Magnus Institute of Neuroscience, The Netherlands; 2Department of Psychiatry, Academic Medical Centre University of Amsterdam, Amsterdam, The Netherlands; 3Department of Psychiatry and Psychology, School of Mental Health and Neuroscience, European Graduate School of Neuroscience (EURON), South Limburg Mental Health Research and Teaching Network (SEARCH), Maastricht University Medical Centre, Maastricht, The Netherlands; 4Department of Psychosis Studies, King's College, King's Health Partners, Institute of Psychiatry, De Crespigny Park, Denmark Hill, London, UK; 5Department of Psychiatry, University Medical Center Groningen, University of Groningen, The Netherlands.
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van Winkel, R., van Beveren, N., Simons, C. et al. AKT1 Moderation of Cannabis-Induced Cognitive Alterations in Psychotic Disorder. Neuropsychopharmacol 36, 2529–2537 (2011). https://doi.org/10.1038/npp.2011.141
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DOI: https://doi.org/10.1038/npp.2011.141
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