title: A review of vulnerability and risks for schizophrenia: Beyond the two hit hypothesis.
abstract: Schizophrenia risk has often been conceptualized using a model which requires two hits in order to generate the clinical phenotype-the first as an early priming in a genetically predisposed individual and the second a likely environmental insult. The aim of this paper was to review the literature and reformulate this binary risk-vulnerability model. We sourced the data for this narrative review from the electronic database PUBMED. Our search terms were not limited by language or date of publication. The development of schizophrenia may be driven by genetic vulnerability interacting with multiple vulnerability factors including lowered prenatal vitamin D exposure, viral infections, smoking intelligence quotient, social cognition cannabis use, social defeat, nutrition and childhood trauma. It is likely that these genetic risks, environmental risks and vulnerability factors are cumulative and interactive with each other and with critical periods of neurodevelopmental vulnerability. The development of schizophrenia is likely to be more complex and nuanced than the binary two hit model originally proposed nearly thirty years ago. Risk appears influenced by a more complex process involving genetic risk interfacing with multiple potentially interacting hits and vulnerability factors occurring at key periods of neurodevelopmental activity, which culminate in the expression of disease state. These risks are common across a number of neuropsychiatric and medical disorders, which might inform common preventive and intervention strategies across non-communicable disorders.
authors.affiliation: Deakin University, IMPACT Strategic Research Centre, School of Medicine, Barwon Health, P.O. Box 291, Geelong, 3220, Australia. Electronic address: justinbdavis19@gmail.com.
authors.forename: Justin
authors.initials: J
authors.lastname: Davis
authors.affiliation: Deakin University, IMPACT Strategic Research Centre, School of Medicine, Barwon Health, P.O. Box 291, Geelong, 3220, Australia.
authors.forename: Harris
authors.initials: H
authors.lastname: Eyre
authors.affiliation: Deakin University, IMPACT Strategic Research Centre, School of Medicine, Barwon Health, P.O. Box 291, Geelong, 3220, Australia; University of Melbourne, Department of Psychiatry, Level 1 North, Main Block, Royal Melbourne Hospital, Parkville, 3052, Australia; Centre for Adolescent Health, Murdoch Children's Research Institute, Melbourne, Australia; Black Dog Institute, Sydney, Australia.
authors.forename: Felice N
authors.initials: FN
authors.lastname: Jacka
authors.affiliation: Deakin University, IMPACT Strategic Research Centre, School of Medicine, Barwon Health, P.O. Box 291, Geelong, 3220, Australia; University of Melbourne, Department of Psychiatry, Level 1 North, Main Block, Royal Melbourne Hospital, Parkville, 3052, Australia.
authors.forename: Seetal
authors.initials: S
authors.lastname: Dodd
authors.affiliation: Deakin University, IMPACT Strategic Research Centre, School of Medicine, Barwon Health, P.O. Box 291, Geelong, 3220, Australia; University of Melbourne, Department of Psychiatry, Level 1 North, Main Block, Royal Melbourne Hospital, Parkville, 3052, Australia.
authors.forename: Olivia
authors.initials: O
authors.lastname: Dean
authors.affiliation: Semel Institute for Neuroscience and Human Behavior, UCLA, United States.
authors.forename: Sarah
authors.initials: S
authors.lastname: McEwen
authors.affiliation: Department of Human Genetics, National Institute of Mental Health and Neurosciences, Bangalore, India.
authors.forename: Monojit
authors.initials: M
authors.lastname: Debnath
authors.affiliation: Queensland Brain Institute, The University of Queensland, Brisbane, 4072, Queensland, Australia; Queensland Centre for Mental Health Research, The Park Centre for Mental Health, Wacol, Queensland 4076, Australia.
authors.forename: John
authors.initials: J
authors.lastname: McGrath
authors.affiliation: Deakin University, IMPACT Strategic Research Centre, School of Medicine, Barwon Health, P.O. Box 291, Geelong, 3220, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Maes
authors.affiliation: Queensland Brain Institute, The University of Queensland, Brisbane, 4072, Queensland, Australia; Orygen, The National Centre of Excellence in Youth Mental Health and Orygen Youth Health Research Centre, 35 Poplar Rd., Parkville, 3052, Australia.
authors.forename: Paul
authors.initials: P
authors.lastname: Amminger
authors.affiliation: Orygen, The National Centre of Excellence in Youth Mental Health and Orygen Youth Health Research Centre, 35 Poplar Rd., Parkville, 3052, Australia; Centre of Youth Mental Health, University of Melbourne, 35 Poplar Rd., Parkville, 3052, Australia.
authors.forename: Patrick D
authors.initials: PD
authors.lastname: McGorry
authors.affiliation: University of Melbourne, Department of Psychiatry, Level 1 North, Main Block, Royal Melbourne Hospital, Parkville, 3052, Australia; Department of Human Genetics, National Institute of Mental Health and Neurosciences, Bangalore, India; Melbourne Neuropsychiatry Centre, The University of Melbourne & Melbourne Health, Parkville, 3052, Australia; Florey Institute for Neuroscience and Mental Health, University of Melbourne, Kenneth Myer Building, 30 Royal Parade, 3052, Parkville, Australia.
authors.forename: Christos
authors.initials: C
authors.lastname: Pantelis
authors.affiliation: Deakin University, IMPACT Strategic Research Centre, School of Medicine, Barwon Health, P.O. Box 291, Geelong, 3220, Australia; University of Melbourne, Department of Psychiatry, Level 1 North, Main Block, Royal Melbourne Hospital, Parkville, 3052, Australia; Queensland Centre for Mental Health Research, The Park Centre for Mental Health, Wacol, Queensland 4076, Australia; Orygen, The National Centre of Excellence in Youth Mental Health and Orygen Youth Health Research Centre, 35 Poplar Rd., Parkville, 3052, Australia; Centre of Youth Mental Health, University of Melbourne, 35 Poplar Rd., Parkville, 3052, Australia; Florey Institute for Neuroscience and Mental Health, University of Melbourne, Kenneth Myer Building, 30 Royal Parade, 3052, Parkville, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Berk
mesh_terms: D004777:Environment; D020022:Genetic Predisposition to Disease; D006801:Humans; D010641:Phenotype; D012307:Risk Factors; D012559:Schizophrenia