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.

MK-801-induced impairments on the trial-unique, delayed nonmatching-to-location task in rats: effects of acute sodium nitroprusside

“…This neurodevelopmental disorder is the consequence of an interaction between genetic susceptibility and environmental factors (Davis et al 2016). Symptom presentation, severity, and response to treatment is highly heterogeneous in this patient population (O'Connor and O'Shea 2015).…”

“…Etiological validity measures how consistent the development of the modeled condition is with the human disorder. The development of schizophrenia is due to an interplay between genetic and environmental factors (Davis et al 2016). Therefore, the acute administration and short-term behavioral changes that follow a single MK-801 injection are indicative of limited etiological validity.…”

Effects of Environmental Enrichment on Nicotine Sensitization in Rats Neonatally Treated with Quinpirole: Analyses of Glial Cell Line-Derived Neurotrophic Factor and Implications towards Schizophrenia

“…The animals were administered saline or nicotine for 8 consecutive days from P38 to P45, and brain tissue was harvested 24 h after the last drug administration on P46. The rationale for studying animals during adolescence was that this developmental period has been identified as particularly vulnerable in individuals diagnosed with schizophrenia [36].…”

Neural mechanisms of MK-801 induced sensitisation

“…The aetiology of schizophrenia is dependent not only on genetic background, but is also influenced by numerous environmental risk factors (van Os et al, 2010). A comprehensive review of all the genetic and environmental risk factors is beyond the theme of this thesis (for recent reviews the reader is referred to: (Davis et al, 2016, Kotlar et al, 2015). …”