Schizophrenia and Influenza at the Centenary of the 1918-1919 Spanish Influenza Pandemic: Mechanisms of Psychosis Risk

Abstract

Associations between influenza infection and psychosis have been reported since the eighteenth century, with acute "psychoses of influenza" documented during multiple pandemics. In the late 20^th century, reports of a season-of-birth effect in schizophrenia were supported by large-scale ecological and sero-epidemiological studies suggesting that maternal influenza infection increases the risk of psychosis in offspring. We examine the evidence for the association between influenza infection and schizophrenia risk, before reviewing possible mechanisms via which this risk may be conferred. Maternal immune activation models implicate placental dysfunction, disruption of cytokine networks, and subsequent microglial activation as potentially important pathogenic processes. More recent neuroimmunological advances focusing on neuronal autoimmunity following infection provide the basis for a model of infection-induced psychosis, potentially implicating autoimmunity to schizophrenia-relevant protein targets including the N-methyl-D-aspartate receptor. Finally, we outline areas for future research and relevant experimental approaches and consider whether the current evidence provides a basis for the rational development of strategies to prevent schizophrenia.

Keywords: autoimmunity; epidemiology; infection; influenza; maternal immune activation (MIA); neurodevelopment; schizophrenia.

Figure 1

Structure of the influenza virus.

Figure 2

Potential interactions between mechanisms related to influenza infection and development of schizophrenia or other psychotic disorders. Arrows indicate possible directions of interaction. Boxes represent different factors or changes which mediate processes possibly leading to the development of psychosis or schizophrenia.