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 Nmethyl-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.

Are we facing a crashing wave of neuropsychiatric sequelae of COVID-19? Neuropsychiatric symptoms and potential immunologic mechanisms

“…Long-term neuropsychiatric complications following SARS-CoV-2 infection are currently unknown and remain to be seen over the next several months to years. Following past influenza pandemics and CoV outbreaks, such complications have been described over highly variable periods of time, from weeks following acute respiratory symptoms in the case of neuromuscular and demyelinating processes, to decades after in-utero exposure to viral infection in the case of schizophrenia onset (Kępińska et al, 2020;Kim et al, 2017;Tsai et al, 2004). Given the global burden of COVID-19 infection, even if delayed neuropsychiatric sequelae are associated with a fraction of cases, the public health implications of such complications will be significant.…”

COVID-19 Infection During Pregnancy and Risk of Neurodevelopmental Disorders in Offspring: Time for Collaborative Research

“…Cumulative studies have demonstrated that acute respiratory virus infections such as CoVs and influenza can lead to long-term neurological and neuropsychiatric symptoms ( 3 , 4 , 5 ). Moreover, there is evidence suggesting an association between prenatal exposure to these respiratory infections and an increased risk of neurodevelopmental disorders in offspring, such as schizophrenia, bipolar disorder, and autism ( 4 , 6 ). The potential for over 100 million women currently pregnant around the world to be exposed to COVID-19 ( 2 ) raises concerns about the possible increased risk of neurodevelopmental disorders in their offspring.…”

Persistent psychotic symptoms following COVID-19 infection

“…During the Spanish influenza pandemic 'psychoses of influenza' were widely reported, and described by Karl Menninger in his case series of 100 patients with mental disturbances associated with influenza infection. He subsequently described two forms of post-influenza psychoses; schizophrenia deliriosa and delirium schizophrenoides, 12,13 the latter 'a psychosis arising in close association with the somatic illness but so colored with the hues and tints of schizophrenia that one feels obliged to give a pessimistic prognosis which is usually belied by the further course of the disease, namely, it's eventual disappearance'. Epidemiological evidence has shown an increased risk of psychosis in people with a history of severe infection 14,15 and genomewide association studies have implicated multiple immune signalling pathways.…”