Inflammation and the two-hit hypothesis of schizophrenia

Abstract

The high societal and individual cost of schizophrenia necessitates finding better, more effective treatment, diagnosis, and prevention strategies. One of the obstacles in this endeavor is the diverse set of etiologies that comprises schizophrenia. A substantial body of evidence has grown over the last few decades to suggest that schizophrenia is a heterogeneous syndrome with overlapping symptoms and etiologies. At the same time, an increasing number of clinical, epidemiological, and experimental studies have shown links between schizophrenia and inflammatory conditions. In this review, we analyze the literature on inflammation and schizophrenia, with a particular focus on comorbidity, biomarkers, and environmental insults. We then identify several mechanisms by which inflammation could influence the development of schizophrenia via the two-hit hypothesis. Lastly, we note the relevance of these findings to clinical applications in the diagnosis, prevention, and treatment of schizophrenia.

Keywords: Animal Models; Biomarkers; Comorbidity; Infection; Inflammation; Schizophrenia.

Figure 1

The two-hit hypothesis of schizophrenia relates to glutamate hypofunction. This figure summarizes how glutamate hypofunction can occur as the outcome of a number of different pathways. An inflammatory event at the early stages of development, either in utero or as an infant or young child, can be considered the first ‘hit.’ This can occur because of environmental stressors, often in the form of an immune event, and is modulated by genetic makeup. Retroviral elements and fatty acids/membrane composition can also influence this stage. After the initial insult, development can occur abnormally, such that neural development and glutamate signaling is altered permanently, or normally. In either case, the immune system may become ‘primed’ for a second insult. This can involve enhanced microglial activity, may be protected by hormonal balance, and can be heavily influenced by genetics, fatty acids/membrane composition, and environmental stressors. After adolescence, glutamate hypofunction can then result from directly from altered development, or from a second ‘hit’ by the primed immune system, possibly via activated microglia. This stage can also be regulated by additional immune insults, environmental stressors, or genetics.