Canetta et al. report a small but robust dose-response relationship between prenatal inflammatory markers and later schizophrenia. It is possible, though unlikely, that the association is one of simple cause and effect, where a single prenatal insult is sufficient in itself to lead to elevated proinflammatory cytokines, altered brain development, and subsequent psychiatric disorder. Urs Meyer and his research group (19) have proposed a “two-hit” model, based on animal work, whereby an early infection, or other inflammatory process, “primes” the developing brain, but the onset of disorder requires a second stressor during the pubertal period. Translated to human terms, we could speculate that exposure to an elevated inflammatory state in prenatal life or early childhood (for example, as a result of prenatal infection, maternal stress, early-life adversity, or obstetric exposures), and possibly in association with a genetic vulnerability toward dysregulation of the immune system (20), may “prime” the brain and lead to vulnerability. This vulnerability state may be expressed, for example, clinically as early psychotic symptoms (21), cognitively as subtle speed of processing deficits (22), or neurologically as disrupted brain connectivity through altered synaptic pruning (23). Further stressors during youth development, such as adolescent bullying, assault, stressful life transitions, relationship breakups, or substance use, may serve to convert the vulnerability into disorder (14). These ideas are presented graphically in Figure 1.
FIGURE 1.Two-Hit Developmental Model of Vulnerability to Psychosis