Inflammation and immunity in schizophrenia: implications for pathophysiology and treatment

Abstract

Complex interactions between the immune system and the brain might have important aetiological and therapeutic implications for neuropsychiatric brain disorders. A possible association between schizophrenia and the immune system was postulated over a century ago, and is supported by epidemiological and genetic studies pointing to links with infection and inflammation. Contrary to the traditional view that the brain is an immunologically privileged site shielded behind the blood-brain barrier, studies in the past 20 years have noted complex interactions between the immune system, systemic inflammation, and the brain, which can lead to changes in mood, cognition, and behaviour. In this Review, we describe some of the important areas of research regarding innate and adaptive immune response in schizophrenia and related psychotic disorders that, we think, will be of interest to psychiatric clinicians and researchers. We discuss potential mechanisms and therapeutic implications of these findings, including studies of anti-inflammatory drugs in schizophrenia, describe areas for development, and offer testable hypotheses for future investigations.

Figure 1. How peripheral immune signals reach the brain to contribute to neuropsychiatric symptoms

(A) Neural pathway: peripheral cytokines activate the vagus nerve, and the signal reaches brain nuclei by retrograde axonal transport. (B) Humoral pathway: panel on right shows macrophage-like cells residing in the CVOs and the CP responding to circulating PAMPs by producing cytokines which enter the brain by volume diffusion. Panel on left shows that inflammation activates cerebral vascular endothelial cells. This leads to increased transmigration of monocytes into the brain, and activation of microglia and perivascular macrophages. All of these cells release proinflammatory cytokines in the brain. Adapted with permission from Dantzer and colleagues. NTS=nucleus tractus solitarius. VLM=ventrolateral medulla. CEA=central amygdala. PVN=periventricular nucleus. SON=supraoptic nucleus. PB=parabrachial nucleus. PAG=periaqueductal grey. BNST=bed nucleus for stria terminalis. CP=choroid plexus. TLR=Toll-like receptor. PAMP=pathogen-associated molecular patterns. CVO=circumventricular organ. PVM=peri-vascular macrophage.

Figure 2. Possible mechanisms of immune-mediated causation of psychosis

TNFα=tumour necrosis factor α. CNS=central nervous system.