Inflammation in Schizophrenia: Pathogenetic Aspects and Therapeutic Considerations

Norbert Müller


Schizophr Bull. 2018;44(5):973-982. 

In This Article

Abstract and Introduction


This paper discusses the current evidence from animal and human studies for a central role of inflammation in schizophrenia. In animal models, pre- or perinatal elicitation of the immune response may increase immune reactivity throughout life, and similar findings have been described in humans. Levels of pro-inflammatory markers, such as cytokines, have been found to be increased in the blood and cerebrospinal fluid of patients with schizophrenia. Numerous epidemiological and clinical studies have provided evidence that various infectious agents are risk factors for schizophrenia and other psychoses. For example, a large-scale epidemiological study performed in Denmark clearly showed that severe infections and autoimmune disorders are such risk factors. The vulnerability-stress-inflammation model may help to explain the role of inflammation in schizophrenia because stress can increase pro-inflammatory cytokines and may even contribute to a chronic pro-inflammatory state. Schizophrenia is characterized by risk genes that promote inflammation and by environmental stress factors and alterations of the immune system. Typical alterations of dopaminergic, serotonergic, noradrenergic, and glutamatergic neurotransmission described in schizophrenia have also been found in low-level neuroinflammation and consequently may be key factors in the generation of schizophrenia symptoms. Further support for the relevance of a low-level neuroinflammatory process in schizophrenia is provided by the loss of central nervous system volume and microglial activation demonstrated in neuroimaging studies. Last but not least, the benefit of anti-inflammatory medications found in some studies and the intrinsic anti-inflammatory and immunomodulatory effects of antipsychotics provide further support for the role of inflammation in this debilitating disease.


Inflammation is a necessary response to infection, harmful chemicals, and tissue damage.[1] In addition to protecting the body, however, it may have harmful effects, as seen in infectious and autoimmune diseases, eg, multiple sclerosis (MS). The contrasting effects of inflammation are also seen in the central nervous system (CNS), where it may be neuroprotective or neurotoxic.[2] Whether the inflammation response has positive or negative effects depends on interactions between environmental factors and various components of the inflammatory response, whereby genetic variation plays an important role in the latter.

The negative effects of inflammation also depend on whether the inflammatory state is acute or chronic. Acute encephalitis in the CNS, eg, can be potentially fatal within a matter of hours or days, whereas chronic inflammation in the CNS may have negative effects for months or years and even over the course of a lifetime. MS is another example of an inflammatory disease that can be both acute, with relapses interspersed with periods of remission, or chronic and progressive. Both the acute and chronic manifestations of MS are purported to be a result of inflammation in the CNS,[3] in the sense of a "smoldering inflammation." The inflammatory mechanisms are hypothesized to differ in the acute and chronic stages, whereas the peripheral immune system is proposed to be closely involved in the acute stage in that macrophages and B- and T-cells invade the CNS, it is thought not to play a role in the chronic phase, in which a local immune response in the CNS is at play that is separate from the peripheral immune system ("compartmentalization" of the inflammatory process).[4,5] This hypothesis is supported by the fact that disseminated activation of microglial cells (which arise partly from the yolk sac and partly reside in the brain as macrophages) is the primary characteristic of chronic MS.[6]

Because MS is a disease of the CNS and can have a waxing and waning or chronic course, claims have often been made that the pathogenetic mechanisms of MS may be similar to those of schizophrenia.[7] Schizophrenia has often been described to be associated with chronic inflammation in the CNS.[8] Symptoms of schizophrenia have been described in several inflammatory diseases, eg, in the encephalitic form of MS;[9] in viral infections of the CNS, eg, herpes simplex virus type 1 (HSV-1),[10] HSV-2,[11] and measles;[12] and in autoimmune diseases, eg, poststreptococcal disorders,[13–16] and system lupus erythematosus and scleroderma.[17–19] However, inflammatory mechanisms differ between MS and schizophrenia, eg, because typical centers of inflammation are not found in schizophrenia. Possible mechanisms of inflammation in schizophrenia are discussed below.