Inflammation in Schizophrenia: Pathogenetic Aspects and Therapeutic Considerations

Norbert Müller

Disclosures

Schizophr Bull. 2018;44(5):973-982. 

In This Article

The Vulnerability-stress-inflammation Model of Schizophrenia

Forty years ago, Zubin and Spring[34] first proposed the vulnerability-stress model of schizophrenia. This model proposes that stress, whether physical or mental, can trigger a psychotic episode. Today, this model has to be expanded to become the vulnerability-stress-inflammation model because inflammation is known to play a role in schizophrenia and can be induced by stress. For example, if an inflammatory response is stimulated in mothers in the second trimester or in the offspring while the CNS is still developing, the offspring have greater vulnerability for schizophrenia. Studies in animals have shown that stress leads to increased levels of pro-inflammatory cytokines.[26] Genetic makeup also contributes to the level of vulnerability to stress, as described in the pathogen-host defense hypothesis.[35] Markers of inflammation and the effects of inflammation on neurotransmitter systems in schizophrenia are described in detail below (see Figure 1).

Figure 1.

Overview of the vulnerability-stress-inflammation model of schizophrenia. Adapted from Ref.41 LPS: lipopolysaccharides; poly I:C: polyinosinic-polycytidylic acid.

Markers of Inflammation

Only a few of the studies on markers of inflammation can be discussed here because of space limitations. Such studies have found degradation products of fibrin, a protein that is increased in inflammatory processes, in brains of schizophrenia patients' postmortem[36] and in the cerebrospinal fluid (CSF) of about 50% of patients with schizophrenia.[37] Furthermore, several studies have observed a blunted type 1 and an increased type 2 cytokine pattern in untreated patients with schizophrenia.[38] A meta-analysis of cytokines in schizophrenia found higher levels of pro-inflammatory cytokines in the peripheral blood in both patients with first-episode schizophrenia and relapsed patients than in healthy controls, but it also found higher levels of some anti-inflammatory cytokines in these patients than in controls.[39] A meta-analysis of cytokines in the CSF showed similar results, ie, higher levels of proinflammatory and lower levels of anti-inflammatory cytokines.[40] A critical discussion of these findings has to consider confounding factors, such as smoking, body mass index, gender, sleep, medication, etc. Moreover, several cytokines act primarily in a paracrine way, and blood levels of these cytokines may not appropriately reflect their function. A general discussion has to mention that the brain is protected from peripheral inflammation by the blood-brain barrier and that an immune activation, including an increase in pro-inflammatory cytokines in the blood, does not reflect the situation in the brain.[41] Nevertheless, different means of communication exist between the peripheral and the CNS immune systems.[41]

An inflammatory process is proposed to be involved in the pathophysiology of at least a subgroup of patients with schizophrenia.[42,43]

The Effect of Inflammation on Neurotransmitters

Disturbance of dopaminergic neurotransmission has long been the primary focus of research into the neurobiology of schizophrenia, and it is clear that schizophrenia involves a dysfunction of the dopamine system.[44] However, the exact relationship between the disturbance and the disease is yet to be elucidated, and results of studies on antidopaminergic drugs are unsatisfactory.

At least two interleukins (ILs) appear to play an important role in the effects on neurotransmitter systems in schizophrenia: IL-1β, which induces rat mesencephalic progenitor cells to be converted into a dopaminergic phenotype,[45–47] and IL-6, which decreases the survival of serotonergic neurons in fetal brain.[48] Although increases in pro-inflammatory cytokines are not specific for schizophrenia and described also in other psychiatric disorders, the interaction between cytokines and neurotransmitters in certain brain regions and in particular during brain development contributes to the pathophysiology of schizophrenia. In a mouse model of viral-like infection, the number of mesencephalic dopaminergic neurons increased in the brains of fetuses after an immune response was elicited in the pregnant dams.[49] The authors proposed that the increase was likely associated with an excess of dopamine in the midbrain, a structure involved in schizophrenia in humans.[49] Latent persistent infections have been proposed to potentially cause imbalances of the immune reaction.[50] Chronic administration of interferon-α in animals, however, is associated with a reduction in the release of striatal dopamine and with anhedonia.[51] This finding points to diverse effects of inflammation on dopaminergic neurotransmission, which may play a role in chronification of schizophrenia. Anhedonia is well known to be a characteristic negative symptom in schizophrenia, and negative symptoms are often found in chronic schizophrenia.[52]

Glutamate, the most abundant neurotransmitter in the CNS, is assumed to be a key factor in the pathophysiology of schizophrenia because of its involvement in cytokine-directed tryptophan/kynurenine metabolism, which is mediated via NMDA receptors, among others. Kynurenic acid is the only known naturally occurring NMDA receptor antagonist in the human CNS[53] and is one of three or more intermediate neuroactive products in the kynurenine pathway. In the proposed mechanism of effect in schizophrenia, a predominant type 2 immune response inhibits indoleamine 2,3-dioxygenase (IDO), which results in increased production of kynurenic acid and consequently in antagonism at NMDA receptors and a lack of glutamate neurotransmission.[54,55] The finding that NMDA receptor antibodies are present in about 10% of unmedicated patients with acute schizophrenia supports the view that NMDA receptor antagonism plays a role in the pathology of schizophrenia.[56,57] However, findings on the relevance of kynurenic acid in schizophrenia are inconsistent. Some studies found increased kynurenic acid levels, mainly in the CSF[58,59] and brains of patients with schizophrenia[60,61] and in animal models of schizophrenia,[62] whereas others found no increase in kynurenic acid levels in the peripheral blood of patients with first-episode schizophrenia[63] or in other groups of schizophrenia patients.[64] An important caveat for many of the studies discussed in this section is that the patient samples are generally not antipsychotic naïve, and antipsychotics can potentially interfere with biomarker levels, including the metabolites of the kynurenic metabolism.[63–65] Moreover, kynurenic acid in the CSF and blood may show different concentrations in schizophrenia because CSF may represent a pathological process better than peripheral blood.

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