Mental disorders are a major clinical and scientific challenge in modern medicine with an estimated prevalence of approximately 17% of the population (1, 2). Schizophrenia is one of the most debilitating psychotic disorders due to the lack of effective treatment (3, 4). Schizophrenia is a chronic psychiatric disorder characterized by faulty perception and withdrawal from reality. Schizophrenia symptomatology comprises positive (delusions, hallucinations), negative symptoms (social withdrawal, apathy) cognitive alterations, disorganized thinking, and psychomotor disturbances (2). The average life expectancy of schizophrenia patients is 10–25 years less than the normal population due to health problems and a higher suicide rate (5–7). Despite its significant social implications, schizophrenia is neglected worldwide (3, 4, 8).

Current treatments for schizophrenia are inefficacious, and there is an unmet clinical need for new and safe therapeutic strategies (9–12). Schizophrenia is usually treated with typical or atypical antipsychotics. Typical antipsychotics often induce significant psychomotor side effects. Atypical antipsychotics are the usual first-line treatment, although they are associated with metabolic syndrome and an increased cardiovascular risk of death (11, 12). An explanation for the inefficacious treatments is the insufficient knowledge about the etiology of schizophrenia. Both groups of antipsychotics are believed to be antagonists for dopamine receptors in the brain, and thus, previous studies mostly focused on the dopaminergic system (13). Although dopaminergic dysfunction contributes to schizophrenia, the mechanisms leading to this dysfunction are unknown. Recent studies demonstrate an abnormal inflammatory profile that can cause neurotransmission dysfunction in schizophrenia (14, 15). Early infections and other immune alterations during pregnancy and development can contribute to schizophrenia and other neurological disorders (16–19). These studies are contemporary with recent investigations demonstrating that vagal stimulation controls both central and peripheral inflammation (20–24) and that vagal stimulation can provide therapeutic advantages for neuropsychiatric disorders, such as depression and epilepsy (25, 26). However, little is known about the potential of this mechanism for treating schizophrenia (27). We reasoned that vagal stimulation may control inflammation and provide novel therapeutic advantages for schizophrenia. In this article, we evaluate this hypothesis by reviewing autonomic vagal dysfunction in psychiatric disorders and discussing the potential of vagal stimulation and alpha-7 cholinergic receptor (α7nAChR) agonists for treating schizophrenia.

Unregulated inflammation induced by infection or trauma results in excessive production of inflammatory cytokines, such as tumor necrosis factor (TNF), interferon-γ (IFN-γ), and interleukins (IL-1β, IL-6, etc.). These cytokines influence the homeostasis of several organs, as well as the central nervous system (CNS) (28).

Despite the traditional view of the brain as an immunologically privileged site, multiple studies have demonstrated that the CNS interacts with peripheral inflammatory cytokines through several pathways, described as follows (29). First, the humoral pathway: peripheral cytokines diffuse into the CNS through circumventricular organs and structures lacking the blood–brain barrier (BBB). Second, the cellular pathway: peripheral immune cells enter the CNS due to alterations in the BBB permeability and through the actions of chemoattractant mediators. Third, the microbiota–gut–brain axis: the microbiota–gut can transmit signals to the brain via the vagus nerve, immune mediators, and microbial metabolites, thereby altering neurotransmission in the CNS (30, 31). Fourth, the recently discovered central lymphatic pathway or the glymphatic system: mediated by functional lymphatic vessels in the CNS (32). In this pathway, extracellular fluids (the cerebrospinal fluid and interstitial fluid) draining from the brain parenchyma to the cervical and lumbar lymph nodes facilitate the traffic of antigens and immune cells affecting peripheral and central inflammation (33). Finally, the neural pathway: the afferent vagus nerve detects peripheral inflammatory cytokines (TNF, IL-1β, IL-6) and transmits signals to the nucleus tractus solitarius, and thereby to the hypothalamus (29, 34). All these pathways serve as immune-to-brain cross talk that facilitate central inflammation and behavioral changes.

A balance between the pro- and anti-inflammatory cytokines is critical for proper brain development (35). Epidemiological studies indicate that infections during development increase the risk of schizophrenia in adulthood (36–39). These studies report an association between elevated maternal inflammatory cytokines levels (especially IL-8 and TNF) and risk of schizophrenia in adult offspring (16, 37). It has been observed in preclinical studies that maternal immune activation in rodents induces inflammatory cytokines (IL-1β, IL-6, TNF) and reduces anti-inflammatory cytokines (IL-10) in both the maternal fluids and in the fetal brain, inducing schizophrenia-like behaviors in the offspring (35, 40). Likewise, direct IL-6 inoculation into pregnant rodents also induces schizophrenia-like abnormalities in the offspring. This effect is prevented by neutralizing IL-6 antibodies, genetic depletion of the IL-6 gene (IL-6 knockout) (35), or overexpression of anti-inflammatory cytokines (IL-10) in the macrophages of pregnant dams (41).

Genetic studies have demonstrated the implications of immune-related genes in schizophrenia (42). A Danish cohort study reported a significant relationship between severe infections and the risk of schizophrenia. A previous history of autoimmune disorders increases the risk of schizophrenia by 36%. This risk of schizophrenia increases up to 60% in patients with a previous history of infection and hospitalization (19). Several clinical studies demonstrate a chronic low-grade inflammation in schizophrenia (43–46). Early studies suggested that this chronic low-grade inflammation may be due to chronically activated macrophages that fail to properly control T-lymphocytes in the so called “macrophage-T-lymphocyte hypothesis” (47). Thereafter, Schwarz et al. (48) suggested that psychotic patients have a T helper cells type 2-profile (Th2) characterized by increased Th2-produced IL-4 and decreased T helper cells type 1 (Th1)-produced IFN-γ (48). In contrast, a shift away from Th2-produced IL-4 and toward Th1-produced IFN-γ was later highlighted, suggesting the involvement of transforming growth factor (TGF)-β in the Th1/Th2 regulation of schizophrenia. Although contradictory, these hypotheses concur that an inflammatory imbalance is involved in schizophrenia (49).

Recent meta-analyses indicate that acute and chronically ill patients demonstrate a low-grade inflammatory profile that correlates with the clinical symptoms of schizophrenia (43, 45, 46) (Table 1). This inflammatory profile was also reported in drug-naïve patients in the first episode of psychosis (45). Since these patients were drug-naïve and in the first manifestation of the disease, it is unlikely that inflammation was related to antipsychotics or duration of illness. Thus, inflammatory cytokines in the peripheral blood were suggested to be either state or trait biomarkers. State biomarkers refer to specific cytokines elevated in schizophrenia and normalized with antipsychotics. Trait biomarkers are cytokines that are elevated in schizophrenia and are not normalized following antipsychotic treatment (43).

The association between biological and environmental factors can have significant implications in schizophrenia (50). In this respect, Monji et al. (51) shed light on the microglia hypothesis of schizophrenia (51). Microglia are the resident macrophages in the CNS (52), and similar to peripheral macrophages, they show different activation states. Basal state microglia (M0) perform phagocytosis and promote neurite outgrowth (53–55). However, both physical (infections) (56) or psychological (early life stress) stressors induce microglial activation (57–62). In response to these events, microglial polarization is triggered, resulting in an inflammatory state (microglia type 1; M1) (63, 64). M1 microglia produce large amounts of inflammatory cytokines (TNF, IL-1, IL-6, IL-12) inducing neuronal cytotoxicity (57, 61, 62). In contrast, anti-inflammatory cytokines (IL-4, IL-10) induce microglial polarization toward an anti-inflammatory state (microglia type 2; M2), critical for homeostasis. The imbalance between these factors affects neurite outgrowth, neuronal connections, and neurotransmitter formation and induces neuronal cytotoxicity, contributing to neuropsychiatric disorders (57, 65–67). Indeed, increased microglial density and microglial activation have been demonstrated in the hippocampus and gray matter of schizophrenic patients, as demonstrated by postmortem and in vivo studies (68–73), and microglial activation has been linked to the pre-suicidal stress associated with schizophrenia (74).

Microglia-produced TNF induces neurotoxicity and neurodegeneration as demonstrated both in vitro (54, 75) and in vivo (76, 77). A typical example is that abnormal microglia activation alters tryptophan metabolism along the kynurenine pathway, producing metabolites that act as N-methyl-d-aspartate receptor (NMDAR)-agonists (quinolinic acid) or -antagonists, such as kynurenic acid (KYNA) (29, 78, 79). NMDAR dysfunction is associated with schizophrenia (80) and NMDAR-antagonists induce positive, negative, and cognitive symptoms in healthy volunteers, similar to those observed in schizophrenia (81, 82). Delusions and hallucinations related to autoantibodies blocking NMDARs were reported in schizophrenic and healthy controls (83, 84). The kynurenine pathway is also linked to oxidative stress. Neuronal apoptosis and structural changes in specific areas of the brain, such as the amygdala, hippocampus, and prefrontal cortex, are related to several psychiatric disorders, including schizophrenia (78). Together these studies demonstrate that inflammation of the CNS can contribute to schizophrenia (43, 45, 46).

The efficacy of antipsychotics may be due to microglial suppression and subsequent neuroprotection (85–87). Atypical antipsychotics inhibit TNF production by the IFN-γ-stimulated microglia (86, 87). Minocycline, a non-psychotic medication with potent effects in inhibiting microglia, has been suggested as an adjuvant in the treatment of schizophrenia (86). However, atypical antipsychotics induce metabolic and cardiovascular dysfunctions (11, 12). Thus, there is an unmet clinical need for new therapeutic strategies to control inflammation and the progression of schizophrenia.

The inter-relationship between the nervous and the immune systems is critical to understand the pathogenesis of schizophrenia. In brief, a reduced parasympathetic tone could contribute to inflammation observed in schizophrenic patients. This mechanism combined with stress-mediated dysfunctions of the α7nAChR can enhance the impairment of the inflammatory reflex, contributing to schizophrenia’s symptoms. In the face of microglial hyperactivation, future investigations controlling microglial activation through innovative approaches, such as VNS and α7nAChR modulation, may provide clinical advantages for treating schizophrenia. As early exposure to stressors induces changes in the inflammatory reflex, a better understanding of the association between biological and environmental factors would potentially improve the diagnosis and treatment of schizophrenia. In this regard, public health interventions controlling stressful events, such as public education and comprehensive approaches to early treatment focusing on individual, social and environmental factors, might be beneficial for mental health promotion and prevention of future psychiatric disorders.

AK proposed the review to the authors and together with HS, LU, and CD-B revised the manuscript. FC-Z and CL suggested the topic for this review, coordinated the research group, drafted and revised this manuscript. FB also drafted and revised the manuscript, and together with AK, HS, and LU was essential in the consideration of the autonomic nervous system. GQ and CH were helpful in providing general information about inflammation. RF participated in the elaboration of the figure. All authors approved the final manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.