Impact of neuroinflammation on brain glutamate and dopamine signalling in schizophrenia: an update

Abstract

Schizophrenia is one of the most severe and chronic psychiatric disorders. Over the years, numerous treatment options have been introduced for schizophrenia. Although they are relatively successful in managing the positive symptoms of schizophrenia, most of the current treatments have a negligible effect on the negative and cognitive symptoms. Thus, none of them could prevent the relapse of psychotic episodes. Among the numerous hypotheses explaining the development and progression of schizophrenia, the cytokine hypothesis explains the role of inflammatory markers as a significant culprit in the development of schizophrenia. Elevated cytokines are reported in animal models and schizophrenic patients. The cytokine hypothesis is based on how increased inflammatory markers can cause changes in the dopaminergic, glutamate, and tryptophan metabolism pathways, like that observed in schizophrenic patients. Reasons, such as autoimmune disease, maternal immune activation, infection, etc., can pave the way for the development of schizophrenia and are associated with the negative, positive and cognitive symptoms of schizophrenia. Thus, there is a need to focus on the significance of anti-inflammatory drugs against these symptoms. The development of new treatment strategies in the management of schizophrenia can provide better therapeutic outcomes in terms of the severity of symptoms and treatment of drug-resistant schizophrenia. This review attempts to explain the association between elevated inflammatory markers and various neurotransmitters, and the possible use of medications like nonsteroidal anti-inflammatory drugs, monoclonal antibodies, statins, and estrogens as adjuvant therapy. Over the years, these hypotheses have been the basis for drug discovery for the treatment of schizophrenia.

Highlights

Activated microglia are involved in the pathogenesis of schizophrenia.

Inflammatory markers induce IDO and tryptophan dioxygenase to increase KYA.

Inflammatory markers influence dopamine and glutamate signalling for psychosis.

Inflammatory markers cause glutamate-mediated excitotoxicity and oxidative stress.

Anti-inflammatory drugs approach discussed for the management of schizophrenia.

Introduction

Schizophrenia, a chronic and severe psychiatric disorder, is a clinical syndrome characterized by variable and fundamentally disruptive psychopathology of perception, cognition, emotion, and other characteristics of behaviour (McGrath et al. 2008). Approximately 1% of the total world population is affected by schizophrenia, and it has an annual incidence of 3.89 to 4.03 per 1000 subjects. Although categorized as a low prevalence disorder, its economic burden is significant and it is ranked among the top 15 causes of disability worldwide (Moreno-Küstner et al. 2018). Schizophrenia is associated with a dysregulation in serotonergic, dopaminergic, glutamatergic, and gamma-aminobutyric acid (GABA) signaling pathways, which manifests into disrupted activity of a wide range of macro- and micro-neuronal circuits and behavioural, cognitive, and social dysfunction. Various etiological factors including neuroanatomic, genetic, neurochemical, and other biological dysregulation, and in utero exposure to bacterial, viral or parasitic infection, are said to be associated with the risk of developing schizophrenia (McGrath et al. 2008; Brown and Derkits 2010). Heredity/ genetic risk factors are responsible for around 81% and varied environmental factors contribute approximately to 11%, respectively of the schizophrenia cases, as evidenced by meta-analysis studies (Sullivan et al. 2003).

The three primary domains of schizophrenic symptoms are negative, positive, and cognitive. Positive symptoms are characterized by hallucinations and delusions whereas negative symptoms include emotional blunting, anhedonia, avolition etc. Furthermore, cognitive deficits related to working memory and executive functions (Shah and González-Maeso 2019; Zamanpoor 2020). Even after several decades of the introduction of antipsychotic therapy, the antipsychotics in existence are less effective towards the negative and cognitive symptoms of schizophrenia, which also happen to be the critical determinants of functional disabilities. Moreover, the effectiveness of antipsychotics towards positive symptoms in all schizophrenic patients is limited (Moghaddam and Javitt 2012). Dose-dependent side effects, some of which are severe to warrant treatment discontinuation, are another limitation of antipsychotics (Muench and Hamer 2010). All these highlight the need for the development of an adjuvant therapy which can supplement the use of antipsychotic medication.

The current understanding of factors contributing to schizophrenia points towards the role of neuronal inflammation in the onset and progression of the disease. Inflammation is common to many disorders such as diabetes mellitus, hypertension, coronary artery disease and also schizophrenia. Inflammation and schizophrenia could be a likely chicken and egg conundrum, with one being a cause or consequence of the other. Therefore, the role of inflammation in the dysregulation of neurotransmitters in the brain leading to the development of the pathological circuit of schizophrenia, is a crucial area of investigation with pharmacotherapeutic implications, and is the focus of this review. Further, the present review also addresses the influence of various drugs that alter the inflammatory mediators in subsiding the positive, negative, and cognitive effects of schizophrenia.

Microglial inflammation and psychosis

Microglial cells, also called macrophages of the brain, are immune cells ubiquitously distributed in the central nervous system (CNS) which strive to maintain homeostasis within the CNS (Fujita and Yamashita 2021). These cells constitute about 10–15% of glial cells of the brain (Salter and Stevens 2017). They are of mesodermal origin, in contrast to other parenchymal cells in the brain, which are of multiple neuroectodermal lineages. Glial cells are broadly classified as astrocytes, oligodendrocytes, ependymal and microglial cells (Tan et al. 2020). Glial cells regulate the immune system by producing both proinflammatory cytokines as well as anti-inflammatory components. They also produce neurotrophic factors and aid in neurodevelopment (Bergink et al. 2014). Microglia presents major histocompatibility complex (MHC) class I and II molecules. MHC II is expressed by antigen-presenting cells (APCs) such as dendritic cells, mononuclear phagocytes and microglia. Microglia plays a significant role in initiating an innate immune response and represent the major APCs in the brain parenchyma that express MHC II in neurodegenerative disease (Barichello et al. 2019; Nimmerjahn et al. 2005). A convincing amount of data shows an integrated relationship between psychiatric disorders and microglial cells. Increased microglial activity is a well-known risk factor for the development of mental illness (Lurie 2018). Post-mortem reports of schizophrenic patients upon evaluation showed increased density of reactive microglia in different subunits of the brain (Mattei et al. 2015). Various factors like infection in the CNS due to bacteria, viruses, and fungi, or factors like multiple sclerosis, aging, dementia, and neurotoxicity in CNS, etc. activate microglial cells. For instance, elevation of inflammatory markers due to influenza virus (Wong et al. 2018), a study conducted by Opsteen et al. 2023 reported chronic immune activation following long SARS-CoV-2 infection, wherein elevation of CD4⁺ and CD8⁺ T-cell was observed (Opsteen et al. 2023). A first case of psychosis due to mRNA-based COVID-19 vaccine was reported in 2021, where a 31-year-old male was showing erratic and bizarre behaviour with auditory hallucination and delusions after one month of mRNA-based COVID-19 vaccine administration. This could be due to an exaggerated immune response to the vaccine, which includes the release of excessive amounts of proinflammatory cytokines (Reinfeld et al. 2021). Further, the COVID-19 pandemic highlighted the connection between respiratory viral infections and the onset of psychosis, with persistent systemic inflammation associated with the development of schizophrenia (Kulaga and Miller 2021).

Activated microglial cells play a significant role in the production of cytokines and early brain development (Salter and Beggs 2014). During maternal immune activation (MIA), pro-inflammatory mediators present in the maternal blood enhance the permeability of the placenta and the fetal blood brain barrier (BBB), thereby letting inflammatory mediators enter the fetal brain. Once the inflammatory markers enter the fetal brain, they activate microglial cells, which in turn release various proinflammatory mediators like tumor necrosis factor alpha (TNF-α), interleukin (IL)−1β, and IL-6 in the brain (Barichello et al. 2019; Estes and McAllister 2016).

In an experimental setup when the maternal immune system was activated by administrating polycytidylic acid (poly I: C) into the maternal body, micro-glial markers were altered subsequently, indicating a considerable degree of microglial activation upon exposure to poly I: C (Hadar et al. 2017). In another study, Sprague Dawley rats that were put in a stressful situation were found to have a drastic increase in mature T-cells that were positive for serum proinflammatory cytokines and intracellular type-2-like cytokine. These led to microglial cell activation and increased neuronal firing in the basolateral amygdala. These events were minimized after abolishing microglial activation. Pratt et al. (2013) injected poly I: C (which mimics viral infection) into pregnant mice on embryonic day 12.5 and then collected the fetal brain on embryonic day 16.5 to check the inflammatory status of microglia. It was found that fetal microglia had expressed various inflammatory markers like IL-1α, IL-9, IL-4, IL-6, granulocyte-macrophage colony-stimulating factor, and macrophage colony-stimulating factor. Apart from infection and certain autoimmune conditions, microglial cells also produce various cytotoxic and proinflammatory factors, like IL-6, TNF-α, and prostaglandin E (PGE) in response to radiation therapy (Cole et al. 2020). Activated microglia produce neurotoxic substances and various cytokines, which in turn leads to neurodegenerative and inflammatory effects in the brain (Barichello et al. 2019; Carson et al. 2006). Since the brain exhibits a limited amount of neuro-regenerative potential, the loss of the considerable number of neurons via immune-mediated toxicity is bound to have a significant detrimental impact (Colton 2009).

Glial cells also express a suite of transporters and receptors for the uptake of neurotransmitters, including glutamate and GABA. This prevents excitotoxicity due to the accumulation of presynaptic-synaptic glutamate. Once taken up by the glial cells, glutamine synthase converts glutamate to glutamine, which is then used as a precursor for both glutamate and GABA (Lago-baldaia et al., 2020). Hence, glutamine synthetase-synthesizing glial cells are an essential component of glutamatergic and GABAergic synapses (Bernstein et al. 2015), and activation of these cells will directly impact these synapses as well.

Inflammatory markers and schizophrenia: clinical evidence

The cytokine hypothesis explains the positive relationship between pro-inflammatory markers and schizophrenia (Goldsmith et al. 2016). Cytokines arising due to both external and internal factors are known to be associated with various pathophysiological processes in the development and progression of schizophrenia, thus leading to a vast array of schizophrenic symptoms (Sommer et al. 2014). These symptoms surface during the phase of late adolescence and continue throughout life.

Shreds of evidence from preclinical and clinical studies have shown persistent elevation in various inflammatory markers like TNF-α, IL-12, IL-1β, IL-6, IL-1, and interferon (IFN)-γ in first onset and acute relapse schizophrenia subjects who were on antipsychotic medications (Miller et al. 2011). Inflammatory markers like cytokines are significant regulators of immune reactions and orchestrate brain development. A drastic rise in their level is seen in medication naïve psychosis patients (Juncal-Ruiz et al. 2018; Upthegrove et al. 2014) and the post-mortem brains of schizophrenic patients (Van Kesteren et al. 2017). These studies indicate a positive association between inflammation and the development of psychosis. A recent meta-analysis showed a positive relationship between inflammatory biomarkers and severity of negative symptoms in the antipsychotic naïve first episode of psychosis (FEP) population (Dunleavy et al. 2022). Meta-analysis has shown elevated levels of pro- and anti-inflammatory cytokines in CSF of relapsed as well as FEP patients, with IL-6 being in the highest concentration along with IL-1, IL-8, IL-1β, TNF-α and TGF-β (Upthegrove et al. 2014; Gallego et al. 2018). In addition to these cytokines, CSF kynurenic acid (KYNA) was elevated in major psychiatric disorders (Wang and Miller 2018). These markers were found to decline after treatment with antipsychotics. This suggests that anti-inflammatory pharmacological interventions may improve clinical outcomes in schizophrenia patients compared to treatment with antipsychotics alone on account of dose-related constraints and mixed effects of the latter. These inflammatory markers are expressed differently and provide unique contributions to the pathophysiological process of schizophrenia. IL-6 which is found to be highly expressed in psychotic patients (Delaney et al. 2019) is associated with increased oxidative stress and might have a possible association with GABAergic dysfunction in the schizophrenia brain (Behrens et al. 2008).

A study on 41 schizophrenic patients with acute psychosis revealed a significant elevation in the levels of IL-6, IL-2R, and IL-8 compared with the control. A positive correlation was found between symptom severity and levels of IL-6 and IL-2R (Dahan et al. 2018). Another case-control study conducted on at-risk mental state subjects (n = 17), patients with psychotic disorder (n = 77) and healthy controls (n = 25) tracked the transition of at-risk mental state subjects to psychosis for a period of 24 months. During this period, 6 out of 17 at-risk mental state subjects who developed psychosis showed an increase in IL-6 levels compared to those who did not. This explains the possibility of IL-6 being a biomarker for early psychotic symptoms; however, studies on large sample sizes are warranted to prove this (Stojanovic et al. 2014). Further, a positive correlation is associated with IL- 1 levels and duration of illness, with a significant rise in its levels during the initial stages of illness (Möller et al. 2015). IL-1β marker is known to initiate the conversion of progenitor cells into dopamine neurons (Potter et al. 1999). Hence a constructive correlation has been found between the severity of schizophrenia and various inflammatory markers (Liu et al. 2010).

Recent studies have suggested that antipsychotic drugs can modulate different immune reactions and Brain Derived Neurotrophic Factor (BDNF) based upon duration of treatment. For instance, 6-week treatment with olanzapine reduced proinflammatory cytokines such as IL-1 β, IFN-γ, IL-6 and TNF-α levels, in schizophrenia patients and increased the proinflammatory cytokines such as IL-10 (Zhao et al. 2024). Additionally, research indicated that eight weeks of atypical antipsychotics treatment significantly reduced blood pro- and anti-inflammatory cytokines in first-episode drug-free schizophrenia patients (Chen et al. 2021).

However, the relationship between antipsychotic treatment and BDNF levels remains to be understood further (Alvarez-Herrera et al. 2020). Zhao et al. 2023; observed treatment of first-episode schizophrenia patients with risperidone for a period of two weeks, led to a significant increase in the BDNF levels along with a decrease in psychotic symptoms (Zhao et al. 2023). In schizophrenic patients, 40 days treatment with risperidone exerted more efficacy than clozapine in decreasing of BDNF levels (Ajami et al., 2014). In contrast, olanzapine or risperidone did not show any significant change in BDNF during a 6-week prospective study in acute schizophrenia patients (Kudlek Mikulic et al. 2017).

A subset of pre-clinical studies belongs to immune activation during the maternal gestational period. These studies emphasized the correlation between maternal immune activation (MIA) during the gestational period and increased incidence of schizophrenia in the lifetime of the offspring. Any condition that activates an immune response in a pregnant mother and increases inflammatory markers is known to increase the risk of developing schizophrenia in the children born to the respective mother during MIA. Apart from this, there is evidence of alteration in neurotransmitter levels after an increase in the concentration of inflammatory cytokines following infection. Also, the development of psychosis and other psychiatric complications after the administration of vaccines and in people infected with human immunodeficiency virus (HIV-1) has been reported (Alciati et al. 2001). Notably, in a case study considering 16 males and 6 females infected with HIV, 8 (36.36%) developed psychotic symptoms. The CSF KYNA was found to be doubled in terms of concentration in patients who had psychotic symptoms compared to those individuals who did not have any psychotic symptoms (Atlas et al. 2007).

In the current context of COVID-19, a large number of individuals infected with SARS-CoV-2 virus have been found to present high rates of psychiatric disorders (Lim et al. 2020; Rentero et al. 2021; Xiao et al. 2022). These disorders include anxiety, mood disorders and symptoms characterized by structural delusional disbelief, thoughts of references, etc., similar to symptoms seen in patients with schizophrenia. A 78-year-old patient who had undergone a kidney transplant and was taking tacrolimus as an immunosuppressant suddenly developed psychotic symptoms. On admission to the hospital, she was found SARS- COV2 positive. Concentrations of IL- 6, IFN-γ -induced protein and IL-8 were found to be high in the CSF of this patient compared to the control samples. The patient was administered hydroxychloroquine for nine days, following which her condition initially improved and again worsened on the thirteenth day. Administration of IL-6 inhibitor, tocilizumab led to an overall improvement in her mental status (Farhadian et al. 2020). These manifestations of psychotic symptoms corroborated the influence of inflammatory markers, due to the damage caused by the virus since studies have shown an increase in inflammatory markers in patients infected with SARS- COV2 infection (Takahashi et al. 2020). Similarly, KYNA: KYA ratio was found to be higher in SARS- COV2 infected patients who have high inflammatory markers (Cai et al. 2021). These inflammatory markers must have altered the various pathways of schizophrenia, resulting in psychotic symptoms.

A few case reports have also been reported about patients developing psychotic symptoms after the administration of various vaccines, including the COVID-19 vaccine (Kuhlman et al. 2018; Reinfeld et al. 2021; Romeo et al. 2021). Although most of these reports did not mention the alterations in the cytokine levels, it is a possibility that the alteration in the cytokines after the administration of the vaccine might have led to the development of psychotic symptoms. Meta-analysis studies have proven the effectiveness of antipsychotics in reducing the levels of the inflammatory marker in schizophrenia subjects (Romeo et al. 2018). In a case-control study carried out on 38 patients with the FEP without any previous exposure to antipsychotic treatment, untreated patients with the FEP had a higher concentration of EGF (endothelial growth factors), IL-4, IL-6, IL gamma, and IFN-γ compared to healthy controls. With administration of antipsychotics, the EGF, IL-2 and IL-4 were significantly reduced along with commendable clinical improvement and suppression of schizophrenic symptoms (Haring et al. 2015). Therefore, the addition of an immunomodulatory adjuvant therapy might prove to be beneficial for psychosis patients and may be considered as an effective treatment strategy for better disease outcomes.

Effect of inflammatory markers on various pathways of schizophrenia

Kynurenic acid pathway and Schizophrenia

This hypothesis is based on KYNA being a broad-spectrum glutamate receptor antagonist that occurs naturally in the brain. An elevated concentration of this compound might initiate psychomimetic behavior in humans (Erhardt et al. 2007). In support of this hypothesis, various studies have shown the elevated concentration of KYNA in schizophrenic subjects (Erhardt et al. 2007; Plitman et al. 2017). Around 60% of KYNA is produced in the peripheral region and then transferred into the brain via amino acid transporters present in the BBB. The other 40% is produced inside the brain by activated glial and immune cells (Vécsei et al. 2013). CSF KYA and KYNA have been found in multiple folds in schizophrenic brains. A case-control study considered 16 verified schizophrenic males in the age group 23–49 years and 29 healthy males in the age group of 18–59 years. The CSF was withdrawn by lumbar puncture after 8 h of fasting and was centrifuged before analyzing for the levels of KYNA and KYA. The results showed elevated levels of CSF KYNA and almost double concentration of CSF KYA in schizophrenic males (Linderholm et al. 2012). KYNA is the degradation product of tryptophan, contributing about 90% towards the degradation product of tryptophan metabolism (Plitman et al., 2017). This pathway is highly sensitive to inflammatory mediators (Schwarcz et al. 2012). About 5% of the tryptophan gets converted into the neurotransmitter serotonin and the hormone melatonin, while the remaining 95% gets converted into N- formyl kynurenine with the help of tryptophan dioxygenase in the liver and indoleamine 2,3-dioxygenase (IDO) in the immune system and brain. The N-formyl kynurenine generated is then converted into KYA with the help of the enzyme formamidase (Lawson et al. 2013; Muneer 2020). KYA in turn gets converted into 3-hydroxy kynurenine and subsequently into 3- hydroxyanthranillic acid with the help of the enzymes kynurenine hydroxy mono-oxygenase and kynureninase, respectively. This 3-hydroxyanthranilic acid with the help of enzyme 3- hydroxyanthranilate-3,4-dioxygenase, gets converted into 2-amino-3-carboxymuconic-6-semialdehyde which then undergoes non-enzymatic cyclization to produce quinolinic acid, which is further converted into nicotinamide adenine dinucleotide (NAD+). 2-amino-3- carboxymuconic-6-semialdehyde can also undergo nonenzymic cyclization to produce acetyl CoA (Badawy 2017). 3- hydroxykynurenine, along with its downstream catabolites and quinolinic acid, are produced in the microglia, whereas KYNA synthesis is carried out in astrocytes, oligodendrocytes and neurons (Tutakhail et al. 2020). The rate-limiting step in this pathway is the conversion of tryptophan to KYA, which is catalyzed by the enzymes IDO and tryptophan dioxygenase (Wu et al. 2014). Elevated KYA and KYNA in schizophrenic patients are due to the induction of IDO and tryptophan 2,3 dioxygenase by IFN-γ and various other inflammatory markers such as TNF-α, IL-6 (Chen 2011) (Fig. 1). A 6-week double-blind placebo-controlled randomized clinical trial considering 100 inpatients with first-episode drug-naive schizophrenia, all of whose IDO levels and the levels of six other inflammatory cytokines IL-1β, IL-6, TNF-α IL-17, IL-4, and IFN-γ were higher than the healthy subjects, all individuals in this study group were administered celecoxib (a COX- 2 inhibitor) or placebo combined with risperidone. Over the six weeks treatment period a significant reduction in IDO and IL-1β, IL-6, TNF-α IL-17, IL-4, IFN-γ levels and a corresponding improvement in positive and negative symptoms were found in the celecoxib-treated group compared to the placebo group (Zhang et al. 2021).

Fig. 1.

The kynurenic acid hypothesis of schizophrenia. Impaired kynurenine pathway metabolism occurs in the prefrontal cortex of individuals with schizophrenia

The elevated metabolites of the KYA pathway are associated with various neuropsychiatric disorders. They lead to N-methyl-D-aspartate (NMDA) receptor hypofunction resulting in psychotic symptoms (Erhardt et al. 2001). Elevation of KYNA is also associated with an increased firing from the dopaminergic neurons of the midbrain mediated through inhibition of GABAergic input, which would otherwise dampen the dopamine neuron activity in the midbrain (Erhardt et al. 2002). Quinolinic acid produced in this pathway is an NMDA receptor agonist (Walker et al. 2013; (Johansson et al. 2013). As a result, it increases the glutamate concentration in the synaptic region by reducing its reuptake by astrocytes, which results in excitotoxic effects in the CNS (Laugeray et al. 2010).

Dopamine, inflammation, and schizophrenia

The classical dopamine hypothesis states that hyperactive dopaminergic transmission in various brain parts due to increased density and sensitivity of dopamine 2 (D2) receptors is responsible for the development of schizophrenia. Contrary to this, the modern dopamine hypothesis states that low dopamine levels in the medial prefrontal cortex and increased dopamine levels in the mesolimbic pathway are responsible for negative and positive symptoms of schizophrenia respectively. The unifying hypothesis of dopamine proposes a common pathway that states that multiple risk factors like genetic, environmental, stress and various others interact and cause dopamine dysregulation in the striatal region, altering signal transmission and cause psychosis (Davis et al. 1991; Howes et al. 2012).

A clinical study concluded that innate immune activation and the release of inflammatory cytokine IL-6 following typhoid vaccination affects reward circuits and substantia nigra function, thus showing significant psychomotor consequences (Brydon et al. 2008). Similarly, studies have also concluded that change in behavior following peripheral administration of IFN-α and various other cytokines is mediated via altered dopaminergic neurotransmission (Shuto et al. 1997; Song et al. 1999). There are various dopamine pathways present in the brain, and alteration of dopamine levels in these pathways are associated with various schizophrenic symptoms. The nigrostriatal pathway that extends from substantia nigra to the caudate nucleus, hypo-activity of this pathway results in extrapyramidal symptoms, hypo-activity or under activity of mesocortical pathway which extends from ventral tegmental area to cortex is known to cause negative, cognitive and affective symptoms of schizophrenia. On the other hand, hyperactivity of mesolimbic pathway is known to mediate positive symptoms of Schizophrenia (Brisch et al. 2014; Patel et al. 2014; Stahl 2007).

Dopamine levels are managed by the following transporters: the membranous dopamine transporter (DAT) and the vesicular monoamine transporter 2 (VMAT2) (Iliopoulou et al. 2021). Dopamine primarily produces its effect by activating G protein-coupled dopamine receptors, which are classified into two groups, i.e., the D1 subgroup containing D1 and D5 and the D2 subgroup containing D2, D3, and D4 (Beaulieu and Gainetdinov 2011) each of these subgroups having a different affinity for dopamine (Mittal et al. 2017). Phenylalanine acts as a precursor for dopamine synthesis. Phenylalanine is converted to tyrosine by phenylalanine hydroxylase in the presence of tetrahydrobiopterin (BH4) as a cofactor. Tyrosine is converted into L- dopa in the presence of tyrosine hydroxylase (TH). Again, in the presence of BH4 as a cofactor, L- dopa gets converted into dopamine in the presence of dopamine decarboxylase (Cunnington and Channon 2010). The cofactor BH4 is a pteridine derivative and is produced by the action of the enzyme guanosine triphosphate (GTP)-cyclo-hydrolase-1. In human monocyte-derived macrophages and dendritic cells, this enzyme, which is highly susceptible to inflammatory markers, produces neopterin instead of BH4, in the presence of inflammatory markers (Geisler et al. 2013), resulting in a significant reduction of BH4 levels (Richardson et al. 2005, 2007) which in turn leads to a reduction in the synthesis of dopamine (Geisler et al. 2013). Peripheral monocytes, T- cells and microglia express dopaminergic receptors. High levels of dopamine stimulate low affinity dopamine receptors including D1, D2, and D4 to induce anti-inflammatory effects on immune cells. On the other hand, reduced dopamine levels stimulate D3 and D5 receptors which are high affinity dopamine receptors and hence trigger an inflammatory response. This effect of altered dopamine levels on the immune system leads to stress and other behavioural changes (Vidal and Pacheco 2020). Apart from expressing dopaminergic receptors on their surface T- cells also have TH, DAT, VMAT2, and catechol-O-methyltransferase, suggesting they have the capacity to uptake, synthesize, store, and release dopamine (Bergquist et al. 1994; Cosentino et al. 2007; Qiu et al. 2004). A study carried on mRNA of human monocyte derived macrophages, indicated the presence of all dopamine receptor subtypes along with DAT, VMAT2, TH and aromatic amino acid decarboxylase (AADC) (Gaskill et al. 2012). Some antipsychotics exert their pharmacological action by blocking the synthesis or storage of dopamine. Antipsychotics like reserpine act by inhibiting VMAT-2, thus preventing the dopamine from getting stored in the storage vesicles and letting it get depleted in the cytoplasm. Administration of the TH inhibitor, alpha methyl para tyrosine, inhibited the synthesis of dopamine, thus reducing the symptoms of schizophrenia (Uno and Coyle 2019). An in vivo study using four rhesus monkeys has shown enhanced striatal extra-synaptic dopamine levels in schizophrenic condition using photon emission tomography studies (Breier et al. 1997). Although no association is found between dopamine active transporters density in the etiology or treatment of schizophrenia (Fusar-Poli and Meyer-Lindenberg 2013), PET neuron-imaging study carried using 18 F-DOPA showed enhanced dopamine production in the dorsal striatum in individuals with ultra-high risk of psychosis (Egerton et al. 2013).

Inflammatory markers like IFN-γ are known to play a significant role in altering dopamine availability and binding; nonhuman primates four weeks after the administration of these inflammatory markers have shown reduced dopamine release from the striatum along with decreased dopamine binding to D2 receptors (Felger et al. 2013). Patients who were suffering from HCV infection when administered with IFN and ribavarin, showed a significant reduction in the activity of the ventral striatum and reduced dopamine turnover in the caudate and putamen. This was accompanied by a significant increase in bilateral radio labeled fluorodopa (¹⁸F-DOPA) uptake in the caudate and putamen (Capuron et al. 2012). In most human cells (Geisler et al. 2013), IFN-γ induces the production of GTP cyclo-hydrolase-I, which initiates the conversion of GTP required for the biosynthesis of 5,6,7,8- BH4. It is a cofactor of many enzymes like phenylalanine-4-hydroxy lase, tyrosine-5-hydroxylase, and nitric oxide synthases. These enzymes play an essential role in the synthesis of neurotransmitters. Thus, activation of GTP cyclohydrolase-I by IFN-γ indirectly leads to enhanced dopamine production by increasing the synthesis of BH4 (Neurauter et al. 2008). On the other hand, activation of GTP- cyclo-hydrolase- by IFN-γ in the human macrophages/ monocytes, which are relatively deficient of 6- pyruvoyl tetrahydrobiopterin synthase, leads to the accumulation of 7,8- dihydro-neopterin triphosphate which subsequently gets converted into neopterin and 7,8 dihydro-neopterin in the presence of phosphates. Thus, neopterin is produced at the expense of tetrahydropteridine (BH4) (Murr et al. 2002; Wirleitner et al. 2002) which is known to produce reactive oxygen species (Razumovitch et al. 2003). These reactive oxygen species readily oxidize oxidation labile BH4 hence resulting in reduced dopamine production (Neurauter et al. 2008).

Inflammation, glutamate and schizophrenia

The glutamate theory of schizophrenia was developed after observing the ability NMDA receptor antagonists to induce psychiatric symptoms. This theory states that hyper-glutamatergic activity in the synaptic regions is responsible for the development of negative, positive, and cognitive symptoms of schizophrenia (Moghaddam & Javitt 2012). Drugs that non-competitively antagonize the NMDA receptors produce positive, negative and cognitive symptoms in healthy individuals, suggesting a close association between dysregulated glutamate receptors and schizophrenia (Paoletti et al. 2013).

This theory is further strengthened by various preclinical trials conducted on rats where systemic administration of NMDA receptor antagonists to rats at doses sufficient to impair cognitive functions and motor stereotypy led to increased glutamate efflux in various regions of the brain (Lorrain et al. 2003). This is similar to that observed in schizophrenia patients, using magnetic resonance spectroscopy (Merritt et al. 2021). Glutamate is an excitatory neurotransmitter acting on the brain and spinal cord via ionotropic glutamate receptors (Paoletti et al. 2013). It performs various activities like controlling the maturation and formation of the synapse, acts as a substrate for the source of energy in oxidative metabolism, and guides various processes in the developing brain (Ryan et al. 2021). Glutamate is produced in pre-synaptic-synaptic neurons, and then vesicular glutamate transporters (VGluT) pack them into secretary vesicles; when the pre-synaptic neurons get excited, they fuse with secretary vesicles and release glutamate into the synaptic cleft. The released glutamate acts on various glutamate receptors and causes rapid clearance of extracellular glutamate, which then either enters the TCA cycle or forms glutamine (Rubio et al. 2012). These receptors are classified into α-amino 3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), kainite receptors, and NMDA receptors (Nakanishi 1992). NMDA receptors are glutamate-gated and have three different subunits Glu1, Glu2, and Glu3. Any malfunction in these NMDA receptors results in various psychological and neurological illnesses. NMDA receptors are glutamate-gated heterotetrameric receptor complexes composed of Glu1, Glu2, and Glu3 subunits and mediate glutamatergic excitatory neurotransmission, hence inducing synaptic plasticity (Paoletti et al. 2013). These receptors are activated by simultaneous binding of glutamate and glycine along with depolarization of the membrane potential, to relieve voltage-dependent magnesium block (Zhu et al. 2016). The glutamate released during the action potential is produced from glutamine supplied by astrocytes (Coyle 2006). Astrocytes in the CNS are subdivided into three types, viz., radial, protoplasmic and fibrous astrocytes (Liddelow and Barres 2015). Among these, protoplasmic astrocytes constitute branching structures, which are further subdivided into finer processes. These processes present on one side of the protoplasmic astrocytes, encapsulate several thousands of synapses, thus producing astrocytic cradles, and the astrocytic cradles that surround the synaptic region have a high distribution of glutamate transporters in them, which play a pivotal role in glutamate clearance (Bushong et al. 2002; Sofroniew and Vinters 2010). Once the glutamate transporters take up the glutamate, it is converted into the inert intermediate glutamine. Glutamine once released, is absorbed by neurons and gets converted into glutamate, which inside the neurons is packed inside the synaptic storage vesicles by the vesicular transporter (VGlu-3). This synaptically-stored glutamate acts as the primary source of glutamate during neurotransmission (Danbolt 2001). Apart from expressing glutamate receptors, astrocytes also express receptors sensitive to various inflammatory mediators like cytokines and chemokines (Hsuchou et al. 2009; Pan et al. 2012). During diseased state, increased inflammatory cytokines like IFN-γ transform these astrocytes into APCs and phagocytic cells, delineated by the elevation of markers of inflammatory activation (toll-like receptors (TLRs), MHC class II receptors, and an intracellular immune receptor system containing the Rig-1-protein complex of the inflammasomes). These inflammasomes are intracellular complexes that can sense danger-associated molecular patterns, which once activated result in the activation of caspase-1, thus converting pro-IL-1 into IL-1β. IL-1β in-turn can activate astrocytes, thus making the astrocytes release a large number of inflammatory mediators, and this state of astrocytes is associated with oxidative stress as well as reduced glutamate clearance, which contributes to excitotoxicity. Astrocytes are divided into two subtypes, viz., A1 and A2. Of these, the A1 type can be induced by inflammatory stimuli (Zamanian et al. 2012). These A1 subtypes are further pathologically subclassified into two categories viz., loss of function type, in which the astrocytes stop performing their normal function (glutamate clearance and/or synaptogenesis), and the gain of function type, wherein the astrocytes exhibit deleterious activities like synaptic destruction, which normally does not occur in resting astrocytes (Sofroniew and Vinters 2010). Once the inflammatory mediators induce these A1 astrocytes, they exhibit their neurotoxic effect by upregulating the components of the complementary cascade, thus causing glutamate-mediated excitotoxicity and inducing oxidative stress (Zamanian et al. 2012) (Fig. 2).

Fig. 2.

Impact of neural inflammation on glutamate excitotoxicity

Gut-brain axis and Schizophrenia

As reported earlier, schizophrenia has been associated with infections contributing to gut dysbiosis (Ju et al. 2023). There exists a complex communication network between the gut and the CNS, which is known as the gut-brain axis. An altered function of this axis, also known as gut dysbiosis, leads to increased permeability of the gut and a rise in systemic inflammation, exacerbating peripheral and central neuroinflammation. Reduction in the gut microbiota diversity in schizophrenic patients, was supported further with preclinical evidence of reduced glutamate and increased GABA (Zheng et al. 2019). Thus, gut dysbiosis predisposes altered glutamate and GABA neurotransmission including tryptophan and serotonin pathway with superimposed neuroinflammation. These factors trigger dopaminergic overactivity in the brain, for manifestating psychosis (Theleritis et al. 2024).

Multiple factors can initiate dysbiosis, including environmental pollutants, antibiotic use and infections that compromise the integrity of the gut, alter the immune responses and result in systemic inflammation (Kearns 2024). Elevated levels of lipopolysaccharides (LPS) and immunoglobulins observed in various neurological conditions support the hypothesis that alteration in gastrointestinal permeability might trigger systemic inflammatory responses (Ghosh et al. 2020). In the brain, the kynurenine pathway, which serves as the primary route for tryptophan metabolism, is significantly impacted by this process. This dysregulation of the kynurenine pathway due to inflammation leads to the production of quinolinic acid- a neurotoxic metabolite; this Quinolinic acid produced in this pathway is an NMDA receptor agonist (Walker et al. 2013; Johansson et al. 2013). As a result, it increases the glutamate concentration in the synaptic region by reducing its reuptake by astrocytes, which results in excitotoxic effects in the CNS (Laugeray et al. 2010).

The future research may envisage newer therapeutic approaches based upon reversing gut dysbiosis and associated neurotransmitter imbalance to curb schizophrenia effectively. One of the promising approach is using psychobiotics, which may confer efficacy by administering commensal gut bacteria as probiotics (Sarkar et al. 2016). Psychobiotics can regulate neurotransmitters by improving diversity for gut microbiota and thereby correcting neurotransmitters imbalances and neuroinflammation. Administration of probiotics and prebiotics, that help in maintaining a healthy gut microbiota, has shown promising results in reducing gut permeability as well as systemic inflammation, and this could be used as an adjuvant therapy to offer a protective effect to the brain by preventing the production of quinolinic acid (Dinan et al. 2013; Sarkar et al. 2016; Xiang et al. 2022).

Scope of anti-inflammatory drugs in the treatment of schizophrenia

Pharmacotherapy with antipsychotics is the mainstay of therapy for schizophrenia. These agents are commonly classified into first-generation (or typical) and second-generation (or atypical) antipsychotics. The former are dopamine receptor antagonists, and the latter are serotonin-dopamine antagonists. The older first-generation agents are associated with extrapyramidal motor side effects and elevation of prolactin levels (Huhn et al. 2019). In the past, immune system modulators have shown promising results as adjuvant therapy, especially when administered during the initial phase of illness. N-acetyl cysteine (NAC) is the most commonly used immunomodulatory agent for this purpose (Pardo-de-Santayana et al. 2021). Many studies have also pointed out the possible anti-inflammatory effect of antipsychotic medications, indicating their role as immunomodulatory agents, along with their action on the dopaminergic and serotonergic systems (Table 1). However, many of these agents also demonstrate induction of pro-inflammatory cytokines and factors, indicating a mixed effect.

Table 1.

Effect of currently used antipsychotics on inflammatory marker(s) and possible significance on schizophrenic effects

Antipsychotic	Inflammatory marker(s) affected	Model	Observations/ Significance	Reference
1st generation antipsychotics
Haloperidol	TNF-α, IL-8, IL-6	Human dendritic cells (DC)	Dose dependent decrease in the production of TNF-α observed in mature DC with haloperidol No significant effect on IL-8, IL-6 production in mature/ immature DC	Chen et al. 2012
	IL-4, IL-10, IFN-γ	Lipopolysaccharide (LPS)-activated peripheral blood mononuclear cells (PBMC) blood culture from FEP patients	Increase in anti-inflammatory markers: IL-4 and IL-10 Decrease in pro-inflammatory marker IFN-γ	Al-Amin et al. 2013
	Inducible nitric oxide synthase (iNOS) (pro-inflammatory)	Murine BV-2 microglial cell lines	Decrease in production of iNOS However, no significant effect seen on levels of anti-inflammatory markers	Racki et al. 2021
	CRP	Human subjects	Increase in median CRP levels after 3 months of treatment with haloperidol compared to baseline levels; however, no net change after 12 months	Diaz et al. 2010
Chlorpromazine	IL-1β and IL-2	Mixed glial cell and microglial cell cultures of rat	Reduction in IL-1β release after 1 and 3 days of exposure at 2 and 20 µM doses, respectively Reduction in IL-1 secretion after 3 days of incubation at 0.2, 2 and 20 µM doses Results of the study suggest that chlorpromazine administration may influence microglial activity in the brain of schizophrenic human subjects	Labuzek et al. 2005
Flupentixol	IL-1β and IL-2	Mixed glial and microglial cell cultures of rat	Reduction in concentration of IL-1β and IL-2 after 1 or 3 days of flupentixol exposure at neuroleptic doses (0.2, 2 and 20 µM)	Kowalski et al. 2004
Trifluperidol	IL-1β and IL-2	Mixed glial and microglial cell cultures of rat	Reduction in concentration of IL-1β and IL-2 after 1 or 3 days of trifluperidol exposure at neuroleptic doses (0.2, 2 and 20 µM)	Kowalski et al. 2004
Spiperone	TNF-α, iNOS and IL- 1β	Murine BV-2 microglial cell lines	Attenuation in the expression of iNOs, IL- 1β and TNF-α genes Attenuation in lipopolysaccharide (LPS)-induced nuclear factor kappa-B (NF-kB) and p38 mitogen-activated protein kinases (p38 MAPK) (which are inducers of pro-inflammatory cytokines and iNOS in glial cells) Attenuation in NO production in ATP-stimulated primary microglial cultures Reduction in neuroblastoma cell death by activated microglia (neuroprotective effect)	Zheng et al. 2008
2nd generation antipsychotics
Olanzapine	CRP	Human subjects	No significant difference between median CRP levels at base line and after both 3 months and 12 months	Diaz et al. 2010
	NO	LPS-activated murine N9 microglial cell line	Suppression of LPS-induced microglial cell activation and NO release Study proposes this to be a mechanism for therapeutic action of olanzapine in schizophrenia	Hou et al. 2006
Clozapine	Total COX activity, PGE2, calcium-independent phospholipase A2 (iPLA2), brain derived neurotrophic factor (BDNF) and drebrin	Male CDF-344 rats	Reduction in COX-1 and total COX activities in brain Reduction in concentration of pro-inflammatory PGE-2 in brain Increase in anti-inflammatory BDNF expression levels in brain Increased production of anti-inflammatory docosahexaenoic acid (DHA) metabolites in brain (evidenced from iPLA2 expression) Increase in expression of postsynaptic marker, drebrin (neuroprotective)	Kim et al. 2012
	iNOS	Neonatal male Wistar rats	Reduction in iNOS immunoexpression in striatal and hippocampus areas Reversal of alteration caused due to poly(I: C) induced microglial activation	Ribeiro et al. 2013
	IL-4, IL- 10 and IFN-γ	LPS-induced peripheral blood mononuclear cells blood culture from FEP patients	Increase in anti-inflammatory markers: IL-4 and IL-10 Decrease in pro-inflammatory marker IFN-γ	Al-Amin et al. 2013
Risperidone	TNF-α, IL- 6, IL- 10 and IL- 4	Human subjects (FEP)	Normalization of elevated IL-6, IL-10 and TNF-α to the levels of those in healthy controls However, significant reduction in IL-4 compared to healthy controls after 10 weeks of treatment	Noto et al. 2014
	IFN-γ-inducible protein 10 (IP-10) and IL-12	Human dendritic cells (in vitro)	Dose dependent decrease in the production of inflammatory mediators IL-12 and IP-10 Decrease in the production of TNF-α at low dose (10−8) M and increase in production TNF-α at high dose (10−6–10−5) M of risperidone Dose dependent increase in the production of 1 L-10, IL-8 and IL- 6	Chen et al. 2012
	CRP	Human subjects	Significant reduction in median CRP levels compared to median baseline CRP levels after 3 months of treatment with risperidone	Diaz et al. 2010
	IL-1β, iNOS, COX, TNF-α	LPS-administered male Wistar Hannover rats	Prevention of increased inflammatory parameters viz., IL-1β, TNF-α, activity of iNOS, COX, p38 MAPK and NF-kB in brain cortex Restoration of levels of deoxyprostaglandins and peroxisome proliferator activated receptor γ	MacDowell et al. 2013
	iNOS	Murine BV-2 microglial cell line	Reduction in production of iNOS Increase in mTORC1 activity compared to control (evidenced by ratio of phosphorylated p70S6K (p-p70S6K) to p70S6K) > > Could be pro-inflammatory	Racki et al. 2021.
Aripiprazole	NO, TNF-α	Murine microglial cell line 6 − 3	Reduction in NO and TNF-α in both IFN-γ-activated and LPS-activated microglia, possibly via suppression of intracellular Ca2+ (required for release of NO and some cytokines)	Kato et al. 2008
	iNOS, CD86 (pro-inflammatory phenotype cell-surface markers), CD206 (anti-inflammatory phenotype marker)	Murine BV-2 microglial cell line	Reduction in production of iNOS Increase in expression of CD206 and CD86 Reduction in mTORC1 activity compared to control (evidenced by ratio of phosphorylated p70S6K (p-p70S6K) to p70S6K) > > Lesser inflammatory action	Racki et al. 2021.
	CRP, IL-1β, IL-6, TNF-α, sTNF-R1, IL-12, IL-23, IL-1Ra, TGF-β1, IL-4, IFN-γ, IL- 10	Human subjects	Reduction in pro-inflammatory markers IL-1β, IL-6, TNF-α, sTNF-R1, IL-12, IL-23*, IL-1Ra, IFN-γ and ratio of IFN-γ:IL-10, after 28 days of treatment Reduction in anti-inflammatory IL-4 and TGF-β1 Significant increase in anti- inflammatory marker IL-10 and / or reduction in ratio of IL-6:IL-10 A significant negative correlation observed between levels of IL-10 levels and PANSS (positive, negative and total) scores after the study *First study to investigate IL-23 levels (main cytokine in brain autoimmune inflammation)	Sobiś et al. 2015
Loxapine	IL-1β and IL-2	LPS-activated mixed glial cells of rat	Reduction in release IL-1β (at 0.2, 2, 10 and 20 µM doses) and IL-2 (at 2, 10 and 20 µM doses)	Labuzek et al. 2005
Quetiapine	IFN-γ, IL- 4 and IL- 10	LPS-activated peripheral blood mononuclear cells blood culture from FEP patients	Increase in anti-inflammatory markers: IL-4 and IL-10 Reduction in pro-inflammatory marker IFN-γ	Al-Amin et al. 2013
	CRP, IL-6, IL-10	Human subjects (with bipolar disorder)	Significant reduction in IL-16 and CRP and restoration to normal levels after 6 weeks of treatment Reduction in IL-10 and IFN-γ levels (not statistically significant)	Ferrari et al. 2022

Non-steroidal anti-inflammatory drugs (NSAIDs) have demonstrated beneficial effect in schizophrenia patients (Sommer et al. 2011). These agents mediate their actions by inhibiting the enzyme cyclo-oxygenase (COX) iso-enzyme, which is subdivided into COX-1 and COX-2. Unlike COX-1, COX-2 is not constitutively expressed in the body and is expressed only during an inflammatory response. Most NSAIDs are non-selective and act on both COX-1 and COX-2, except a few like celecoxib which are very specific to COX-2 and inhibits only COX-2 (Ghlichloo and Gerriets, 2023). A randomized, double-blind placebo control trial on 70 schizophrenic patients who were administered aspirin as an adjuvant therapy showed significant improvement in the symptoms of schizophrenia, especially with more remarkable improvement seen in those with higher alteration in the immune markers (Laan et al. 2010). A meta-analysis considering 62 randomized, double-blind trials which had 2914 patients meeting the inclusion criteria showed the significant role of aspirin in improving the overall positive and negative symptom score in the positive and negative syndrome scale when compared to antipsychotic drug monotherapy (Cho et al. 2019). Celecoxib has also shown significant improvement in positive, negative and general psychopathology scores even in first-episode schizophrenia patients. In a prospective randomized double-blind study conducted on 50 patients with acute exacerbation of schizophrenia, and who were randomly assigned into risperidone plus placebo and risperidone plus celecoxib group, patients who were in the risperidone plus celecoxib group showed a more significant improvement in symptoms in terms of positive and negative syndrome scale (Müller et al. 2002). There is contradicting evidence on the use of NSAIDs for improvement in schizophrenia. One meta-analysis study states that anti-inflammatory drugs lead to a significant improvement in positive and negative syndrome scale as well as sub-scores of the positive and negative symptoms of schizophrenia (Sommer et al. 2011). Conversely, another meta-analysis denied any such benefit of anti-inflammatory drugs over placebo on the positive and negative syndrome scale, when used along with antipsychotics (Nitta et al. 2013). Again, several randomized controlled trials have shown the benefit of aspirin in improving the negative symptoms, total positive and negative syndrome scale and general psychopathology in schizophrenia subjects (Laan et al. 2010). In a randomized double-blind placebo-controlled study conducted on 1000 schizophrenia patients, with antipsychotics and adjuvant therapy with either placebo or aspirin, the aspirin treated group had better clinical improvement in terms positive and negative syndrome scale, compared to placebo, after a follow-up period of three months. This effect was more prominent in patients with altered immune status (Laan et al. 2010). However, owing to the gastrointestinal and various other side effects anti-inflammatory drugs on long term use, a more detailed study is warranted with respect to the appropriate dosing of anti-inflammatory drugs in schizophrenia patients. Moreover, since the studies used to assess the benefit of anti-inflammatory drugs in schizophrenia were mostly done on a small sample size of patients and for a short period of time, more detailed studies considering large sample size and large duration should be considered to establish appropriate conclusions.

As discussed in previous sections, microglial activation plays a significant role in the inflammation and progression of schizophrenia. Minocycline, a second-generation tetracycline antibiotic with strong anti-inflammatory properties that inhibit microglial activation, can play a massive role in the management of schizophrenia. This is demonstrated in methamphetamine-induced psychotic mice models, wherein minocycline administration showed improvement in cognitive symptoms (Mizoguchi et al. 2008). Similarly, even in humans, minocycline has shown improvement in the negative symptoms of schizophrenia (Chen et al. 2018). Other meta-analysis studies have also proven the superiority of minocycline in resolving negative symptoms when compared to antipsychotic monotherapy alone (Cho et al. 2019; Solmi et al. 2017).

Apart from anti-inflammatory drugs, various other pharmacotherapeutic options that help to curb cytokine levels can be used as therapy adjuvants for schizophrenia. Antibody immunotherapy is currently used in various immune-related disorders like inflammatory bowel disease and rheumatoid arthritis, where the monoclonal antibodies (mAbs) target the cytokines and their receptors. (Chan and Carter 2010). In an 8-week open label clinical trial with the concomitant administration of i.v. tocilizumab (an IL-6 inhibitor) every 4 weeks along with the non-clozapine antipsychotic drugs, there was a significant improvement in BACS (brief assessment of cognition in schizophrenia), and verbal fluency after 4 weeks, compared to baseline levels. However, there was no improvement in the psychopathology, highly sensitive CRP or cytokine levels (Miller et al. 2016). In a randomized double-blind placebo-controlled trials considering 36 patients administered with 8 mg/kg of three-monthly doses of placebo or tocilizumab, there was no significant improvement in the positive negative or cognitive symptoms in the group which received tocilizumab when compared to the group that received the placebo. The authors state that this might be due to the inability of tocilizumab to cross the BBB (Girgis et al. 2018). This significant limitation of mAbs in having limited ability to cross the BBB is on account of their polarity and large size. On the contrary, in another randomized double-blind placebo-controlled study (Weickert et al. 2019) twenty seven schizophrenic patients with elevated peripheral inflammatory markers, were administered with subcutaneous injection of canakinumab 150 mg or placebo respectively. Here, canakinumab administration showed significant improvement in the positive symptoms when the trial participants were assessed in the eighth week. Most of these studies have been conducted on relatively small sample sizes. Due to the differences in the outcome of these different studies, it is necessary to conduct a study with large sample size and for a longer duration of action.

NAC is a glutathione precursor with both anti-inflammatory and antioxidant properties making it useful in the management of neurodegenerative diseases (Tardiolo et al. 2018). Abnormal amount of dopamine and glutamate metabolism in schizophrenic patients leads to oxidative stress resulting due to glutathione deficiency, which contributes to pathogenesis of schizophrenia (Tharoor et al. 2018). NAC exhibits both anti- inflammatory and neuroprotective function and has shown to stop the effect of inflammatory stimuli in rats with reduction in TNFα, IL-1β and IL-6 levels, (Palacio et al. 2011). Clinical studies have shown improvement in the Positive and Negative Syndrome Scale (PANSS) total and negative symptoms but no improvement in the PANSS positive score following the administration of NAC (Farokhnia et al. 2013; Tharoor et al. 2018). In a meta-analysis of randomized controlled trials of FEP and schizophrenia, NAC as adjuvant therapy for a period of 24 weeks or more, showed an improvement in the negative and total scores on the PANSS scale, along with some beneficial effect on the cognition in terms of working memory (Yolland et al. 2020). Besides this, studies have also shown the effect of drugs like statins, which possess anti-inflammatory properties, to improve the positive and negative symptoms of schizophrenia (Nomura et al. 2018). However, some other randomized controlled trials stated that there was no significant difference between statin and placebo groups (Ghanizadeh et al. 2014). Along with the improvement of schizophrenic symptoms, the lipid-lowering effect of statins might also help to reduce the cardiovascular side effects of antipsychotic drugs. Therefore, further detailed studies would be helpful in confirming the effectiveness of statins in schizophrenia patients. Apart from this, augmentation of estrogen therapy is also discussed as a possible approach in the management of schizophrenia, owing to reduction in disease severity seen in women who hit puberty and beyond, followed by increase in severity of the disease the women experience at or after menopause (Brand et al. 2021). However, more studies are needed to be done to decide on the implication of this therapeutic plan.

Conclusion

There is a well-established relationship between inflammation and schizophrenia, at least in a subset of patients. If inflammation contributes even partly to the pathophysiology of schizophrenia, then treatments as ordinary as conventional anti-inflammatory drugs may strike at the root of the disease process. Inflammatory hypotheses converge with the existing hypothesis such as the dopaminergic and glutamatergic origin. The addition of anti-inflammatory drugs might enable clinicians to reduce the dose of antipsychotic drugs which will further help in reducing the prevalence of treatment-resistant schizophrenia. Since antipsychotics cannot be combined for their increased effectiveness due to their similar mechanism of action and side effects, the addition of other immunomodulatory agents along with the antipsychotics might prove as a promising treatment option. Notwithstanding, further studies conducted in-depth are required to find an effective immunomodulatory drug targeting the designated pathway associated with the pathology of schizophrenia to provide a more personalized approach to the patients.

Author contributions

Usha Nayak wrote the first draft of the manuscript and modified it subsequently. Usha Nayak, Jyothsna Manikkath and Devinder Arora contributed to revising, editing, fact-checking, and finalizing the manuscript. Jayesh Mudgal contributed to conceptualising, supervising, designing, and finalizing the manuscript. The final manuscript was reviewed and approved by all authors.

Funding

Open access funding provided by Manipal Academy of Higher Education, Manipal.

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Competing interests

The authors declare no competing interests.