Coronavirus disease 2019 (COVID-19)

COVID-19 is an excellent example of neuropsychiatric complications in acute neuroinflammation. The previous Spanish flu epidemic of 1918–1919, the severe acute stress respiratory syndrome (SARS) and the Middle East respiratory syndrome showed that the damage from these virus infections of the respiratory tract is not limited to the lung. Immunopathological studies on a cohort of COVID-19 patients in the Netherlands in the first 3 months of 2020 reported that an extensive inflammatory response was present not only in the lungs, but also in the heart, liver, kidney, and the brain (Schrink et al., 2020). In the brain itself, extensive inflammation was seen in the olfactory bulbs and medulla oblongata, reflecting the loss of smell and many of the CNS symptoms (Banerjee and Vikswanath, Reference Banerjee and Viswamath2020). The COVID-19 virus may enter through the angiotensin-converting enzyme two receptors (ACE-2) which are present on endothelial cells of cerebral vessels (Garg Reference Garg2020) and also likely by crossing the damaged blood–brain barrier (BBB), which is highly susceptible to peripheral immune changes (Schwartz et al., Reference Schwartz, Kipris, Rivets and Prat2013) and certainly under the characteristic cytokine storm of COVID-19.

Many cases of neuropsychiatric disorders have now been reported in COVID-19 patients, less than 1 year since the pandemic started (Cothran et al., Reference Cothran, Kellman, Singh, Beck, Powell, Bolton and Tam2020; Huang and Zhao Reference Huang and Zhao2020; Rogers et al., Reference Rogers, Chesney, Oliver, Pollak, McGuire, Fusar-Poli, Zandi, Lewis and David2020; Troyer et al., Reference Troyer, Kohn and Hong2020). Neurological manifestations occur early in the illness (Orsucci et al., Reference Orsucci, Ienco, Nocita, Napolitano and Vista2020). Delirium, from hypoxia and metabolic abnormalities (Garg Reference Garg2020), particularly occurred in the more vulnerable aged population and those with dementia (Butler et al.,Reference Butler, Pollak, Rooney, Michael and Nicholson2020; Mcloughlan et al.,2020). Acute neuropsychiatric symptoms which include altered mental status, psychosis, and suicidal ideation (Chacko et al., Reference Chacko, Job, Caston, George, Yacoub and Cáceda2020; Correa-Palacio et al., Reference Correa-Palacio, Hernandez-Huerta, Gómez-Arnau, Loeck and Caballero2020; Ferrando et al., Reference Ferrando, Klepacz, Lynch, Shahar, Dornbush, Smiley, Miller, Tavakkoli, Regan and Bartell2020; Finatti et al., Reference Finatti, Pigato, Pavan, Toffanin and Favaro2020; Ng et al., Reference Ng, Yeo, Lim and Chee2020; Sher Reference Sher2020; Valdés-Florido et al., Reference Valdés-Florido, López-Díaz, Palermo-Zeballos, Martínez-Molina, Martín-Gil, Crespo-Facorro and Ruiz-Veguilla2020) were the second most common presentation. Encephalopathy or encephalitis occurred in younger patients as well (Varatharaj et al., Reference Varatharaj, Thomas, Ellul, Davies, Pollak, Tenorio, Sultan, Easton, Breen, Zandi, Coles, Manji, Al-Shahi Salman, Menon, Nicholson, Benjamin, Carson, Smith, Turner, Solomon, Kneen, Pett, Galea, Thomas and Michael2020). An increase of stress response is reflected in the low mood, anxiety, and severe fatigue, which may persist in about 20% of patients following their apparent full recovery (Rogers et al.,Reference Rogers, Chesney, Oliver, Pollak, McGuire, Fusar-Poli, Zandi, Lewis and David2020; Sterdolt and Verkhratsky 2020). PTSD also occurred (Mazza et al., Reference Mazza, De Lorenzo, Conte, Poletti, Vai, Bollettini, Melloni, Furlan, Ciceri, Rovere-Querini and Benedetti2020), as well as Guillain-Barré syndrome (Garg Reference Garg2020; Webb et al., Reference Webb, Wallace, Martin-Lopez and Yogarajah2020) and other forms of neuropathy and myopathy (Ottaviani et al., Reference Ottaviani, Boso, Tranquillini, Gapeni, Pedrotti, Cozzio, Guarrera and Giometto2020). Severe and debilitating fatigue and myalgia could be present, and elevated creatine kinase levels indicate serious myopathy (Garg Reference Garg2020; Orsucci et al., Reference Orsucci, Ienco, Nocita, Napolitano and Vista2020). Cognitive defects (Troyer et al., Reference Troyer, Kohn and Hong2020; Zhou et al, Reference Zhou, Lu, Chen, Wei, Wang, Lyu, Shi and Hu2020) may persist for many months after apparent recovery. The damage to neuronal networks initiated by the COVID-19 virus and sustained by the chronic inflammation and disruption of metabolic homoeostasis is likely to result in the long-term CNS disabilities, and the term “long COVID” has been applied in the UK and Ireland.

Both acute and long-term neuropsychiatric consequences of viral infections have been documented historically (Davydow et al., Reference Davydow, Desai, Needham and Bienvenu2008). These include schizophrenia cases in the 1918 Spanish flu (Kępińska et al., Reference Kępińska, Iyegbe, Vernon, Yolken, Murray and Pollak2020), depression, anxiety, and PTSD cases in SARS (Mak et al., Reference Mak, Chu, Pan, Yiu and Chan2009), and Parkinson’s symptoms with H5N1 influenza (Henry et al., Reference Henry, Smeyne, Jang, Miller and Okun2010).

The immediate impact of the COVID-19 virus is attributed to its binding to the widely distributed ACE-2, which is distributed along the respiratory and gastrointestinal epithelium as well as endothelial cell surfaces. The spread of the virus into the brain occurs following a high viral load coupled with susceptibility due to the age of the patient, abnormal or over-reactive immune function, chronic medical illness, and frequently a history of neurotropic virus infections (Razanamahery et al., Reference Razanamahery, Malinowski, Humbert, Brunel, Lepiller, Chirouze and Bouiller2020; Singhou Reference Singhou2020). The spread of the virus through the brain is heterogeneous but in experimental studies it has been shown to rapidly infect the olfactory bulbs (approximately after 4 days) and later the piriform cortex (Perlman et al, Reference Perlman, Evans and Afift2020). The remainder of the cortex, hypothalamus, basal ganglia, and brain stem are affected later. Microglia are important regulators of COVID-19 expression in the brain since their ablation results in increased viral loads, 7–8 days post-infection. Neurons appear to be the main targets of infection in vivo (Mangale et al., Reference Mangale, Syage, Ekiz, Skinner, Cheng, Stone, Brown, O’Connell, Green and Lane2020). As ACE-2 receptors are expressed in the olfactory lining, a main target for COVID-19, this likely accounts for the anosmia and hypo-osmia experienced early in the infection, which occurs with a frequency of 12–32% (Lechien et al, Reference Le chien, Chiesa-Estomba, De Siati, Horoi, Le Bon, Rodriguez, Dequanter, Blecic, El Afia, Distinguin, Chekkoury-Idrissi, Hans, Delgado, Calvo-Henriquez, Lavigne, Falanga, Barillari, Cammaroto, Khalife, Leich, Souchay, Rossi, Journe, Hsieh, Edjlali, Carlier, Ris, Lovato, De Filippis, Coppee, Fakhry, Ayad and Saussez2020), and loss of smell results from the neurodegenerative effect of the virus on the olfactory bulbs. Dinein and kinesin have been identified as the proteins responsible for the transmission of the virus and the nucleus solitarius of the brain stem is preferentially affected (Wu et al.,Reference Wu, Xu, Chen, Duan, Hashimoto, Yang, Liu and Yang2020), accounting for the central effects of the virus on breathing.

C-reactive protein (CRP) is a commonly used early marker to grade the severity of systemic inflammation from infection (Nehring et al., Reference Nehring, Goyal, Bansal and Patel2020). Relatively mild to moderate elevations are seen in obesity, diabetes, depression, periodontitis, sedentary lifestyle and cigarette smoking rheumatoid arthritis, myocardial infarction, pancreatitis, and bronchitis, but marked and severe elevations in CRP (more than 10.0 mg/dL and >50.0 mg/dL, respectively) require acute bacterial or viral infections, systemic vasculitis or major trauma. In early-stage COVID-19, CRP levels show a positive correlation with lung lesions and disease severity (Wang, Reference Wang2020). Importantly, only a subset of COVID-19 patients shows severe elevations in CRP, for which there appears to be emerging evidence of genetic susceptibility (Zeberg and Pääbo, Reference Zeberg and Pääbo2020).

The vulnerability of the elderly to severe COVID-19 infection is well known. Ageing is usually associated with overall neurodegenerative changes and diminished homoeostatic brain mechanisms. In ageing, synaptic plasticity decreases, brain metabolism is reduced, and the vulnerability to exogenous toxins is increased. The increases in specific pro-inflammatory cytokines have been correlated with specific symptoms of the virus infection. For example, IL-1 beta has been linked to depression in later life, IL-6 with anhedonia and suicidal behaviour, while tumour necrosis factor (TNF)-alpha and IL-2 have been linked to apathy and motor inhibition (Thomas Reference Thomas2005; Schmidt 2016).

Apart from psychological support and treatment of accompanying neuropsychiatric disorders such as anxiety, depression, psychosis, and neuropathic and myopathic pain (Drożdżal et al., Reference Drożdżal, Rosik, Lechowicz, Machaj, Szostak, Majewski, Rotter and Kotfis2020), management of the neuroinflammation is important. Intravenous immunoglobulins (Novak Reference Novak2020) and careful steroidal immunosuppressant therapy appear to be useful in some cases to avoid complications (Rajabally et al., Reference Rajabally, Goedee, Attarian and Hartung2020). A recent report summarised the recommendations from the Italian Societies of Neurology, Cinical Neurophysiology, and Peripheral Nervous System Association in the management of COVID-19 immune-mediated neuropathies (Dubbioso et al., Reference Dubbioso, Nobile-Orazio, Manganelli, Santoro, Briani, Cocito, Tedeschi, Di Lazzaro and Fabrizi2020).

Because of the very recent occurrence of the pandemic, much still has to be learned about the chronic effects of the virus on the brain and behaviour. However, it is already apparent that its impact, both direct and indirect, could result in neuroprogressive changes (as seen in Parkinson’s disease (PD)) and long-term neuropsychiatric consequences. Increased vigilance for all neuropsychiatric symptoms in patients with COVID-19 is certainly warranted (Brown et al., Reference Brown, Gray, Lo Monaco, O’Donoghue, Nelson, Thompson, Francey and McGorry2020). Minimising the relevance of the psychiatric aspects of COVID-19 and mistakenly explaining that “sometimes an abnormal behavior in an abnormal situation is a normal behavior” could be an unforgivable mistake (Steardo and Verkhratsky, 2020).

Autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS)

Compared to the multiple neuropsychiatric consequences of COVID-19 infection, acute neuroinflammation causing a specific psychiatric disorder is highlighted in PANDAS (Frick and Pittenger Reference Frick and Pittenger2016). PANDAS is a medical emergency, in which sudden and severe OCD, with cognitive and behavioural symptoms, developed in children after streptococcal infection. The exact neuro-mechanism is still unclear. It is not known whether serotonin (5HT) or other types of neurons were involved or damaged (Chiarello et al., 2017; Jasper-Fayer et al., 2017), but there is evidence suggesting that human anti-brain autoantibodies induced by Streptococcus pyogenes infections target DA receptors (Cox et al., Reference Cox, Sharma, Leckman, Zuccolo, Zuccolo, Kovoor, Swedo and Cunningham2013; Cunningham and Cox Reference Cunningham and Cox2016; Orefici et al., Reference Orefici, Cardona, Cox, Cunningham, Ferretti, Stevens and Fischetti2016). Acute infections in adults have not been reported to cause OCD, but depression is a fairly common consequence, as reported in influenza (Bornand et al. 2016). Acute systematic inflammation induced by endotoxin also may precipitate sad mood (Benson et al., Reference Benson, Brinkhoff, Lueg, Roderigo, Kribben, Wilde, Witzke, Engler, Schedlowski and Elsenbruch2017) and exacerbation of schizophrenic symptoms has been reported with oseltamivir administration (Lan et al., Reference Lan, Liu and Chen2015). Penicillin, azithromycin, intravenous immunoglobulin, plasma exchange, tonsillectomy, cognitive behaviour therapy, non-steroidal anti-inflammatory drug (NSAID), and corticosteroids (CSs) have been used in the treatment of PANDAS. The rationale and efficacy of antibiotics and immunomodulatory therapies have been reviewed and discussed (Burchi and Pallanti Reference Burchi and Pallanti2018; Sigra et al., Reference Sigra, Hesselmark and Bejerot2018).

Traumatic brain injury (TBI)

Acute physical trauma to the brain, as in boxing and after head injury, triggers a reactive inflammatory process. Though inflammation serves defence and neuroprotective purposes in the early stages when the brain sustains physical injuries, it is a double-edged sword (Loane and Kumar Reference Loane and Kumar2016; Konoshi and Kiyama Reference Konishi and Kiyama2018). The consequences of inflammation are dictated by multiple local and systematic cues of the host. It is hard to predict which direction the multiple processes will end up, but the results could be quite different. In physical head injuries, hyperactivation of glutaminergic (Glu) neurotransmission after injury may result in neuronal death. Amantadine is neuroprotective, supposedly through its N-methyl-D-aspartate receptor (NMDAR) antagonist action. The antioxidants glutathione and N-acetylcysteine reduce brain damage and improve recovery, glial limitans breakdown, and parenchymal cell death by up to approximately 70%, suggesting that reactive oxidative stress may be a primary inducer of cell death and inflammation after focal brain injury (Corps et al. Reference Corps, Roth and McGavern2015). The benefit of NSAIDs is controversial as they block both the tissue damaging and repair-promoting aspects of inflammation. Likewise, the benefit of systemic glucocorticoid treatment in COVID-19 patients is not straightforward (Keller et al., Reference Keller, Kitsis, Arora, Chen, Agarwal, Ross, Tomer and Southern2020). Glucocorticoid administration appears beneficial when CRP levels are high (greater than 20.0 mg/dL) but harmful when CRP levels are low (less than 10 mg/dL), perhaps due to the association between glucocorticoid use and delayed viral clearance (Keller et al., Reference Keller, Kitsis, Arora, Chen, Agarwal, Ross, Tomer and Southern2020).

In traumatic brain injury (TBI), salsalate, an unacetylated salicylate, has been found to be effective, through blockade of NF-κB, pro-inflammatory gene expression and nitrite secretion by microglia, increasing expression of genes associated with neuroprotection and neurogenesis, including neuropeptides, oxytocin, and thyrotropin-releasing hormone (Lagraoui et al. Reference Lagraoui, Sukumar, Latoche, Maynard, Dalgard and Schaefer2017). Apart from these small molecules, cell-based therapeutics are being pursued as well, to manipulate the immune response into a neuroprotective direction (Xiong et al. Reference Xiong, Mahmood and Chopp2018). Apart from neurodegenerative disorders triggered by chronic neuroinflammation post-TBI, it is important to mention that about 1/3 of ischemic stroke patients with neuroinflammation also end up with post-stroke depression. Low mental health literacy in many elderly subjects may result in patients not being able to voice the mental symptoms properly, making a diagnosis difficult (Lee et al., Reference Lee, Tang, Leung, Yu and Cheung2009). Though there were some studies on the relationship between brain areas affected by inflammation and the subsequent development of depression, the specific neurocircuits affected are unclear, and anti-inflammatory measures again seemed to be beneficial in these patients (Villa et al. Reference Villa, Ferrari and Moretti2018).

The cause for the widespread CNS damage following acute neuroinflammation, whether it is from viral or bacterial infections, or physical trauma, appears to be an acute activation and subsequent dysregulation of the immune system (Becher et al., Reference Becher, Bechmann and Greter2006; Rostami and Ciric 2013; Kostic et al., Reference Kostic, Stojanovic, Marjanovic, Zivkovic and Cvetanovic2015), especially the eicosanoids and cytokine systems (cytokine and eicosanoid storms). Cytokine activations in inflammation has been well studied. Eicosanoids and related bioactive lipid mediators derived from polyunsaturated fatty acids were viewed as pro-inflammatory until recently when unique eicosanoids and related docosanoids with anti-inflammatory and pro-resolution functions were discovered (Dennis and Norris Reference Dennis and Norris2015).

Autoimmune encephalitis includes those with systematic lupus erythematosus (Bendorius et al., Reference Bendorius, Po, Muller and Jeltsch-David2018), cases of autoimmune anti-NMDAR antibodies (Kayser and Dalmau Reference Kayser and Dalmau2016), or anti-GABA (γ-aminobutyric acid) receptor antibodies. Regarding anti-GABA antibody encephalitis (Dalmau Reference Dalmau2017), there may be differences in vulnerability in terms of age, as the antibodies in childhood cases appeared to be more viral-related while adult cases are more tumour-related (Spatola et al., Reference Spatola, Petit-Pedrol, Simabukuro, Armangue, Castro, Barcelo Artigues, Julià Benique, Benson, Gorman, Felipe, Caparó Oblitas, Rosenfeld, Graus and Dalmau2017), highlighting the age effect on vulnerability of inflammation again. Kawasaki disease is a good example of age-dependent vulnerability. The excessive inflammatory response is seen in a minority of preschool infants, with Asian ancestry being a suspected vulnerability factor, while adults in the same household rarely experience anything more serious than transient conjunctivitis (Chen et al, 2018; personal communication).

In summary, there are neuropsychiatric consequences following acute neuroinflammation. Apart from the potency of the causative agent such as COVID-19, or SARS, or streptococci bacteria, and co-existing medical disorders such as diabetes and cardiovascular disorders, age appears to be an important factor for susceptibility. Other factors, including genotype, determine the pro- or anti-inflammatory outcome of initial immune responses, selectivity of neuroinflammatory insult, neuronal vulnerability, and the neuropsychiatric consequences.

Dementia and ACh neurons

ACh neurons appear to be particularly vulnerable to neuroinflammation. ACh neuronal deaths in the basal forebrain occur early in AD (Whitehouse et al., Reference Whitehouse, Price, Clark, Coyle and DeLong1981) but not in normal ageing (McQuail et al., Reference McQuail, Riddle and Nicolle2011). On the other hand, the ACh system has been discovered to exert significant modulatory action on the immune system (Gatta et al., Reference Gatta, Mengod, Reale and Tata2020; Hoover Reference Hoover2017). Muscarinic and nicotinic receptors stimulate pro- and anti-inflammatory cytokines, respectively, to modulate the immune/inflammatory responses (Di Bari et al., Reference Di Bari, Di Pinto, Reale, Mengod and Tata2017). Acetylcholine esterase inhibitors (AChI) or vagal nerve stimulation modulate neuroinflammation via the α7 nicotinic acetylcholine receptor (Treinin et al., Reference Treinin, Papke, Nizri, Ben-David, Mizrachi and Brenner2017).

PD and DA neurons

The susceptibility or vulnerability of DA neurons to neuro- and peripheral inflammation is demonstrated in PD (Matheoud et al., Reference Matheoud, Cannon, Voisin, Penttinen, Ramet, Fahmy, Ducrot, Laplante, Bourque, Zhu, Cayrol, Le Campion, McBride, Gruenheid, Trudeau and Desjardins2019). DA-dependent motor function being easily testable, urinary tract, and chest infections have been reported to cause transient worsening of PD symptoms. Neuromelanin is a catecholamine-derived pigment in DA neurons of the substantia nigra and also in norepinephrine neurons of the locus coeruleus. They are both known to be damaged by inflammation in PD. A close relationship has been described between iron, DA, and neuromelanin. Excess iron or DA is toxic. Excess DA is converted into neuromelanin, and excess iron is chelated by neuromelanin, which also removes pesticides and some other oxidants. Microglia become activated when this DA–iron neuromelanin balance is lost (Fedorow et al., Reference Fedorow, Tribl, Halliday, Gerlach, Riederer and Double2005; Haining and Achat-Mendes Reference Haining and Achat-Mendes2017), resulting in neuronal death. In PD, it is the neurons containing neuromelanin that degenerate (Zecca et al., Reference Zecca, Zucca, Wilms and Sulzer2003, Reference Zecca, Casella, Albertini, Bellei, Zucca, Engelen, Zadlo, Szewczyk, Zareba and Sarna2008; Zucca et al., Reference Zucca, Segura-Aguilar, Ferrari, Muñoz, Paris, Sulzer, Sarna, Casella and Zecca2017). Similar to the relationship between ACh neurons and the immune system, dysregulation of DA transmission may also induce dysfunction in the immune system (Vidal and Pacheco Reference Vidal and Pacheco2019). Astrocyte DA D2 receptor (DRD2) was also shown to modulate immunity through αB-crystallin (CRYAB), which is part of the small heat shock protein family and is anti-neuroinflammatory (Shao et al., Reference Shao, Zhang, Tang, Zhang, Zhou, Yin, Zhou, Huang, Liu, Wawrousek, Chen, Li, Xu, Zhou, Hu and Zhou2013; Zhang et al., Reference Zhang, Chen, Wu, Manaenko, Yang, Tang, Fu and Zhang2015)

Affective disorders and NMDARs (glutamate)

Chronic neuroinflammation appeared to be present in some patients with affective disorders. Transition into depression in these patients has been attributed to the activation of the toxic kynurenine metabolic pathway, resulting in the formation of toxic quinolinic acid, an NMDAR agonist (Leonard Reference Leonard2010, Reference Leonard2015, Reference Leonard2017, 2018; Müller Reference Müller2010; Müller and Schwarz Reference Müller and Schwarz2006, Reference Müller and Schwarz2007; Dantzer and Walker Reference Dantzer and Walker2014; Won and Kim Reference Won and Kim2016; Dantzer Reference Dantzer2017). Bringing in this inflammatory toxicity factor, an integrated toxic brain hypothesis of depression (Tang et al., 2017a) would supplement the other two hypotheses of depression, namely the amine hypothesis (Bunney Reference Bunney1975) and the stress hypercortisolemia hypothesis (Duman and Monteggia Reference Duman and Monteggia2006). In addition to the neurotoxic effects on neurons and astroglia cells, quinolinic acid is also an important substrate for nicotinamide adenine dinucleotide (NAD+), a key component of the electron transport system. As discussed by Leonard (2018), in severe depression, the synthesis of NAD+ is reduced. Unlike non-nervous tissues, brain energy metabolism is largely dependent on glucose and the transport of glucose across the BBB is an insulin-dependent process. As the resistance of the insulin receptors is increased in the inflammatory state associated with severe depression, the transport of glucose into the brain is compromised. The concurrent increase in the activity of superoxide dismutase and the rise in reactive oxygen species further compromise the integrity of neurons and, in addition, damage the mitochondria (Burkunina et al., Reference Burkunina, Pariante and Zunszain2015). As a result of the damage to the mitochondria, the synthesis of ATP and other high-energy intermediates is decreased. These metabolic changes caused by the neurotoxins and metabolic stress help to understand the causes of the neurodegenerative changes associated with chronic depression, particularly in elderly patients.

OCD and anxiety disorders

Recently, heightened inflammatory activities have been described in patients suffering from PTSD, fear, and anxiety disorders (Frick and Pittenger Reference Frick and Pittenger2016; Attwells et al., Reference Attwells, Setiawan, Wilson, Rusjan, Mizrahi, Miler, Xu, Richter, Kahn, Kish, Houle, Ravindran and Meyer2017; Michopoulos et al., Reference Michopoulos, Powers, Gillespie, Ressler and Jovanovic2017; Zaas et al., 2017).

This is also the case in OCD. Altered gut flora has been discovered in OCD (Turna et al., 2016; Reference Turna, Grosman Kaplan, Patterson, Bercik, Anglin, Soreni and Van Ameringen2019) and in animal models (Scheepers et al., 2019). Pregnancy may induce OCD with gut flora changes in pregnancy suggested as possible causes (Rees Reference Rees2014). Reintroduction of beneficial microbes and probiotics into the gut has been proposed as a possible treatment for OCD.

Psychosis

Early clinical evidence arose from epidemiological studies of the 1957 influenza pandemic in which maternal infection during pregnancy was found to correlate with the development of schizophrenia in the offspring in later life (Brown and Patterson,Reference Brown and Patterson2011; Mednick et al,Reference Mednick, Machon, Huttunen and Bonett1988). A growing body of experimental and clinical evidence supports the role of neuroinflammation in the pathophysiology of psychosis and schizophrenia (Doorduin et al., Reference Doorduin, deVries, Willemsen, de Groot, Dierckx and Klein2009), with theories pinpointing parvalbumin interneuron development impacted by inflammation and NMDAR hypofunction (Barron et al., Reference Barron, Hafizi and Mizrahi2017; Najjar et al., Reference Najjar, Steiner, Najjar and Bechter2018). These parvalbumin interneurons are fast spiking GABAergic neurons that synchronise the pyramidal neurons in the cortex and contribute to the generation of cognitive processes and working memory (Zandi et al., Reference Zandi, Irani, Lang, Waters, Jones, McKenna, Coles, Vincent and Lennox2011). Support for the importance of neuroinflammation in schizophrenia and psychosis also comes from genetic studies. Multiple genome-wide association studies implicate the major histocompatibility site on chromosome 6, in particular compliment C4 within the human leucocyte antigen. C4 is involved in pathogen opsonisation and synaptic pruning which could be involved in the initiation of the early disruption of the neuronal network in schizophrenia (Sekar et al., Reference Sekar, Bialas, de Rivera, Davis, Hammond, Kamitaki, Tooley, Presumey, Baum, Van Doren, Genovese, Rose, Handsaker, Daly, Carroll, Stevens and McCarroll2016).

Post-mortem studies of schizophrenic patients have also demonstrated the presence of activated microglia in brain tissue, though results of several studies are inconsistent or confined to a limited number of brain regions and without a specific selection of the patients studied. An early positive emission study using 14C-PK-11195, a peripheral benzodiazepine receptor ligand, showed that neuroinflammation occurred in the hippocampus of schizophrenic patients in the psychotic phase of the illness (Doorduin et al., Reference Doorduin, deVries, Willemsen, de Groot, Dierckx and Klein2009). Later positron emission tomography (PET) studies using a more specific radioligand showed no difference between medicated and drug-naïve first episode psychosis or schizophrenia compared to healthy controls (Hafizi et al., Reference Hafizi, Tseng, Rao, Selvanathan, Kenk, Bazinet, Suridjan, Wilson, Meyer, Remington, Houle, Rusjan and Mizrahi2017; Coughlin et al., Reference Coughlin, Wang, Ambinder, Ward, Minn, Vranesic, Kim, Ford, Higgs, Hayes, Schretlen, Dannals, Kassiou, Sawa and Pomper2016). This suggests that neuroinflammation may be confined to a subgroup of patients and present at an early stage of the illness.

A meta-analysis by Miller et al., (Reference Miller, Buckley, Seabolt, Mellor and Kirkpatrick2011) of 40 studies involving over 2500 schizophrenic patients found that the pro-inflammatory cytokines, TNF-alpha, interferon (IFN)-gamma, IL-12, and IL2 receptor were consistently increased independent of the stage of the illness, suggesting that these cytokines might be trait markers. Conversely, IL-1 beta, IL-6, and TGF-beta were positively associated with the active phase of the illness and were therefore possible state markers.

Finally, celecoxib, a cyclo-oxygenase 2 inhibitor, can enhance the efficacy of risperidone and amisulpride in the treatment of chronic schizophrenia (Muller 2010; Muller et al., 2010), while the anti-inflammatory tetracycline, minocycline, improves the negative symptoms and cognitive dysfunction of schizophrenic patients in the early and acute phases of the disorder (Levkovitz et al., 2009).

MS and 5-HT

Although disruption of the BBB and demyelination are known consequences of neuroinflammation in MS, an interesting relationship between 5-HT and MS exists. 5-HT disturbances of gut origin have been suggested to play a pivotal role in demyelinating disorder, including MS (Malinova et al., Reference Malinova, Dijkstra and de Vries2018). PET showed differential expression of 5-HT transporters in several brain regions in relapsing MS. Lower levels of serotonin reuptake transporters (SERTs) have been reported in the cingulate cortex, the thalamus, insula, and hippocampus, with higher SERTs in the prefrontal cortex. Lower SERT in the insula was correlated with depression scores (Hesse et al., Reference Hesse, Moeller, Petroff, Lobsien, Luthardt, Regenthal, Becker, Patt, Thomae, Seese, Meyer, Bergh and Sabri2014).

Chronic stress causes widespread health problems, including malignancies, ageing, gastrointestinal disorders, and skin problems. Psychological stress and mental disorders have been shown to activate the peripheral immune system (Bendorius et al., Reference Bendorius, Po, Muller and Jeltsch-David2018). The composition of gut microbes, which are far away from the brain, is known to be affected by psychological factors, including pregnancy-related stress, and vice versa (Rees Reference Rees2014). Toxic metabolites generated from pathological microbes in the gut could travel to the CNS and trigger neuroinflammation. Thus, a dynamic triple relationship exists between the CNS, immune system, and gut axis and this intricate balance could be lost in the presence of external insults or stress. Dysregulation of the eicosanoids and cytokine systems is suspected to be the mediator of the psychological stress-damaging effects (Umamaheswaran et al., Reference Umamaheswaran, Dasari, Yang, Lutgendorf and Sood2018).

A neuroprotective role of the endocannabinoid system and a modulating role of the cannabinoid receptor 1 (CB1) have been debated, using data from animal models (Zoppi et al., Reference Zoppi, Pérez Nievas, Madrigal, Manzanares, Leza and García-Bueno2011; Rabasa et al., Reference Rabasa, Pastor-Ciurana, Delgado-Morales, Gómez-Román, Carrasco, Gagliano, García-Gutiérrez, Manzanares and Armario2015). The potential neuroprotective usage of anti-inflammatory CB1 and CB2 agonists would need further research (Mastinu et al., Reference Mastinu, Premoli, Ferrari-Toninelli, Tambaro, Maccarinelli, Memo and Bonini2018).

In these different neuropsychiatric disorders, finding the clues to address the specificity and vulnerability issue of chronic neuroinflammation is important. It is difficult to accept general inflammation as the aetiology of any specific neuropsychiatric disorder, as one would have to explain why the same inflammation would end up with neurodegeneration in some patients and depression, OCD, or schizophrenia in others. In fact, the same difficulty happened in the early hypercortisolemia hypothesis of depression; a question of whether it is the inflammation or hypercortisolemia that created the neurocircuit damage or suppressed neurogenesis (Lau et al. Reference Lau, Qiu, Helmeste, Lee, Tang, So and Tang2007; Qiu et al. Reference Qiu, Helmeste, Samaranayake, Lau, Lee, Tang and So2007). The damages are not specific to depression (Tang et al., Reference Tang, Helmeste and Leonard2012; Tang et al., 2017b).