key: cord-0823497-bdh4efdm
authors: van Vuren, Esmé Jansen; Steyn, Stephan F.; Brink, Christiaan B.; Möller, Marisa; Viljoen, Francois P.; Harvey, Brian H.
title: The neuropsychiatric manifestations of COVID-19: Interactions with psychiatric illness and pharmacological treatment
date: 2021-01-01
journal: Biomed Pharmacother
DOI: 10.1016/j.biopha.2020.111200
sha: 3f3dff889c90b1d57a5aa1c3b42ea7b2a09829fd
doc_id: 823497
cord_uid: bdh4efdm

The recent outbreak of the corona virus disease (COVID-19) has had major global impact. The relationship between severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection and psychiatric diseases is of great concern, with an evident link between corona virus infections and various central and peripheral nervous system manifestations. Unmitigated neuro-inflammation has been noted to underlie not only the severe respiratory complications of the disease but is also present in a range of neuro-psychiatric illnesses. Several neurological and psychiatric disorders are characterized by immune-inflammatory states, while treatments for these disorders have distinct anti-inflammatory properties and effects. With inflammation being a common contributing factor in SARS-CoV-2, as well as psychiatric disorders, treatment of either condition may affect disease progression of the other or alter response to pharmacological treatment. In this review, we elucidate how viral infections could affect pre-existing psychiatric conditions and how pharmacological treatments of these conditions may affect overall progress and outcome in the treatment of SARS-CoV-2. We address whether any treatment-induced benefits and potential adverse effects may ultimately affect the overall treatment approach, considering the underlying dysregulated neuro-inflammatory processes and potential drug interactions. Finally, we suggest adjunctive treatment options for SARS-CoV-2-associated neuro-psychiatric symptoms.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), first identified in Wuhan, China, in December 2019 [1] , has experienced progressive spread across the world in 2020. The virus, known as the novel coronavirus, causes a disease coined the 'Coronavirus Disease of 2019 (COVID-19)', that has affected human activities on an unprecedented scale. The rapid spread was fuelled by international travel and globalisation, combined with an infection that can be transmitted in the early asymptomatic phase. The illness remains an enigma, and we remain puzzled by its unknown novelty, and sometimes overwhelmed by the potential threat and observed devastation. Currently, no historical data is available to accurately predict the associated risks, death rates and other acute and long-term complications of the disease. Although promising anti-COVID-19 vaccines are being developed or are in the process of being approved, no pharmacological-effective prevention, containment strategies and/or cure is available.

While generally recognised for its often-lethal respiratory effects in especially vulnerable individuals, other potential complications, such as its effect on mental illnesses are receiving growing attention. In fact, coronavirus infections are also known as neurotropic viral infections; defined as viruses with an affinity for the nervous system [2] . In this regard, Song and colleagues [3] demonstrated SARS-CoV-2 neuro-invasion in human cell cultures and post-mortem studies. In this review, we focus on psychiatric disorders against the backdrop of this viral outbreak and discuss the potential mechanisms responsible for the interplay between these conditions. We also address the therapeutic benefits and potential adverse effects associated with treating the presenting neuropsychiatric condition and how such treatment may alter the course of SARS-CoV-2 infection in an afflicted individual. Such knowledge may reveal new avenues for identifying novel treatment interventions for SARS-CoV-2 associated neuropsychiatric complications.

The immunological features and pathological impact [4, 5] . These can be classified into four main aspects namely, (i) viral replication in innate immune cells, (ii) dysregulated immune response, (iii) cytokine storm, and (iv) antibody-mediated response [4, 5] . SARS-CoV-2 is part of the Coronaviridae family,

subfamily Coronavirinae, which are large, enveloped, single-stranded RNA viruses [6] . Importantly, these viruses are roughly spherical and with notable 'crown-like' large spikes of glycoprotein [2, 6] , from whence their name is derived. Following breaching of the initial anatomical and chemical defensive barriers of the host organism, the SARS-CoV-2 mediates viral entry into cells through binding to the angiotensin-converting enzyme 2 (ACE-2) receptor of the host cell as shown in Figure 1 . The receptor binding domain is positioned within the spike of the virus in such a way, that it is hidden and evades immune surveillance [7] . Once in the cytoplasm, the virus escapes the innate immunity response by either releasing viral endoribonuclease (RNase) activity or by forming replication organelles in host cell J o u r n a l P r e -p r o o f membranes to protect the recognition of viral RNA by the innate immune sensors [8, 9] . consequences, involving multiple organs that includes the brain, in which case the adaptive immune response may be overwhelmed.

Inflammatory mechanisms are essential protective responses against infection or injury to maintain tissue homeostasis (review by Bennet and Molofsky [48] ). It involves processes to mobilize defensive cells, such as macrophages that release inflammatory mediators such as cytokines, limiting the spread of pathogens and initiating tissue repair. Regarding inflammation within the CNS, a great deal of interest has focussed on the role of microglial cells, which together with astrocytes are involved in the mediation and modulation of the inflammatory processes [49] . Microglia function as the 'macrophages' of the CNS and can be activated in response to pro-or anti-inflammatory signals [50] . Upon activation, these resident innate immune cells release factors, such as pro-inflammatory cytokines, eicosanoids/prostanoids, nitric oxide (NO) and neurotrophic factors when activated by immunological stimuli, that exert a defence response and promotes tissue restoration [51] . However, when acute inflammation fails to cease after the original insult is cleared, it can lead to aggravated activation of microglia that further enhances pro-inflammatory cytokine production and oxidative stress [51] , causing destruction of healthy tissue and eventual impaired brain function [52, 53] . In addition, injury-or toxininduced disruption of the blood-brain barrier can lead to the infiltration of inflammatory mediators and pathogens residing in the circulation, which can further exacerbate inflammation in the CNS (see [54] for review). anxiety-related disorders [67, 68] when compared with their respective healthy controls, while therapeutic use of pro-inflammatory cytokines, like IFN, are known to induce depressive symptoms [69] .

This is now discussed.

There is evidence to suggest that an inflammatory state in psychiatric patients plays a role in their treatment response [70] . For instance, depressive symptoms are frequent among patients diagnosed with inflammatory disorders (rheumatoid arthritis, asthma, Lupus and ulcerative colitis), while immunomodulatory drugs improve these symptoms. Moreover, ustekinumab (anti-IL-12/23 antibody) and sirukumab (anti-IL-6 antibodies) show antidepressant effects [71] . Conversely, elevated concentrations of soluble IL-2 receptor (sIL-2R) have been described in treatment resistant psychosis [72] , whereas increased levels of IL-6 and IFN-γ are associated with poor treatment response in first episode psychosis patients [73] . Similarly, baseline gene expression of IL-1β, IL-6 and TNF-α increases in treatment-resistant depression [74] [75] [76] . These studies therefore highlight that add-on antiinflammatory agents may be an important approach in the treatment of psychiatric disorders, especially in patients with an inflammatory state at baseline. Indeed, in a recent review Areaga-Henríquez et al. [77] indicated that the use of infliximab (an anti-TNFα agent), minocycline (tetracycline antibiotic) or eicosapentaenoic acid (omega-3 fatty acid) improve treatment response in depressed patients with J o u r n a l P r e -p r o o f increased baseline CRP/IL-6 levels. Similarly, Kohler et al. [78] reported that celecoxib (a cyclooxygenase (COX)-2 inhibitor), lovastatin or simvastatin (hydroxy-methylglutaryl (HMG)-coenzyme (Co)A inhibitors), minocycline, pioglitazone (a thiazolidinedione), modafinil (a psychostimulant) and dexamethasone (corticosteroid) are similarly effective as add-on treatments to commonly used selective serotonin reuptake inhibitors (SSRIs) for depression. In fact, these augmentation strategies may be superior to SSRIs alone or placebo in reducing depressive symptoms [78] . However, in schizophrenia, these anti-inflammatory agents only have a small benefit for positive symptoms [79] . On the other hand, tocilizumab (an anti-IL-6 agent) improves cognitive symptoms, whereas minocycline and pregnenolone (an endogenous steroid) improve negative symptoms in these patients (review by

Melbourne et al. [80] ).

On the other hand, a recent study describes dose-dependent neural plasticity impairment in mice following both proinflammatory (lipopolysaccharide (LPS)) and anti-inflammatory (ibuprofen, a nonsteroidal anti-inflammatory drug) states [81] . Since disordered neuroplasticity is central to a number of psychiatric illnesses [82] , this highlights that a pro-inflammatory and an immunosuppressive state may influence a psychiatric illness and its response to treatment. Further on paradoxical actions associated with targeting the immune response, antioxidant compounds may act either as anti-or pro-oxidants depending on prevailing redox-inflammatory conditions in the cell. This is especially relevant when psychiatric illness severity or pathobiology changes over time. These studies clearly indicate that for psychiatric drugs to be effective, inflammation needs to be closely managed.

Psychotic disorders such as schizophrenia are characterized by abnormally high mesolimbic dopamine (DA) signalling in the brain that mediates positive psychotic symptoms [83, 84] , while decreased mesocortical DA signalling is associated with cognitive and negative psychotic symptoms [83] . Such altered dopaminergic signalling could be mediated by inflammation due to the negative effects of cytokines on DA synthesis, packaging, release and reuptake [85] (Figure 3 ). Indeed, maternal inflammation in humans is associated with later-in-life psychopathology including schizophrenia (review by Depino [86] ). Clinical studies have shown that elevated maternal cytokine levels, such as C-reactive protein (CRP) and IL-8, increase the risk for schizophrenia spectrum disorders in the adult offspring [87, 88] . Similarly, individuals that were exposed to elevated maternal levels of anti-inflammatory cytokines (i.e. IL-4, IL-5, and IL-13) were significantly less likely to develop psychosis in adulthood [89] . Indeed, TNF-α increases DA and 5-HT metabolites in the nucleus accumbens of schizophrenia patients [90] .

Animal studies, in turn, have found that prenatal inflammation enhance DA levels in the nucleus accumbens and induce behavioural alterations characteristic of schizophrenia in adult rat offspring [91] .

Similarly, TNF-α increases DA and 5-HT metabolites in the nucleus accumbens of mice [92] . Such ongoing stressors, as well as infectious stressors, may lead to microglial activation, enhanced central inflammation and hippocampal damage [93, 94] that could, at least in part, explain the dopaminergic overdrive observed in psychosis [95] . In fact, increased DA release is reported in the striatum of antipsychotic drug-naïve schizophrenia patients exposed to psychological stress [96] . Other neurotransmitters implicated in the pathophysiology of psychosis and that are influenced by J o u r n a l P r e -p r o o f inflammation include 5-HT, norepinephrine (NE) and glutamate [83, 97] as shown in Figure 3 . For example, tryptophan-kynurenine metabolism modulates 5-HT as well as glutamate signalling [98] , while disordered tryptophan-kynurenine metabolism together with a pro-inflammatory state and changes in regional brain DA levels, have been described in an animal model of schizophrenia [99] . Trace amines, also relevant when discussing the stress-inflammation cascade in psychosis (review by Gainetdinov et al. [100] ) modulate inflammatory cytokine production in macrophages via actions on. trace amine associated receptor 1 (TAAR1). TAAR1 in turn modulates monoaminergic neurotransmission, preventing hyperdopaminergic and hypoglutamatergic activity [101] , therefore implicating TAAR1 not only in immune-inflammatory disorders [102] , but in the control of monoamine-driven psychotic behaviours [103] .

Antipsychotics have distinct, albeit variable preclinical effects on immune-inflammatory cascades (as shown in Table 1) , possibly due to different animal models being used. In a carrageenan-induced inflammatory rat model, haloperidol increases the inflammatory response [104] whereas trifluoperazine [105] and aripiprazole exhibit anti-inflammatory activities [106] . The activation of NF-kB, a crucial transcription factor in inflammation, depends on the phosphorylation of IκBα by IκB kinase (IKKβ), which has been shown to be blocked by thioridazine, thereby inducing anti-inflammatory effects [107] .

Clozapine also exerts anti-inflammatory effects in an autoimmune encephalomyelitis mouse [108] and social isolation reared (SIR) models [99] . Another study using the SIR model found that while olanzapine reversed the alterations in hepatic GSH-dependent defences, it induced no antiinflammatory effect [109] . Olanzapine has also been associated with aortic inflammation in mice [110] and altered microbiota (associated with chronic inflammatory disease states as review by Hand et al. Although preclinical evidence suggests a pro-inflammatory profile for haloperidol [104] , clinical data do not concur [115] . Clinical studies that support the anti-inflammatory properties of antipsychotic drugs ( clozapine, which is reserved for treatment resistant schizophrenia, has been known to induce numerous serious pro-inflammatory side effects such as agranulocytosis and myocarditis in up to 50% of patients within the first month of treatment [121] . More evidence of clozapine's pro-inflammatory effects relates to an increase in TNF-α and soluble TNF-α receptors observed in schizophrenia patients following 6 weeks of treatment [122] . However, one study observed immunosuppressive actions of clozapine after 6 months of treatment in first episode paranoid schizophrenia patients [119].

Reviewing the above-mentioned evidence, it becomes evident that antipsychotic drugs affect inflammatory mechanisms, and more specifically cytokine levels, although studies have yielded different results [80, 123] . In fact, many studies have highlighted paradoxical anti-and pro-inflammatory actions. This makes it difficult to predict how each drug will perform under different pathological conditions and where neuro-progression is involved.

J o u r n a l P r e -p r o o f

Decreased monoaminergic neurotransmission has been established as a main cause of depressive symptoms, such as decreased mood and energy, inability to feel pleasure (anhedonia), loss of interest and motivation, and decreased alertness [83, 124] . Here the tryptophan-kynurenine pathway is also relevant. Multiple inflammatory signalling pathways seem to activate indoleamine 2,3 dioxygenase (IDO) that causes breakdown of the 5-HT precursor, tryptophan (review by Miller et al. [125] ).

Inflammation-induced reduction of 5-HT causes a depressive-like state in rodents [126] , with similar findings reported in drug naïve major depressive disorder (MDD) patients [127] . Inflammation also increases expression of the 5-HT transporter (SERT), thereby increasing 5-HT reuptake, and reducing its synaptic availability [128] . This action downregulates hippocampal 5-HT receptor expression that eventually contributes to depressive symptoms [129] (Figure 3 ). It is noteworthy that chronic unpredictable stress increases oxidative stress in the prefrontal cortex and striatum of rats [130] , that can exacerbate central inflammation (review by Bakunina et al. [131] ), thereby perpetuating the stress response and contributing to altered monoaminergic neurotransmission levels and the progression of MDD [132] . Altered antioxidant enzyme activity (such as superoxide dismutase) together with increased levels of lipid peroxidation [133] leads to cytokine-induced oxidative stress that is associated with MDD [132] . A resultant reduction in neurotrophin levels [134] and compromised function and adaptive plasticity of these areas [135] suggests the brain to be less likely to overcome and learn from adverse environmental conditions. NO-cyclic guanosine monophosphate (cGMP) signalling is also disturbed in patients with MDD [136] , while NO signalling has been suggested to modulate inflammatory pathways that underlie the pathophysiology of MDD [137, 138] . Indeed, chronic stress enhances hippocampal constitutive NOS activity in stress sensitive rats, thereby implicating dysfunctional glutamatergic NMDA-NO activity as a vulnerability factor in MDD [139] . Importantly, both nNOS-and iNOS-derived NO levels were altered in the limbic brain regions of stressed animals [140] . These alterations may contribute to the development of behavioural and endocrine abnormalities that compromise adaptation to stress and increase vulnerability to MDD. COX-2, a rate-limiting enzyme for prostaglandin E2 (PGE2) synthesis, is also significantly elevated in chronically stressed rats, while its inhibition reverses depression-like behaviours via suppressing glial activation, oxidative stress and neuronal apoptosis [141] . These altered and sensitive redox states in turn drive many of the behavioural manifestations associated with MDD [142, 143] .

Approved antidepressants that primarily target the altered monoaminergic levels in MDD, also display anti-inflammatory properties [144] that contribute towards clinical improvement as shown in Table 1 . In a rat model of tonic-clonic seizures, sertraline exerted anti-inflammatory properties [145] . Similarly, fluvoxamine decreased the expression of inflammatory genes in a carrageenan injection model of inflammation in rats [146] . Modulators of NO and cGMP signalling exert antidepressant effects in patients with MDD or in the animal studies [147] . In fact, NO and cGMP signalling is targeted by a variety of known antidepressants in animal models of depression [148] . Not surprising, COX-2 inhibitors may have value in bipolar disorder and as adjunctive treatments in treatment resistant depression [149, 150] . Ketamine, an antagonist of the N-methyl-D-aspartate (NMDA) receptor, has rapid-onset antidepressant properties [151] , while presenting with anti-inflammatory effects [152] . Interestingly, ketamine's activity on inflammation seems to be related to duration of treatment [153] . In this respect, J o u r n a l P r e -p r o o f long-term treatment is effective in bolstering a failed response to imipramine in a gene X environment model of antidepressant resistance [154] . An inflammatory component is known to contribute to clinical cases of treatment resistance [155] , which may partially explain how ketamine may re-establish response [156] .

In patients diagnosed with MDD, Szałach, Lisowska and Cubała [157] found that paroxetine, venlafaxine, desvenlafaxine, imipramine, amitriptyline and agomelatine significantly decrease the expression of inflammatory genes and also reduce inflammasome activity. Blood cytokine levels were found to be significantly reduced after 12-weeks of antidepressant therapy (sertraline, venlafaxine, citalopram, or mirtazapine) in patients newly diagnosed with MDD [158] . Importantly, the drop in these cytokines was seen only in patients who demonstrated a clinical response to treatment. Considering NO, elevated plasma nitrate levels have been described in depressive states as well as being involved in depression symptoms during interferon-alpha therapy [69, 159] . In a study with patients suffering from ischemic heart disease and depression, serum nitrite and nitrate levels were significantly decreased following paroxetine treatment but not nortriptyline, with paroxetine shown to be a more potent inhibitor of NOS than nortriptyline [160] . .

What is apparent from data described above is that antidepressants have variable pro-and antiinflammatory effects, which may be a function of chemical class as well as illness progression.

Bipolar disorder is a chronic and cyclic mental disorder, characterized by unusual mood swings between mania/hypomania and depression [161] . Due to the disease's course, often unremitting, it frequently results in cognitive deficits over time, Furthermore, the partial effectiveness of current available drugs often necessitates polypharmacy. The immune system and neuro-inflammation plays a central role in its pathophysiology, especially in disease course, while also providing targets for novel antiinflammatory and antioxidant treatments, e.g.non-steroidal anti-inflammatory drugs, N-acetylcysteine and GSK3 inhibitors [162] . Manic-like symptoms and inflammation have been described in the ouabain model of mania, a rodent model relevant to bipolar disorder [163] . Here aspirin, a commonly used antiinflammatory agent, partially reversed manic-like symptoms as well as decreased expression of brainderived neurotrophic factor, IFN-Ƴ and Toll-like receptor 3, frequently found in bipolar disorder patients.

Carbamazepine induces anti-inflammatory effects in a dose dependent manner in rats [164] , an effect not observed with valproate [165] . Lamotrigine also exhibits anti-inflammatory properties in mice after LPS exposure [166] . In the recently published study [167] , it was demonstrated that T lymphocytes of patients suffering from bipolar disorder treated with lithium or valproate, are characterized by proinflammatory activity, characterized by decreased proliferative activity and increased susceptibility to apoptosis. On the other hand, valproate treatment for 12 weeks had no effect on pro-inflammatory cytokines in patients diagnosed with bipolar depression [168] .

Anxiety or fear, as well as worry, are present in all anxiety-related disorders [169, 170] . Anxiety symptoms are mainly associated with dysfunctional amygdala-centred circuits whereas worry J o u r n a l P r e -p r o o f symptoms are connected with cortico-striato-thalamocortical (CSTC) loop dysfunctions, both involving disturbances of 5-HT and gamma-aminobutyric acid (GABA) [83] . Other messengers associated with anxiety include 5-HT, melatonin [171] , the NO-cGMP pathway [172, 173] , glutamate [174] and the neuropeptides oxytocin and vasopressin [175] . Interestingly, all these pathways are inter-related with redox processes, e.g. melatonin has antioxidant properties [176] , the glutamate-NOS pathway stimulates oxidative stress [173] , while vasopressin and oxytocin have protective effects under conditions of oxidative stress in vitro [177] . Chronic stress alters the structural integrity of GABAergic neurons [178] that disinhibits the amygdala [179] , most likely accounting for the increased worry symptoms ( in anxiety-related disorders is undisputed [191] . Interestingly, various peripheral benzodiazepine receptor ligands exert anti-inflammatory actions [192] . The anxiolytic, etifoxine [193, 194] , induces anxiolytic and anti-inflammatory effects via actions on the GABAA receptor and mitochondrial 18-kDa translocator protein (TSPO), [195] , the latter responsible for its anti-inflammatory properties (review by [196] .

Taken together, psychological stress may increase the risk of psychiatric disease and even shape the course of disease via inflammatory pathways [197] as shown in Figure 3 . This interaction is particularly J o u r n a l P r e -p r o o f relevant when considering pharmacological treatment of psychiatric disorders in the presence of infectious diseases that could exacerbate central inflammation.

The psychosocial effects of SARS-CoV-2 are prompting an unprecedented increase in the prevalence of especially anxiety disorders, which in turn can hasten the development of several other co-morbid psychiatric illnesses, like mood disorders (depression and bipolar disorder), schizophrenia, substance abuse etc. To this extent, viral infections, such as influenza, varicella-zoster, herpes simplex, human immunodeficiency and hepatitis C virus infections are associated with increased risk for depression and/or anxiety [198] [199] [200] . Importantly, although a recent longitudinal study did not associate common viral infections with increased risk for mental disorders [201] , the prevalence of depression symptoms in the United States increased three-fold from pre-COVID to post-COVID [202] , with similar observations in other countries [203] [204] [205] [206] . And although the exact mechanism for this increase remains unknown, these patients will generally receive standard pharmacological treatments for these mental disorders, viz. antidepressants, antipsychotics etc. As noted earlier, a secondary effect of these aforementioned medicines will be to suppress an over-active inflammatory response and while this may be good in terms of the psychiatric illnesses being treated, this action will also lower the natural ability and mental illnesses [207, 208] we will briefly review the three-way interaction between the SARS-CoV-2-induced inflammatory response, the course of viral and psychiatric conditions, and how this interaction may modulate response to psychotropic drug treatment.

A number of viruses are capable of invading and affecting the CNS [209] , still the main reason for this

is not yet fully understood. One working hypothesis postulates that the brain lacks immune-competent cells, making it an ideal site for viruses to reside in, forming a so called viral reservoir [209] .

Alternatively, viral infections not known to infect neurons, such as the human immunodeficiency virus (HIV), can still induce CNS effects, such as HIV dementia (HIV D), also known as HIV-associated neurocognitive disorder (HAND). Although this mechanism is not yet fully understood, certain HIV proteins (gp120 and Tat) are presumed to be transported into the CNS where they trigger cellular apoptotic mechanisms that cause neuronal dysfunction and/or death (see [210] [211] [212] [213] for review).

In general, psychiatric patients may already be at higher risk of contracting viral infections because of a myriad of contributing factors, such as a chronically dysregulated innate immune system, altered/impaired cognitive and higher motor functioning, and sometimes deficient personal hygiene [214] [215] [216] [217] . Regardless, immune system dysregulation is central to the severity of pathogenic coronavirus infections [218] [219] [220] . who developed life-threatening pneumonia [221] . These autoantibodies disable or neutralize type I IFNs, thereby inhibiting or reducing the inflammatory response to prevent pathogen-induced inflammation. Further, at least 3.5% of patients with life-threatening pneumonia had genetic IFN defects [222] , that when interpreted together with the aforementioned results, highlight the key role that central inflammation plays in COVID-19 symptomology. Such an increase in viral-induced inflammation is not characteristic of COVID-19. A similar phenomenon is reported in HIV-positive patients and is partly responsible for the high prevalence rates of depression amongst these patients [223, 224] .

Downstream effects of such a cytokine storm may include increased neuro-inflammation, reduced neuroplasticity and monoaminergic neurotransmission and increased neuronal death [223] , as referred to earlier.

Several psychiatric diseases have been linked to viral infections, although no particular virus has to date been unequivocally established as a causative agent [198, [225] [226] [227] . Extra-pulmonary symptoms, including febrile seizures, loss of consciousness, convulsion, ataxia, status epilepticus, encephalitis, myelitis, neuritis and multiple sclerosis have been observed in patients infected with influenza, thereby highlighting the virus' capacity to cause neurological complications [228] . Indeed, obsessive compulsive disorder (OCD) is also causally linked to early life infection with influenza or other pathogens [229] . Regarding viral infections of the CNS, recent work revealed that human endogenous retrovirus W env (HERV-W env), which appears to play a role in the neurodevelopment of schizophrenia [230] , may contribute to neuropathology and disease progression by regulating the expression of immunological NO synthase (NOS), thereby increasing NO production and microglial migration [231] .

Overall, these neurobiological alterations are associated with increased oxidative stress that in turn drive many of the monoamine changes typical of positive and negative schizophrenia-related symptoms [232, 233] . inflammation-induced lung injury in rats. Cong et al recently noted that blockade of α2A-AR inhibits TNFα, IL-6, and IL-10 production in activated alveolar macrophages [234] . Furthermore, they demonstrate that NE down-regulates NF-κB activation, suggesting that α2A-AR deficiency ameliorates lung injury by increasing NE concentrations in lung tissues and inhibiting the activation of alveolar macrophages.

Given the role of the α2A-AR in mood regulation and antidepressant action [235] , α2 modulating drugs such as mirtazapine may present with a bi-modal action in treating both ARDS and psychopathology in SARS-CoV-2 infected patients. Having earlier noted the role of the NO-cGMP pathway in psychiatry and inflammation, it is noteworthy that the phosphodiesterase-5 (PDE-5) inhibitor sildenafil, which bolsters tissue brain and peripheral levels of cGMP, has been proposed as a suitable intervention in ARDS [236] . Furthermore, pre-clinical work have established its antidepressant actions [237] , thus affording it as a useful adjunctive treatment option in SARS-CoV-2 associated psychopathology.

Effective antiviral drugs should not only prevent host cell infection but also inhibit or at least reduce the exaggerated viral-induced immune response. Specifically related to SARS-CoV-2, several drugs are being investigated, with remdesivir and chloroquine (and hydroxychloroquine) receiving the most attention [238] . Remdesivir selectively inhibits viral replication, whereas chloroquine seems to block viral entry and to attenuate cytokine production [238] . [243, 244] . These contrasting statements have attracted reactions from various scientists and restarted the search for an effective treatment strategy [245] . Nonetheless, other antivirals generally only target viral replication with no primary or direct effect on the accompanying inflammation and should therefore not have significant effects on psychiatric symptom development. In this regard, sofosbuvir-based anti-hepatitis C regimens have been associated with improved mood via its kynurenine enhancing effects [246] , whereas NE-affecting antidepressants have been reported to reduce the antiviral properties of the anti-hepatitis C drug, IFN-α [247] , suggesting a minor, yet sensitive interplay between antivirals and CNS-acting drugs.

We have earlier highlighted how psychotropic drugs can modify the immune response. Antipsychotics may increase an individual's risk for viral and/or bacterial infections [248] . In this regard, a higher risk for pneumonia has been observed with antipsychotic-use [249] , an affect that could involve a psychotropic-caused anti-inflammatory effect. This response may also be compounded by the immune activating properties of co-administered immunomodulators (and other antivirals) [247] . Despite these concerns, the anti-SARS-CoV-2 effects of chlorpromazine (and other psychotropics) have been suggested [250] . These possible protective effects are based on the structural similarities between certain psychotropics, especially tricyclic antidepressants, phenothiazine antipsychotics and methylene blue, and investigational anti-SARS-CoV-2 drugs, such as chloroquine. These compounds are all cationic amphiphilic drugs with hydrophobic aromatic ring or ring systems, with a hydrophilic side chain containing an ionizable amine functional group, that could potentially alter host cell properties, reducing viral penetration and replication [251] . Of note, a recent clinical study associated fluvoxamine, an SSRI antidepressant, with a lower likelihood of clinical deterioration in symptomatic COVID-19 patients, over a 15-day treatment period, relative to placebo controls [252] . Future studies should investigate this promising avenue of research.

Conversely, antivirals (e.g. efavirenz, maraviroc, oseltamivir etc.) are known to cause CNS-associated adverse effects, such as mood and sleep disorders and hallucinations [253] . Within the SARS-CoV-2 context, chloroquine is also known to cause similar CNS-related adverse effects [239] . Although the exact mechanisms involved in these CNS adverse effects are unknown, it may include altered neuroplasticity [254] , via direct (programmed necrosis, cell lysis and/or by inducing apoptosis and necroptosis [255] [256] [257] ) or indirect mechanisms [257] , such as the activation of toll-like receptor signalling receptors (TLRs) 3, 7, and 8. The latter leads to increased free radical production and inflammation and ultimately neuronal damage.

A recent review has also addressed the neuropsychiatric side effects of anti-HIV drugs like efavirenz, which is purported to involve disturbances in the mitochondrial-immune-inflammatory-redox cascade [258] . In fact, mitochondrial dysfunction is considered a fundamental mechanism in the pathogenesis of many drug-induced toxicities [259, 260] , as well as in the pathogenesis of mood disorders [261, 262] , by causing increased oxidative stress and neuro-inflammation, decreased neuroplasticity and disordered monoaminergic transmission.

Pharmacokinetic interactions between anti-SARS-CoV-2 and psychotropic drugs also exist, including azithromycin-induced cytochrome inhibition [263] , that could increase the risk for mentioned psychotropic-associated side effects. Finally, immune reconstitution inflammatory syndrome (IRIS), associated with initiating antiretroviral treatment (ART), is a paradoxical phenomenon that worsens or even unmasks subclinical, untreated infections, via an exaggerated inflammatory response once the immune system starts to recover [264] . Therefore, despite the mentioned CNS adverse effects of antivirals, this paradoxical reaction may itself contribute to worsening of psychiatric conditions via supplemented neuro-inflammation.

Taken together, a sensitive interplay between the viral-induced inflammation and underlying neuroinflammation exist that may have aggravating effects in sensitive individuals. Further, a possible antagonistic net-effect of antiviral and anti-psychiatric combinations may also exist, despite certain antiviral mechanisms being beneficial in terms of neuro-inflammation and psychiatric symptomology.

Therefore, adjunctive treatment strategies may be of therapeutic value to optimize clinical outcome.

In order to bolster both the containment of SARS-CoV-2 infection, as well as treat any presenting psychopathology that will not introduce any additional risk of worsening the outcome of either illness, the knowledge outlined in the previous sections may be called upon to devise and test novel adjunctive treatment options. Although numerous drugs are under investigation as COVID-19 treatment options (review by Manhas et al. [265] ), adjunctive treatment options could prove useful, and despite requiring further investigation, clinically available options are briefly discussed below.

Agomelatine (a melatonin (MT) 1 and 2 agonist with 5-HT2C antagonistic properties) reduces plasma and brain IL-1β and IL-6 levels and prevents microgliosis and astrogliosis in rat models [266, 267] .

Clinically, 12-week agomelatine treatment is associated with reduced CRP levels [268] . Therefore, agomelatine could prove beneficial in the treatment of COVID-19, due to its antioxidant, antiinflammatory and antiapoptotic properties [269] . In fact, high doses MT may have a beneficial role in patients treated for SARS-CoV-2-induced pneumonia, in terms of reduced time to clinical improvement and even possible lower mortality rates [270] . Given its inherent anxiolytic and antidepressant properties [271] [272] [273] , agomelatine could be a useful medicine to consider in COVID-19 related mood and anxiety disorders.

Antioxidants, which for all intents and purposes would include anti-inflammatory agents, seem to have state-dependent effects depending on the redox condition of the cell. This implies that such compounds may act differently depending on the progressive state of the illness in question [274, 275] , e.g. a waxing and waning of symptoms, or where the illness gets progressively worse over time. α-Lipoic acid is an antioxidant that may lower all-cause mortality in SARS-CoV-2 infected patients [276] . Indeed, lipoic acid was shown to protect against RNA virus-induced gliotoxicity [277] and inhibit viral replication of HIV [278] . Further, a recent review by Diniz et al. [279] , highlights the possible adjunctive properties of natural antioxidants, especially flavonoids, for conventional antiviral therapies. In this report, the authors identify specific corona virus proteins that are targeted by these natural antioxidants to contribute towards the observed antiviral properties. This is in addition to their ROS reducing properties that inhibit viral signalling and ultimately replication abilities. Various plant species may hold potential as they have already been shown to alter CNS neurotransmission [280] and poses anti-COVIDcontributing properties (for detailed reviews, see Ahmad et al. [281] and Khanna et al. [282] ). For example, Sceletium tortuosum may be of interest as it has mild anti-inflammatory properties, without hindering an adequate immune response to acute immune challenges [283] , and also exerts antiretroviral effects by inhibiting HIV enzymes and proteases [284] . Mangosteen pericarp extract has been demonstrated to have antidepressant and procognitive properties in rodent models [285] , as well as bolster the antipsychotic effects of haloperidol [285, 286] . Interestingly, gamma mangostin, a constituent of this extract, inhibits C19MP (a main protease of SARS-CoV-2), with improved binding affinity versus other known inhibitors, such as lopinavir and ritonavir [287] . Similarly, thymoquinone, a constituent of Nigella sativa [288] is best known for its potent antioxidant properties that contribute to the downregulation of pro-inflammatory cytokines, making it a possible candidate to avert MODS (review by Ahmad et al. [289] ). In terms of SARS-CoV-2, thymoquinone can prevent viral binding to the ACE2 receptors via modulating the heat shock protein cell surface [290] . In critical patients with ARDS, enteral diets with ω-3 PUFAs improved oxygenation and reduced the duration of mechanical ventilation and intensive care stay [291] . However, caution must be taken as fish oil feeding in mice has shown to alter the immune response to influenza [292] and delay viral clearance [293] . Another notable antioxidant is melatonin which has been suggested to benefit patients with myocardial injury and respiratory complications in COVID-19 patients [294] . When considered with its earlier mentioned (see Agomelatine) role as anti-COVID-19 adjunctive therapy [270] , melatonin is a strong candidate that requires further investigation Similarly, oxytocin-vasopressin exert actions on redox systems [177] while J o u r n a l P r e -p r o o f their delicate balance is implicated in anxiety disorders [175] . In this regard, oxytocin has been noted to have potential as an adjuvant treatment in COVID-19 infection [295] .

Clonidine, an α2 AR antagonist, has been identified as a novel in vitro anti-influenza agent that could protect against influenza-induced pulmonary damage by inhibiting viral replication [296] . Clonidine might also be beneficial in the treatment of SARS-CoV-2-related psychiatric symptom development as it may treat psychosis and anxiety as shown in a patient with schizophrenia [297] as well as attention deficit hyperactivity disorder [298] .

That the nucleocapsid protein of SARS-CoV activates COX-2 expression [299] , led to Tomera et al. [300] suggesting that conservation of SARS-CoV-2 nucleocapsid N protein N2 sequences with celecoxib, a COX-2 inhibitor, treatment may mitigate the effects of direct viral transactivation of COX-2 expression in infected cells. Moreover, it has been shown that celecoxib significantly reduced TNF-α and IL-6 cytokine levels in mice infected with influenza-A when compared to controls [301] , further emphasizing the anti-inflammatory role of COX-2 inhibitors in viral infections.

Celecoxib also has potential beneficial mood elevating effects, as an adjunctive treatment [78] that could contribute towards clinical improvement of SARS-CoV-2-infected patients.

Dexamethasone is a high potency glucocorticoid. A preliminary report by the RECOVERY Collaborative

Group [302] showed that the use of dexamethasone resulted in lower 28-day mortality among hospitalized SARS-CoV-2 patients who received either invasive mechanical ventilation or oxygen alone, but not among those receiving no respiratory support. Similarly, the use of intravenous dexamethasone, in addition to standard care resulted in a statistically significant increase in the number of ventilator-free days in SARS-CoV-2 patients [303] . However, treatment with dexamethasone aggravated depressive behaviour in rats [304] and mice [305] , which could prove problematic in these patients, considering the prevalence of psychiatric conditions, associated with COVID-19. Based on the mentioned preclinical studies, dexamethasone could worsen underlying psychiatric conditions by increasing oxidative stress, inflammation and inducing dysregulated glutamatergic neurotransmission [306] [307] [308] .

Lithium salts have antidepressant/antimanic/mood stabilizing properties as well as having proinflammatory effects [309] . The latter appears beneficial in some disorders associated with immunological deficits, such as HIV and systemic lupus erythematosus (SLE) [310, 311] . In this regard, lithium has diverse effects on inflammatory mediators, such as modulating the expression of several inflammatory genes including IκB-α, TRAF3, Tollip, and NF-κB1/p50, while it inhibits NF-κB activity by lowering nuclear translocation of NF-κB in LPS-activated macrophages [312] . Animal studies have also shown lithium to either decrease [313] or increase activity of the NO-cGMP pathway [314, 315] .

Recently, Pietruczuk et al. [167] demonstrated that T lymphocytes of patients suffering from bipolar disorder that were treated with lithium or valproate, are characterized by pro-inflammatory activity, decreased proliferative activity and increased susceptibility to apoptosis. Finally, a case report by

Spuch et al. [316] showed that lithium carbonate improved inflammatory activity and immune response in patients with severe SARS-CoV-2 infection.

Minocycline, a tetracycline, is a protein synthesis inhibiting antibacterial with anti-inflammatory, immunomodulatory and neuroprotective properties [317] . Minocycline may be a preferred alternative to azithromycin as it may mitigate the risk of azithromycin-associated QT prolongation and cardiac arrythmias [318] . Indeed, minocycline was shown to prevent respiratory syncytial virus infection [319] and to reduce HIV replication and reactivation by altering the cellular environment [320] . It may also be an alternative to azithromycin due to a penchant of the latter for drug-drug interactions [318] .

Mitochondrial rejuvenators and modulators. Cationic amphiphilic drugs with hydrophobic aromatic ring or ring systems, especially with a hydrophilic side chain containing an ionizable amine functional group, like methylene blue, have mitochondrial rejuvenating actions [147] , including enhancing mitophagy [321] , increasing cellular oxygen consumption and delaying mitochondrial dysfunction [322] . N-acetyl cysteine (NAC) too has beneficial effects on mitochondrial function, as well as potent antioxidant

properties [323] . A case report by Alamdari et al. [324] showed that treatment of SARS-CoV-2 patients with a combination of methylene blue, vitamin C and NAC could increase the survival rate of these patients, possibly due to anti-inflammatory and anti-oxidative effects. Indeed, methylene blue is effective in inactivating various RNA viruses, including influenza [325] . Methylene blue [147] and NAC [326] have been proposed to have beneficial mood elevating effects. Mitochondrial modulators could potentially be anti-SARS-CoV-2 augmentation strategies because of the role optimal mitochondrial function (and consequent reduced oxidative stress) play in the immune response. Mitochondria contain mitochondrial antiviral signalling (MAVS) proteins in their membrane that can contribute towards antiviral defence mechanisms by regulating anti-inflammatory responses [327, 328] . Melatonin has recently been proposed as adjuvant anti-SARS-CoV-2 option due to its mitochondrial enhancing properties [329] . Therefore, mitochondrial modulators may present a novel drug target to induce antiviral effects [330] .

Activation of NF-ĸB by antiviral pathogens may contribute to apoptosis and enhance inflammation (review by Ludwig & Olivier [331] ). Inactivation of the NF-ĸB pathway was shown to inhibit influenza-A viral replication [332] . The digitalis alkaloids, digoxin and ouabain, are recognised as NF-ĸB antagonists [333] . Cho and colleagues [334] reported that both compounds inhibited over 99% of SARS-CoV-2 replication, leading to viral inhibition at the post entry stage of the viral life cycle. However, pathological increases in the production of endogenous ouabain-like compounds was shown to play a role in the pathophysiology of mood disorders (review by Christo & El-Mallakh [335] ). Therefore, these patients need to be monitored for possible psychiatric side-effects induced by these compounds.

Phosphodiesterase inhibitors: Selective PDE-4 inhibitors (e.g. ibudilast and rolipram) may attenuate the cytokine storm in SARS-CoV-2, through their action on glia, especially upstream inhibition of proinflammatory molecules and the regulation of pro-inflammatory/anti-inflammatory balance [336] . PDE-5 inhibitors (e.g. sildenafil and tadalafil) could be useful as adjunctive SARS-CoV-2 treatment by counteracting the Ang-II-mediated downregulation of AT-1 receptor and reducing pro-inflammatory cytokines [337] . Indeed, sildenafil seems promising for the treatment of otherwise fatal HIV-related J o u r n a l P r e -p r o o f pulmonary hypertension in patients infected with HIV [338] . Moreover, these agents display preclinical anxiolytic and mood elevating properties [172, 237, 339] .

Pioglitazone is a peroxisome proliferator-activated receptor (PPAR)-γ agonist that has been shown to provide protection in mice infected with highly pathogenic and pandemic strains of influenza virus [340] .

Consequently, Carboni et al. [341] hypothesized that pioglitazone could potentially be used to reduce the cytokine storm, associated with SARS-CoV-2, at least in those patients that have a manifest condition of metabolic syndrome.

Rapamycin, an mTOR inhibitor, may enhance the antiviral actions of aplaviroc and vicriviroc, used specifically in maraviroc-resistant strains of HIV [342, 343] . The mTOR pathways may offer valuable targets to control cell injury, oxidative stress, mitochondrial dysfunction, and the onset of hyperinflammation, a significant disability associated with COVID-19 [344] . The mTOR pathway is also a critical messenger in antidepressant action, being recognized as the target for the rapid antidepressant actions of ketamine and rapastinal [345, 346] , and hence may have relevance in COVID-19 associated mood disorders.

Selective serotonin-targeting antidepressants: SSRIs have recently been investigated for their adjunctive benefit in the treatment of COVID-19. In this regards, fluoxetine was effective in decreasing SARS-CoV-2 viral expression [347] , while others associated SSRI-treatment with lower risk of death or intubation in hospitalized patients with SARS-CoV-2 infection [252, 348] . The beneficial effects could in part be ascribed to the anti-inflammatory effects of SSRIs [145, 146, 349] . In fact, fluoxetine and citalopram have been shown to display anti-inflammatory properties by inhibiting endosomal TLRs, a class of pattern recognition receptors that recognize bacterial or viral pathogen-associated molecular patterns and play a key role in innate immune responses to suppress pro-inflammatory cytokines [350] .

Tryptophan-kynurenine modulators, such as allopurinol, inhibit xanthine oxidase as well as tryptophan 2,3-dioxygenase (TDO), thereby modulating the formation of kynurenine and the depletion of tryptophan for 5-HT synthesis. The tryptophan-kynurenine pathway plays an important mediating role in inflammation-induced psychopathology [98] . An early report suggested that treatment with allopurinol, in combination with a chemically modified superoxide dismutase (a scavenger of O2), improved the survival rate of influenza virus-infected mice [351] .

In brief, one needs to identify the risks, identify the patients at risk and indicate a risk management strategy (see Figure 1 ).

From the review it follows that SARS-CoV-2 poses risk of psychological trauma, neuro-inflammation and the induction of a dysfunctional immune system that may ultimately impact on the nervous system.

Psychiatric disease increases vulnerability of the individual to disease modulating factors. Given the redox-inflammatory actions of psychotropic medicines, comorbid SARS-CoV-2 infection and its treatments may alter how patients respond to these drugs, so that a triple factor interaction between SARS-CoV-2 as disease, psychiatric disease and psychotropic drug response may ensue. The picture J o u r n a l P r e -p r o o f gets more complex when dealing with patients with multiple comorbidities and/or when multi-drug treatment is prescribed. It therefore becomes important to be able to predict and evaluate the likelihood and potential magnitude of the involved risk.

Lastly, the risk may be managed by monitoring SARS-CoV-2 patients with psychiatric co-morbidity closely in terms of clinical response and, when applicable and possible, by also measuring appropriate biomarkers of inflammation and immune response. Broad, non-specific markers of immune inflammation include CRP, erythrocyte sedimentation rate (ESR) and plasma viscosity, as well as procalcitonin as marker of immune response [352] . These are probably the most practical to implement as indicators of enhanced inflammation and increased risk. In addition, biomarkers of haemodynamics may also be useful, such as fibrinogen, P-selectin, D-dimer and Von Willebrand Factor that seems to be associated with progression of SARS-CoV-2 and inflammation, as precursors to a cytokine storm [353, 354] . Elevated cortisol and adrenocorticotropic hormone (ACTH) are not only markers of biological stress but have also been associated with psychiatric disease [82] . Other experimental and more specific biomarkers, which may not always be practical to measure in clinical and limited resource settings, include CD4+ T cells, CD14+, CD16+, inflammatory monocytes, IL-2, IL-7, IL-10, granulocyte colony-stimulating factor (G-CSF), IP-10, MCP-1, macrophage inflammatory protein 1α (MIP-1α), TNF and S protein: V483A, L455I, F456V and G476S [355] . Lately the ACE-2 receptor has been implicated as potential binding domain for SAB-CoV-2 [356] . In this regard a link has also been proposed between ACE-2 and dopa decarboxylase expression, with the latter involved in the synthesis of DA and 5-HT.

The levels of both DA and 5-HT are closely associated with several psychiatric disorders and may in future turn out to be important biomarkers for psychiatric complications of SARS-CoV-2.

Monitoring and clinical response should prompt the clinician to record response, adjust treatment and continue monitoring. In the end, findings should be reported so that the broader health community can learn, enhance treatment and optimise therapeutic outcome.

The current SARS-CoV-2 pandemic is the third serious Coronavirus outbreak within the last 20 years, 

BHH conceptualized and designed the layout of the paper, and contributed to preparation of the manuscript; EJVV and SS jointly first-authored the paper, researched, collated and prepared the first draft; EJVV prepared the tables and figures (assisted by CBB); all other authors contributed various sections of the manuscript.

The authors declare no conflict of interest. Sceletium tortuosum ↓ anxiety, depression [378] anti-inflammatory [283] ↓ viral enzymes and proteases [284] Thymoquinone ↑ spatial memory and slowdown of Alzheimer's disease complications [288, 379] ↓ NO and ROS; modulating (inhibit) NF-κB and antioxidant enzyme nuclear factor 2 heme oxygenase-1 (Nrf2/HO-1) [288, 289, 380] ↓ viral entry into host cell [290] 

Clonidine ↓ psychosis, anxiety [297, 298] -↓ viral replication [296] 

Celecoxib ↑ mood [78] ↓ IL-6, TNF-α [301] ↓ viral transactivation of COX-2 [299, 300] Glucocorticoids Dexamethasone ↑ depression [78, 304, 305] ↑ oxidative stress, inflammation [306] [307] [308] -Lithium antidepressant [309] ↓ NF-κB [312] ↑ pro-inflammatory activity [167] ↑ NO-cGMP pathway activity [315] -

Agomelatine anxiolytic, antidepressant [266, 267] ↓ CRP, IL-1β, IL-6 [263, 264, 267] Tetracyclines Minocycline ↑ mood [77, 78] ↓ inflammation [317] ↓ viral replication and reactivation [320] 

Methylene Blue ↑ mood [147] antioxidant [324] Inactivates RNA viruses [325] ↑ MAVS [330] J o u r n a l P r e -p r o o f N-acetyl cysteine ↑ mood [381] antioxidant [382] ↑ MAVS [330] mTOR inhibitors Rapamycin antidepressant [345, 346] ↓ oxidative stress, hyperinflammation [344] ↑ antiviral activity [342, 343] 

Ouabain ↑ mood disorders [335] ↓ NF-κB [333] ↓ viral replication [334] Digoxin -↓ NF-κB [333] ↓ viral replication [334] 

Allopurinol ↓ inflammation-induced psychopathology [98] ↓ inflammation [98] -

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Mitochondria and mood: mitochondrial dysfunction as a key player in the manifestation of depression

Mitochondria in neurodegenerative diseases

Emerging and experimental treatments for COVID-19 and drug interactions with psychotropic agents

Immune reconstitution inflammatory syndrome in HIV-infected patients

Covid-19 pandemic and current medical interventions

Modulation of the inflammatory response in rats chronically treated with the antidepressant agomelatine

Chronic agomelatine treatment prevents comorbid depression in the post-status epilepticus model of acquired epilepsy through suppression of inflammatory signaling

Effect of agomelatine treatment on C-reactive protein levels in patients with major depressive disorder: an exploratory study in "real-world

Agomelatine could prevent brain and cerebellum injury against LPS-induced neuroinflammation in rats

Melatonin as adjuvant treatment for coronavirus disease 2019 pneumonia patients requiring hospitalization (MAC-19 PRO): a case series

Studies into the anxiolytic actions of agomelatine in social isolation reared rats: role of corticosterone and sex

Agomelatine for the treatment of generalized anxiety disorder: a meta-analysis

Agomelatine versus other antidepressive agents for major depression

Effect of chronic N-acetyl cysteine administration on oxidative status in the presence and absence of induced oxidative stress in rat striatum

A randomized, single-blind, group sequential, active-controlled study to evaluate the clinical efficacy and safety of α-lipoic acid for critically ill patients with coronavirus disease 2019 (COVID-19)

Alpha-lipoic acid effects on brain glial functions accompanying double-stranded RNA antiviral and inflammatory signaling

Alpha-lipoic acid is an effective inhibitor of human immuno-deficiency virus (HIV-1) replication

Natural antioxidants: a review of studies on human and animal coronavirus

Pharmacological actions of the South African medicinal and functional food plant Sceletium tortuosum and its principal alkaloids

An alternative approach to minimize the risk of coronavirus (Covid-19) and similar infections

Herbal immune-boosters: substantial warriors of pandemic Covid-19 battle

Immunomodulatory effects of Sceletium tortuosum (Trimesemine™) elucidated in vitro: implications for chronic disease

Sceletium tortuosum demonstrates in vitro anti-HIV and free radical scavenging activity

Studies on haloperidol and adjunctive αmangostin or raw Garcinia mangostana linn pericarp on bio-behavioral markers in an immuneinflammatory model of schizophrenia in male rats

Garcinia mangostana Linn displays antidepressant-like and pro-cognitive effects in a genetic animal model of depression: a biobehavioral study in the flinders sensitive line rat

Molecular docking evaluation of some Indonesian's popular herbals for a possible COVID-19 treatment

Preclinical and clinical effects of Nigella sativa and its constituent, thymoquinone: a review

Covid-19 and thymoquinone: connecting the dots

Natural products may interfere with SARS-CoV-2 attachment to the host cell

Omega-3 polyunsaturated fatty acids in critically ill patients with acute respiratory distress syndrome: a systematic review and meta-analysis

Fish oil-fed mice have impaired resistance to influenza infection

Fish oil feeding delays influenza virus clearance and impairs production of interferon-γ and virus-specific immunoglobulin A in the lungs of mice

Therapeutic algorithm for use of melatonin in patients with COVID-19

Oxytocin as a potential adjuvant against COVID-19 infection, Endocrine, metabolic & immune disorders drug targets (2020) Epub ahead of print

Stimulation of alpha2-adrenergic receptors impairs influenza virus infection

Successful treatment of auditory hallucinations in a schizophrenia patient with clonidine, Dusunen Adam: The journal of psychiatry neurological sciences

Reduction of anxiety after treatment with transdermal clonidine, The bulletin of the American Society of hospital pharmacists

Nucleocapsid protein of SARS-CoV activates the expression of cyclooxygenase-2 by binding directly to regulatory elements for nuclear factor-kappa B and CCAAT/enhancer binding protein

Hospitalized COVID-19 patients treated with celecoxib and high dose famotidine adjuvant therapy show significant clinical responses

Pharmacologic inhibition of COX-1 and COX-2 in influenza A viral infection in mice

Dexamethasone in hospitalized patients with COVID-19 -Preliminary report

Effect of dexamethasone on days alive and ventilator-free in patients with moderate or severe acute respiratory distress syndrome and COVID-19: the CoDEX randomized clinical trial

Role of aspirin and dexamethasone against experimentally induced depression in rats

Behavioral and molecular alterations in mice resulting from chronic treatment with dexamethasone: relevance to depression

4′-Dichlorodiphenyl diselenide reverses a depressive-like phenotype, modulates prefrontal cortical oxidative stress and dysregulated glutamatergic neurotransmission induced by subchronic dexamethasone exposure to mice

Sex-related differential response to dexamethasone in endocrine and immune measures in depressed in-patients and healthy controls

Glia-and tissue-specific changes in the kynurenine pathway after treatment of mice with lipopolysaccharide and dexamethasone

Lithium in the treatment of major depressive disorder

Lithium salts in AIDS and AIDS-related dementia

Impact of lithium alone and in combination with antidepressants on cytokine production in vitro

The effect of lithium on inflammation-associated genes in lipopolysaccharide-activated raw 264.7 macrophages

Inositol triphosphate, cyclic AMP, and cyclic GMP in rat brain regions after lithium and seizures

Lithium modulation of cortical cyclic nucleotides: evidence for the Yin-Yang hypothesis

Evidence that lithium induces a glutamatergic: nitric oxide-mediated response in rat brain

Does lithium deserve a place in the treatment against COVID-19? A preliminary observational study in six patients, case report

Anti-inflammatory and antiviral effects of minocycline in enterovirus 71 infections

Cardiac safety and potential efficacy: two reasons for considering minocycline in place of azithromycin in COVID-19 management

Antibiotic minocycline prevents respiratory syncytial virus infection

Minocycline attenuates HIV infection and reactivation by suppressing cellular activation in human CD4+ T cells

Methylene blue reduces acute cerebral ischemic injury via the induction of mitophagy

Methylene blue delays cellular senescence and enhances key mitochondrial biochemical pathways

The chemistry and biological activities of Nacetylcysteine

Application of methylene blue -vitamin C -N-acetyl cysteine for treatment of critically ill COVID-19 patients, report of a phase-I clinical trial

Plasma treated with methylene blue and light: clinical efficacy and safety profile

Diet quality, dietary inflammatory index and body mass index as predictors of response to adjunctive N-acetylcysteine and mitochondrial agents in adults with bipolar disorder: A sub-study of a randomised placebo-controlled trial

Virus-induced changes in mitochondrial bioenergetics as potential targets for therapy

NLRX1 is a regulator of mitochondrial antiviral immunity

Melatonin: roles in influenza, COVID-19, and other viral infections

Mitochondrial interactome: a focus on antiviral signaling pathways

Influenza viruses and the NF-κB signaling pathway-towards a novel concept of antiviral therapy

Cirsimaritin inhibits influenza A virus replication by downregulating the NF-κB signal transduction pathway

Ouabain activates NFκB through an NMDA signaling pathway in cultured cerebellar cells

Antiviral activity of digoxin and ouabain against SARS-CoV-2 infection and its implication for COVID-19

Possible role of endogenous ouabain-like compounds in the pathophysiology of bipolar illness

Commentary: Phosphodiesterase 4 inhibitors as potential adjunct treatment targeting the cytokine storm in COVID-19

Targeting the NO-cGMP-PDE5 pathway in COVID-19 infection. The DEDALO project

Sildenafil as treatment for human immunodeficiency virus-related pulmonary hypertension in a child

Investigating the role of protein kinase-G in the antidepressant-like response of sildenafil in combination with muscarinic acetylcholine receptor antagonism

Peroxisome proliferator-activated receptor and AMPactivated protein kinase agonists protect against lethal influenza virus challenge in mice

Can pioglitazone be potentially useful therapeutically in treating patients with COVID-19?

Reduction of CCR5 with low-dose rapamycin enhances the antiviral activity of vicriviroc against both sensitive and drug-resistant HIV-1

Rapamycin enhances aplaviroc anti-HIV activity: implications for the clinical development of novel CCR5 antagonists

The mechanistic target of rapamycin (mTOR): novel considerations as an antiviral treatment and possibilities for COVID-19

The glycine site of NMDA receptors: a target for cognitive enhancement in psychiatric disorders

Role of the mTOR signaling pathway in the rapid antidepressant action of ketamine

The serotonin reuptake inhibitor Fluoxetine inhibits SARS-CoV-2

Can selective serotonin reuptake inhibitors have a neuroprotective effect during COVID-19?

Does escitalopram reduce neurotoxicity in major depression?

Fluoxetine and citalopram exhibit potent antiinflammatory activity in human and murine models of rheumatoid arthritis and inhibit toll-like receptors

Dependence on O2-generation by xanthine oxidase of pathogenesis of influenza virus infection in mice

Use of multiple inflammatory marker tests in primary care: using clinical practice research datalink to evaluate accuracy

COVID-19-associated hyperviscosity: a link between inflammation and thrombophilia?

D-dimer, Von Willebrand factor, P-Selectin and their interactions with endothelial cells, platelets and erythrocytes

The trinity of COVID-19: immunity, inflammation and intervention

Comparative genetic analysis of the novel coronavirus (2019-nCoV/SARS-CoV-2) receptor ACE2 in different populations

Duloxetine prevents the effects of prenatal stress on depressive-like and anxiety-like behavior and hippocampal expression of pro-inflammatory cytokines in adult male offspring rats

The anti-inflammatory role of SSRI and SNRI in the treatment of depression: a review of human and rodent research studies

Fluvoxamine maleate normalizes striatal neuronal inflammatory cytokine activity in a Parkinsonian rat model associated with depression

Augmentation of antidepressant effects of venlafaxine by agomelatine in mice are independent of kynurenine pathway

Activation of indoleamine 2, 3-dioxygenase pathway by olanzapine augments antidepressant effects of venlafaxine in mice

Role of chronic administration of antidepressant drugs in the prenatal stress-evoked inflammatory response in the brain of adult offspring rats: involvement of the nlrp3 inflammasome-related pathway

Anti-inflammatory effects of antidepressants: possibilities for preventives against Alzheimer's disease

Inhibition of glial inflammatory activation and neurotoxicity by tricyclic antidepressants

Amitriptyline inhibits the MAPK/ERK and CREB pathways and proinflammatory cytokines through A3AR activation in rat neuropathic pain models

The effect of repeated amitriptyline and desipramine administration on cytokine release in C57BL/6 mice

Imipramine reverses alterations in cytokines and BDNF levels induced by maternal deprivation in adult rats

Effects of agomelatine on oxidative stress in the brain of mice after chemically induced seizures

Agomelatine and duloxetine synergistically modulates apoptotic pathway by inhibiting oxidative stress triggered intracellular calcium entry in neuronal PC12 cells: role of TRPM2 and voltage-gated calcium channels

Ketamine and peripheral inflammation

Ketamine alleviates depressive-like behaviors via down-regulating inflammatory cytokines induced by chronic restraint stress in mice

Effects of olanzapine on plasma levels of catecholamine metabolites, cytokines, and brain-derived neurotrophic factor in schizophrenic patients

The influence of risperidone and ziprasidone on plasma cytokine in patients with schizophrenia

Effects of clozapine and olanzapine on cytokine systems are closely linked to weight gain and drug-induced fever

The underlying mechanisms for olanzapine-induced hypertriglyceridemia

Effects of olanzapine on the elevation of macrophage infiltration and pro-inflammatory cytokine expression in female rats

Plasma levels of leptin and endogenous immune modulators during treatment with carbamazepine or lithium

Sceletium-a review update

Nigella sativa L. seeds modulate mood, anxiety and cognition in healthy adolescent males

Thymoquinone treatment modulates the Nrf2/HO-1 signaling pathway and abrogates the inflammatory response in an animal model of lung fibrosis

Diet quality, dietary inflammatory index and body mass index as predictors of response to adjunctive N-acetylcysteine and mitochondrial agents in adults with bipolar disorder: a sub-study of a randomised placebo-controlled trial

The chemistry and biological activities of Nacetylcysteine