**6. COVID-19: a catalyst for novel psychiatric paradigms - part 2**

#### **6.1 The virus and madness**

The connection between viruses, and psychiatric disorders has been around for many centuries. In the ancient world, Thucydides reported "total and immediate loss of memory" in the survivors of "plague of Athens", a disease suggestive of viral encephalitis [87, 88]. In our time, MRI studies have associated herpes simplex encephalitis, a condition marked by amnesia, with specific neuroimaging markers, linking viruses to cognition [89]. In addition, novel genetic studies have demonstrated that the HK2 retrovirus, frequently detected in the genome of drug addicts, was an ancestral pathogen incorporated into human DNA [90]. Over the past century, numerous studies linked in utero or early postnatal viral infections with the development of schizophrenia and autism later in life [91]. For example, women pregnant during the 1964 rubella epidemic in the United States gave birth to offspring that frequently developed autism or schizophrenia, suggesting that other viruses, probably including COVID-19, may have similar outcomes [92, 93]. In addition, obsessive–compulsive disorder (OCD), schizophrenia, attention deficit hyperactivity disorder (ADHD) and Tourette syndrome were traced to prenatal viral infections [94]. Neurodegenerative disorders, especially Parkinson's disease (PD), were documented to surge after prior pandemics, including the 1918 influenza, suggesting that COVID-19 may promote neurodegeneration [95]. On the positive side, the SARS-CoV-2 virus may prompt the development of novel PD therapies, including angiotensin receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEi) that have demonstrated efficacy in animal models [96].

Aside from linking prenatal viral exposure to severe psychiatric illness, several new studies reported that dormant CNS viruses could also engender this pathology [97]. For example, a recent report found that compared to controls, patients with schizophrenia demonstrated higher titers of Borna disease virus (BDV) immune complexes [98]. Others have connected influenza A, varicella-zoster, herpes simplex, hepatitis C and human immunodeficiency virus with the development of serious psychiatric disorders [99].

Autoantibodies against NMDARs, demonstrated in some schizophrenia patients, were recently found to be the result of molecular mimicry between the M2 protein of influenza A virus and NMDARs [100, 101]. Indeed, several large epidemiological studies found increased prevalence of autoimmune diseases in patients with schizophrenia, indicating that autoantibodies may be the result of either molecular mimicry or virus-induced modifications in human proteins [102]. For example, the molecular resemblance between an H1N1 influenza antigen and human hypocretin molecule triggers narcolepsy as virus-induced hypocretin modification may elicit autoantibodies [103]. Along these lines, the NMDAR partial

antagonist, memantine, utilized in Alzheimer's disease (AD), was found to possess immunosuppressant properties [39, 103, 104]. Indeed, prior studies have demonstrated memantine efficacy against Trypanosoma cruzi, a disease with established autoimmune pathogenesis [105].

Untreated patients with schizophrenia were reported to be at high risk of COVID-19 complications, probably due to SARS-CoV-2-associated neuroinflammation, an established risk factor of many psychiatric disorders. On the other hand, psychotropic drugs with anti-inflammatory properties may lower the SARS-CoV-2-mediated neuroinflammation, explaining the protective effects of these agents [24, 106].

#### **6.2 COVID-19 and acquired antioxidant defects**

According to the two-hit paradigm presented here, the COVID-19 prognosis is likely determined by the status of premorbid redox reserves, especially those comprised of the antioxidant enzymes G6PD and GPX. These proteins maintain homeostasis by neutralizing ANG II-activated NADPH oxidase (NOX) [107]. NOX upregulation was documented in patients with neurodegenerative disorders, schizophrenia, and suicidal behaviors, linking CNS pathology to redox system failure [108–110].

G6PD is a potent antioxidant enzyme that lowers NOX by upregulating the synthesis of NADPH and glutathione (GSH) [111]. Conversely, G6PD deficiency was associated with hemolysis and endothelial dysfunction caused by lower GSH and increased oxidative stress [111].

We surmise that the SARS-CoV-2 virus engenders acquired deficits of G6PD and GPX via ANG II-aldosterone upregulated NOX [112] (**Figure 4**). When COVID-19 induced deficiency of antioxidant enzymes occurs on the background of a hereditary G6PD deficit (observed in some populations with ancestral exposure to malaria), the resultant redox failure trigger COVID-19 critical illness [113] (**Figure 4**).

Several recent studies have supported this model as they established that G6PD deficient individuals, including many African Americans, are more likely to develop COVID-19 critical illness [6, 7, 114–116]. Moreover, G6PD deficiency was associated with cardiovascular disease, hypertension, liver fibrosis and iron dyshomeostasis, indicating the importance of redox balance in this pathology [117–121].

#### *6.2.1 Malaria and COVID-19 prognosis*

Malaria is an old enemy of mankind that throughout the past centuries exacted a heavy toll on the population of Africa and the surrounding regions. Residents of these areas have gradually developed phenotypes of plasmodium-resistant erythrocytes, including G6PD deficiency, thalassemia, and hemoglobin C, to protect against malaria [122]. Although these modified red blood cells may block plasmodial ingress, individuals with these changes are more susceptible to hemolysis and iron-mediated oxidative stress that in turn promote infections, hypertension, cancer and neuropsychiatric disorders [123–126]. Indeed, both *Plasmodium falciparum* and the SARS-CoV-2 virus induce redox dysfunctions conducive to these pathologies.

Neuropsychiatric manifestations of malaria have been known since the ancient era however, they were more thoroughly studied only in World War I when French Army physicians encountered malaria during the campaign in Northern Greece [127–129]. More recent studies demonstrated that ROS play a major role in the pathogenesis of malaria and the CNS manifestations of this infection. For example, excessive ROS were shown to directly activate nucleotide-binding oligomerization domain-like receptor family, pyrin domain-containing-3 (NLRP3) inflammasomes, molecular

*COVID-19: A Catalyst for Novel Psychiatric Paradigms - Part 1 DOI: http://dx.doi.org/10.5772/intechopen.96940*

#### **Figure 4.**

*The SARS-CoV-2 virus causes oxidative stress by inhibiting both GPX (directly) and G6PD (indirectly via ANG II and aldosterone-upregulated NOX). Individuals with hereditary G6PD deficiency are at higher risk for developing COVID-19 critical illness as the loss of antioxidant enzymes is more profound and oxidative stress higher.*

structures involved in numerous pathological processes, including t psychiatric disorders [130, 131]. Interestingly, some antipsychotic drugs, including clozapine, function as NLRP3 inhibitors, indicating anti-neuroinflammatory properties [132]. The SARS-CoV-2 interactome established that viral protein OPR3a can activate NLRP3 directly, suggesting a pathway for virus-induced neuroinflammation [133, 134].

Several studies reported that *Plasmodium falciparum*-infected red blood cells externalize PS, a phenomenon observed in severe COVID-19 illness [135]. On the other hand, CPZ was demonstrated to bind PS, promoting eryptosis (elimination of infected red blood cells) with improvement of malaria symptoms [136, 137]. Interestingly antimalarial drugs, chloroquine and hydroxychloroquine operate by inhibiting the EP, a common mechanism of action with some antipsychotic drugs, including CPZ [138]. Since erythrocytes with externalized PS were also documented hypertension, further studies are needed to clarify the role of PS in illness and eryptosis as a possible therapeutic intervention [138, 139]. Indeed, CPZ has been utilized routinely in the emergency treatment of uncontrolled hypertension, indicating a possible role of eryptosis in addition to the well-established CPZ effects on alpha-adrenergic receptors [140].

#### *6.2.2 Malaria exposure and the risk of COVID-19*

Population groups throughout the world with exposure to malaria during the previous centuries were found to be at higher risk of hereditary G6PD deficiency and antioxidant failure. This background increases the odds not only of viral infections but also of other redox disorders, including hypertension, cancer and cardiac disease. For example, 12.2% of African American males and 4.1% of females are G6PD deficient, indicating a potentially higher risk of COVID-19 complications [141]. Indeed, novel studies found a 2.4 percent higher COVID-19 mortality in African Americans compared to Whites, Asians or Latinos [142].

Moreover, the lower GSH and nitric oxide (NO) levels in African Americans compared to other groups, places this population at higher risk of both hypertension and prostate cancer, suggesting that the SARS-CoV-2 infection may precipitate these complications [143–149]. In this regard, African Americans with COVID-19 should be routinely assessed for G6PD deficiency and supplemented with the widely available antioxidant, N-acetylcysteine [150].

Oxidative stress was demonstrated to directly trigger hypertension by resetting the CNS baroreflex, therefore the G6PD-deficient individuals could be more prone to COVID-19-related cardiovascular complications [151]. On the other hand, ARBs and ACEi lower ANG II-mediated ROS, likely averting these complications [152–157]. Indeed, the lower utilization of ARBs and ACEi in the treatment of hypertensive African Americans may place this population at higher risk of COVID-19 critical illness [158]. Although numerous clinical trials supported the efficacy of ARBs and ACEi in African Americans, these drugs are rarely utilized in this population as an initial therapeutic options [158, 159]. This is significant as both ARBs and ACEi appear to lower COVID-19 mortality rate, probably by dampening oxidative stress-ACE-2 downregulation. For example, a novel study found that COVID-19 patients treated with ACEi or ARBs at the time of initial infection had fewer unfavorable outcomes and lower mortality rate compared to individuals unexposed to these drugs [160].

Taken together, the SARS-CoV-2-upregulated ANG II, triggers hypertension and cardiovascular disease by augmenting oxidative stress and altering the baroreceptor setting. Individuals with G6PD deficiency are at increased risk of both hypertension and COVID-19 critical illness, indicating alignment with the two-hit paradigm presented here.
