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COVID-19 Long-Term Neuropsychiatric Symptoms: Tackling the Issue

Ezio Bettini, Ph.D., Manager Plate Based Assay, Discovery Electrophysiology. In vitro Pharmacology, Aptuit (Verona) Srl, an Evotec Company
Paolo Manfredi, M.D., Chief Scientific Officer, Relmada Therapeutics
Stephen M. Stahl, M.D., Ph.D, Adjunct Professor of Psychiatry, University of California San Diego, Chairman, Neuroscience Education Institute

COVID-19 Long Term Neuropsychiatry Effects

Since the COVID-19 pandemic began, it has become increasingly clear that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cannot be simply defined as a respiratory virus only targeting the respiratory system and lungs. On the contrary, Sars-Cov-2 virus, showed an ability to infect multiple cell types, mainly due to the widespread tissue distribution of its main receptor target ACE2, and an ability to trigger a dysregulated immune response, so causing a variety of symptoms, ranging from mild to severe and affecting multiple tissues and organs (Gupta et al, 2020). Reports of acute neuropsychiatry and neurological symptoms in COVID-19 patients have been numerous during the pandemic and were recently clustered in three distinct groups: anosmia and hypogeusia; dizziness, headache, and limb weakness; photophobia, mental state change, hallucination, vision and speech problem, seizure, stroke, and balance disturbance (Mirfazeli et al, 2020). The discovery that Sars-Cov-2 virus, or a relevant virus protein such as spike 1 protein (S1), can reach the brain, has provided the biological substrate for reported neuropsychiatric and neurological symptoms in COVID-19 (Meinhardt et al 2020, Rhea et al 2020).

Moreover, there has been growing concern that COVID-19 survivors might be at increased risk of long term sequelae, extending far beyond acute infection, even among those who experience mild illness (CDC: 2021 Apr 8): long COVID is the name used for referring to the range of symptoms that can last weeks or months after first being infected with the virus that causes COVID-19 or can appear weeks after infection. Anxiety and depression are amongst the major symptoms manifested in people experiencing long COVID. A recent report, published in Lancet Psychiatry, estimated the risks of major neurological and psychiatric conditions in the 6 months after COVID-19 diagnosis, by analysing health records of more than 230,000 patients, mostly from the United States (Taquet et al, 2021). It was discovered that a stunning more than 33% of COVID-19 survivors had been diagnosed with neurological or psychiatric illnesses within six months, with nearly 13% receiving their first neuropsychiatric diagnosis. These disorders were significantly more common in COVID-19 patients than in comparison groups of people who recovered from flu or other respiratory infections over the same time period. Anxiety, at 17%, and mood disorders, at 13%, were the most common, and did not appear to be related to how mild or severe the patient’s COVID-19 infection had been (Taquet et al, 2021).

Possible Mechanism of COVID-19 Long Term Neuropsychiatry effects

A recent article published in the JAMA Psychiatry journal reviewed possible mechanisms leading to COVID-19 long term neuropsychiatry effects (Boldrini et al 2021). Neuro-inflammatory mediators are hypothesized to play a relevant role in the sequela of events which can finally culminate in long term COVID neuropsychiatric symptoms. Among neuro-inflammatory mediators, a major role could be played by quinolinic acid (QA), a breakdown metabolite of the amino acid tryptophan and an endogenous inflammatory mediator with neurotoxic potential. QA mediates its neurotoxic effects by activating N-methyl-D-aspartate receptor (NMDAR). QA is normally present in nanomolar concentrations in the brain. However, increased levels of QA can be produced by activated macrophages and microglia in pathological conditions. Accumulation of endogenous QA has been implicated in the aetiology of neurological diseases and psychiatric disorders, including depression. An increase in plasma QA levels has been reported in COVID-19 patients (Collier et al, 2021; Thomas et al, 2020).

Innovative Approach for a Sustainable Treatment

In a collaborative study with Relmada Therapeutics, we studied esmethadone and its ability to antagonise quinolinic acid effects in recombinant CHO cells expressing different isoforms of human NMDAR (Bettini et al: manuscript in preparation). Esmethadone is a very safe and well tolerated NMDAR channel blocker, which showed rapid and robust efficacy in Phase 3 trials for the treatment for major depressive disorder (MDD) (Fava et al: manuscript submitted). In our studies, Esmethadone showed potential for reducing increases in calcium influx induced by QA alone or in combination with sub-saturating concentrations of L-glutamate. Because of the hypothesized mechanism of action, the strong signal for efficacy for patients with MDD, and a very favorable safety, tolerability, and pharmacokinetic profile, esmethadone has the potential to be tested in controlled trials for prevention and treatment of complications secondary to COVID-19.


Boldrini M, Canoll PD, Klein RS. How COVID-19 affects the brain. JAMA Psychiatry. 2021 Mar 26.

CDC: 2021 Apr 8:

Collier ME, Zhang S, Scrutton NS, Giorgini F. Inflammation control and improvement of cognitive function in COVID-19 infections: is there a role for kynurenine 3-monooxygenase inhibition? Drug Discov Today. 2021 Feb 18:S1359-6446(21)00075-1.

Gupta A, Madhavan MV, Sehgal K et al. Extrapulmonary manifestations of COVID-19. Nat Med 26, 1017–1032 (2020).

Meinhardt J, Radke J, Dittmayer C et al. Olfactory transmucosal SARS-CoV-2 invasion as a port of central nervous system entry in individuals with COVID-19. Nat Neurosci 24, 168–175 (2021).

Mirfazeli FS, Sarabi-Jamab A, Jahanbakhshi A et al. Neuropsychiatric manifestations of COVID-19 can be clustered in three distinct symptom categories. Sci Rep 10, 20957 (2020).

Rhea EM, Logsdon AF, Hansen KM et al. The S1 protein of SARS-CoV-2 crosses the blood–brain barrier in mice. Nat Neurosci 24, 368–378 (2021).

Taquet M, Luciano S, Geddes JR, Harrison PJ. Bidirectional associations between COVID-19 and psychiatric disorder: retrospective cohort studies of 62 354 COVID-19 cases in the USA. Lancet Psychiatry 8(2):130-140 (2021).

Thomas T, Stefanoni D, Reisz JA, Nemkov T, Bertolone L, Francis RO, Hudson KE, Zimring JC, Hansen KC, Hod EA, Spitalnik SL, D’Alessandro A. COVID-19 infection alters kynurenine and fatty acid metabolism, correlating with IL-6 levels and renal status. JCI Insight.5(14):e140327 (2020).