Serotonin deficiency and psychiatric long COVID: both caused specifically by the virus itself or an adaptive general stress response?

Excerpt

Infections with the COVID-19 virus and its aftermath, the long COVID syndrome, are far from being understood considering their underlying biological and psychological mechanisms [1]. In this context, antidepressants with serotonergic actions have been increasingly examined and discussed as to whether they can influence the course and severity of COVID-19 [2, 3] and presumably, long COVID too (with regard to long COVID, see Table 1). Postulated mechanisms include an attenuation of an overshooting pro-inflammatory response on cellular virus entry as well as direct antiviral effects [2, 3]. A recent publication in Cell seems to shed more light on this enigma [4]. Wong et al. found reduced plasma serotonin levels in mice infected with SARS-CoV2 as well as in a small clinical cohort of patients seeking treatment for long COVID. Interestingly, reduced plasma serotonin occurred also during the acute infection period, but not in people who were fully recovered after COVID-19 [4]. Although serotonin plasma levels, which are themselves in large parts dependent on the gut microbiota, do not automatically reflect the situation in brain compartments, a recent finding should be outlined in this context. Richter et al. demonstrated by transcranial sonography that the raphe nuclei of patients with long COVID depression were characterized by a hypo-echogenicity suggesting a dysfunction of the cerebral serotonergic system [5]. A bridge between gut microbiota peripheral and central serotonin levels is mediated by the vagal tone, which is low at depressive conditions corresponding to low serotonin levels [4, 6]. At this juncture, it should be furthermore outlined that beyond depression and anxiety symptoms, an acquired as well as a constitutive serotonin deficiency might account for altered memory and hippocampal synaptic plasticity [4, 7], which could explain also some tenacious cognitive symptoms of long COVID including executive dysfunctions. Taken together, there is increasing evidence that cerebral serotonergic dysfunctions could be responsible for psychiatric COVID-19 sequelae. However, are these dysfunctions really caused by the virus itself, e.g., initiated by dropping peripheral serotonin levels as Wong et al. suggested [4]? Preliminary results describe a missing prevention of long COVID by SARS-CoV2-specific antivirals. Vice versa, cases have been identified with symptoms assigned to long COVID, but without a history for SARS-CoV2 infection [8]. These findings cannot support the viral genesis of behavioral long COVID symptoms. At this point, we emphasize that long COVID covers a number of of behavioral features of a common chronic stress response, which itself is also significantly related to a decrease in serotonin neurotransmission [9] and suggested to activate pro-inflammatory states. At the moment, it is not ruled out that the circumstances around, and negative expectations toward, the virus infection, are more responsible for psychiatric long COVID symptoms (or post-viral symptoms in general) than the specific virus itself. …