Immunopsychiatry after COVID-19

Immunopsychiatry can be defined as the study of immune-inflammatory pathways in order to identify pathogenetic mechanisms, and targets for treatment, in psychiatric conditions: under the premises that interactions between the immune system and the central nervous system are crucial for brain homeostasis and function, and their disruption has major consequences on mental health. With its terrible burden of disease inflicted on mankind, the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection provided a natural experiment, to provocatively test the relationship between inflammation and mood disorders. Consistent systematic reviews and meta-analyses now affirm that COVID-19 survivors show persistent psychopathology and neurocognitive impairment, with clinically significant depressive psychopathology being reported in around 35% of patients. The cluster of Post-Acute Sequelae of COVID-19 (PASC) symptoms typically emerge after the acute phase of illness, when patients are no longer positive to SARS-CoV-2, including dyspnoea, hypoxia, joint and muscle pain, paraesthesia, dysgeusia, anosmia, fatigue; and, unrelated to the above, neuropsychiatric and neurocognitive symptoms with depression, anxiety, insomnia, difficulties in sustained attention and memory, which worsen over the months. Psychopathological features are the same observed in Major Depressive Disorder, distributing along the same gradient of severity, and including a typically melancholic cognitive vulnerability with self-reproach and depressive cognitive style in evaluating events. Neurocognitive impairment could possibly separate from depression in the long term, but not in the first 6 months after infection, and it is largely overlapping with persistent cognitive deficits described in severe mood disorders. Brain correlates are the same observed in Major Depressive Disorder and in Bipolar Disorder, involving spread disruption of white matter microstructure, reduced grey matter volumes in anterior cingulate cortex, and abnormal functional connectivity in the cortico-limbic circuitries: all the above, being proportional to the degree of persistent systemic inflammation, and not to the severity of the acute illness and of the breadth of exposure to stressful events during the pandemic. We suggest that post-COVID depression provides an invaluable model illness for the study of immune-inflammatory mechanisms involved in the pathogenesis of mood disorders, to identify new targets for treatment, with the aim of restoring mental health and brain homeostasis.