Interstitial pneumonia was the first manifestation to be recognized as caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); however, in just a few weeks, it became clear that the coronavirus disease-2019 (COVID-19) overrun tissues and more body organs than just the lungs, so much so that it could be considered a systemic pathology. Several studies reported the involvement of the conjunctiva, the gut, the heart and its pace, and vascular injuries such as thromboembolic complications and Kawasaki disease in children and toddlers were also described. More recently, it was reported that in a sample of 214 SARS-CoV-2 positive patients, 36.4% complained of neurological symptoms ranging from non-specific manifestations (dizziness, headache, and seizures), to more specific symptoms such hyposmia or hypogeusia, and stroke. Older individuals, especially males with comorbidities, appear to be at the highest risk of developing such severe complications related to the Central Nervous System (CNS) involvement. Neuropsychiatric manifestations in COVID-19 appear to develop in patients with and without pre-existing neurological disorders. Growing evidence suggests that SARS-CoV-2 binds to the human Angiotensin-Converting Enzyme 2 (ACE2) for the attachment and entrance inside host cells. By describing ACE2 and the whole Renin Angiotensin Aldosterone System (RAAS) we may better understand whether specific cell types may be affected by SARS-CoV-2 and whether their functioning can be disrupted in case of an infection. Since clear evidences of neurological interest have already been shown, by clarifying the topographical distribution and density of ACE2, we will be able to speculate how SARS-CoV-2 may affect the CNS and what is the pathogenetic mechanism by which it contributes to the specific clinical manifestations of the disease. Based on such evidences, we finally hypothesize the process of SARS-CoV-2 invasion of the CNS and provide a possible explanation for the onset or the exacerbation of some common neuropsychiatric disorders in the elderly including cognitive impairment and Alzheimer disease.

BACKGROUND The subsequent waves of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic have represented a dramatic health emergency characterized by significant consequences on mental health. Diachronic variations in the incidence rates of acute relapse of psychiatric disorders may represent significant "sentinel events" for assessing the mental health response to an unprecedented stressful event. AIM To investigate the variation in psychiatric hospitalization rates and differences in sociodemographic and clinical-psychopathological peculiarities at Bologna "Maggiore" General Hospital Psychiatric Ward (GHPW) between the first two waves SARS-CoV-2 pandemic and the same periods of the previous 3 years. The secondary purpose of the study was to suggest a diachronic response pathway to stress by reporting additional literature data on coping strategies. METHODS This observational and retrospective study collected information on admission to the GHPW at the "Maggiore" Hospital in Bologna in the index periods defined as follows: the first period between February 24, 2020 and April 30, 2020 (first epidemic wave) and the second period between October 8, 2020, and January 7, 2021 (second pandemic wave). Absolute numbers and proportion of admitted patients, their sociodemographic and clinical-psychopathological characteristics were compared with the same parameters recorded in the two same periods of the previous 3 years. No strict inclusion or exclusion criteria were provided in the data collection to collect information on all patients requiring acute psychiatric hospitalization. RESULTS During the first wave, there was a significant reduction in hospitalization rates, although there was a simultaneous increase in compulsory hospitalizations and the acute relapse of schizophrenia spectrum and other psychotic disorders. During the second wave, hospitalization rates reached those recorded during the same period of the previous 3 years, mainly due to the rise of bipolar and related disorders, depressive disorders, anxiety disorders, trauma- and stressor-related disorders and suicidal behaviors. CONCLUSION The coping strategies adopted during the first wave of the SARS-CoV-2 pandemic protected the vulnerable population from the general risk of clinical-psychopathological acute relapse, even if they increased the susceptibility to run into schizophrenia spectrum and other psychotic disorder relapses. In the medium-long term (as in the second pandemic wave), the same strategies do not play protective roles against the stress associated with the pandemic and social restriction measures. Indeed, during the second wave of the SARS-CoV-2 pandemic, an increase in total hospitalization rate, suicidal behaviors and the incidence rate of bipolar and related disorders, depressive disorders, anxiety disorders, trauma- and stressor-related disorders was observed.

Informed consent statement:The informed consent statement was waived.

The debate around optimal target dose for first-line antidepressants (ADs) is still ongoing. Along this line, therapeutic drug monitoring (TDM) represents one of the most promising tools to improve clinical outcome. Nevertheless, a few data exist regarding the concentration-effect relationship of first-line ADs which limits TDM implementation in routine clinical practice. We conducted the first patient-level concentration-response mega-analysis including data acquired by us previously and explored the concentration dependency of first-line AD (206 subjects). Further, new data on mirtazapine are reported (18 subjects). Hamilton Depression Rating Scale-21 administered at baseline, at month 1 and month 3 was used as the measure of efficacy to assess antidepressant response (AR). When pooling all four first-line ADs together, normalized plasma levels and AR significantly fit a bell-shaped quadratic function with a progressive increase of AR up to around the upper normalized limit of the therapeutic reference range with a decrease of AR at higher serum levels. Our results complement the available evidence on the issue and the recent insights gained from dose-response studies. A concentration-dependent clinical efficacy, such as previously demonstrated for tricyclic compounds, also emerge for first-line ADs. Our study supports a role for TDM as a tool to optimize AD treatment to obtain maximum benefit.

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