A baby girl with TBX1 haploinsufficiency who died after elective cardiac repair surgery due to suspected enteroviral meningitis

Introduction: TBX1 haploinsufficiency is an inborn error of immunity with the phenotype of DiGeorge Syndrome. DiGeorge Syndrome has variable immunodeficiency associated with grade of thymic hypoplasia ranging from mild with no infections to severe requiring thymus implant. Enterovirus is an example of an opportunistic infection that can be fatal in these patients. Case Presentation: A 1 year old girl with TBX1 haploinsufficiency complicated by Tetralogy of Fallot, pulmonary atresia, high arched palate, and vesicovaginal fistula presented for elective cardiac repair surgery from another country due to failure to thrive and cyanosis. She had no prior infectious history but was on sulfamethoxazole-trimethoprim for prophylaxis. She was asymptomatic with a negative COVID test but no other infectious studies performed. Immediately postoperatively, she was febrile and nasal respiratory viral panel was positive for rhinovirus/enterovirus with increased procalcitonin and leukocytosis with left shift. She decompensated with multi-organ failure and cardiac arrest on postoperative day two. She was cannulated to veno-arterial extracorporeal membrane oxygenation (ECMO). Pre-operatively, she had a normal absolute lymphocyte count. No thymus tissue was observed in surgery. She had profound CD3 lymphopenia to 130 cells/cmm when critically ill. Enteroviral meningitis was suspected as no infectious, cardiac, or other pathology could be identified causing decompensation. Enteroviral serum polymerase chain reaction (PCR) test was negative while lumbar puncture deferred due to clinical status. She was treated with immunoglobulin. Offlabel investigational drug pocapavir was considered but deferred to patient's irreversible neurological status. The patient was disconnected from ECMO and expired. Discussion(s): Though we cannot confirm that this patient had enteroviral meningitis, invasive enteroviral infections are associated with elevated transaminases, coagulopathy, and seizures all present in our patient. There has also been reported negative serum enteroviral PCR but positive CSF enteroviral PCR in an immunodeficient patient. Additionally, this case highlights the importance of immunologic evaluation in patients with DiGeorge Syndrome and questions if asymptomatic viral screening for viruses like enterovirus should be considered pre-operatively in patients with inborn errors of immunity. This case highlights potential treatment options for invasive enteroviral infections in patients with inborn errors of immunity: high dose immunoglobulin, fluoxetine, and pocapavir.Copyright © 2023 Elsevier Inc.

Transverse myelitis 48 hours after the administration of an mRNA COVID 19 vaccine

Background Vaccinations against SARS-CoV-2 have been a topic of political, social, and medical intrigue since the declaration of the COVID-19 pandemic in early 2020. The vaccine side effects have been relatively mild to date, with few observed systemic effects. Case presentation A 69-year-old previously healthy female presented with symptoms of asymmetric bilateral lower and upper extremity weakness 2 days after vaccination with the Pfizer-BioNTech mRNA vaccine. MRI of the cervical spine revealed a non-compressive myelitis extending from C3-4 to T2-3. Common known causes of transverse myelitis were ruled out by diagnostic techniques. Conclusions Transverse myelitis is a rare autoimmune disorder that has been shown to have a temporal association with vaccination in the past. With a progressively partisan societal view on vaccinations, it is important for clinicians to remain vigilant on documenting potential associations without encouraging fear of causation.Copyright © 2021 The Author(s)

Efficacy and safety of adding fluoxetine to the treatment regimen of hospitalized patients with non-critical COVID-19 pneumonia: A double-blind randomized, placebo-controlled clinical trial.

INTRODUCTION: Selective serotonin reuptake inhibitors are considered the drugs, whose effectiveness in viral pandemics has been studied. The aim of this study was to evaluate of adding fluoxetine to the treatment regimen of patients with COVID-19 pneumonia. METHODS: This study was a double-blind randomized placebo controlled clinical trial .36 patients in the fluoxetine and 36 patients in the placebo group were enrolled. Patients in the intervention group were first treated with fluoxetine 10 mg for 4 days and then the dose of 20 mg was continued for 4 weeks. Data analysis was conducted using SPSS V. 22.0. RESULTS: There was no statistically significant difference between the two groups in terms of clinical symptoms at the beginning of the study and also the score of anxiety and depression, oxygen saturation at the time of hospitalization, mid-hospitalization and discharge periods. The need for mechanical ventilator support (p = 1.00), the need for admission in the intensive care unit (ICU) (p = 1.00), rate for mortality (p = 1.00), and discharge with relative recovery (p = 1.00) were not significantly different between the two groups. The distribution of CRP within the study groups showed a significant decrease during different time periods (p = 0.001), and although there was no statistically significant difference between the two groups on the first day (p = 1.00) and at discharge (p = 0.585), mid-hospital CRP showed a significant decrease in the fluoxetine group (p = 0.032). CONCLUSION: Fluoxetine resulted in a faster reduction of patients' inflammation without association with depression and anxiety.

Fluoxetine plus lithium for treatment of mental health impairment in Long Covid.

Purposes: (1) To summarize the mental conditions that may accompany persistent symptoms following acute infection by SARS-CoV-2, often termed Long Covid; (2) to formulate treatment based upon the brain cells that are dominantly affected. Methods: (1) Review the reports relating to the mental symptoms occurring in Long Covid. (2) Review the drugs that address the brain cells affected in Long Covid, and suggest pharmacotherapy for those patients whose response to psychotherapy is suboptimal. Results: Long Covid affects ~ 10% of patients infected by SARS-CoV-2, and mental symptoms affect ~ 20% of persons with Long Covid. The brain cell-types that have been demonstrated as dominantly affected in Long Covid are astrocytes, oligodendrocytes, neurons, endothelial cells/pericytes, and microglia. Lithium and fluoxetine each address all of those four cell-types. Low dosage of each is likely to be well-tolerated and to cause neither clinically important adverse events (AE) nor serious adverse events (SAE). Conclusion: For those patients whose response to psychotherapy is suboptimal, lithium and fluoxetine should be administered in combination for both depth of benefit and reduction of dosages.

Potential Role of the Antidepressants Fluoxetine and Fluvoxamine in the Treatment of COVID-19.

Mapping non-canonical cellular pathways affected by approved medications can accelerate drug repurposing efforts, which are crucial in situations with a global impact such as the COVID-19 pandemic. Fluoxetine and fluvoxamine are well-established and widely-used antidepressive agents that act as serotonin reuptake inhibitors (SSRI-s). Interestingly, these drugs have been reported earlier to act as lysosomotropic agents, inhibitors of acid sphingomyelinase in the lysosomes, and as ligands of sigma-1 receptors, mechanisms that might be used to fight severe outcomes of COVID-19. In certain cases, these drugs were administered for selected COVID-19 patients because of their antidepressive effects, while in other cases, clinical studies were performed to assess the effect of these drugs on treating COVID-19 patients. Clinical studies produced promising data that encourage the further investigation of fluoxetine and fluvoxamine regarding their use in COVID-19. In this review, we summarize experimental data and the results of the performed clinical studies. We also provide an overview of previous knowledge on the tissue distribution of these drugs and by integrating this information with the published experimental results, we highlight the real opportunity of using these drugs in our fight against COVID-19.

Selective serotonin reuptake inhibitors: New hope in the fight against COVID-19.

The emerging COVID-19 pandemic led to a dramatic increase in global mortality and morbidity rates. As in most infections, fatal complications of coronavirus affliction are triggered by an untrammeled host inflammatory response. Cytokine storms created by high levels of interleukin and other cytokines elucidate the pathology of severe COVID-19. In this respect, repurposing drugs that are already available and might exhibit anti-inflammatory effects have received significant attention. With the in vitro and clinical investigation of several studies on the effect of antidepressants on COVID-19 prognosis, previous data suggest that selective serotonin reuptake inhibitors (SSRIs) might be the new hope for the early treatment of severely afflicted patients. SSRIs' low cost and availability make them potentially eligible for COVID-19 repurposing. This review summarizes current achievements and literature about the connection between SSRIs administration and COVID-19 prognosis.

Antiviral and Anti-Inflammatory Activities of Fluoxetine in a SARS-CoV-2 Infection Mouse Model.

The coronavirus disease 2019 (COVID-19) pandemic continues to cause significant morbidity and mortality worldwide. Since a large portion of the world's population is currently unvaccinated or incompletely vaccinated and has limited access to approved treatments against COVID-19, there is an urgent need to continue research on treatment options, especially those at low cost and which are immediately available to patients, particularly in low- and middle-income countries. Prior in vitro and observational studies have shown that fluoxetine, possibly through its inhibitory effect on the acid sphingomyelinase/ceramide system, could be a promising antiviral and anti-inflammatory treatment against COVID-19. In this report, we evaluated the potential antiviral and anti-inflammatory activities of fluoxetine in a K18-hACE2 mouse model of SARS-CoV-2 infection, and against variants of concern in vitro, i.e., SARS-CoV-2 ancestral strain, Alpha B.1.1.7, Gamma P1, Delta B1.617 and Omicron BA.5. Fluoxetine, administrated after SARS-CoV-2 infection, significantly reduced lung tissue viral titres and expression of several inflammatory markers (i.e., IL-6, TNFα, CCL2 and CXCL10). It also inhibited the replication of all variants of concern in vitro. A modulation of the ceramide system in the lung tissues, as reflected by the increase in the ratio HexCer 16:0/Cer 16:0 in fluoxetine-treated mice, may contribute to explain these effects. Our findings demonstrate the antiviral and anti-inflammatory properties of fluoxetine in a K18-hACE2 mouse model of SARS-CoV-2 infection, and its in vitro antiviral activity against variants of concern, establishing fluoxetine as a very promising candidate for the prevention and treatment of SARS-CoV-2 infection and disease pathogenesis.

Antidepressant Use and Its Association with 28-Day Mortality in Inpatients with SARS-CoV-2: Support for the FIASMA Model against COVID-19.

To reduce Coronavirus Disease 2019 (COVID-19)-related mortality and morbidity, widely available oral COVID-19 treatments are urgently needed. Certain antidepressants, such as fluvoxamine or fluoxetine, may be beneficial against COVID-19. We included 388,945 adult inpatients who tested positive for SARS-CoV-2 at 36 AP-HP (Assistance Publique-Hôpitaux de Paris) hospitals from 2 May 2020 to 2 November 2021. We compared the prevalence of antidepressant use at admission in a 1:1 ratio matched analytic sample with and without COVID-19 (N = 82,586), and assessed its association with 28-day all-cause mortality in a 1:1 ratio matched analytic sample of COVID-19 inpatients with and without antidepressant use at admission (N = 1482). Antidepressant use was significantly less prevalent in inpatients with COVID-19 than in a matched control group of inpatients without COVID-19 (1.9% versus 4.8%; Odds Ratio (OR) = 0.38; 95%CI = 0.35-0.41, p < 0.001). Antidepressant use was significantly associated with reduced 28-day mortality among COVID-19 inpatients (12.8% versus 21.2%; OR = 0.55; 95%CI = 0.41-0.72, p < 0.001), particularly at daily doses of at least 40 mg fluoxetine equivalents. Antidepressants with high FIASMA (Functional Inhibitors of Acid Sphingomyelinase) activity seem to drive both associations. These treatments may reduce SARS-CoV-2 infections and COVID-19-related mortality in inpatients, and may be appropriate for prophylaxis and/or COVID-19 therapy for outpatients or inpatients.

A Case of Autosarcophagy in a Pediatric Patient With Depression

BACKGROUND: Self-mutilating behavior in the pediatric population is associated with psychiatric and psychosocial factors. Autosarcophagy, or self-cannibalism, is an extremely rare form of self-mutilation and is predominantly seen with psychosis or substance use.1 We report a case of oral autosarcophagy in a pediatric patient in the absence of substance use or psychosis. OBJECTIVE: To learn about autosarcophagy and its treatment in the pediatric population and to explore other neuropsychiatric disorders in which it is a predominant manifestation. METHODS: Review of a case using electronic medical records and relevant literature. Key terms: 'autosarcophagy,' 'body focused repetitive behavior,' 'oral self injury,' 'pediatric self-mutilation' using Medscape and Google Scholar. RESULTS: We present a 14-year-old female with history of seizure disorder in full remission, depression, self-cutting behavior, and suicidal ideation with 2 psychiatric hospitalizations, who presented to the pediatric emergency department with oral bleeding after eating one-third of her tongue over the course of a month. Evaluation was notable for poverty of speech and constricted affect. Patient stated she was 'trying to remove an infection' and alleviate discomfort. She denied that this behavior was an attempt to end her life but endorsed past suicidal ideations and cutting behavior. History revealed emergency room evaluation for aggressive behavior and episodes of volitional enuresis. We diagnosed major depressive disorder, recurrent episode in remission without psychosis. Drug screen, complete blood count, complete metabolic panel, COVID-19, urinalysis, thyroid-stimulating hormone, head computed tomography, and beta-human chorionic gonadotropin were negative. Patient continued home oral medications aripiprazole 10 mg daily, fluoxetine 30 mg daily, and levetiracetam 500 mg twice daily and was discharged the next day. CONCLUSIONS: Self-harm is observed in 17.2% of adolescents, 13.4% of young adults, and 5.5% of older adults.2 Cases of self-mutilation in pediatric patients typically present as cutting, burning, or head banging.3 Our differential diagnoses include borderline personality disorder due to repeated impulsivity and self-harm, and body focused repetitive behavior disorder (obsessive-compulsive disorder-related disorder), which presents with repetitive strain injuries and dental malocclusions. Treatment of self-mutilation involves treating the underlying psychiatric condition with psychotropic medications.4,5 In pediatric patients, dialectical behavioral therapy has been shown to reduce parasuicidal behaviors after 1 year of therapy.6 Our patient, under constant 24-hour observation, was cleared by medical, psychiatric, and dental teams. The patient followed up with outpatient psychotherapy and psychiatry. We are presenting this rare case for clinicians to identify and manage pediatric patients presenting with unique forms of self-harm tendencies.

ANTICOV: Initiating a platform adaptive trial for COVID outpatients in Africa

Introduction/ Background: Early evidence on mortality and ICU intervention rates for SARS-CoV-2 patients, and modelling of COVID in Africa, prompted calls for treatment to prevent progression of mild/moderate COVID. WHO's SOLIDARITY trial aimed to prevent death in hospitalized patients and others looked at prevention, but no trials assessed treatment for mild/moderate cases. Methods: The challenge was to rapidly launch a large and flexible study. A consortium of African research institutions already part of the COVID response and additional technical partners developed a Target- Product-Profile and a clinical protocol to allow percountry adaptation while maintaining key common features. ANTICOV is an adaptive platform trial in 13 African countries, testing two treatment arms (700 max./arm), nitazoxanide/inhaled ciclesonide and ASAQ/ivermectin, in patients with mild/moderate SARS-CoV-2 infection and symptoms up to 7 days before randomisation. ANTICOV has submitted an amendment to test fluoxetine/inhaled budesonide. Ancillary studies are conducted in a subset of countries. Results: This unique, diverse, 26-partner consortium was established rapidly. The protocol was ready for submission by mid-June 2020, and funding was quickly granted, thanks to clear needs and the experience of consortium members. 9 of 13 countries have started recruitment. Despite support from AVAREF, approval processes per country took longer than hoped, and approved drug importation was also a bottleneck. Changes in diagnostic referral impacted recruitment, so active screening was established in some countries. An interim analysis was conducted after 300 patients were randomized with no treatment interruption resulting;the next is planned after 750 patients are randomized. Impact: ANTICOV is driven by a unique research alliance to respond to region/context-specific treatment and pandemic control, unlike much of global research to date. In a context of emerging variants and inequitable vaccine access, effective therapeutics to prevent disease progression globally but prioritized only by the African region until recently. Conclusion: ANTICOV was set up collaboratively, bringing experience and know-how from diverse African and European leaders to find treatment adapted to the needs of low-resource settings. It was rapidly developed and financially supported. Results will be shared quickly. Future pandemic preparedness will require similarly established networks and expedited funding.

The Acid Ceramidase Is a SARS-CoV-2 Host Factor.

SARS-CoV-2 variants such as the delta or omicron variants, with higher transmission rates, accelerated the global COVID-19 pandemic. Thus, novel therapeutic strategies need to be deployed. The inhibition of acid sphingomyelinase (ASM), interfering with viral entry by fluoxetine was reported. Here, we described the acid ceramidase as an additional target of fluoxetine. To discover these effects, we synthesized an ASM-independent fluoxetine derivative, AKS466. High-resolution SARS-CoV-2-RNA FISH and RTqPCR analyses demonstrate that AKS466 down-regulates viral gene expression. It is shown that SARS-CoV-2 deacidifies the lysosomal pH using the ORF3 protein. However, treatment with AKS488 or fluoxetine lowers the lysosomal pH. Our biochemical results show that AKS466 localizes to the endo-lysosomal replication compartments of infected cells, and demonstrate the enrichment of the viral genomic, minus-stranded RNA and mRNAs there. Both fluoxetine and AKS466 inhibit the acid ceramidase activity, cause endo-lysosomal ceramide elevation, and interfere with viral replication. Furthermore, Ceranib-2, a specific acid ceramidase inhibitor, reduces SARS-CoV-2 replication and, most importantly, the exogenous supplementation of C6-ceramide interferes with viral replication. These results support the hypotheses that the acid ceramidase is a SARS-CoV-2 host factor.

Antidepressant Drugs and COVID-19: A Review of Basic and Clinical Evidence.

The COVID-19 pandemic has encouraged the repurposing of existing drugs as a shorter development strategy in order to support clinicians with this difficult therapeutic dilemma. There is evidence to support the theory that some antidepressants can reduce concentrations of different cytokines in humans and animals and, recently, the antiviral activity of some antidepressants against SARS-CoV-2 has been reported. The aims of this narrative review are to evaluate the possible role of antidepressants in the treatment of COVID-19 infection and the possible benefits and risks of patients taking antidepressants for mental disorders and COVID-19 infection. A review was performed to analyse the current literature to identify the role of antidepressant medication in the treatment of COVID-19 patients. The electronic search was completed in MEDLINE and MedRxiv/BioRxiv for published literature and in ClinicalTrials.gov for ongoing clinical trials. The results show some evidence from preclinical data and observational studies about the possible efficacy of some specific antidepressants for treating COVID-19 infection. In addition, two published phase II studies testing fluvoxamine showed positive results for clinical deterioration and hospitalization rate versus a placebo. Seven ongoing clinical trials testing fluvoxamine, fluoxetine, and tramadol (as per its anti-inflammatory and antidepressant effect) are still in the early phases. Although the available evidence is limited, the sum of the antiviral and anti-inflammatory preclinical studies and the results from several observational studies and two phase II clinical trials provide the basis for ongoing clinical trials evaluating the possible use of antidepressants for COVID-19 infection in humans. Further investigations will be needed to support the possible use of antidepressants for this application.

Quality Improvement Developments Following Pediatric Resuscitation and VA Extracorporeal Membrane Oxygenation Support due to a Massive Intentional Antidepressant Overdose

Introduction: The COVID-19 pandemic caused a significant increase in suicide attempts in teenagers. Fluoxetine and Wellbutrin have been prescribed to adolescents to treat depression. Overdosing on these medications can cause seizures, arrhythmias, and cardiogenic shock. We report on a patient who presented with a normal physical assessment following a massive antidepressant drug overdose, but quickly deteriorated, and required VA Extracorporeal Membrane Oxygenation (ECMO). Gaps identified in this case prompted us to assess our ECPR protocol, which led to areas for quality improvement. Case Review: A teenage male presented to our ED after intentionally ingesting Fluoxetine, Wellbutrin, and Hydroxyprogesterone. Fluid boluses, vasopressor infusions and multiple doses of epinephrine were administered, but his hemodynamic instability persisted. Concerns regarding cannulation, team activation and coordination of care during ECPR were areas identified as requiring improvement during a case review. The team was activated and cannulated the patient for VA ECMO. At hour eighty-five, he was hemodynamically stable, including normal sinus rhythm and resolved hypotension, and was removed from ECMO. He was successfully extubated, weaned to room air, and discharged with plans for outpatient therapy. Quality Improvement: An updated process for notifying team members for ECPR cannulation was implemented. Simulation scenarios, which are held quarterly, were developed, with clearly delineated roles, and emphasis on timing of chest compressions with minimal pauses during cannulation. Annual ECPR web-based education is mandatory. Improvements in the time to cannulation and team member interactions were noted during subsequent ECPR scenarios. Timing of team notification and cannulations continues to be tracked.

Antidepressant-Like Effect of Traditional Medicinal Plant Carthamus Tinctorius in Mice Model through Neuro-Behavioral Tests and Transcriptomic Approach

Major depression disorder (MDD) has become a common life-threatening disorder. Despite the number of studies and the introduced antidepressants, MDD remains a major global health issue. Carthamus tinctorius (safflower) is traditionally used for food and medical purposes. This study investigated the chemical profile and the antidepressant-like effect of the Carthamus tincto-rius hot water extract in male mice and its mechanism using a transcriptomic analysis. The antidepressant effect of hot water extract (50 mg/kg and 150 mg/kg) was investigated in mice versus the untreated group (saline) and positive control group (fluoxetine 10 mg/kg). Hippocampus transcriptome changes were investigated to understand the Carthamus tinctorius mechanism of action. The GC-MS analysis of Carthamus tinctorius showed that hot water extract yielded the highest amount of oleamide as the most active ingredient. Neuro-behavioral tests demonstrated that the safflower treatment significantly reduced immobility time in TST and FST and improved performance in the YMSAT compared to the control group. RNA-seq analysis revealed a significant differential gene expression pattern in several genes such as Ube2j2, Ncor1, Tuba1c, Grik1, Msmo1, and Casp9 related to MDD regulation in 50 mg/kg safflower treatment as compared to untreated and fluoxetine-treated groups. Our findings demonstrated the antidepressant-like effect of safflower hot water extract and its bioactive ingredient oleamide on mice, validated by a significantly shortened immobility time in TST and FST and an increase in the percentage of spontaneous alternation.

Sustainable regeneration of a honeycomb carbon aerogel used as a high-capacity adsorbent for Fluoxetine removal

Pharmaceuticals and personal care products (PPCPs) harm ecosystems and human health. The focus is now being put on regulating discharges at wastewater treatment plants (WWTPs). Stressful and lonely lifestyles, accentuated by the COVID-19 outbreak, have led to an increase in the consumption of antidepressants, particularly in the form of Fluoxetine (FLX). A highly effective process for the removal of PPCPs is of key importance for the economic feasibility of the process in the industry. Consequently, a high-capacity adsorption/regeneration system is crucial to solving this problem. In this study, the removal of FLX by an adsorption process and the subsequent in situ regeneration of the adsorbent was evaluated in successive cycles. NQ40 honeycomb 3D carbon aerogel was employed as a high-capacity adsorbent, obtaining uptakes of 125.24 mg/g. A detailed study of NQ40 and the mechanisms governing the adsorption process was conducted, with chemisorption and intra-particle diffusion playing the main role. A Fenton and a Fenton-like process with peroxymonosulfate (PMS) were evaluated for regeneration purposes, finding hydrogen peroxide to be more efficient in removing a high concentration of FLX. A regeneration capacity of 98.85% was achieved in the first NQ40 adsorption-regeneration cycle and 98.04% in the second one, without negatively affecting the structural characteristics of NQ40. Therefore, with a high porosity, low density, high biocompatibility, high chemical stability and 3D structural stability, this aerogel is at the forefront of novel high-capacity adsorbent materials for industrial-scale use in WWTPs.

Differential Molecular Responses of Zebrafish Larvae to Fluoxetine and Norfluoxetine

The occurrence of psychopharmaceuticals in aquatic ecosystems is a growing problem. Fluoxetine (FL) and its metabolite norfluoxetine (NF) are selective serotonin reuptake inhibitors. Although they may be potentially harmful to non-target species, available knowledge on the effects of NF is sparse, relative to FL. This study aimed at contributing to the body of knowledge about the modes-of-action (MoA) of these compounds and their underlying mechanisms eliciting hazardous effects during the early development of the teleost model zebrafish (Danio rerio). One hour post-fertilisation (hpf), embryos were exposed up to 80 hpf to these compounds at levels found in surface waters and higher (FL, 0.0015 and 0.05 µM;NF, 0.00006 and 0.0014 µM). Developmental anomalies were observed at 8, 32 and 80 hpf. Larvae were collected at 80 hpf to assess the expression of 34 genes related to FL and NF MoA and metabolism, using qPCR (quantitative reverse transcription PCR). Results showed that both compounds elicited an increased frequency of embryos exhibiting abnormal pigmentation, relative to controls. Gene expression alterations were more pronounced in FL- than in NF-exposed larvae. Cluster Analysis revealed two groups of genes discriminating between the drugs. for their marked opposing responses. Globally, downregulation of gene expression was typical of FL, whilst upregulation or no alteration was found for NF. These clusters identified were linked to the adrenergic pathway and to the retinoid and peroxisome proliferator-activated nuclear receptors. Overall, our data contradict the prevailing notion that NF is more toxic than FL and unveiled the expression levels of genes drd2b, 5-ht2c and abcc2 as possible markers of exposure to FL.

Antidepressant and Antipsychotic Drugs Reduce Viral Infection by SARS-CoV-2 and Fluoxetine Shows Antiviral Activity Against the Novel Variants in vitro.

Repurposing of currently available drugs is a valuable strategy to tackle the consequences of COVID-19. Recently, several studies have investigated the effect of psychoactive drugs on SARS-CoV-2 in cell culture models as well as in clinical practice. Our aim was to expand these studies and test some of these compounds against newly emerged variants. Several antidepressants and antipsychotic drugs with different primary mechanisms of action were tested in ACE2/TMPRSS2-expressing human embryonic kidney cells against the infection by SARS-CoV-2 spike protein-dependent pseudoviruses. Some of these compounds were also tested in human lung epithelial cell line, Calu-1, against the first wave (B.1) lineage of SARS-CoV-2 and the variants of concern, B.1.1.7, B.1.351, and B.1.617.2. Several clinically used antidepressants, including fluoxetine, citalopram, reboxetine, imipramine, as well as antipsychotic compounds chlorpromazine, flupenthixol, and pimozide inhibited the infection by pseudotyped viruses with minimal effects on cell viability. The antiviral action of several of these drugs was verified in Calu-1 cells against the B.1 lineage of SARS-CoV-2. By contrast, the anticonvulsant carbamazepine, and novel antidepressants ketamine, known as anesthetic at high doses, and its derivatives as well as MAO and phosphodiesterase inhibitors phenelzine and rolipram, respectively, showed no activity in the pseudovirus model. Furthermore, fluoxetine remained effective against pseudoviruses with common receptor binding domain mutations, N501Y, K417N, and E484K, as well as B.1.1.7 (alpha), B.1.351 (beta), and B.1.617.2 (delta) variants of SARS-CoV-2. Our study confirms previous data and extends information on the repurposing of these drugs to counteract SARS-CoV-2 infection including different variants of concern, however, extensive clinical studies must be performed to confirm our in vitro findings.

P.0404 Rapid antidepressant response to first-line selective serotonin reuptake inhibitors in post-COVID-19 depression

Introduction: Depression was reported in 30–40% of patients at one, three, and six months following COVID-19 [1]. The host immune response to SARS-CoV-2 infection and related severe systemic inflammation seems to be the main mechanism contributing to the development of post-COVID depression. Emerging literature suggests anti-inflammatory and antiviral properties of antidepressants in the treatment of SARS-CoV-2 infection [2]. We hypothesized that post-COVID depression, triggered by infection and sustained by systemic inflammation, could particularly benefit from antidepressants. Thus, the present study aims to investigate the efficacy of SSRI in treating post-COVID depression. Methods: We included 58 adults patients who showed depressive episodes in the six months following COVID-19. We excluded patients if they showed: other psychiatric comorbidities, ongoing treatment with antidepressants or neuroleptics, somatic disease and medications known to affect mood. The severity of depression was rated at baseline and after for four weeks from the start of the treatment on the Hamilton Depression Rating Scale (HDRS) and response was considered when the patients achieved a 50% HDRS reduction after treatment. Statistical analyses to compare group means and frequencies (Student's t-test, Pearson χ2 test) were performed. To investigate changes in HDRS scores over time, repeated measures ANOVAs (according to sex, mood disorder history, and antidepressant molecule) were performed. Results: We found that 53 (91%) patients showed a clinical response to antidepressant treatment. Age, sex, mood disorder history, and hospitalization for COVID did not affect the response rate. Patients were treated with sertraline (n=26), citalopram (n=18), paroxetine (n=8), fluvoxamine (n=4), and fluoxetine (n=2). From baseline to follow-up, patients showed a significant decrease over time of HDRS score (F=618.90, p<0.001), irrespectively of sex (0.28, p=0.599), mood disorder history (F=0.04, p=0.834), and drug used (F=1.47, p=0.239). Discussion: Common knowledge highlights that among antidepressant-treated patients, response rates are moderate (40–60%). On the contrary, we observed a rapid response to the first-line antidepressants in more than 90% of patients irrespectively of clinical variables, thus suggesting a higher antidepressant response rate in post-COVID depression. The pathophysiology of post-COVID neuropsychiatric sequelae mainly entails severe systemic inflammation and subsequent neuroinflammation. In this context, we have previously found that one and three months after COVID-19, the severity of depression was predicted by the baseline systemic immune-inflammation index (SII) [3,4]. Furthermore, we found a protective effect of the IL-1β and IL-6 receptor antagonist against post-COVID depression possibly associated with their effect in dampening SII [5]. Mounting evidence suggests that antidepressants may a) decrease markers of inflammation;b) may inhibit acid sphingomyelinase preventing the infection of epithelial cells with SARS-CoV-2;c) may prevent the COVID-19 related cytokine storm by stimulating the σ-1 receptor;d) may exert antiviral effects via lysosomotropic properties;e) may inhibit platelets activation [2]. In conclusion, we hypothesized that post-COVID depression could particularly benefit from antidepressants since this molecules have anti-inflammatory and antiviral properties, pass the BBB and accumulate in the CNS, thus preventing the neuro-inflammation triggered by SARS-CoV-2 and associated with post-COVID depression. No conflict of interest

P.0403 Disticnt effects of SSRIs therapy in patients with the first episode of major depressive disorder/generalized anxiety disorder after COVID-19 disease

Introduction: The World Health Organization postulated Coronavirus Disease 2019 (COVID-19) caused by SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus-2) is a pandemic situation in the whole world [1]. Although the main damaging of SARS-Cov-2 in the human organism is linked to its severe acute respiratory illness, a new coronavirus, SARS-CoV-2 implicates in the various central nervous system impairments and deteriorations [1,2]. The major clinical outcomes of COVID-19 in the brain are associated with its deleterious neurological and mental health actions [3]. Currently, we do not know exactly how actually SARS-CoV-2 might negatively alter the brain functions in humans. Today, there are limited findings concerning the studying of neuropsychiatric action for SARS-Cov-2 in humans after COVID-19 disease. The aim of the present study was to compare the efficacy of SSRIs (escitalopram, sertraline and fluoxetine) for 6 months therapy on the affective profile of man and women with the first Major Depressive Disorder (MDD) or Generalized Anxiety Disorder (GAD) cases following COVID-19 disease without any previous psychiatric diagnosis. Methods. For the assessment of affective profile in man and women (30-55 years) with the first MDD or GAD cases after COVID-19 disease, we used the different tests: Montgomery-Asberg Depression Rating Scale (MADRS) and anxiety scale (ShARS Scale). The hormonal and Vitamin D3 levels in the serum blood were measured by immune-enzyme analysis before and after SSRIs therapy. Results. After 6 months of SSRIs therapy, MADRS Scale showed a significant improvement of the depressive manifestations in both men and women with the first MDD case after COVID-19 (p%26lt;0,05). However, these patients of both gender demonstrated significantly high anxiety level by ShARS Scale. We found that SSRIs were able to reduce anxiety level only on 25%25 in man or on 35%25 in women with the first MDD case after COVID-19 before treatment (p%26lt;0,05). Interestingly, MADRS Scale showed a similar improvement of the depressive manifestations in both men and women with the first GAD case after COVID-19 treated with SSRIs for 6 months (p%26lt;0,05). Also, women with the first GAD case after COVID-19 treated with SSRIs had the parameters of their affective profile that were similarly to those of control group. The reduction of depressive symptoms in women with the first GAD case after COVID-19 treated with SSRIs was associated with restoration of cortisol concentrations in the serum blood compared to the initial levels. Conclusion: Thus, our pilot clinical study clearly demonstrated that SSRIs treatment have a beneficial effect on the depressive symptoms in patients of both gender with the first MDD or GAD cases after COVID-19. However, SSRIs therapy alone failed to produce the decrease of anxiety in the patients of both gender with the first MDD or GAD cases after COVID-19. In light of the demonstrated data, the importance of truly adequate treatment to the long-term neuropsychiatric outcomes of COVID-19 in patients of both gender, further randomized clinical trials involving new pharmacological therapies are needed in the future. No conflict of interest

Analysis of the impact of antidepressants and other medications on COVID-19 infection risk in a chronic psychiatric in-patient cohort.

BACKGROUND: During the first wave of the coronavirus disease 2019 (COVID-19) pandemic, patients with confirmed cases in New York State accounted for roughly 25% of total US cases, with psychiatric hospital in-patients at particularly high risk for COVID-19 infection. AIMS: The beneficial effects of mental health medications, such as selective serotonin reuptake inhibitors (SSRIs), on the severity of COVID-19 disease outcomes have been documented. Protective effects against infection have also been suggested for these medications. We therefore tested the hypothesis that medication use modifies the risk of COVID-19 infection in a long-stay, chronic in-patient psychiatry setting, where the potential for exposure was likely uniform across the facility, and where these medications were routinely prescribed. METHOD: This was a retrospective cohort study of an adult psychiatric facility operated by the New York State Office of Mental Health. Current medication information and COVID-19 status was collected from electronic medical records for 165 people who were in-patients during the period January to July 2020, and logistic regression was employed to model the main effects of medication use on COVID-19 infection. RESULTS: A significant protective association was observed between antidepressant use and COVID-19 infection (odds ratio (OR) = 0.33, 95% CI 0.15-0.70, adjusted P < 0.05). Analysis of individual antidepressant classes showed that SSRI, serotonin-norepinephrine reuptake inhibitor and the serotonin-2 antagonist reuptake inhibitor classes of antidepressants, drove this protective effect. Exploratory analyses of individual antidepressants demonstrated an association between lower risk of infection and fluoxetine use (P = 0.023), as well as trazodone use (P = 0.001). CONCLUSIONS: The novel finding of reduced COVID-19 infection risk for psychiatric in-patients taking antidepressants, suggests that antidepressants may be an important weapon in the continued fight against COVID-19 disease. This finding may become particularly salient for in-patient settings if vaccine-resistant strains of the virus appear.