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Introduction: Alzheimer pathology (AD) is characterized by the deposition of amyloid beta (Aß) and chronic neuroinflammation, with the NLRP3 inflammasome playing a significant role. This study demonstrated that the OCD drug fluvoxamine maleate (FXN) can potently ameliorate AD pathology in 5XFAD mice by promoting autophagy-mediated clearance of Aß and inhibiting the NLRP3 inflammasome. Methods: We used mice primary astrocytes to establish the mechanism of action of FXN against NLRP3 inflammasome by using various techniques like ELISA, Western blotting, confocal microscopy, Immunofluorescence, etc. The anti-AD activity of FXN was validated in transgenic 5XFAD mice following two months of treatment. This was followed by behavior analysis, examination of inflammatory and autophagy proteins and immunohistochemistry analysis for Aß load in the hippocampi. Results: Our data showed that FXN, at a low concentration of 78 nM, induces autophagy to inhibit NF-κB and the NLRP3 inflammasome, apart from directly inhibiting NLRP3 inflammasome in primary astrocytes. FXN activated the PRKAA2 pathway through CAMKK2 signaling, leading to autophagy induction. It inhibited the ATP-mediated NLRP3 inflammasome activation by promoting the autophagic degradation of NF-κB, resulting in the downregulation of pro-IL-1ß and NLRP3. The anti-NLRP3 inflammasome effect of FXN was reversed when autophagy was inhibited by either genetic knockdown of the PRKAA2 pathway or pharmacological inhibition with bafilomycin A1. Furthermore, FXN treatment led to improved AD pathology in 5XFAD mice, resulting in significant improvements in various behavioral parameters such as working memory and neuromuscular coordination, making their behavior more similar to that of wild-type animals. FXN improved behavior in 5XFAD mice by clearing the Aß deposits from the hippocampi and significantly reducing multiple inflammatory proteins, including NF-κB, GFAP, IBA1, IL-1ß, TNF-α, and IL-6, which are associated with NF-κB and NLRP3 inflammasome in the brain. Moreover, these changes were accompanied by increased expression of autophagic proteins. Discussion: Our data suggest that FXN ameliorates AD pathology, by simultaneously targeting two key pathological features: Aß deposits and neuroinflammation. As an already approved drug, FXN holds potential as a candidate for human studies against AD.

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Selective serotonin reuptake inhibitors (SSRIs) are typically prescribed for treating major depressive disorder (MDD) due to their high efficacy. These drugs function by inhibiting the reuptake of serotonin [also termed 5-hydroxytryptamine (5-HT)], which raises the levels of 5-HT in the synaptic cleft, leading to prolonged activation of postsynaptic 5-HT receptors. Despite the therapeutic benefits of SSRIs, this mechanism of action also disturbs the neuroendocrine response. Hypothalamic-pituitary-adrenal (HPA) axis activity is strongly linked to both MDD and the response to antidepressants, owing to the intricate interplay within the serotonergic system, which regulates feeding, water intake, sexual drive, reproduction and circadian rhythms. The aim of the present review was to provide up-to-date evidence for the proposed effects of SSRIs, such as fluoxetine, citalopram, escitalopram, paroxetine, sertraline and fluvoxamine, on the endocrine system. For this purpose, the literature related to the effects of SSRIs on the endocrine system was searched using the PubMed database. According to the available literature, SSRIs may have an adverse effect on glucose metabolism, sexual function and fertility by dysregulating the function of the HPA axis, pancreas and gonads. Therefore, considering that SSRIs are often prescribed for extended periods, it is crucial to monitor the patient closely with particular attention to the function of the endocrine system.

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INTRODUCTION: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a causative agent of coronavirus disease 2019 (COVID-19), a very contagious systemic disease dominantly affecting the respiratory tract. Recent findings oppose earlier suggestions that selective serotonin reuptake inhibitors (SSRIs) might be protective during acute SARS-CoV-2 infection, prompting the current study. METHODS: The institutional registry of a tertiary referral center was retrospectively evaluated for SSRI use and associated clinical outcomes among hospitalized COVID-19 patients with mostly severe and critical disease. RESULTS: Among 1,558 patients, there were 78 (5%) exposed to SSRI during hospitalization. SSRI users in comparison to non-users did not significantly differ in their demographic characteristics, comorbidity profile or the severity of COVID-19 symptoms and associated inflammatory response at admission. In multivariate analyses adjusted for clinically meaningful variables, SSRI use was significantly associated with higher risks of death, mechanical ventilation, intensive care unit treatment, and bacteremia, whereas no significant relationship with risks of venous, arterial thrombosis, and major bleeding was present. Patients with less severe initial COVID-19 presentation, lower inflammatory burden, higher platelet count, lower cumulative comorbidity burden, presence of hyperlipidemia, atrial fibrillation, chronic heart failure and nonexposed to acetylsalicylic-acid had higher mortality associated with SSRI use. CONCLUSIONS: Findings of the current study validate findings of higher mortality but also report higher tendency for respiratory deterioration, intensive care unit treatment, and bacteremia associated with SSRI use among hospitalized COVID-19 patients. These findings also suggest the potential contribution of cardiovascular comorbidities to detrimental clinical course of SSRI exposed patients.

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The RSCI and PubMed search databases have requested publications over the past 40 years on the search queries «fluvoxamine¼, «anxiety-depressive disorders¼, «anxiety¼, «depression¼, «comorbidity¼, devoted to the effectiveness of fluvoxamine in various variants of disorders of the anxiety-depressive spectrum, anxiety depressions. The data of the above studies indicate that fluvoxamine (Zovart San) in doses of 50-300 mg / day is a highly effective remedy for the treatment of not only anxiety depressions and genesis (psychogenic, organic, mixed, autochthonous-endogenous) and severity (up to psychotic), but also a wider range of anxiety-depressive disorders, including adaptation disorders, obsessive-compulsive disorder, somatized, dysmorphic, insomniac symptom complexes and eating disorders. A wide range of clinical effects of fluvoxamine is due to its main and additional mechanisms of action: blockade of serotonin reuptake, σ1-agonist activity and the effect on the metabolism of melatonin and neurosteroids catabolism.

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This case report examines the possible correlation between the clozapine/norclozapine ratio and the occurrence of constipation and paralytic ileus. We present the case of a 42-year-old patient diagnosed with schizoaffective disorder undergoing clozapine therapy. Despite intensive treatment with clozapine, haloperidol, valproic acid and biweekly electroconvulsive therapy sessions for over a year, florid psychotic symptoms and fluctuating mood swings persisted. Therefore, valproic acid was replaced by carbamazepine, a potent inducer of several CYP450-enzymes. To maintain clozapine plasma levels, fluvoxamine, a CYP1A2-inhibitor, was introduced at a dose of 25 mg before this switch. After addition of carbamazepine, there was a significant decline in clozapine levels, necessitating an increase in fluvoxamine dosage to 50 mg. Five weeks later the patient was admitted to a general hospital with a diagnosis of paralytic ileus. Treatment with enemas proved effective. Drug concentration analysis revealed a 2.5-fold increase in norclozapine levels in the weeks preceding hospital admission, resulting in an inverted clozapine/norclozapine ratio. Treatment with clozapine, carbamazepine and fluvoxamine was continued as the patient demonstrated clinical improvement on carbamazepine. Concurrently, an intensive laxative regimen was initiated. Two weeks later, the patient was readmitted to the general hospital due to suspected paralytic ileus and faecal vomiting, once again displaying an inverted clozapine/norclozapine ratio. We discuss potential mechanisms contributing to the occurrence of the paralytic ileus in this patient, including the antagonism of muscarinic M3 receptors by both clozapine and norclozapine, as well as the agonism of delta-opioid receptors by norclozapine. This case highlights the potential significance of both the clozapine/norclozapine ratio and absolute norclozapine levels as risk factors for constipation and paralytic ileus in patients on clozapine therapy.

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INTRODUCTION: Fluvoxamine is used in children and adolescents ('youths') for treating obsessive compulsive disorder (OCD) but also off-label for depressive and anxiety disorders. This study aimed to investigate the relationship between fluvoxamine dose and serum concentrations, independent correlates of fluvoxamine concentrations, and a preliminary therapeutic reference range (TRR) for youths with OCD and treatment response. METHODS: Multicenter naturalistic data of a therapeutic drug monitoring service, as well as prospective data of the 'TDM Vigil study' (EudraCT 2013-004881-33), were analyzed. Patient and treatment characteristics were assessed by standardized measures, including Clinical Global Impressions-Severity (CGI-S) and -Change (CGI-I), with CGI-I of much or very much improved defining treatment response and adverse drug reactions using the Udvalg for Kliniske Undersogelser (UKU) Side Effect Rating Scale. Multivariable regression analysis was used to evaluate the influence of sex, age, body weight, body mass index (BMI), and fluvoxamine dose on fluvoxamine serum concentrations. RESULTS: The study included 70 youths (age = 6.7-19.6 years, OCD = 78%, mean fluvoxamine dose = 140.4 (range = 25-300) mg/d). A weak positive correlation between daily dose and steady-state trough serum concentrations was found (rs = 0.34, p = 0.004), with dose variation explaining 16.2% of serum concentration variability. Multivariable correlates explaining 25.3% of the variance of fluvoxamine concentrations included higher fluvoxamine dose and lower BMI. Considering responders with OCD, the estimated TRR for youths was 55-371 ng/mL, exceeding the TRR for adults with depression of 60-230 ng/mL. DISCUSSION: These preliminary data contribute to the definition of a TRR in youth with OCD treated with fluvoxamine and identify higher BMI as a moderator of lower fluvoxamine concentrations.

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Fluvoxamine is a major antidepressant of the selective serotonin-reuptake inhibitor class, previously studied as a drug that improves cognitive memory by enhancing hippocampal cell division and proliferation. Valproic acid (VPA) is a commonly used antiepileptic drug and mood stabilizer that has negative effects on cognitive memory as it inhibits cellular division and proliferation in the hippocampus. This study assessed the protective effects of fluvoxamine treatment versus the memory impairment, decreased hippocampal cellular proliferation, and weight loss produced by VPA treatment. The cognitive memory of 40 male Sprague-Dawley rats was assessed by the novel object location (NOL) test. Immunostaining by Ki67 and glutathione peroxidase 1 (GPX-1) was performed to quantify the number of dividing cells in the subgranular zone (SGZ) of the dentate gyrus and to assess the antioxidant activity of different treatments, respectively. Results showed that the VPA group had fewer Ki67-positive cells than the control group (p < 0.001), indicating reduced hippocampal proliferation. In contrast, the VPA and fluvoxamine combination group showed increased proliferation (p < 0.001) compared to VPA alone. Notably, fluvoxamine treatment significantly differed in cell counts compared to other groups (p < 0.001). Fluvoxamine also attenuated the weight loss caused by VPA (p < 0.0001). Our data suggested that fluvoxamine therapy attenuated the VPA-induced decrease in SGZ cellular proliferation, memory, and weight in rats.

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SARS-CoV-2 infection can cause severe pneumonia, wherein exacerbated inflammation plays a major role. This is reminiscent of the process commonly termed cytokine storm, a condition dependent on a disproportionated production of cytokines. This state involves the activation of the innate immune response by viral patterns and coincides with the biosynthesis of the biomass required for viral replication, which may overwhelm the capacity of the endoplasmic reticulum and drive the unfolded protein response (UPR). The UPR is a signal transduction pathway composed of three branches that is initiated by a set of sensors: inositol-requiring protein 1 (IRE1), protein kinase RNA-like ER kinase (PERK), and activating transcription factor 6 (ATF6). These sensors control adaptive processes, including the transcriptional regulation of proinflammatory cytokines. Based on this background, the role of the UPR in SARS-CoV-2 replication and the ensuing inflammatory response was investigated using in vivo and in vitro models of infection. Mice and Syrian hamsters infected with SARS-CoV-2 showed a sole activation of the Ire1α-Xbp1 arm of the UPR associated with a robust production of proinflammatory cytokines. Human lung epithelial cells showed the dependence of viral replication on the expression of UPR-target proteins branching on the IRE1α-XBP1 arm and to a lower extent on the PERK route. Likewise, activation of the IRE1α-XBP1 branch by Spike (S) proteins from different variants of concern was a uniform finding. These results show that the IRE1α-XBP1 system enhances viral replication and cytokine expression and may represent a potential therapeutic target in SARS-CoV-2 severe pneumonia.

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The cutting-edge combination of fluvoxamine (FVM) and ivermectin (IVM) has been presented as a proposed dosage form for the treatment of COVID-19 infections in early diagnosed patients. The main objective of this work is to develop simple, sensitive, and efficient methods for the synchronous quantification of FVM and IVM without any prior separation. Four green UV-methods were employed for the synchronous quantification, namely: Fourier functions convolution of absorption spectra, FFAS, Fourier functions convolution of derivative spectra of absorption curves, FFDS, Fourier function convolution of ratio spectra of absorption curves, FFRS and the dual-wavelength method, DWM. FFRS and DWM approaches can be able to reconcile the two components' significantly interfering spectrum presented in this commixture. Good linearity was checked in the range of 5-40, and 2.5-25 µg/mL for the FVM, and IVM, respectively. All approaches developed have been recommended in compliance with ICH principles. Furthermore, the approaches' greenness was predestined by "National Environmental Method Index" (NEMI), "Analytical GREEnness metric (AGREE)", the "Analytical Eco-Scale", and the "Green Analytical Procedure Index" (GAPI). In addition, spider diagram was utilized for the assessment of the greenness index of the solvent used. Beside greenness, the sustainability of our methods was investigated using the HEXAGON tool. Continuing the constant pursuit of greenness, drug-drug interactions (DDIs) between FVM & IVM were predicted by insilico tools to ensure the safety of the suggested mixture as a preliminary step before invitro and in vivo studies. Because they were deemed sustainable, affordable, and successful, the suggested UV-methods may be used for routine quality control investigations of the indicated formulations FVM & IVM.

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Background: Repurposed drugs with host-directed antiviral and immunomodulatory properties have shown promise in the treatment of COVID-19, but few trials have studied combinations of these agents. The aim of this trial was to assess the effectiveness of affordable, widely available, repurposed drugs used in combination for treatment of COVID-19, which may be particularly relevant to low-resource countries. Methods: We conducted an open-label, randomized, outpatient, controlled trial in Thailand from October 1, 2021, to June 21, 2022, to assess whether early treatment within 48-h of symptoms onset with combinations of fluvoxamine, bromhexine, cyproheptadine, and niclosamide, given to adults with confirmed mild SARS-CoV-2 infection, can prevent 28-day clinical deterioration compared to standard care. Participants were randomly assigned to receive treatment with fluvoxamine alone, fluvoxamine + bromhexine, fluvoxamine + cyproheptadine, niclosamide + bromhexine, or standard care. The primary outcome measured was clinical deterioration within 9, 14, or 28 days using a 6-point ordinal scale. This trial is registered with ClinicalTrials.gov (NCT05087381). Findings: Among 1900 recruited, a total of 995 participants completed the trial. No participants had clinical deterioration by day 9, 14, or 28 days among those treated with fluvoxamine plus bromhexine (0%), fluvoxamine plus cyproheptadine (0%), or niclosamide plus bromhexine (0%). Nine participants (5.6%) in the fluvoxamine arm had clinical deterioration by day 28, requiring low-flow oxygen. In contrast, most standard care arm participants had clinical deterioration by 9, 14, and 28 days. By day 9, 32.7% (110) of patients in the standard care arm had been hospitalized without requiring supplemental oxygen but needing ongoing medical care. By day 28, this percentage increased to 37.5% (21). Additionally, 20.8% (70) of patients in the standard care arm required low-flow oxygen by day 9, and 12.5% (16) needed non-invasive or mechanical ventilation by day 28. All treated groups significantly differed from the standard care group by days 9, 14, and 28 (p < 0.0001). Also, by day 28, the three 2-drug treatments were significantly better than the fluvoxamine arm (p < 0.0001). No deaths occurred in any study group. Compared to standard care, participants treated with the combination agents had significantly decreased viral loads as early as day 3 of treatment (p < 0.0001), decreased levels of serum cytokines interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and interleukin-1 beta (IL-1ß) as early as day 5 of treatment, and interleukin-8 (IL-8) by day 7 of treatment (p < 0.0001) and lower incidence of post-acute sequelae of COVID-19 (PASC) symptoms (p < 0.0001). 23 serious adverse events occurred in the standard care arm, while only 1 serious adverse event was reported in the fluvoxamine arm, and zero serious adverse events occurred in the other arms. Interpretation: Early treatment with these combinations among outpatients diagnosed with COVID-19 was associated with lower likelihood of clinical deterioration, and with significant and rapid reduction in the viral load and serum cytokines, and with lower burden of PASC symptoms. When started very soon after symptom onset, these repurposed drugs have high potential to prevent clinical deterioration and death in vaccinated and unvaccinated COVID-19 patients. Funding: Ped Thai Su Phai (Thai Ducks Fighting Danger) social giver group.

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BACKGROUND: There is high inter-individual variability in clozapine metabolism due to genetic and non-genetic differences. Patient-specific factors such as smoking, inflammation indicated by elevated C-reactive protein (CRP), and certain concurrent medications have a significant influence on clozapine metabolism. AIM: To assess which patient-specific factors best explain variability in clozapine metabolism estimated by clozapine concentration to dose (C/D) ratios. METHODS: A retrospective cohort analysis using electronic medical data was conducted on 172 inpatients at the BC Psychosis Program. Patients with normal renal and liver function were included if they were on clozapine and had at least one steady-state plasma concentration. The degree of influence of each factor on the variability of clozapine metabolism in the entire cohort and subgroups stratified by fluvoxamine use was evaluated using multiple linear regression analysis of C/D ratios. RESULTS: Model fit testing showed that the entire cohort model accounts for 52.7% of C/D ratio variability, while the no fluvoxamine and fluvoxamine models accounted for 40.8% and 43.8%. In the entire cohort (n = 172), fluvoxamine use explained the highest variance, and C/D ratios were higher by 30.6% on average. The second strongest predictor was elevated CRP > 10 mg/L, and C/D ratios were higher by 22.9% on average. Subsequently, obesity, nonsmoker status, and female sex explained a significant but modest proportion of variance. Among participants on fluvoxamine (n = 58), only fluvoxamine dose was associated with an increase, and for every 25 mg increase in dose, C/D ratios increased by 5% on average. CONCLUSION: In a clinical population, this study replicated the relationship between reduced rate of clozapine metabolism and the use of fluvoxamine, elevated CRP, obesity, nonsmoking status, and female sex; and the magnitude of the effects were large enough to be clinically relevant.

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BACKGROUND: Fluvoxamine is one of the selective serotonin reuptake inhibitors (SSRIs) that are regarded as the first-line drugs to manage mental disorders. It has been also recognized with the potential to treat inflammatory diseases and viral infection. However, the effect of fluvoxamine on autoimmune diseases, particularly type 1 diabetes (T1D) and the related cellular and molecular mechanisms, are yet to be addressed. METHOD: Herein in this report, we treated NOD mice with fluvoxamine for 2 weeks starting from 10-week of age to dissect the impact of fluvoxamine on the prevention of type 1 diabetes. We compared the differences of immune cells between 12-week-old control and fluvoxamine-treated mice by flow cytometry analysis. To study the mechanism involved, we extensively examined the characteristics of CD4+ T cells with fluvoxamine stimulation using RNA-seq analysis, real-time PCR, Western blot, and seahorse assay. Furthermore, we investigated the relevance of our data to human autoimmune diabetes. RESULT: Fluvoxamine not only delayed T1D onset, but also decreased T1D incidence. Moreover, fluvoxamine-treated NOD mice showed significantly attenuated insulitis coupled with well-preserved ß cell function, and decreased Th1 and Th17 cells in the peripheral blood, pancreatic lymph nodes (PLNs), and spleen. Mechanistic studies revealed that fluvoxamine downregulated glycolytic process by inhibiting phosphatidylinositol 3-kinase (PI3K)-AKT signaling, by which it restrained effector T (Teff) cell differentiation and production of proinflammatory cytokines. CONCLUSION: Collectively, our study supports that fluvoxamine could be a viable therapeutic drug against autoimmunity in T1D setting.

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BACKGROUND: Antidepressant-induced paradoxical anxiety is a fairly common phenomenon seen in patients who are initiated on antidepressants. However, akathisia is a very uncommon manifestation of antidepressants. Much more rarely, antidepressants are also associated with the emergence of motor and vocal tics. This case adds to the growing literature of rare adverse events induced by antidepressants and aims to stimulate future research into the mechanism and risk factors of this phenomenon. CASE PRESENTATION: In this case report, we describe a patient with panic disorder and co-morbid Crohn's disease who developed worsening anxiety, akathisia and vocal tics upon initiation of fluvoxamine. This is the first case report to describe the emergence of both akathisia and vocal tics in the same patient following antidepressant initiation. After discontinuation of fluvoxamine, the patient's symptoms resolved. CONCLUSION: Antidepressant-induced akathisia and tics are often distressing both to the patient and their loved ones, and can be very puzzling to the clinician. It is important for clinicians to recognise that, although rare, antidepressants can adverse effects. When these symptoms arise, it should prompt immediate discontinuation of the offending antidepressant.

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Expansion of the GGGGCC-RNA repeat is a known cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), which currently have no cure. Recent studies have indicated the activation of Sigma-1 receptor plays an important role in providing neuroprotection, especially in ALS and Alzheimer's disease. Nevertheless, the mechanisms underlying Sigma-1R activation and its effect on (G4C2)n-RNA-induced cell death remain unclear. In this study, we demonstrated that fluvoxamine is a Sigma-1R agonist that can increase chaperone activity and stabilize the protein expression of Pom121 in (G4C2)31-RNA-expressing NSC34 cells, leading to increased colocalization at the nuclear envelope. Interestingly, fluvoxamine treatment increased Pom121 protein expression without affecting transcription. In C9orf72-ALS, the nuclear translocation of TFEB autophagy factor decreased owing to nucleocytoplasmic transport defects. Our results showed that pretreatment of NSC34 cells with fluvoxamine promoted the shuttling of TFEB into the nucleus and elevated the expression of LC3-II compared to the overexpression of (G4C2)31-RNA alone. Additionally, even when used alone, fluvoxamine increases Pom121 expression and TFEB translocation. To summarize, fluvoxamine may act as a promising repurposed medicine for patients with C9orf72-ALS, as it stabilizes the nucleoporin Pom121 and promotes the translocation of TFEB in (G4C2)31-RNA-expressing NSC34 cells.

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BackgroundFluvoxamine is increasingly used in the treatment for depressive disorder in adolescents. However， little research has been done on the effect of fluvoxamine on lipid metabolism， and the disordered lipid metabolism would cause severe harm to the health of patients and affect relevant prognosis. ObjectiveTo analyze the effect of fluvoxamine on lipid metabolism in adolescent patients with depressive disorder and to investigate the safety of fluvoxamine treatment. MethodsFrom June 2022 to June 2023， 60 adolescent patients with depressive disorder were involved， who met the diagnostic criteria of International Classification of Diseases， tenth edition （ICD-10） and received inpatient treatments in Shanxi Mental Health Center. These cases were randomly divided into study group （receiving fluvoxamine treatment） and control group （receiving sertraline treatment） with 30 cases in each group. The treatment period was 4 weeks. At baseline as well as 2 weeks and 4 weeks after treatment， both groups' indexes of fasting lipid metabolism were measured， including serum total cholesterol （TC）， triglycerides （TG）， high-density lipoprotein （HDL） and low-density lipoprotein （LDL）， and Hamilton Depression Scale-17 item （HAMD-17） was adopted. The levels of lipid metabolism indexes and HAMD-17 score were compared between the two groups at different follow-up time points. ResultsFor HAMD-17 score， the time effect was statistically significant （F=849.687， P<0.01）， while the inter-group effect and interaction effect was not statistically significant （F=0.033， 1.760， P>0.05）. For TC levels， the inter-group effect was not statistically significant （F=1.461， P=0.232）， but the time effect and interaction effect were statistically significant （F=13.129， 5.029， P<0.05 or 0.01）. The time effect and the inter-group effect of TG level were not statistically significant （F=0.825， 0.185， P>0.05）， but the interaction effect was statistically significant （F=7.577， P=0.004）. For HDL levels， the time effect， inter-group effect and interaction effect were not statistically significant （F=1.079， 0.160， 1.877， P>0.05）. For LDL levels， there was no statistical significance in the inter-group effect （F=0.019， P=0.891）， while statistical significance was observed in both time effect and interaction effect （F=6.721， 9.075， P<0.01）. ConclusionFluvoxamine and sertraline have curative effectiveness of same level on adolescent depression disorder， and short-term application of fluvoxamine has little effect on lipid metabolism indexes of patients. ［www.chictr.org.cn number： ChiCTR2300074129］

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In this study, fluvoxamine maleate sustained-release pellet system tablets were prepared and were used to evaluate their release behaviors in vitro. Fluvoxamine maleate pellets were prepared using centrifugal-spherization method and coated by fluidized bed as bottom-spray. The multi-unit sustained-release pellets and appropriate excipients for prescription volumes were mixed uniformly and then compressed to tablets. Screening and determining the optimal formulation of drug loaded pellets through L8 (24) Taguchi experiment. Using Minitab software to design a DOE experiment with 24 partial factors, including material temperature, fan speed, atomization pressure, and spray rate to optimize the bottom spray coating process. Taking monostearate glycerol ester with a particle size of 24-40 mesh as the main diluent for tableting to relieve the delamination phenomenon between pellets and excipients during tablet pressing and reduce mechanical damage to the coating film. By examining the powder fluidity indexes such as angle of repose, bulk density, tapped density, and Hausner ratio of mixed particles, it was found that the flowability and compressibility are good and suitable for direct compression. Evaluate the basic properties of the sustained-release tablets, investigate the in vitro release behavior and study the release mechanism. The results of in vitro release test showed that the self-made sustained-release tablets could disintegrate into independent pellet units in phosphate buffer at pH 6.8 and release slowly within 24 h, which conformed to the first-order drug release model. The fluvoxamine maleate sustained-release pellet system tablets meet the requirements of preparation design and has a great commercial prospect.

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This systematic review and meta-analysis of randomised controlled trials (RCTs) aimed to evaluate the efficacy, safety, and tolerability of fluvoxamine for the outpatient management of COVID-19. We conducted this review in accordance with the PRISMA 2020 guidelines. Literature searches were conducted in MEDLINE, EMBASE, International Pharmaceutical Abstracts, CINAHL, Web of Science, and CENTRAL up to 14 September 2023. Outcomes included incidence of hospitalisation, healthcare utilization (emergency room visits and/or hospitalisation), mortality, supplemental oxygen and mechanical ventilation requirements, serious adverse events (SAEs) and non-adherence. Fluvoxamine 100 mg twice a day was associated with reductions in the risk of hospitalisation (risk ratio [RR] 0.75, 95% confidence interval [CI] 0.58-0.97; I 2  = 0%) and reductions in the risk of healthcare utilization (RR 0.68, 95% CI 0.53-0.86; I 2  = 0%). While no increased SAEs were observed, fluvoxamine 100 mg twice a day was associated with higher treatment non-adherence compared to placebo (RR 1.61, 95% CI 1.22-2.14; I 2  = 53%). In subgroup analyses, fluvoxamine reduced healthcare utilization in outpatients with BMI ≥30 kg/m2 , but not in those with lower BMIs. While fluvoxamine offers potential benefits in reducing healthcare utilization, its efficacy may be most pronounced in high-risk patient populations. The observed non-adherence rates highlight the need for better patient education and counselling. Future investigations should reassess trial endpoints to include outcomes relating to post-COVID sequelaes. Registration: This review was prospectively registered on PROSPERO (CRD42023463829).

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OBJECTIVE: To identify the frequency of administration of fluvoxamine, to determine the main targets of the drug and the expediency of its use in depression of various genesis in children and adolescents. MATERIAL AND METHODS: To assess the frequency of prescribing fluvoxamine, 195 medical histories of patients who were inpatients in the children's department of the Mental Health Research Center in 2023 were analyzed. To assess the dynamics of depression during treatment with fluvoxamine, a clinical group was formed of 12 patients aged 10 to 15 years (age 13.1±3.6 years) who received fluvoxamine for the treatment of depression with comorbid obsessive-compulsive and anxiety-phobic disorders. Clinical and psychopathological, psychometric (Hamilton Depression Rating Scale - HDRS) and statistical research methods were used. RESULTS: In total, in 2023, fluvoxamine was received by 20% (n=37) of all inpatient patients of child age (from 7 to 16 years). All patients received combination therapy. The therapeutic targets were comorbid depressive, obsessive-compulsive and anxiety symptoms developing in the structure of nosologically heterogeneous states, with the dominance of schizophrenic spectrum disorders. Against the background of the use of the drug fluvoxamine for 4 weeks in the clinical group, there was a significant reduction in depressive symptoms on the HDRS. Adverse events during complex therapy were observed in 20% of patients, but were not severe, did not require discontinuation of therapy and were unreliably associated with the use of fluvoxamine. CONCLUSION: The use of the fluvoxamine provides reduction of depressive symptoms within the framework of various nosologies, and is characterized by sufficient safety. The variety of therapeutic targets of the fluvoxamine, including antidepressant, anti-anxiety, cognitive effects, is certainly a significant advantage of the studied fluvoxamine for use in childhood.

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BACKGROUND: Fluvoxamine (FVX) has been proposed as a potential treatment for severe COVID-19 by the σ-1 receptor agonist, which can reduce cytokine production. However, the efficacy of FVX remains controversial. METHODS: A historical retrospective cohort study was conducted in mild to moderate COVID-19 patients, 2:1 ratio of standard of care (SOC) and FVX treatments to assess the effectiveness of FVX in preventing deterioration by the fifth day of treatment. RESULTS: Of 752 eligible patients, 234 received FVX while 518 received SOC, and there was no significant difference in the effectiveness of FVX and SOC in preventing clinical deterioration. On the fifth day after treatment, 86.1 % of patients in the FVX-treated group did not experience clinical deterioration compared to 78.7 % in the SOC group. Notably, the FVX group had higher rates of pneumonia development and hospitalization, requiring more oxygen supplementation while showing less reduction in viral shedding than the SOC group. However, no difference in mechanical ventilation use, ICU admission, and survival was observed. CONCLUSION: Fluvoxamine treatment is failed to demonstrate effectiveness in preventing deterioration in mild to moderate COVID-19 and may lead to a higher incidence of pneumonia, hospitalization, and oxygen supplementation, necessitating careful consideration before prescribing the drug for COVID-19.

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Depression is the major mental illness which causes along with loss of interest in daily life, a feeling of hopelessness, appetite or weight changes, anger and irritability. Due to the hepatic first-pass metabolism, the absolute bioavailability of fluvoxamine (FVM) after oral administration is about 50%. By avoiding the pre-systemic metabolism, nasal delivery would boost bioavailability of FVM. Additionally, the absorption is anticipated to occur more quickly than it would via the oral route because of the existence of microvilli and high vasculature. A nonionic surfactant, cholesterol and an arachidonic acid-carboxymethyl chitosan (AA-CMCS) conjugate were used to develop FVM-loaded novasomes. To investigate the effects of surfactant concentration, AA-CMCS conjugate concentration and stirring speed on the novasomes' characteristics, a Box-Behnken design was used. The dependent variables chosen were zeta potential, polydispersity index and particle size. The AA-CMCS conjugate was confirmed by 1H-NMR and FTIR. Using Design Expert software (version 7; Stat-Ease Inc., Minneapolis, MN, USA), novasomes were further optimized. The chosen optimal formulation (NAC8) was made up of AA-CMCS conjugate, Span 60 and cholesterol. Particle size, zeta potential and PDI values for NAC8 formulation were 101 nm, -35 mV and 0.263, respectively. The NAC8 formulation's DSC and TGA analysis demonstrated that the medication had been uniformly and amorphously distributed throughout the novasomes. The NAC8 formulation showed 99% and 90% FVM release and permeation, respectively, and the novasome adherence time was 24 h. An improved antidepressant effect along with five-fold increase in bioavailability of FVM was observed after trans-nasal administration of NAC8 formulation compared to the reference commercially available Flumin® tablets. FVM-loaded novasomes administered via the nasal route may therefore constitute an advancement in the management of depression.