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Scoping Review Study Protocol

Selective serotonin reuptake inhibitors (SSRIs) have anti‐inflammatory properties that may have clinical utility in treating severe pulmonary manifestations of COVID‐19. SSRIs exert anti‐inflammatory effects at three mechanistic levels: (a) inhibition of proinflammatory transcription factor activity, including NF‐κB and STAT3; (b) downregulation of lung tissue damage and proinflammatory cell recruitment via inhibition of cytokines, including IL‐6, IL‐8, TNF‐α, and IL‐1β; and (c) direct suppression inflammatory cells, including T cells, macrophages, and platelets. These pathways are implicated in the pathogenesis of COVID‐19. In this review, we will compare the pathogenesis of lung inflammation in pulmonary diseases including COVID‐19, ARDS, and chronic obstructive pulmonary disease (COPD), describe the anti‐inflammatory properties of SSRIs, and discuss the applications of SSRIS in treating COVID‐19‐associated inflammatory lung disease., Selective serotonin reuptake inhibitors (SSRIs) have anti‐inflammatory effects on transcription factor activity, cytokine expression profiles, and suppression of innate and adaptive immune cells. These anti‐inflammatory properties may be useful in treating pulmonary inflammation, especially in the case of COVID‐19.

Contrary to the common belief that antidepressant-induced sexual dysfunction resolves upon discontinuation of the medication, Csoka and Shipko (2006) found that the symptoms can persist in a small proportion of patients after discontinuation - a syndrome they called "Post-SSRI Sexual Dysfunction" (PSSD). While the prevalence of sexual side effects during antidepressant treatment ranges from 36% to 98%, there is still no data on the prevalence of PSSD (Bahrick, 2006). PSSD differs from conventional sexual side effects in particular by symptoms such as genital numbness and the lack of euphoria after an orgasm. In addition, patients who are suffering from PSSD also describe emotional and cognitive symptoms that they attribute to taking or stopping the antidepressant (Bala, Nguyen & Hellstrom, 2018). Bahrick (2008) emphasizes that there is currently no optimal diagnostic tool for PSSD. This makes it difficult for patients and treatment providers to make a reliable diagnosis, which in turn can have a negative impact on treatment. Since women are often not sufficiently included in research due to their hormonal fluctuations, a separate consideration of the sexes is necessary in this topic area too - because sexual interest is expressed differently in each cycle phase (Friedrich, Ahrendt, Halstrick, Foth & Probst, 2015). A total of 2 groups are examined in the study. There is one experimental group (PSSD) and one healthy control group. The experimental group consists of female subjects who show PSSD symptoms and have taken SSRIs or SNRIs in the past. The primary aim of the study is to determine if there is a relationship between the menstrual cycle and PSSD symptoms.

Purpose The purpose of this study was to assess the possible relation between use of antidepressant (AD) drugs, that is, tricyclic ADs, selective serotonin reuptake inhibitors (SSRIs), and atypical ADs (AAs), and the risk of hospitalization for cardiovascular (CV) events among older patients with previous CV diseases. Methods A nested case-control study was carried out among patients aged 65 years and older from 5 Italian health care territorial units who were discharged for CV disease during 2008 to 2010. The cohort was composed by 344,747 individuals, and of these, 97,739 (28%) experienced hospital admission for CV events (myocardial infarction, arrhythmia, stroke, heart failure) during follow-up (until 2014) and were included as cases. Up to 5 controls were randomly selected and matched to each. A conditional logistic regression was fitted to estimate the risk of CV events associated with ADs past or current use. A within-patient comparison was performed by the case-crossover design to account the effect of depression. Findings Current users of SSRIs and AAs were at increased risk of CV events with odds ratios of 1.25 (95% confidence interval, 1.21-1.29) and 1.31 (1.25-1.37), respectively. An increased risk of arrhythmia and stroke was associated with current use of SSRIs and AAs, whereas an increased risk of heart failure was detected with current use of any ADs. The results were confirmed by the case-crossover approach. Implications Evidence that AD use is associated with an increased risk of CV events in accordance with specific mechanisms of action among older people with CV disease was added by this study.

Background: Selective serotonin reuptake inhibitors (SSRIs) use may be associated with development of subdural hematoma (SDH). Objectives: To estimate SDH risk associated with antidepressant use, including when combined with antithrombotics, or nonsteroidal anti-inflammatory drugs (NSAIDs). Patients/Methods: We performed this case-control study based on Danish registries. We included 10 885 incident cases of SDH and 435 379 matched general population controls. We calculated odds ratios (95% confidence interval) adjusted for comorbidity, co-medication, education level, and income (aOR). Results: We found that current use of SSRIs (aOR1.32 [1.25-1.38]) and non-SSRIs (aOR 1.19 [1.13-1.26]) was associated with a higher SDH risk, compared with non-use of antidepressants. Risks were higher with short duration of current use (eg, 3 years of current use: 1.04 [0.93-1.17] for SSRI and 1.12 [0.98-1.28] for non-SSRIs). Combined use of antidepressants with either antithrombotics or NSAIDs yielded similar ORs to those observed for single use of antithrombotics or NSAIDs. Stronger associations were observed for antidepressants combined with both vitamin K antagonists (VKAs) and NSAIDs (SSRI, VKA, & NSAID: aOR 5.51 [2.70-11-22]; non-SSRI, VKA, & NSAID: 6.81 [2.37-19-60]). Conclusions: Antidepressant use was associated with higher risk of SDH that seemed largely restricted to first year of treatment. In absolute terms this risk is judged to be small, given the low SDH incidence rate. With one possible exception (triple use of antidepressants, NSAIDs, and VKAs), risk estimates of SDH for combined regimens of antidepressants with antithrombotics or NSAIDs provided little evidence of interactions.

Studies on psychotropic medications decrease, discontinuation, or switch have uncovered withdrawal syndromes. The present overview aimed at analyzing the literature to illustrate withdrawal after decrease, discontinuation, or switch of psychotropic medications based on the drug class (i.e., benzodiazepines, nonbenzodiazepine benzodiazepine receptor agonists, antidepressants, ketamine, antipsychotics, lithium, mood stabilizers) according to the diagnostic criteria of Chouinard and Chouinard [Psychother Psychosom. 2015;84(2):63–71], which encompass new withdrawal symptoms, rebound symptoms, and persistent post-withdrawal disorders. All these drugs may induce withdrawal syndromes and rebound upon discontinuation, even with slow tapering. However, only selective serotonin reuptake inhibitors, serotonin noradrenaline reuptake inhibitors, and antipsychotics were consistently also associated with persistent post-withdrawal disorders and potential high severity of symptoms, including alterations of clinical course, whereas the distress associated with benzodiazepines discontinuation appears to be short-lived. As a result, the common belief that benzodiazepines should be substituted by medications that cause less dependence such as antidepressants and antipsychotics runs counter the available literature. Ketamine, and probably its derivatives, may be classified as at high risk for dependence and addiction. Because of the lag phase that has taken place between the introduction of a drug into the market and the description of withdrawal symptoms, caution is needed with the use of newer antidepressants and antipsychotics. Within medication classes, alprazolam, lorazepam, triazolam, paroxetine, venlafaxine, fluphenazine, perphenazine, clozapine, and quetiapine are more likely to induce withdrawal. The likelihood of withdrawal manifestations that may be severe and persistent should thus be taken into account in clinical practice and also in children and adolescents.

Classification of hypochondriasis as an obsessive-compulsive and related disorder in the International Classification of Diseases 11th Revision (ICD-11) has generated new heuristics for treatment of this common, chronic and disabling disorder. Standard treatment involves cognitive behaviour therapy (CBT) or selective serotonin reuptake inhibitors (SSRIs), but no meta-analysis has so far considered hypochondriasis as a structured diagnosis or assessed the role of medication. A clearer understanding of the relative effectiveness of these interventions and identification of clinically relevant factors moderating the treatment response is needed for clinical guideline development.The current systematic review and meta-analysis of interventions for hypochondriasis was preregistered on PROSPERO (CRD42020185768) and follows PRISMA guidelines. We searched MEDLINE, PsycINFO, and Cochrane Library databases until July 2021 for randomized controlled trials (RCTs) of interventions for patients diagnosed with hypochondriasis (or historical diagnostic equivalents). We assessed aspects of study quality using: the CONSORT Checklist for evaluation of RCTs, the Cochrane Risk of Bias 2 tool, researcher allegiance and treatment fidelity. The primary outcome was improvement in hypochondriasis symptoms, comparing intervention and control groups at trial endpoint. Moderator variables were assessed using subgroup and meta-regression analyses.Searches identified 13 randomised controlled trials (RCTs) (N = 1405); 12 included CBT (N = 1212) and three included SSRI (N = 193) arms as the experimental intervention. Random effects meta-analysis yielded a moderate-to-large effect size for CBT versus all controls (g = -0.70 [95% CI -0.99 to -0.41], k = 18, ICBT and SSRIs are effective in the acute treatment of hypochondriasis, with some indication that intervention at a younger age produces better outcomes for CBT. In the case of CBT, effect sizes appear to have been significantly inflated by the use of wait list controls, and researcher allegiance bias. We recommend that a definitive, adequately controlled trial, designed with respect to the methodological issues raised in this meta-analysis, is needed to determine the magnitude effects for CBT and SSRIs with confidence and the long-term effect of treatments, to inform mental health service provision for this overlooked patient group.

Einf��hrung Die Thrombolysetherapie ist eine etablierte Behandlung des isch��mischen Schlaganfalls. Das Auftreten einer symptomatischen intrazerebralen Blutung (sICB) ist eine klinisch relevante Komplikation. Bereits vor unserer Analyse war bekannt, dass Selektive Serotonin-Wiederaufnahmehemmer (SSRI) einen Einfluss auf die Thrombozytenaggregation haben. Die Studienlage bez��glich des Einflusses von SSRI auf eine Thrombolyse-assoziierte intrazerebrale Blutung war bis zu dem Zeitpunkt nicht eindeutig. In dieser Arbeit wird der Einfluss von einer Komedikation von SSRI mit Thrombozytenaggregationshemmer (TAH) und oralen Antikoagulantien (OAK) auf das Risiko einer sICB, das funktionelle Outcome und die Mortalit��t untersucht. Methoden Zwischen Januar 2005 und Dezember 2015 wurden 1282 Patienten (mittleres Alter 74,0 Jahre, 49% weiblich) mit einem isch��mischen Schlaganfall mit Thrombolysetherapie in der Charit��-Universit��tsmedizin Berlin, Campus Benjamin Franklin in einem prospektiv angelegten Thrombolyseregister eingeschlossen.Die Daten zur SSRI-Einnahme wurden retrospektiv basierend auf Aktenlage erg��nzt. Zur Beurteilung der Sicherheit der Thrombolysetherapie unter SSRI, wurden die Patienten bez��glich folgender Endpunkte mittels bin��r logistischer Regressionsanalyse verglichen: ��� Auftreten einer sICB gem���� Kriterien der SITS-MOST ��� Gutes Outcome nach drei Monaten (modified Rankin Skala (mRS) 0-2) ��� Tod innerhalb von drei Monaten (mRS 6) Ergebnisse Insgesamt bestand bei 3,1 % (n=40) der 1282 analysierten Patienten eine SSRI- Vormedikation. Eine sICB nach SITS-MOST lag bei 3,5 % (n=45) und ein gutes Drei- Monats-Outcome bei 49,01 % (n=629) vor. Eine sICB trat unter vorbestehender SSRI- Therapie nicht statistisch signifikant h��ufiger auf (3,4 % in der Kontroll- versus. 7,5 % in der SSRI-Gruppe, unadjustierte OR 2,32 (95 % CI 0,69-7,82), adjustierte OR 1,97 (95 % CI 0,57-6,86)). Es gab keine signifikante Erh��hung der Blutungswahrscheinlichkeit unter einer Komedikation mit SSRI und TAH (7,4 %, unadjustierte OR 2,94 (95 % CI 0,65-13,36)). Aufgrund der niedrigen Fallzahl konnte keine Aussage bez��glich der Blutungswahrscheinlichkeit unter SSRI- und OAK- Komedikation getroffen werden. Eine SSRI-Vormedikation war negativ mit dem Auftreten eines guten Outcomes assoziiert (49,9 % in der Kontroll- versus. 22,5 % in der SSRI-Gruppe, unadjustierte OR 0,29 (95 % CI 0,14-0,62), adjustierte OR 0,34 (95 % CI 0,13-0,87)). Die Mortalit��t nach drei Monaten war bei Patienten mit SSRI-Vorbehandlung nicht statistisch signifikant ver��ndert (17,5% in der Kontroll- versus 37,5 % in der SSRI-Gruppe, unadjustierte OR 2,83 (1,47-5,45), adjustierte 2,36 (95 % CI 0,98-5,70)). Schlussfolgerung In dieser retrospektiven, monozentrischen Auswertung war eine vorbestehende SSRI- Behandlung bei Patienten mit einem isch��mischen Schlaganfall und Thrombolysetherapie selten. Es ergab sich kein Hinweis auf eine relevante Risikoerh��hung f��r eine sICB unter einer SSRI-Vormedikation. Allerdings scheinen Patienten mit einer SSRI-Vormedikation h��ufiger ein schlechtes Outcome nach einem isch��mischen Schlaganfall mit Thrombolyse zu haben. Daher sollten diese Patienten eine m��glichst intensive und bedarfsgerechte Fr��hrehabilitation erhalten., Introduction Thrombolytic therapy is an established treatment for ischemic stroke. The occurrence of symptomatic intracerebral hemorrhage (sICB) is a clinically relevant complication. Even before our analysis, it was known that selective serotonin reuptake inhibitors (SSRI) have an influence on platelet aggregation. The study situation regarding the influence of SSRIs on thrombolysis-associated intracerebral hemorrhage was inconclusive at that time. In this work, the influence of a comedication with SSRIs and antiplatelet drugs (TAH) or oral anticoagulants (OAK) on the risk of sICB, functional outcome, and mortality is investigated. Methods Between January 2005 and December 2015, 1282 patients (mean age 74.0 years, 49 % female) with ischemic stroke receiving thrombolytic therapy were included in a prospectively designed thrombolysis registry at Charit��-Universit��tsmedizin Berlin, Campus Benjamin Franklin. Data on the use of SSRIs were added retrospectively based patient files. To assess the safety of thrombolytic therapy with SSRIs, patients were compared with respect to the following end points using binary logistic regression analysis: ��� Occurrence of sICB according to SITS-MOST criteria ��� Good outcome at three months (modified Rankin Scale (mRS) 0-2). ��� Death within three months (mRS 6) Results Among 1282 patients SSRI premedication was present in 3.1 % (n=40). A sICB after SITS-MOST occurred in 3.5 % (n=45) and a good three-month outcome in 49.01 % (n=629). A sICB did not occur statistically significantly more frequently with pre-existing SSRI therapy (3.4 % in the control versus 7.5 % in the SSRI group, unadjusted OR 2.32 (95% CI 0.69-7.82), adjusted OR 1.97 (95 % CI 0.57-6.86)). There was no significant increase in bleeding risk under comedication with SSRI and TAH (7.4 %, unadjusted OR 2.94 (95 % CI 0.65-13.36)). Due to the low number of cases, no conclusion could be drawn regarding SSRI and OAK comedication. SSRI premedication was negatively associated with the occurrence of a good outcome (49.9 % in the control versus 22.5 % in the SSRI group, unadjusted OR 0.29 (95 % CI 0.14-0.62), adjusted OR 0.34 (95 % CI 0.13-0.87)). Mortality at three months was not statistically significantly different in patients with SSRI pretreatment (17.5 % in the control versus 37.5 % in the SSRI group, unadjusted OR 2.83 (1.47-5.45), adjusted 2.36 (95 % CI 0.98-5.70)). Conclusion In this retrospective, monocentric evaluation, preexisting SSRI treatment was rare in patients with ischemic stroke and thrombolytic therapy. There was no evidence of a relevant increase in risk for sICB while receiving SSRI premedication. However, patients with SSRI premedication seem to have a poor outcome after ischemic stroke with thrombolysis more frequently. Therefore, these patients should receive the most intensive and individualized early rehabilitation as possible.

Autism spectrum disorder (ASD) affects reciprocal social interaction and produces abnormal repetitive, restrictive behaviors and interests. The diverse causes of ASD are divided into genetic alterations and environmental risks. The prevalence of ASD has been rising for several decades, which might be related to environmental risks as it is difficult to consider that the prevalence of genetic disorders related to ASD would increase suddenly. The latter includes (1) exposure to medications, such as valproic acid (VPA) and selective serotonin reuptake inhibitors (SSRIs) (2), maternal complications during pregnancy, including infection and hypertensive disorders of pregnancy, and (3) high parental age. Epidemiological studies have indicated a pathogenetic role of prenatal exposure to VPA and maternal inflammation in the development of ASD. VPA is considered to exert its deleterious effects on the fetal brain through several distinct mechanisms, such as alterations of γ-aminobutyric acid signaling, the inhibition of histone deacetylase, the disruption of folic acid metabolism, and the activation of mammalian target of rapamycin. Maternal inflammation that is caused by different stimuli converges on a higher load of proinflammatory cytokines in the fetal brain. Rodent models of maternal exposure to SSRIs generate ASD-like behavior in offspring, but clinical correlations with these preclinical findings are inconclusive. Hypertensive disorders of pregnancy and advanced parental age increase the risk of ASD in humans, but the mechanisms have been poorly investigated in animal models. Evidence of the mechanisms by which environmental factors are related to ASD is discussed, which may contribute to the development of preventive and therapeutic interventions for ASD.

Graphical abstract, Highlights • Drug-induced valvular heart disease (DI-VHD) is reminiscent of carcinoid heart disease. • DI-VHD is mediated through 5-hydroxytryptamine 2β receptor signaling pathways. • Serotonergic agents interacting with this 2β receptor may cause carcinoid-like VHD. • DI-VHD must be considered in patients with no reasons for showing VHD and using SSRI. • Echocardiographic surveillance is warranted in patients on serotonergic drugs, including SSRI.

Background Depression is a leading cause of psychiatric morbidity in the modern world, and the introduction of selective serotonin reuptake inhibitors (SSRIs) is a revolution in the treatment of depression. Vilazodone, a novel SSRI and 5-HT1A partial agonist, received FDA approval in 2011 to treat the major depressive disorder (MDD) in adults. This study conducted in India aimed to evaluate the efficacy and safety of vilazodone when compared to escitalopram or placebo in patients with MDD. Methods This was a prospective, multicentre, randomized, comparative study of 375 participants over eight weeks of treatment with either vilazodone (10-40mg/day) or escitalopram (10-40 mg/day) or placebo in adult patients with MDD. Primary efficacy was assessed using the Hamilton Rating Scale for Depression (HAM-D-17); secondary efficacy was assessed using the Montgomery-Asberg Depression Rating Scale (MADRS) score and Hamilton Anxiety Scale (HAM-A) score. Safety parameters included adverse events (AEs), clinical laboratory results, vital signs, electrocardiogram ( ECG), and Columbia-Suicide Severity Rating Scale (C-SSRS). Results Mean change in the HAM-D-17 total score from baseline to week 8 for vilazodone, escitalopram, and placebo-treated patients in intent-to-treat (ITT) population was: -18.9 (± 7.49), -17.8 (± 6.06), and -7.4 (± 6.32); in ITT population (with Last Observation Carried Forward( LOCF) imputation) was: -17.9 (± 7.71), -17.4 (± 6.19), and -6.4 (± 6.84), and in per-protocol (PP) population was: -19.1 (± 7.20), -17.8 (± 6.08), and -7.7 (± 6.29), respectively. The upper limit of 95% CI (0.56 (ITT); 0.90 (ITT with LOCF Imputation); 0.23 (PP)) of difference in HAM-D-17 between vilazodone 40mg and escitalopram 40mg, which is lower than the defined non-inferiority margin (3.56), proving non-inferiority. The difference between vilazodone 40mg, escitalopram 40mg, and the placebo was statistically significant (p

Learning-induced neuroplastic changes, further modulated by content and setting, are mirrored in brain functional connectivity (FC). In animal models, selective serotonin reuptake inhibitors (SSRIs) have been shown to facilitate neuroplasticity. This is especially prominent during emotional relearning, such as fear extinction, which may translate to clinical improvements in patients. To investigate a comparable modulation of neuroplasticity in humans, 99 healthy subjects underwent three weeks of emotional (matching faces) or non-emotional learning (matching Chinese characters to unrelated German nouns). Shuffled pairings of the original content were subsequently relearned for the same time. During relearning, subjects received either a daily dose of the SSRI escitalopram or placebo. Resting-state functional magnetic resonance imaging was performed before and after the (re-)learning phases. FC changes in a network comprising Broca's area, the medial prefrontal cortex, the right inferior temporal and left lingual gyrus were modulated by escitalopram intake. More specifically, it increased the bidirectional connectivity between medial prefrontal cortex and lingual gyrus for non-emotional and the connectivity from medial prefrontal cortex to Broca's area for emotional relearning. The context dependence of these effects together with behavioral correlations supports the assumption that SSRIs in clinical practice improve neuroplasticity rather than psychiatric symptoms per se. Beyond expanding the complexities of learning, these findings emphasize the influence of external factors on human neuroplasticity.

Generalized anxiety disorder (GAD) sometimes exists in the background of social withdrawal and school refusal. Although clinical evidence suggests that selective serotonin reuptake inhibitors (SSRIs) are an effective treatment for GAD, they are not officially approved for GAD in Japan. In addition, it has been established that the use of SSRIs increases the risk for suicide and activation syndrome among young individuals. As such, there is currently little domestic clinical experience in prescribing SSRIs to young patients with GAD. The authors report two cases involving 10-year-old patients with GAD who were treated successfully with escitalopram and experienced subsequent improvement in social withdrawal and school refusal. One patient had autistic spectrum disorder and exhibited self-harm associated with anxiety symptoms, requiring careful use of SSRIs under hospitalization. The other patient was treated at an outpatient clinic without any side effects. In each case, improvement of anxiety symptoms with the use of SSRIs facilitated the introduction of psychoeducation and psychotherapy. It is important to accurately diagnose GAD, which may exist in the background of patients exhibiting social withdrawal and school refusal, and to treat the disorder appropriately. J. Med. Invest. 67 : 355-357, August, 2020.

Pharmaceuticals are ubiquitous in aquatic environments, yet little is known regarding their impacts on ecological processes. Selective serotonin reuptake inhibitors (SSRIs) are frequently prescribed human antidepressants and have been shown to alter crayfish behavior. These behavioral alterations are particularly relevant as crayfish play a central role in freshwater ecosystems and often reach high biomass in anthropogenically influenced environments commonly exposed to pharmaceutical contamination. Using a 14‐d artificial stream experiment, we exposed spinycheek crayfish (Faxonius limosus) to citalopram, a common SSRI, at an environmentally realistic concentration (0.5 µg/L). We used a Y‐shaped flume to quantify the effects of SSRI exposure on crayfish behavior and food/conspecific preference. We also tested the interacting effects of citalopram and crayfish on habitat‐specific and whole‐stream ecosystem functions and biomass. Crayfish exposed to SSRIs exhibited increased boldness (time to emerge from shelters; P

Primary blast injury can result in depression-like behavior in the long-term. However, the effects of the selective serotonin reuptake inhibitor (SSRI) on the depression induced by mild blast traumatic brain injury (bTBI) in the long-term remain unclear. We generated a mouse model of mild bTBI using laser-induced shock wave (LISW) and administered an SSRI to mice by oral gavage for 14 days after LISW exposure. This study aimed to investigate the mechanisms of SSRI-mediated alleviation of depression-like behavior induced by mild bTBI. Animals were divided into three groups: sham, LISW-Vehicle, and LISW-SSRI. LISW was applied to the head of anesthetized mice at 0.5 J/cm2. Twenty-eight days after the LISW, mice in the LISW-SSRI group exhibited reduced depression-like behavior, a significant increase in the number of cells co-stained for 5-bromo-2'-deoxyuridine (Brd-U) and doublecortin (DCX) in the dentate gyrus (DG) as well as increased brain-derived neurotrophic factor (BDNF) and serotonin levels in the hippocampus compared to the sham and LISW-Vehicle groups. Additionally, levels of phosphorylated cAMP response element binding protein (pCREB) in the DG were significantly decreased in the LISW-Vehicle group compared to that in the sham group. Importantly, pCREB levels were not significantly different between LISW-SSRI and sham groups suggesting that SSRI treatment may limit the downregulation of pCREB induced by mild bTBI. In conclusion, recovery from depression-like behavior after mild bTBI may be mediated by hippocampal neurogenesis induced by increased BDNF and serotonin levels as well as the inhibition of pCREB downregulation in the hippocampus.

Флувоксамин является одним из старейших селективных ингибиторов обратного захвата серотонина, до сих пор использующихся в клинической практике. В последние годы в ряде исследований продемонстрирована его эффективность при COVID-19. В статье приводятся результаты клинических исследований флувоксамина при COVID-19, а также рассматриваются механизмы, лежащие в основе противовоспалительных, антикоагулянтных и противовирусных свойств препарата., Fluvoxamine is one of the oldest selective serotonin reuptake inhibitors that is still used in clinical practice. Over the last few years, a number of studies have demonstrated its efficacy in COVID-19. The paper presents findings from clinical trials involving fluvoxamine in COVID-19. The mechanisms underlying anti-inflammatory, anticoagulant, and antiviral properties of this drug are covered in detail.

Objective: Since several recent meta-analyses report a dose-response relationship for the antidepressant effect of the selective serotonin reuptake inhibitors (SSRIs), we investigated how these drugs are dosed in clinical practice. Methods: Through linkage of nation- or region-wide registers, we describe SSRI doses in 50,365 individuals residing in Region Västra Götaland, Sweden, with an incident diagnosis of depression and initiating SSRI treatment between 2007 and 2016. The primary question was to elucidate to what extent these individuals had been prescribed a daily dose that according to recent meta-analyses is required to elicit the maximum antidepressant effect, that is >20 mg citalopram, >10 mg escitalopram, >10 mg fluoxetine, >10 mg paroxetine or >50 mg sertraline. Results: In all, 21,049 (54%) out of 38,868 individuals

Currently, there is an unmet need for treatments promoting post-stroke functional recovery. The aim of this study was to evaluate and compare the dose-dependent effect of delayed atomoxetine or fluoxetine therapy (starting on post-stroke day 5), coupled with limited physical exercise (2 hours daily voluntary wheel running; post-stroke days 9 to 42), on motor recovery of adult male mice after photothrombotic stroke. These drugs are selective norepinephrine or serotonin reuptake inhibitors indicated for disorders unrelated to stroke. The predetermined primary end-point for this study was motor function measured in two tasks of spontaneous motor behaviors in grid-walking and cylinder tests. Additionally, we quantified the running distance and speed throughout the study, the number of parvalbumin-positive neurons in the medial agranular cortex and infarct volumes. Both sensorimotor tests revealed that neither limited physical exercise nor a drug treatment alone significantly facilitated motor recovery in mice after stroke. However, combination of physical exercise with either of the drugs promoted restoration of motor function by day 42 post-stroke, with atomoxetine being a more potent drug. This was accompanied by a significant decrease in parvalbumin-positive inhibitory interneurons in the ipsilateral medial agranular cortex of mice with recovering motor function, while infarct volumes were comparable among experimental groups. If further validated in larger studies, our observations suggest that add-on atomoxetine or fluoxetine therapy coupled with limited, structured physical rehabilitation could offer therapeutic modality for stroke survivors who have difficulty to engage in early, high-intensity physiotherapy. Furthermore, in light of the recently completed Assessment oF FluoxetINe In sTroke recoverY (AFFINITY) and Efficacy oF Fluoxetine-a randomisEd Controlled Trial in Stroke (EFFECTS) trials, our observations call for newly designed studies where fluoxetine or atomoxetine pharmacotherapy is evaluated in combination with structured physical rehabilitation rather than alone. This study was approved by the Texas Tech University Health Sciences Center Institutional Animal Care and Use Committee (protocol # 16019).

Studies have suggested that fluoxetine might improve neurological recovery after stroke, but the results remain inconclusive. The EFFECTS (Efficacy oF Fluoxetine – a randomisEd Controlled Trial in Stroke) reached its recruitment target of 1500 patients in June 2019. The purpose of this article is to present all amendments to the protocol and describe how we formed the EFFECTS trial collaboration in Sweden. Methods In this investigator-led, multicentre, parallel-group, randomised, placebo-controlled trial, we enrolled non-depressed stroke patients aged 18 years or older between 2 and 15 days after stroke onset. The patients had a clinical diagnosis of stroke (ischaemic or intracerebral haemorrhage) with persisting focal neurological deficits. Patients were randomised to fluoxetine 20 mg or matching placebo capsules once daily for 6 months. Results Seven amendments were made and included clarification of drug interaction between fluoxetine and metoprolol and the use of metoprolol for severe heart failure as an exclusion criterion, inclusion of data from central Swedish registries and the Swedish Stroke Register, changes in informed consent from patients, and clarification of design of some sub-studies. EFFECTS recruited 1500 patients at 35 centres in Sweden between 20 October 2014 and 28 June 2019. We plan to unblind the data in January 2020 and report the primary outcome in May 2020. Conclusion EFFECTS will provide data on the safety and efficacy of 6 months of treatment with fluoxetine after stroke in a Swedish health system setting. The data from EFFECTS will also contribute to an individual patient data meta-analysis. Trial registration EudraCT 2011-006130-16. Registered on 8 August 2014. ISRCTN, ISRCTN13020412. Registered on 19 December 2014. ClinicalTrials.gov: NCT02683213. Retrospectively registered on 2 February 2016.

Objective:to identify the structure and clinical features of affective disorders (AD) and efficiency of antidepressants in in-patients with chronic coronary artery disease (ChCAD), living in Tomsk and the Tomsk Region.Materials andмethods.At a heart center, 1,131 patients with ChCAD were examined: in 290 persons (25.6%) AD were revealed, among them 72.1% were men (n= 209) and 27.9% were women (n= 81). Mean age of women was (63.5 ± 9.4) years and in men (57.9 ± 7.2) years (р= 0.004). AD structure, main syndromes, severity of depression and anxiety according to data of self-questionnaires and clinical scales before and after antidepressant therapy (predominantly with selective serotonin reuptake inhibitors (SSRI)) were studied. Comparative analysis of clinical indices of CAD respective from AD, presence of antidepressant therapy and its efficiency was performed.Results.Chronic AD were found in 45% of patients. Newly diagnosed depressive episodes made up 24.5% and recurrent depressive disorder (RDD) was 24%. 6.5% were bipolar affective disorders (BAD), predominantly bipolar II disorders. Depressive syndrome in 91.7% of patients had the second significant component (more frequently 54.8%). Characteristic of the clinical picture was dominance of complaints of bodily discomfort and pain, anergy and anhedonia. Moderate mental disturbances made up 49.0% (CGI). AD manifested at the age of 48 (40–55) years and preceded development of ChCAD. Natural course of AD was observed in 52.4% of cases. 47.6% (138/290) of patients received antidepressants, and only in 42% (58/138) clinically significant improvement was noted (more than 50% according to CGI). It was difficult to encourage patient adherence to long-term therapy (30–50% according to CGI). Physical activity tolerance (PAT) according to data of veloergometry increased in responders. Psychopharmaco- and psychotherapy should be included into rehabilitative programs for patients with ChCAD and AD.

Background: Depression is a common psychiatric comorbidity in individuals with Down syndrome (DS), particularly adults, with an estimated lifetime prevalence of at least 10%. The current literature on the treatment of depression in adults with DS is limited to case series published more than two decades ago, prior to the widespread use of modern antidepressant medications such as selective serotonin reuptake inhibitors (SSRIs). The purpose of this retrospective chart review study was to examine the effectiveness, tolerability, and safety of SSRIs for depression in adults with DS. Methods: Medical records of 11 adults with DS and depression were reviewed. Assignment of scores for severity (S) of symptoms of depression and improvement (I) of symptoms with treatment with an SSRI was made retrospectively using the Clinical Global Impression Scale (CGI). Demographic and clinical characteristics of the study population, SSRI name, dose, and duration of treatment; and adverse effects were also recorded. Results: All 11 patients (7 male, 4 female; mean age = 27.2 years, range 18–46 years) completed a 12-week treatment course with an SSRI. The median duration of time after initiation of the SSRI covered by record review was 2.1 years, with a range of 24 weeks to 6.7 years. Nine of the 11 patients (82%; 95% CI 52%, 95%) were judged responders to SSRIs based on a rating of “much improved” or “very much improved” on the CGI-I after 12 weeks of treatment (median time of follow-up was 14.4 weeks, with a range of 12.0–33.0 weeks). Adverse effects occurred in four patients (36%). The most common adverse effects were daytime sedation and anger. Conclusions: In this preliminary retrospective study, the majority of patients responded to a 12-week course of SSRI treatment and some tolerated long-term use. Controlled studies are needed to further assess the efficacy, tolerability, and safety of SSRIs for the treatment of depression in adults with DS.

Patients with type 2 diabetes mellitus have more risk to develop depression. Fluoxetine (FLX), a selective serotonin reuptake inhibitor (SSRI), is drug for mood and anxiety disorders. Previous studies showed that FLX could induce weight loss in non-depressed clinically overweight individuals. Although the anti-appetite effect of FLX is well-documented, its potential effects on metabolic abnormalities have not been investigated. In this study, we want to investigate whether FLX could be a therapeutic drug against high fat diet (HFD)-induced metabolic disorder. We generated metabolic disorders and depressed mouse model by feeding HFD for 12 weeks at the age of 8 weeks. Then, mice were intraperitoneally injected once daily with FLX (10 mg/kg or 20 mg/kg) for four weeks. Our results showed that FLX alleviated the HFD-induced metabolic dysfunctions and depressive phenotypes in mice. FLX improved systemic glucose homeostasis, at least in part, by improving visceral white adipose tissue (vWAT) insulin signaling. Moreover, FLX reduced circulating plasma leptin level, and decreased the expression of adipose triglyceride lipase (ATGL) and peroxisome proliferator-activated receptor gamma (PPARγ) in vWAT. Our data revealed that FLX also reduced the triglyceride (TG) accumulation in vWAT. Therefore, these findings suggest that FLX exhibits significant potential on comorbidity of metabolic disorder and depression in mice.

Mood spectrum disorders and medications used to treat these disorders, such as atypical antipsychotic drugs (AA), are associated with metabolic and endocrine side effects including obesity, dyslipidemia, hyperglycemia and increased risk of fractures. Antidepressant medications, including selective serotonin reuptake inhibitors (SSRI), have also been reported to increase fracture risk in some patients. The pharmacology underlying the increased risk of fractures is currently unknown. Possible mechanisms include alternations in dopaminergic and/or serotonergic signaling pathways. As these medications distribute to the bone marrow as well as to the brain, it is possible that drug-induced fractures are due to both centrally mediated effects as well as direct effects on bone turnover. Given the growing patient population that is prescribed these medications for both on- and off-label indications, understanding the level of risk and the mechanisms underlying drug-induced fractures is important for informing both prescribing and patient monitoring practices.

Fluoxetine is an antidepressant, a selective serotonin reuptake inhibitor (SSRI) used primarily in the treatment of major depression, panic disorder and obsessive compulsive disorder. Chiral separation of racemic fluoxetine is necessary due to its enantioselective metabolism. In order to develop a suitable method for chiral separation of fluoxetine, cyclodextrin (CD) modified capillary electrophoresis (CE) was employed. A large number of native and derivatized, neutral and ionized CD derivatives were screened to find the optimal chiral selector. As a result of this process, heptakis(2,3,6-tri-O-methyl)-β-CD (TRIMEB) was selected for enantiomeric discrimination. A factorial analysis study was performed by orthogonal experimental design in which several factors are varied at the same time to optimize the separation method. The optimized method (50 mM phosphate buffer, pH = 5.0, 10 mM TRIMEB, 15 °C, + 20 kV, 50 mbar/1 s, detection at 230 nm) was successful for baseline separation of fluoxetine enantiomers within 5 min. Our method was validated according to ICH guidelines and proved to be sensitive, linear, accurate and precise for the chiral separation of fluoxetine.

Objective Increased inflammation and oxidative stress have been shown in Major Depressive Disorder (MDD), although there is significant heterogeneity across studies. Whether markers of inflammation and oxidative stress are associated with antidepressant treatment response in MDD is currently unclear. The goals of the present study are to investigate markers of inflammation and oxidative stress in unmedicated MDD subjects and controls and test the relationship between these markers and antidepressant response in MDD subjects. Methods Interleukin (IL)-6, tumor necrosis factor (TNF)-α, C-reactive protein, F2-isoprostanes, 8-OH 2-deoxyguanosine (8-OHdG), glutathione peroxidase, glutathione, and vitamin C were quantified in blood samples from 50 unmedicated MDD subjects and 55 healthy controls. Depression symptom severity was rated with the 17-item Hamilton Depression Rating Scale (HDRS). All subjects were somatically healthy and free from medications that could interfere with inflammation and oxidative stress markers. A subgroup of 22 MDD subjects underwent open-label selective serotonin reuptake inhibitor (SSRI) antidepressant treatment for eight weeks, after which blood sampling and the HDRS were repeated. Antidepressant treatment “response” was defined as ≥50% decrease in HDRS ratings over 8 weeks of treatment. Results After controlling for the effects of age, sex, body mass index and smoking, MDD subjects had significantly higher levels of IL-6 (p < 0.001), TNF-α (p < 0.001), 8-OHdG (p = 0.018), and F2-isoprostanes (p = 0.012). Compared to Responders, Non-responders to SSRI antidepressant treatment had higher levels of F2-isoprostanes at baseline (p = 0.006), and after eight weeks of treatment (p = 0.031). Non-responders showed a significant increase in 8-OHdG over the course of treatment (p = 0.021), whereas Responders showed a significant decrease in IL-6 over the course of treatment (p = 0.019). Conclusion Our results are in line with previous reports of increased levels of markers of inflammation and oxidative stress in MDD. Moreover, poorer antidepressant treatment response was related to higher baseline levels of the major oxidative stress marker, F2-isoprostanes, in vivo. Further, antidepressant response was associated with changes in oxidative (8-OHdG) and inflammatory (IL-6) markers.

Purpose: This study aims to systematically review studies quantifying the associations between antidepressants (ADs) use and the risk of cardiovascular (CV) outcomes. Methods: Medline was searched to October 2015 for full text articles in English. Prospective cohort and case-control studies were admitted if they investigated the relationship between current use of ADs as a whole, tricyclic antidepressants (TCAs) or selective serotonin reuptake inhibitors (SSRIs), and the onset CV events. Summary relative risks (RRs) with confidence intervals (CIs) were calculated using random-effects or fixed-effects models. Results: A total of 99,367 incident cases of CV outcomes who met inclusion criteria were identified from 22 observational studies. Compared with no users of ADs, use of SSRIs was associated with an increased risk of cerebrovascular disease (RRs, 1.24; 95% CI, 1.15 to 1.34), while the use of TCA was associated with an increased risk of acute heart disease (RRs, 1.29; 95% CI, 1.09 to 1.54). Conclusions: The results of this meta-analysis have to be taken with caution because even though an increased risk of cerebrovascular and acute heart disease was observed respectively in SSRIs and TCA users, the estimates are characterized by a high between study heterogeneity. Moreover, it was not possible to distinguish between the effects of ADs and depression itself. Further well-designed studies are required to confirm this association

Purpose This study explored and compared the effects of depression and antidepressants on sexual dysfunction in men with diabetes mellitus (DM). Patients and Methods Patients older than 18 years who had been newly diagnosed with DM (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] code 250) between 1999 and 2010 were identified from Taiwan’s National Health Insurance Research Database and were followed up until 2013. Patients with preexisting depression or sexual dysfunction were excluded. A total of 636,210 patients with DM were enrolled. These patients were divided into two groups: DM with comorbid depression and a matched cohort without depression. The groups were followed up until the end of 2010 for the first diagnosis of sexual dysfunction (ICD-9-CM codes 302.70, 302.71, 302.72, 302.74, 302.75, 302.76, 302.79, 607.84, and V417). A Cox proportional hazard model and a Cox regression model with time-dependent covariates were applied. Results Patients with DM and depression had a higher risk of sexual dysfunction than those with DM without depression (hazard ratio [HR] = 1.44; 95% confidence interval [CI], 1.33–1.55). The risk of sexual dysfunction was lower in the subgroup who used antidepressants (per 28 cumulative defined daily doses [cDDDs]), HR = 0.96; 95% CI, 0.94–0.97). A significantly lower incidence of sexual dysfunction was also associated with the use of selective serotonin reuptake inhibitors (SSRIs, per 28 cDDD). The adjusted HR was 0.95 (95% CI, 0.93–0.97). Subgroup analysis indicated that SSRI use was significantly associated with an amelioration of erectile dysfunction (per 28 cDDD), with an HR of 0.95 (95% CI, 0.92–0.97). Conclusion Male patients with DM and depression are at increased risk of sexual dysfunction. Antidepressant use had a small inverse association with the risk of sexual dysfunction in men with DM and depression. Antidepressants, in particular SSRIs, did not increase the risk of sexual dysfunction in this population.

Antibiotic resistance of Helicobacter pylori, a spiral bacterium associated with gastric diseases, is a topic that has been intensively discussed in last decades. Recent discoveries indicate promising antimicrobial and antibiotic-potentiating properties of sertraline (SER), an antidepressant substance. The aim of the study, therefore, was to determine the antibacterial activity of SER in relation to antibiotic-sensitive and antibiotic-resistant H. pylori strains. The antimicrobial tests were performed using a diffusion-disk method, microdilution method, and time-killing assay. The interaction between SER and antibiotics (amoxicillin, clarithromycin, tetracycline, and metronidazole) was determined by using a checkerboard method. In addition, the study was expanded to include observations by light, fluorescence, and scanning electron microscopy. The growth inhibition zones were in the range of 19–37 mm for discs impregnated with 2 mg of SER. The minimal inhibitory concentrations (MICs) and minimal bactericidal concentrations (MBCs) counted for 2–8 µg/mL and 4–8 µg/mL, respectively. The time-killing assay showed the time-dependent and concentration-dependent bactericidal activity of SER. Bacteria exposed to MBCs (but not sub-MICs and MICs ≠ MBCs) underwent morphological transformation into coccoid forms. This mechanism, however, was not protective because these cells after a 24-h incubation had a several-fold reduced green/red fluorescence ratio compared to the control. Using the checkerboard assay, a synergistic/additive interaction of SER with all four antibiotics tested was demonstrated. These results indicate that SER may be a promising anti-H. pylori compound.

Escitalopram is one of selective serotonin reuptake inhibitor antidepressants. As an S-enantiomer of citalopram, it shows better therapeutic outcome in depression and anxiety disorder treatment because it has higher selectivity for serotonin reuptake transporter than citalopram. The objective of this study was to determine the direct inhibitory effect of escitalopram on 5-hydroxytryptamine type 3 (5-HT3) receptor currents and study its blocking mechanism to explore additional pharmacological effects of escitalopram through 5-HT3 receptors. Using a whole-cell voltage clamp method, we recorded currents of 5-HT3 receptors when 5-HT was applied alone or co-applied with escitalopram in cultured NCB-20 neuroblastoma cells known to express 5-HT3 receptors. 5-HT induced currents were inhibited by escitalopram in a concentration-dependent manner. EC50 of 5-HT on 5-HT3 receptor currents was increased by escitalopram while the maximal peak amplitude was reduced by escitalopram. The inhibitory effect of escitalopram was voltage independent. Escitalopram worked more effectively when it was co-applied with 5-HT than pre-application of escitalopram. Moreover, escitalopram showed fast association and dissociation to the open state of 5-HT3 receptor channel with accelerating receptor desensitization. Although escitalopram accelerated 5-HT3 receptor desensitization, it did not change the time course of desensitization recovery. These results suggest that escitalopram can inhibit 5-HT3 receptor currents in a non-competitive manner with the mechanism of open channel blocking.

Background Less than half of patients with major depressive disorder (MDD) respond to their first antidepressant trial. Our understanding of the underlying mechanisms of selective serotonin reuptake inhibitors (SSRIs) remains poor, and there is no reliable method of predicting treatment response. Methods Thirty-seven MDD subjects and 41 healthy controls, somatically healthy and medication-free for at least six weeks, were recruited, and plasma serotonin (5-HT) levels were assessed at baseline. Twenty-six of the MDD subjects were then treated in an open-label manner with clinically appropriate doses of sertraline for 8 weeks, after which plasma 5-HT levels were again assessed. Response to treatment was defined as an improvement of 50% or more on the Hamilton Depression Rating Scale. Results Non-responders to sertraline treatment had significantly lower pre-treatment 5-HT levels compared to both healthy controls and responders (F = 4.4, p = 0.004 and p = 0.036, respectively). There was a significant decrease in 5-HT levels over treatment in all MDD subjects (t = 6.2, p = 0.000003). The decrease was significantly more prominent in responders compared to non-responders (t = 2.1, p = 0.047). There was no significant difference in post-treatment 5-HT levels between responders and non-responders. Limitations The study had a modest sample size. 5-HT levels in plasma may not reflect 5-HT levels in the brain. Conclusions The results indicate that SSRI response may be facilitated by adequate baseline plasma 5-HT content and that successful SSRI treatment is associated with greater decreases in circulating 5-HT. Plasma 5-HT content may be a predictor of SSRI treatment outcome. Potential underlying mechanisms are discussed.

Serotonin affects several brain functions including cognition. The serotonin transporter (SERT) regulates brain serotonin levels through reuptake into neurons. The gene encoding this transporter, the SERT gene, has several functional polymorphisms affecting the number of transporters and thereby the serotonin levels. SERT gene expression may be important for cognition and selective serotonin reuptake inhibitors (SSRI) may improve cognition post stroke. We therefore examined the association between SERT genotypes, cognitive function and early treatment with the SSRI citalopram among non-depressed Caucasian stroke patients. >bold<>italic/italic<>/bold< SERT gene polymorphisms in 270 non-depressed first-ever acute ischemic stroke patients randomized to citalopram, >italic/italic< = 130, or placebo, >italic/italic< = 140, were investigated. Patients were genotyped for a length polymorphism (L = long and S = short allele) and a single nucleotide polymorphism (A/G substitution) dividing the L-allele into L>sub/sub< and L>sub/subsub/subsub/subsub/subsub/sub< and L>sub/subsub/subsub/subsub/subbold<>italic/italic<>/bold< Stratified by genotype groups, there were no statistically significant differences in SDMT scores between randomization groups. Placebo-treated patients with low SERT expression genotypes, however, tended to have lower mean SDMT scores (at 1 month: 30.2, SD 10.8) compared to citalopram-treated patients (33.6, SD 13.7). Within the placebo group, the low genotype expression patients had significantly lower adjusted mean SDMT scores at 1 month compared to the high genotype expression patients (adjusted mean difference of -6 points, CI -12.0 to -0.05). We found similar results at 6 months, although not statistically significant. The genotype expression was not associated with SDMT scores among citalopram-treated patients. >bold<>italic/italic<>/bold< There was no difference in cognition between citalopram and placebo-treated patients according to the genotype group. Our results indicate, however, that low expression SERT genotype may contribute to reduced cognitive function post stroke as placebo-treated patients with low SERT expression tended to score lower on the SDMT. The significant difference in SDMT scores between low and high expression patients was present only in the placebo-treated group, thereby warranting further exploration of the potential effect of early citalopram treatment on cognitive functioning. Our results are preliminary and need replication in larger-scale studies.

Elevation of serotonin via postnatal fluoxetine (PNFlx) treatment during critical temporal windows is hypothesized to perturb the development of limbic circuits thus establishing a substratum for persistent disruption of mood-related behavior. We examined the impact of PNFlx treatment on the formation and maintenance of perineuronal nets (PNNs), extracellular matrix (ECM) structures that deposit primarily around inhibitory interneurons, and mark the closure of critical period plasticity. PNFlx treatment evoked a significant decline in PNN number, with a robust reduction in PNNs deposited around parvalbumin (PV) interneurons, within the CA1 and CA3 hippocampal subfields at postnatal day 21 in Sprague-Dawley rat pups. While the reduction in CA1 subfield PNN number was still observed in adulthood, we observed no change in colocalization of PV-positive interneurons with PNNs in the hippocampi of adult PNFlx animals. PNFlx treatment did not alter hippocampal parvalbumin, calretinin, or reelin-positive neuron numbers in PNFlx animals at P21 or in adulthood. We did observe a small, but significant increase in somatostatin (SST)-positive interneurons in the DG subfield of PNFlx-treated animals in adulthood. This was accompanied by altered GABA-A receptor subunit composition, increased dendritic complexity of apical dendrites of CA1 pyramidal neurons, and enhanced neuronal activation revealed by increased c-Fos-positive cell numbers within hippocampi of PNFlx-treated animals in adulthood. These results indicate that PNFlx treatment alters the developmental trajectory of PNNs within the hippocampus, raising the possibility of a disruption of critical period plasticity and the establishment of an altered excitation-inhibition balance within this key limbic brain region.Significance StatementClinical and preclinical studies indicate that developmental exposure to fluoxetine programs persistent dysregulation of mood-related behaviors. This is hypothesized to involve the disruption of the normal development of key brain regions, such as the hippocampus that regulate mood behaviors. We show that postnatal exposure to fluoxetine alters hippocampal perineuronal nets (PNNs), extracellular matrix structures that regulate plasticity and mark the closure of critical periods. The decline in PNNs is noted in early postnatal life, and persists into adulthood in specific hippocampal subfields. Adult animals with a history of postnatal fluoxetine exposure exhibit altered numbers of somatostatin interneurons, GABA receptor subunit expression and neuronal activation within the hippocampus. This indicates that postnatal fluoxetine disrupts the normal developmental trajectory of the hippocampus.

After spinal cord injury, the upward conduction of the spinal cord is lost, resulting in the loss of micturition control, which manifests as detrusor sphincter dyssynergia and insufficient micturition. Studies have shown that serotonergic axons play important roles in the control of the descending urination tract. In this study, mouse models of moderate spinal cord contusions were established. The serotonin agonists quipazine (0.2 mg/kg), 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DAPT, 0.1 mg/kg), buspirone (1 mg/kg), sumatriptan (1 mg/kg), and rizatriptan (50 mg/kg), the serotonin reuptake inhibitors fluoxetine (20 mg/kg) and duloxetine (1 mg/kg), and the dopamine receptor agonist SKF-82197 (0.1 mg/kg) were intraperitoneally administered to the model mice 35 days post-injury in an acute manner. The voided stain on paper method and urodynamics revealed that fluoxetine reduced the amount of residual urine in the bladder and decreased bladder and external urethral sphincter pressure in a mouse model of moderate spinal cord injury. However, fluoxetine did not improve the micturition function in a mouse model of severe spinal cord injury. In contrast, the other serotonergic drugs had no effects on the micturition functions of spinal cord injury model mice. This study was ethically approved by the Institutional Animal Care and Use Committee of Jiangsu Province Hospital of Chinese Medicine (approval No. 2020DW-20-02) on September 11, 2020.

Background Central post-stroke pain (CPSP) is a type of neuropathic pain caused by dysfunction in the spinothalamocortical pathway. However, no animal studies have examined comorbid anxiety and depression symptoms. Whether the typical pharmacological treatments for CPSP, which include antidepressants, selective serotonin reuptake inhibitors (SSRIs), and anticonvulsants, can treat comorbid anxiety and depression symptoms in addition to pain remains unclear? The present study ablated the ventrobasal complex of the thalamus (VBC) to cause various CPSP symptoms. The effects of the tricyclic antidepressants amitriptyline and imipramine, the SSRI fluoxetine, and the anticonvulsant carbamazepine on pain, anxiety, and depression were examined. Results The results showed that VBC lesions induced sensitivity to thermal pain, measured using a hot water bath; mechanical pain, assessed by von Frey test; anxiety behavior, determined by the open-field test, elevated plus-maze test, and zero-maze test; and depression behavior, assessed by the forced swim test. No effect on motor activity in the open-field test was observed. Amitriptyline reduced thermal and mechanical pain sensitivity and anxiety but not depression. Imipramine suppressed thermal and mechanical pain sensitivity, anxiety, and depression. Fluoxetine blocked mechanical but not thermal pain sensitivity, anxiety, and depression. However, carbamazepine did not affect pain, anxiety, or depression. Conclusion In summary, antidepressants and SSRIs but not anticonvulsants can effectively ameliorate pain and comorbid anxiety and depression in CPSP. The present findings, including discrepancies in the effects observed following treatment with anticonvulsants, antidepressants, and SSRIs in this CPSP animal model, can be applied in the clinical setting to guide the pharmacological treatment of CPSP symptoms.

Selective serotonin reuptake inhibitors are commonly used in the treatment of many psychiatric diseases today. Their common side effects consist of gastrointestinal side effects, sexual dysfunction, headache, insomnia, and sedation, whereas hematological side effects have been reported, although rarely. In this article, we presented a case of thrombocytopenia, which is a rare side effect emerging after the escitalopram use, belonging to a 19-year-old female patient who had a generalized anxiety disorder and no hematological history was noted. We aimed to discuss the development mechanism of thrombocytopenia due to the escitalopram use.

Introduction: Hyponatremia can be a common but often overlooked side effects of psychotropics drugs. Most patients with drug-induced hyponatremia are asymptomatic and diagnosis is made incidentally following routine blood tests. Objectives: The aim of the study was to understand the pattern of hyponatremia in patients using selective serotonin reuptake inhibitors (SSRI) and serotonin dopamine antagonists (SDA). Materials and Methods: All inpatients and outpatients who were diagnosed with International Classification of Diseases-10 psychiatric disorders and undergoing treatment with SSRI, SDA, or combination of both for the same, were included in the study after simple random sampling, subject to inclusion and exclusion criteria. Statistical Analysis Used: Categorical variables were observed as numbers and percentages. Continuous variables were evaluated as mean ± standard deviation. A Chi-square test was done to find the association between categorical variables. SPSS (IBM) version 21 was used for data analysis. Results: In 150 patients, we found hyponatremia in 17 patients (11.33%). About 66–75 age group patients had maximum found cases of hyponatremia (66.66%). About 20.31% of females found hyponatremia. Among SSRIs, 16% of individuals had hyponatremia whereas among SDA it was 6%. Patients who were taking both SSRIs and SDA total prevalence of hyponatremia was 12%. Conclusions: Older age groups and females had higher chances of hyponatremia while taking SSRIs and SDAs. Among SSRIs, escitalopram had maximum percentage of hyponatremia, whereas fluvoxamine had minimum. Among SDAs, risperidone had maximum percentage, whereas quetiapine had minimum percentage of hyponatremia. Patients who were taking both fluoxetine + olanzapine or fluoxetine + risperidone had higher percentage of hyponatremia.

Objective We conducted a narrative review to investigate whether antidepressant therapy, including the use of selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs) or the use of supportive drugs (i.e., citicoline or choline alfoscerate) as a substitute for antidepressant therapy, reduces depression in patients with cerebrovascular diseases. Methods A systematic search of the PubMed and Web of Science databases was performed, including review articles and other studies to identify additional citations. Only 4 of 1566 publications met the inclusion/exclusion criteria and were selected. Results Studies showed that post-stroke depression (PSD) could be treated with antidepressant therapy, as well as supportive drugs such as citicoline or choline alfoscerate, which may have antidepressant effects. Conclusions The findings support the efficacy of citicoline as a treatment for depression. Studies aimed to discover the characteristics of these psychostimulants in relation to PSD treatment should be performed.

Given the failure to develop disease-modifying therapies for Alzheimer’s disease (AD), strategies aiming at preventing or delaying the onset of the disease are being prioritized. While the debate regarding whether depression is an etiological risk factor or a prodrome of AD rages on, a key determining factor may be the timing of depression onset in older adults. There is increasing evidence that untreated early-onset depression is a risk factor and that late-onset depression may be a catalyst of cognitive decline. Data from animal studies have shown a beneficial impact of selective serotonin reuptake inhibitors on pathophysiological biomarkers of AD including amyloid burden, tau deposits and neurogenesis. In humans, studies focusing on subjects with a prior history of depression also showed a delay in the onset of AD in those treated with most selective serotonin reuptake inhibitors. Paroxetine, which has strong anticholinergic properties, was associated with increased mortality and mixed effects on amyloid and tau deposits in mice, as well as increased odds of developing AD in humans. Although most of the data regarding selective serotonin reuptake inhibitors is promising, findings should be interpreted cautiously because of notable methodological heterogeneity between studies. There is thus a need to conduct large scale randomized controlled trials with long follow up periods to clarify the dose-effect relationship of specific serotonergic antidepressants on AD prevention.

Dystonia is a movement disorder whose main feature is a sustained or intermittent muscle contraction causing abnormal, often repetitive, movements. Cervical dystonia (CD) is a type of focal dystonia affecting cervical muscles leading to abnormal postures and movements of the head, neck, and shoulders. Pathological laughter and crying are a condition characterized by uncontrollable episodes of laughter and crying. It occurs without any apparent triggering stimulus or in response to a stimulus which had not resulted in cry or laughter before the onset of the condition. It is characterized as a disorder of emotional expression rather than a disorder of feelings. The purpose of presenting this case report is that this patient presented with pathological laughter and CD without any other neurological complications which are a very rare and unusual presentation.

Objective The objective of this study was to characterise international trends in the use of psychotropic medication, psychological therapies, and novel therapies used to treat obsessive–compulsive disorder (OCD). Methods Researchers in the field of OCD were invited to contribute summary statistics on the characteristics of their samples. Consistency of summary statistics across countries was evaluated. Results The study surveyed 19 expert centres from 15 countries (Argentina, Australia, Brazil, China, Germany, Greece, India, Italy, Japan, Mexico, Portugal, South Africa, Spain, the United Kingdom, and the United States) providing a total sample of 7,340 participants. Fluoxetine (n = 972; 13.2%) and fluvoxamine (n = 913; 12.4%) were the most commonly used selective serotonin reuptake inhibitor medications. Risperidone (n = 428; 7.3%) and aripiprazole (n = 415; 7.1%) were the most commonly used antipsychotic agents. Neurostimulation techniques such as transcranial magnetic stimulation, deep brain stimulation, gamma knife surgery, and psychosurgery were used in less than 1% of the sample. There was significant variation in the use and accessibility of exposure and response prevention for OCD. Conclusions The variation between countries in treatments used for OCD needs further evaluation. Exposure and response prevention is not used as frequently as guidelines suggest and appears difficult to access in most countries. Updated treatment guidelines are recommended., Author V. B. would like to acknowledge all the staff at the numerous research centres throughout the world and their participants who contributed valuable data to this large data base. V. B. would also like toacknowledge Prof. Naomi Fineberg and the International College of Obsessive‐Compulsive Spectrum Disorders (ICOCS) who supportedthis project by circulating his invitation to participate in the surveyto its members.This study was sponsored by Nepean Medical Research Founda-tion Grant, Pfizer Neuroscience Grant, National Natural Science Foun-dation of China (Grant 81371340), and Spanish MINECO GrantPSI2013‐44733‐R.

Background The associations between depression and immunity were investigated by measuring the scores of Hamilton Rating Scale for Depression (HRSD) and peripheral lymphocyte parameters in patients with major depressive disorder (MDD). Methods Forty-nine patients with MDD were recruited and their clinical symptoms are evaluated with 17-item HRSD which was factorized using the confirmatory factor analysis (i.e., depression factor, insomnia factor, and anxiety factor). Basic immunologic variables such as CD4, CD8, and CD56-positive cell numbers were measured by flow cytometry. Natural killer cell activity (NKCA) was also assessed by ELISA method using K-562 cells as target cells. All patients were treated for 4 weeks with selective serotonin reuptake inhibitors. Immunologic and clinical variables were measured both at baseline and after medication. Results CD8-positive cell number was increased (p

Spinocerebellar ataxias are dominantly inherited neurodegenerative disorders with no disease-modifying treatment. We previously identified the selective serotonin reuptake inhibitor citalopram as a safe and effective drug to be repurposed for Machado-Joseph disease. Pre-symptomatic treatment of transgenic (CMVMJD135) mice strikingly ameliorated mutant ataxin-3 (ATXN3) pathogenesis. Here, we asked whether citalopram treatment initiated at a post-symptomatic age would still show efficacy. We used a cohort of CMVMJD135 mice that shows increased phenotypic severity and faster disease progression (CMVMJD135hi) compared to the mice used in the first trial. Groups of hemizygous CMVMJD135hi mice were orally treated with citalopram. Behavior, protein analysis, and pathology assessment were performed blindly to treatment. Our results show that even when initiated after symptom onset, treatment of CMVMJD135hi mice with citalopram ameliorated motor coordination and balance, attenuating disease progression, albeit to a lesser extent than that seen with pre-symptomatic treatment initiation. There was no impact on ATXN3 aggregation, which contrasts with the robust reduction in ATXN3-positive inclusions observed in CMVMJD135 mice, when treated pre-symptomatically. Post-symptomatic treatment of CMVMJD135hi mice revealed, however, a limited neuroprotective effect by showing a tendency to repair cerebellar calbindin staining, and to increase the number of motor neurons and of NeuN-positive cells in certain brain regions. While supporting that early initiation of treatment with citalopram leads to a marked increase in efficacy, these results strengthen our previous observation that modulation of serotonergic signaling by citalopram is a promising therapeutic approach for Machado-Joseph disease even after symptom onset., European Regional Development Funds (FEDER), through the Competitiveness Factors Operational Programme (COMPETE), and by National funds, through the Foundation for Science and Technology (FCT), under the scope of the project POCI-01-0145-FEDER-007038. This article has been developed under the scope of the project NORTE-01-0145-FEDER-000013, supported by the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the FEDER. This work was also supported by FCT and COMPETE through the projects [PTDC/SAU-GMG/112617/2009] (to PM) and [EXPL/BIM-MEC/0239/2012] (to AT-C), by FCT through the project [POCI-01-0145-FEDER-016818 (PTDC/NEU-NMC/3648/2014)] (to PM), by National Ataxia foundation (to PM and to AT-C), and by Ataxia UK (to PM). SE, SD-S, SO, and AT-C were supported by the FCT individual fellowships, SFRH/BD/78554/2011, SFRH/BD/78388/2011, PD/BD/127818/2016, and SFRH/BPD/102317/2014, respectively. FCT fellowships are co-financed by POPH, QREN, Governo da República Portuguesa, and EU/FSE, info:eu-repo/semantics/publishedVersion

Introduction: Depression and Metabolic syndrome both are the two major public health issues. The depressive patients are at higher risk for Cardiovascular Disease (CVD). The use of antidepressant medication has been linked to CVD. Major depression is associated with activation of the inflammatory response. Aim: To investigate the presence of metabolic syndrome, cardiovascular risk and inflammatory marker levels in depressed patients and compare it with healthy population without depression. Materials and Methods: Cross-sectional analysis was undertaken on 94 patients with the diagnosed depressive disorder from Department of Psychiatry, Sawai Man Singh Medical College Jaipur, Rajasthan, India and 50 healthy controls from the general population. The Body Mass Index (BMI), waist circumference, blood sugar, lipid parameters and high sensitive C-Reactive Protein (hs-CRP) were measured in both groups. Depressive symptoms were measured using MontgomeryAsberg Depression Rating Scale (MADRS), antidepressant medication use {Selective Serotonin Reuptake Inhibitor (SSRI)} was also reported. Metabolic syndrome prevalence was assessed based on International Diabetes Federation (IDF) guidelines. Results: The depressive subjects showed statistically significant increased blood glucose (p=0.007), and decreased High Density Lipoprotein Cholesterol (HDLC) (p=0.001) values. There were statistically significant increased hs-CRP values (3.30±2.61 mg/L) in users of SSRI antidepressant medication compared to healthy controls (1.96±0.70 mg/L). The prevalence of metabolic syndrome in depressed patients was 42.36%. Conclusion: Depressive patients are at higher risk for CVD due to a high prevalence of metabolic syndrome. These patients should be regularly monitored for CVD risk factors.

Human models of emotional processing suggest that the direct effect of successful antidepressant drug treatment may be to modify biases in the processing of emotional information. Negative biases in emotional processing are documented in depression, and single or short-term dosing with conventional antidepressant drugs reverses these biases in depressed patients prior to any subjective change in mood. Antidepressant drug treatments also modulate emotional processing in healthy volunteers, which allows the consideration of the psychological effects of these drugs without the confound of changes in mood. As such, human models of emotional processing may prove to be useful for testing the efficacy of novel treatments and for matching treatments to individual patients or subgroups of patients.Los modelos humanos de procesamiento emocional sugieren que el efecto directo de un tratamiento antidepresivo exitoso puede consistir en la modificación de las distorsiones en el procesamiento de la información emocional. Las distorsiones negativas en el procesamiento emocional están documentados en la depresión, y el empleo de antidepresivos convencionales en dosis única o por corto tiempo revierte estas distorsiones en los pacientes depresivos previo a cualquier cambio subjetivo en el ánimo. Los tratamientos con antidepresivos también modulan el procesamiento emocional en voluntaries sanos, por lo que hay que tener en cuenta los efectos psicológicos de estos fármacos y no confundirlos con los cambios en el ánimo. Asimismo los modelos humanos de procesamiento emocional pueden resultar útiles para probar la eficacia de nuevos tratamientos y para adaptar las terapias a pacientes individuales o subgrupos de ellos.D'après les modèles humains du traitement des émotions, un antidépresseur efficace agirait directement en en modifiant les distorsions de traitement de l'information émotionnelle. Ces dernières sont documentées dans la dépression et inversées avant tout modification subjective de l'humeur, chez des patients déprimés, lors de traitement court ou à dose unique par des antidépresseurs classiques. Les antidépresseurs modulent également le traitement de l'information émotionnelle chez les volontaires sains, ce qui permet d'envisager les effets psychologiques de ces médicaments sans les confondre avec les changements d'humeur. Ainsi, des modèles humains de traitement de l'information émotionnelle pourraient être utilisés pour tester l'efficacité de nouveaux médicaments et les adapter individuellement ou à des sous-groupes de patients.

Vilazodone is a selective serotonin reuptake inhibitor and a 5-HT1A receptor partial agonist that is approved for treatment of major depressive disorder in adults in the USA and Mexico. The efficacy, safety, and tolerability of vilazodone for generalized anxiety disorder (GAD) were investigated in a clinical trial (NCT01766401 ClinicalTrials.gov). Participants (18–70 years, inclusive) who met Diagnostic and Statistical Manual of Mental Disorders, 4th ed., text revision, criteria for GAD were randomized (1 : 1) to placebo or flexible-dose vilazodone (20–40 mg/day) for 8 weeks of double-blind treatment. Primary and secondary efficacy parameters were changes from baseline to week 8 in Hamilton Rating Scale for Anxiety and Sheehan Disability Scale total scores, respectively. Analysis was based on a mixed-effects model for repeated measures approach on the intent-to-treat population. The intent-to-treat population comprised 395 patients (placebo=197, vilazodone=198); 77% completed the study. The least squares mean difference in change from baseline to week 8 in the Hamilton Rating Scale for Anxiety total score was statistically significant for vilazodone versus placebo [−1.50 (−2.96, −0.04), P=0.0438]. The mean change from baseline to week 8 in the Sheehan Disability Scale total score for vilazodone versus placebo was not statistically significant. Adverse events were reported in 60% of placebo-treated and 83% of vilazodone-treated patients. This was a positive clinical trial of 20–40 mg/day vilazodone versus placebo in the treatment of GAD.

Sexual dysfunction commonly occurs with major depressive disorder (MDD). Vilazodone, a selective serotonin reuptake inhibitor and 5-HT1A receptor partial agonist antidepressant approved for the treatment of MDD in adults, was evaluated to determine its effects on sexual function. The primary study was a double-blind, randomized, controlled trial comparing vilazodone 20 and 40 mg/day with placebo; citalopram 40 mg/day was an active control (NCT01473381; http://www.clinicaltrials.gov). Post-hoc analyses evaluated change from baseline to week 10 on the Changes in Sexual Functioning Questionnaire (CSFQ); no inferential statistics were performed. CSFQ scores increased for women [1.2 (citalopram) to 3.0 (vilazodone 40 mg)] and men [1.2 (vilazodone 40 mg) to 3.5 (placebo)] in all treatment groups. Greater changes in CSFQ scores were seen in responders [women: 2.33 (citalopram) to 5.06 (vilazodone 40 mg); men: 2.26 (vilazodone 40 mg) to 4.35 (placebo)] versus nonresponders. CSFQ change from baseline was small for patients with normal baseline sexual function; in patients with baseline sexual dysfunction, CSFQ scores improved across groups [women: 2.35 (citalopram) to 4.52 (vilazodone 40 mg); men 2.83 (vilazodone 40 mg) to 6.43 (placebo)]. Across treatment groups, baseline sexual function improved in women and men, MDD responders, and patients with baseline sexual dysfunction.

Adverse outcome pathways (AOPs) organize knowledge on the progression of toxicity through levels of biological organization. By determining the linkages between toxicity events at different levels, AOPs lay the foundation for mechanism-based alternative testing approaches to hazard assessment. Here, we focus on growth impairment in fish to illustrate the initial stages in the process of AOP development for chronic toxicity outcomes. Growth is an apical endpoint commonly assessed in chronic toxicity tests for which a replacement is desirable. Based on several criteria, we identified reduction in food intake to be a suitable key event for initiation of middle-out AOP development. To start exploring the upstream and downstream links of this key event, we developed three AOP case studies, for pyrethroids, selective serotonin reuptake inhibitors (SSRIs) and cadmium. Our analysis showed that the effect of pyrethroids and SSRIs on food intake is strongly linked to growth impairment, while cadmium causes a reduction in growth due to increased metabolic demands rather than changes in food intake. Locomotion impairment by pyrethroids is strongly linked to their effects on food intake and growth, while for SSRIs their direct influence on appetite may play a more important role. We further discuss which alternative tests could be used to inform on the predictive key events identified in the case studies. In conclusion, our work demonstrates how the AOP concept can be used in practice to assess critically the knowledge available for specific chronic toxicity cases and to identify existing knowledge gaps and potential alternative tests., Chemosphere, 120, ISSN:0045-6535, ISSN:1879-1298

Glioblastoma multiforme (GBM) is recognized as a most aggressive brain cancer with the worst prognosis and survival time. Owing to the anatomic location of gliomas, surgically removing the tumour is very difficult and avoiding damage to vital brain regions during radiotherapy is impossible. Therefore, therapeutic strategies for malignant glioma must urgently be improved. Recent studies have demonstrated that selective serotonin reuptake inhibitors (SSRIs) have cytotoxic effect on certain cancers. Considering as a more superior SSRI, escitalopram oxalate exhibits favourable tolerability and causes generally mild and temporary adverse events. However, limited information is revealed about the influence of escitalopram oxalate on GBM. Therefore, an attempt was made herein to explore the effects of escitalopram oxalate on GBM. The experimental results revealed that escitalopram oxalate significantly inhibits the proliferation and invasive ability of U‐87MG cells and significantly reduced the expressions of cell cycle inhibitors such as Skp2, P57, P21 and P27. Notably, escitalopram oxalate also induced significant apoptotic cascades in U‐87MG cells and autophagy in GBM8401 cells. An animal study indicated that escitalopram oxalate inhibits the proliferation of xenografted glioblastoma in BALB/c nude mice. These findings implied that escitalopram oxalate may have potential in treatment of glioblastomas.

Background In current psychiatric practice, antidepressants are widely and with ever-increasing frequency prescribed to patients. However, several scientific biases obfuscate estimates of antidepressants’ efficacy and harm, and these are barely recognized in treatment guidelines. The aim of this mini-review is to critically evaluate the efficacy and harm of antidepressants for acute and maintenance treatment with respect to systematic biases related to industry funding and trial methodology. Methods Narrative review based on a comprehensive search of the literature. Results It is shown that the pooled efficacy of antidepressants is weak and below the threshold of a minimally clinically important change once publication and reporting biases are considered. Moreover, the small mean difference in symptom reductions relative to placebo is possibly attributable to observer effects in unblinded assessors and patient expectancies. With respect to trial dropout rates, a hard outcome not subjected to observer bias, no difference was observed between antidepressants and placebo. The discontinuation trials on the efficacy of antidepressants in maintenance therapy are systematically flawed, because in these studies, spontaneous remitters are excluded, whereas half of all patients who remitted on antidepressants are abruptly switched to placebo. This can cause a severe withdrawal syndrome that is easily misdiagnosed as a relapse when assessed on subjective symptom rating scales. In accordance, the findings of naturalistic long-term studies suggest that maintenance therapy has no clear benefit, and non-drug users do not show increased recurrence rates. Moreover, a growing body of evidence from hundreds of randomized controlled trials suggests that antidepressants cause suicidality, but this risk is underestimated because data from industry-funded trials are systematically flawed. Unselected, population-wide observational studies indicate that depressive patients who use antidepressants are at an increased risk of suicide and that they have a higher rate of all-cause mortality than matched controls. Conclusion The strong reliance on industry-funded research results in an uncritical approval of antidepressants. Due to several flaws such as publication and reporting bias, unblinding of outcome assessors, concealment and recoding of serious adverse events, the efficacy of antidepressants is systematically overestimated, and harm is systematically underestimated. Therefore, I conclude that antidepressants are largely ineffective and potentially harmful.