SSRI Fluoxetine Research Articles

Fluoxetine attenuates the anxiolytic effects of the probiotic VSL#3 in a stress-vulnerable genetic line of aves in the chick social-separation stress test, a dual screening assay

Anxiety disorders represent one of the most common and debilitating illnesses worldwide. However, the development of novel therapeutics for anxiety disorders has lagged compared to other mental illnesses. A growing body of research suggests the gut microbiota plays a role in the etiopathology of anxiety disorders and may, therefore, serve as a novel target for their treatment through the use of probiotics. The use of dietary supplements like probiotics is increasing and their interaction with pharmacotherapies is not well understood. Utilizing the chick social-separation stress test, the primary aim of this study was to evaluate the commercially-available multi-strain probiotic found in VSL#3 for potential anxiolytic-like and/or antidepressant-like effects in the stress-vulnerable Black Australorp genetic line. A secondary aim was to evaluate the interaction between probiotics and the SSRI fluoxetine. Animals were treated with either saline, probiotics, fluoxetine, or probiotics + fluoxetine for 8 days prior to exposure to a 90-min isolation stressor that produces both a panic-like (i.e., anxiety-like) state followed by a state of behavioral despair (i.e., depression-like). The 8-day probiotic regimen produced anxiolytic-like effects but did not attenuate behavioral despair. Fluoxetine failed to significantly alter behavior in either of the two phases. Moreover, the combination of fluoxetine with probiotics attenuated the anxiolytic-like effects of probiotics. The fluoxetine + probiotics combination had no effect on behavioral despair. The results of the current study align with other preclinical studies and some clinical trials suggesting probiotics may offer beneficial effects on anxiety. Investigations examining the anxiolytic-like mechanism of probiotics are needed before any conclusions can be made. Additionally, as the use of probiotics becomes more popular, research on the interactions between probiotic-microbiota and psychotropic medications is necessary.

Efficacy of Pharmacotherapies for Bulimia Nervosa: A Systematic Review and Meta-Analysis.

The main purpose was to evaluate the efficacy and tolerability of different medications used to treat bulimia nervosa (BN). Randomized controlled trials (RCTs) were identified from published sources through searches in PubMed, Cochrane Library, Web of Science, and Embase from inception to November 2022. Primary outcomes were changes in the frequency of binge eating episodes and vomiting episodes from baseline to endpoint. Secondary outcomes were differences in the improvement of scores in depressive symptoms, tolerability (dropout due to adverse events) and weight change. The literature search ultimately included 11 drugs, 33 studies and 6 types of drugs, 8 trials with TCAs (imipra-mine, desipramine), 14 with SSRIs (fluoxetine, citalopram and fluvoxamine), 6 with MAOIs (phenelzine, moclobemide and brofaromine), 3 with antiepileptic drugs (topiramate), 1 with mood stabilizers (lithium), and 1 with amphetamine-type appetite suppressant (fenfluramine). The reduction in binge eating episodes was more likely due to these drugs than the placebo, and the SMD was -0.4 (95% CI -0.61 ∼ -0.19); the changes in the frequency of vomiting episodes (SMD = -0.16, 95% CI -0.3 ∼ -0.03); weight (WMD = -3.05, 95% CI -5.97 ∼ -0.13); and depressive symptoms (SMD =-0.32, 95% CI -0.51 ∼ -0.13). However, no significant difference was found in dropout due to adverse events (RR = 1.66, 95% CI 1.14 ∼ 2.41). This meta-analysis indicates that most pharmacotherapies decreased the frequency of binge-eating and vomiting episodes, body weight, and depressive symptoms in BN patients, but the efficacy was not significant. In each drug the efficacy is different, treating different aspects, different symptoms to improve the clinical performance of bulimia nervosa.Appeared originally in BMC Pharmacol Toxicol 2023; 24:72.

Esketamine for resistant depression in older people with cognitive impairment: a case report

IntroductionDepression represents a significant challenge in terms of disability among the elderly population and its responsiveness to conventional treatment approaches tends to diminish in this population group. Esketamine has shown both effectiveness and safety in addressing treatment-resistant depression in older patients.ObjectivesCurrently, there is a lack of available literature regarding the use of esketamine in the treatment of patients experiencing both cognitive decline and treatment-resistant depression (TRD). We administered esketamine to a 79-year- old patient to evaluate the effectiveness and tolerance of the medication.MethodsWe recruited a 79 year old female referred to the outpatient clinics of Pavia suffering from TRD with current Severe Depressive Episode (scoring 42 on the MADRS) with cognitive impairment (MMSE 16/30). The patient was on a fourth-line treatment. First-line treatment was started with paroxetine 40 mg from september 2021 to May 2022, switched to sertraline 50 mg. Second-line treatment with quetiapine 150 mg from June 2022 to December 2022 failed, despite optimal compliance for both lines of treatment. Then third line treatment with fluoxetine 20 mg, olanzapine 10 mg was initiated from December 2022 to May 2023. Study duration was 12 weeks. Anamnestic data and psychometric (MADRS, HAMD-21, HAM-A) and cognitive (MMSE and MoCA TEST) assessment were collected from medical records at baseline (T0), one month (T1) and three month (T2) follow-ups.ResultsMADRS, HAM-A and HAM-D values decreased significantly at T1 and T2 follow-ups. T0: MADRS 42, HAM-D 33, HAM-A 54; T1: MADRS 18, HAM-D 12, HAM-A 15; T2: MADRS 4, HAM-D 5, HAM-A 10. We also observed an improvement in cognitive test: T0: MMSE 16/30, MoCA test 4/30; T1: MMSE 18/30, MoCA test 6/30; T2: MMSE 20/30, MoCA test 8/30. The patient reported one episode of hypertension treated with clonidine after two moth of treatment, and mild prolonged motor slowing lasting about two hours after esketamine in the first month.ConclusionsThis case documented a successful treatment using intranasal esketamine in combination with an SSRI (Fluoxetine) for an older individual with cognitive impairment and a persistent anxiety-depressive syndrome. This approach was employed as a therapeutic intervention after multiple unsuccessful attempts with other antidepressant medications. Our findings confirmed the safety and tolerability of esketamine in an elderly female with cognitive impairment. Although a minor improvement in cognitive abilities has been noted, secondary dysfunction attributable to vascular-based cognitive decline remained. In terms of cognitive tolerance, derivatives of ketamine could potentially serve as an alternative to electroconvulsive therapy in cases of treatment-resistant depression, potentially improving short-term cognitive outcomes.Disclosure of InterestNone Declared

Decreased Brain Serotonin in rbfox1 Mutant Zebrafish and Partial Reversion of Behavioural Alterations by the SSRI Fluoxetine.

RBFOX1 functions as a master regulator of thousands of genes, exerting a pleiotropic effect on numerous neurodevelopmental and psychiatric disorders. A potential mechanism by which RBFOX1 may impact these disorders is through its modulation of serotonergic neurotransmission, a common target for pharmacological intervention in psychiatric conditions linked to RBFOX1. However, the precise effects of RBFOX1 on the serotonergic system remain largely unexplored. Here we show that homozygous rbfox1sa15940 zebrafish, which express a shorter, aberrant rbfox1 mRNA, have significantly reduced serotonin levels in telencephalon and diencephalon. We observed that the acute administration of fluoxetine partially reverses the associated behavioural alterations. The hyperactive phenotype and altered shoaling behaviour of the rbfox1sa15940/sa15940 zebrafish could be reversed with acute fluoxetine exposure in the Open Field and the Shoaling test, respectively. However, in the other paradigms, hyperactivity was not diminished, suggesting a distinct intrinsic motivation for locomotion in the different paradigms. Acute fluoxetine exposure did not reverse the alterations observed in the aggression and social novelty tests, suggesting the involvement of other neurological mechanisms in these behaviours. These findings underscore the importance of investigating the intricate working mechanisms of RBFOX1 in neurodevelopmental and psychiatric disorders to gain a better understanding of the associated disorders along with their pharmacological treatment.

(100) Urinary and Gynecologic Adverse Events Associated with Ssri Use

Abstract Introduction SSRIs are the most prescribed psychiatric drug in the United States, with approximately 40% of patients reporting side effects to their provider (1,2). It is accepted that side effects of SSRIs may include sexual dysfunction, including decreased libido and anorgasmia (3,4). However, the safety of SSRIs on the functions of the genitourinary and reproductive systems in real-world settings remains unclear. Objective The aim of this study was to identify urinary and gynecologic adverse events associated with SSRIs using data from the FDA Adverse Events Reporting System (FAERS). Secondarily, we identify variability of adverse events across individual SSRIs. Methods A specialized software to analyze adverse events, OpenVigil 2.1, was used to query the FAERS data. We defined 445 search terms related to genitourinary and reproductive system related events. We performed disproportionality analysis to identify associations between search terms and SSRIs as a class, then each SSRI (fluoxetine, sertraline, paroxetine, escitalopram, citalopram). Subgroup analysis was performed to stratify adverse events by age. Results Adverse events related to SSRI usage include a variety of genitourinary and reproductive system related side effects, not limited to sexual dysfunction. Gynecologic bleeding, urinary retention, hypersexuality emerged as surprisingly statistically significant signals across females. Statistically significant adverse events related to sexual dysfunction were present up to age 60, with the strongest signals found in the 40-59 years age group. Urinary symptoms were most prevalent in the 0-18 years and over 60 years age group. Of the SSRIs, citalopram had the strongest association with sexual disorders and dysfunction. Conclusions In this study, we offer the most granular side effect profile of SSRIs related to the urinary and reproductive systems to date. While the pathophysiology of each adverse event remains unclear, an understanding of potential risks of these drugs is valuable in the management of patients taking SSRIs, particularly in the event of rare side effects that are often not associated with SSRI use. These are important considerations for clinical practice as side effects of SSRIs can impact treatment compliance and patient quality of life.

Efficacy of pharmacotherapies for bulimia nervosa: a systematic review and meta-analysis

ObjectiveThe main purpose was to evaluate the efficacy and tolerability of different medications used to treat bulimia nervosa (BN).MethodsRandomized controlled trials (RCTs) were identified from published sources through searches in PubMed, Cochrane Library, Web of Science, and Embase from inception to November 2022. Primary outcomes were changes in the frequency of binge eating episodes and vomiting episodes from baseline to endpoint. Secondary outcomes were differences in the improvement of scores in depressive symptoms, tolerability (dropout due to adverse events) and weight change.ResultsThe literature search ultimately included 11 drugs, 33 studies and 6 types of drugs, 8 trials with TCAs (imipramine, desipramine), 14 with SSRIs (fluoxetine, citalopram and fluvoxamine), 6 with MAOIs (phenelzine, moclobemide and brofaromine), 3 with antiepileptic drugs (topiramate), 1 with mood stabilizers (lithium), and 1 with amphetamine-type appetite suppressant (fenfluramine). The reduction in binge eating episodes was more likely due to these drugs than the placebo, and the SMD was -0.4 (95% CI -0.61 ~ -0.19); the changes in the frequency of vomiting episodes (SMD = -0.16, 95% CI -0.3 ~ -0.03); weight (WMD = -3.05, 95% CI -5.97 ~ -0.13); and depressive symptoms (SMD = -0.32, 95% CI -0.51 ~ -0.13). However, no significant difference was found in dropout due to adverse events (RR = 1.66, 95% CI 1.14 ~ 2.41).ConclusionsThis meta-analysis indicates that most pharmacotherapies decreased the frequency of binge-eating and vomiting episodes, body weight, and depressive symptoms in BN patients, but the efficacy was not significant. In each drug the efficacy is different, treating different aspects, different symptoms to improve the clinical performance of bulimia nervosa.

0972 The Utility of CSF Orexin Testing in Investigating for Narcolepsy Type-1 in a Patient with Diencephalic Mass

Abstract Introduction Narcolepsy type 1 (NT1) is characterized by pathologic hypersomnolence, REM intrusion phenomena, including cataplexy, and orexin deficiency. The diagnosis of NT1 is established based on the presence of bone fide cataplexy and supportive PSG and MSLT testing which requires patients to achieve sufficient sleep duration and regularity and discontinue centrally acting medications that might alter REM sleep. In cases where there is a high index of suspicion for NT1, CSF orexin deficiency is helpful to support the diagnosis of NT1. This is particularly true when PSG-MSLT are not feasible, CNS medication cannot be discontinued, or cataplexy cannot be validated. Report of case(s) A 16 year old girl presented for evaluation of excessive daytime sleepiness in the setting of suprasellar germinoma which was resected and treated with chemoradiation at age 11. She subsequently developed panhypopituitarism and severe hypersomnolence in the setting of sleep-wake schedule irregularities, variability of sleep duration, refractory delayed sleep phase disorder, and snoring. She reported episodic weakness in the setting of negative triggers, which was atypical for cataplexy. Her medications included modafinil, amphetamine-dextroamphetamine, and the SSRI fluoxetine. Physical examination depicted normal airways. Epworth Sleepiness Scale score was 18. Screening polysomnography showed a sleep efficiency of 78%, sleep latency of 46.5 minutes, REM latency 2 hours, AHI of 0/hr, and periodic limb movements of 35/hr without arousals. While the REM latency on polysomnography was inconsistent with NT1, the clinical history of a diencephalic mass and chemoradiation was suggestive of secondary NT1. She was unable to proceed with PSG-MSLT due to her psychiatrist's advice against discontinuing her SSRI and her difficulty in maintaining sleep-wake regularity. An evaluation for CSF orexin was performed establishing a normal level of 337 pg/mL (reference level of 200 pg/mL in healthy individuals), ruling out orexin deficiency /narcolepsy type 1. The patient was subsequently improved with wake-promoting antidepressants and light therapy in the AM. Conclusion This case illustrates the value of CSF orexin testing in the setting of diencephalic lesions in patients unable to undergo formal narcolepsy testing. Support (if any)

The role of serotonin in modulating common waxbill behaviour

Serotonin or 5-hydroxytryptamine (5-HT) is a monoaminergic neurotransmitter that is known to influence behaviour in various animal species. Its actions, however, are complex and not well-understood yet. Here, we tested whether and how two 5-HT receptor agonists and a 5-HT receptor antagonist influence behaviour in common waxbills (Estrilda astrild), focusing on aggression, movement and feeding. We applied acute administration of either 8-OH-DPAT (a 5-HT1A receptor agonist), fluoxetine (a selective serotonin reuptake inhibitor; SSRI) or WAY 100,635 (a 5-HT1A receptor antagonist), and then quantified behaviour in the context of competition for food. Waxbills treated with the SSRI fluoxetine showed an overall decrease of aggressive behaviour, activity and feeding, while we found no significant effects of treatment with the other serotonergic enhancer (8-OH-DPAT) or with the antagonist WAY 100,635. Since both 8-OH-DPAT and WAY 100,635 act mainly on 5-HT1A receptor pathways, while fluoxetine more generally affects 5-HT pathways, our results suggest that receptors other than 5-HT1A are important for serotonergic modulation of waxbill behaviour.Significance statementThe serotonergic system is of interest for current behavioural research due to its influence on a range of behaviours, including aggression, affiliative behaviour, feeding and locomotion in various species. There are, however, numerous discrepancies regarding the behavioural effects of serotonin across studies. We used acute pharmacological manipulations of the serotonergic system in common waxbills, using two serotonin enhancers (8-OH-DPAT and fluoxetine) and a serotonin blocker (WAY 100,635). Behavioural effects of these pharmacological manipulations on aggressiveness, movement and feeding, during tests of competition over food, indicated an anxiogenic-like effect of fluoxetine, but not of 8-OH-DPAT and WAY 100,635. This suggests a distinct role for different serotonergic pathways on waxbill behaviour.

Individual behavioral profiling as a translational approach to assess treatment efficacy in an animal model of post-traumatic stress disorder.

A major challenge in treating post-traumatic stress disorder (PTSD) continues to be the large variability in responsiveness to pharmacotherapy. Only 20-30% of patients experience total remission to a specific treatment, while others demonstrate either partial remission or no response. However, this heterogeneity in response to pharmacotherapy has not been adequately addressed in animal models, since these analyze the averaged group effects, ignoring the individual variability to treatment response, which seriously compromises the translation power of such models. Here we examined the possibility of employing an "individual behavioral profiling" approach, originally developed to differentiate between "affected" and "exposed-unaffected" individuals in an animal model of PTSD, to also enable dissociating "responders" or "non-responders" after SSRI (fluoxetine) treatment. Importantly, this approach does not rely on a group averaged response to a single behavioral parameter, but considers a cluster of behavioral parameters, to individually characterize an animal as either "responder" or "non-responder" to the treatment. The main variable to assess drug efficacy thus being the proportion of "responders" following treatment. Alteration in excitatory/inhibitory (E/I) balance has been proposed as being associated with stress-related psychopathology. Toward a functional proof of concept for our behaviorally-based characterization approach, we examined the expression patterns of α1 and α2 subunits of GABAA receptor, and GluN1 and GluN2A subunits of the NMDAR receptor in the ventral hippocampus, as well as electrophysiologically local circuit activity in the dorsal dentate gyrus (DG). We demonstrate that with both parameters, treatment "responders" differed from treatment "non-responders," confirming the functional validity of the behavior-based categorization. The results suggest that the ability to respond to fluoxetine treatment may be linked to the ability to modulate excitation-inhibition balance in the hippocampus. We propose that employing the "individual behavioral profiling" approach, and the resultant novel variable of the proportion of "recovered" individuals following treatment, offers an effective translational tool to assess pharmacotherapy treatment efficacy in animal models of stress and trauma-related psychopathology.

BDNF exon IV promoter methylation and antidepressant action: a complex interplay

BackgroundBDNF exon IV promoter methylation is a potential biomarker for treatment response to antidepressants in MDD. We have previously shown CpG-87 methylation as a successful biomarker for the prediction of non-response to monoaminergic antidepressants like the SSRI Fluoxetine or the SNRI Venlafaxine. This study aimed to dissect the biological evidence and mechanisms for the functionality of CpG-87 methylation in a cell culture model.ResultsWe observed a significant interaction between methylation and antidepressant-mediated transcriptional activity in BDNF exon IV promoter. In addition, antidepressant treatment increased the promoter methylation in a concentration-dependent manner. Further single CpG methylation of -87 did not change the promoter activity, but methylation of CREB domain CpG-39 increased the transcriptional activity in an antidepressant-dependent manner. Interestingly, DNMT3a overexpression also increases the BDNF exon IV transcription and more so in Venlafaxine-treated cells.ConclusionsThe study strengthens the previously reported association between antidepressant treatment and BDNF exon IV promoter methylation as well as hints toward the mechanism of action. We argue that potential CpG methylation biomarkers display a complex synergy with the molecular changes at the neighboring CpG positions, thus highlighting the importance of epiallele analyses.

QEEG Predictors of Treatment Response in Major Depressive Disorder- A Replication Study from Northwest India.

Background: Predicting treatment response with antidepressant is a challenging task for clinicians and researchers. An important limitation of an antidepressant trial is the increased time spent before an adequacy of trial can be decided. Quantitative Electroencephalography has shown some evidence in identifying early changes seen with antidepressants. No data has been reported from Indian population on its predictive capabilities. Aim: To examine whether early changes in frontal and prefrontal theta value in QEEG could predict antidepressant treatment response. Methods: Structured clinical assessments were conducted at baseline and after one week in a sample of treatment-seeking adults with major depressive disorder (n = 50). Patients were started on SSRI (Escitalopram, fluoxetine, paroxetine or sertraline) and followed for 8 weeks. QEEG recordings were carried out at baseline and week 1 and its parameters (relative theta power and cordance) were assessed to identify its predictive value for treatment response. Treatment response was assessed using Hamilton depression rating scale with 50% reduction after 8 weeks being considered as response. Results: Mean age of the sample was 39 ± 10 years and majority of them were females (64%). A significant reduction was found in relative frontal theta value (p = 0.021) from baseline to one week in responders. However, linear regression revealed that this change could not predict the treatment response (p = 0.37). Conclusions: QEEG changes are observed in initial phase of antidepressant treatment but these changes can't predict the treatment response.

Fluvoxamine and fluoxetine in the treatment of patients with the novel coronavirus infection

Depression is the most common mental illness in the world, affecting 4.4 % of the world's population. There is a large number of depression types, each of which is characterized by signs atypical for other types: a seasonal pattern, increased anxiety, psychotic features, melancholy, and many others. Each type of depression may respond to certain types of pharmacological treatment better than others, but despite a variety of treatment methods, depressive disorders remain difficult to treat due to many factors, including the relatively high relapse rate during treatment and the adverse side effects of the drugs used. This article discusses the use of SSRIs fluoxetine and fluvoxamine in the treatment of depressive disorders and their impact on the COVID-19 course.

SSRIs treatment did not completely restore affective state in patients with the initial clinically confirmed major depressive disorder/generalized anxiety disorder after COVID-19 disease

IntroductionThe major clinical outcomes of COVID-19 in the brain are associated with its deleterious neurological and mental health actions.Today, there are limited findings concerning the studying of neuropsychiatric action for SARS-Cov-2 in humans after COVID-19 disease.ObjectivesThe aim of the present study was to compare the efficacy of SSRIs (escitalopram, sertraline and fluoxetine) for 6 months therapy on the affective profile of man and women with the clinically confirmed Major Depressive Disorder (MDD) or Generalized Anxiety Disorder (GAD) cases following COVID-19 disease.Methods. For the assessment of affective profile in man and women (30-55 years) with the initial clinically confirmed MDD or GAD cases after COVID-19 disease, we used the different tests: Montgomery-Asberg Depression Rating Scale (MADRS) and anxiety scale (ShARS Scale). The hormonal and monoamines levels in the serum blood were measured by ELISA tests before and after SSRIs therapy.Results After 6 months of SSRIs therapy, MADRS Scale showed a incomplete disappearance of the depressive/anxiety manifestations in both men and women with the initial clinically confirmed MDD case after COVID-19 (p<0,05). We found that SSRIs were able to reduce depression/anxiety levels only on 20% in man or on 30% in women with the initial MDD case after COVID-19 before treatment.ConclusionsSSRIs treatmet alone failed to produce the decrease of depression/anxiety in the patients of both gender with the initial MDD or GAD diagnosis after COVID-19. The further randomized clinical trials involving new pharmacological therapies for psychiatric pations after COVID-19 disease are needed.DisclosureNo significant relationships.

A Review on Pharmacokinetic and Pharmacodynamic Drug Interactions of Adrenergic β-blockers with Clinically Relevant Drugs-An Overview

Adrenergic β-blockers are used to treat many conditions, including hypertension, cardiac arrhythmias, heart failure, angina pectoris, migraine, and tremors. The majority of the β-blockers including Propranolol, Metoprolol, Acebutolol, Alprenolol, Betaxolol, Carvedilol, Nebivolol and Oxprenolol are metabolised majorly by CYP2D6, and Bisoprolol is primarily metabolised by CYP3A4 enzymes. The drugs inhibiting or inducing them may alter the pharmacokinetics of those β-blockers. The plasma concentrations of Propranolol might be elevated by the concomitant use of drugs, such as SSRIs (Fluoxetine, Paroxetine), SNRIs (Duloxetine) and Cimetidine, while the plasma concentrations of Metoprolol increased by the concurrent use of SSRIs (Fluoxetine, Paroxetine), Amiodarone, Celecoxib, Cimetidine, Terbinafine, and Diphenhydramine. β-blockers can also interact pharmacodynamically with drugs, including fluoroquinolones, antidiabetic agents and NSAIDs. In addition, β-blockers may interact with herbs, such as curcumin, Ginkgo biloba, Schisandra chinensis, green tea, guggul, hawthorn, St. John's wort and Yohimbine. This article focuses on clinically relevant drug interactions of β-blockers with commonly prescribed medications. In addition to Pharmacokinetics and Pharmacodynamics of the drug interactions, recommendations for clinical practice are highlighted. The prescribers and the pharmacists are needed to be aware of the drugs interacting with β-blockers to prevent possible adverse drug interactions.

Early Developmental Exposure to Fluoxetine and Citalopram Results in Different Neurodevelopmental Outcomes

Although selective serotonin reuptake inhibitors are commonly prescribed for prenatal depression, there exists controversy over adverse effects of SSRI use on fetal development. Few studies have adequately isolated outcomes due to SSRI exposure and those due to maternal psychiatric conditions. Here, we directly investigated outcomes of exposure to widely-used SSRIs Fluoxetine and Citalopram on the developing nervous system of Xenopus laevis tadpoles, using an integrative experimental approach. We exposed tadpoles to low doses of Citalopram and Fluoxetine during a critical developmental period and found that different experimental groups displayed opposing behavioral effects. While both groups showed reduced schooling behavior, the Fluoxetine group showed increased seizure susceptibility and reduced startle habituation. In contrast, Citalopram treated tadpoles had decreased seizure susceptibility and increased habituation. Both groups had abnormal dendritic morphology in the optic tectum, a brain area important for behaviors tested. Whole-cell electrophysiological recordings of tectal neurons showed no differences in synaptic function; however, tectal cells from Fluoxetine-treated tadpoles had decreased voltage gated K+ currents while cells in the Citalopram group had increased K+ currents. Both behavioral and electrophysiological findings indicate that cells and circuits in the Fluoxetine treated optic tecta are hyperexcitable, while the Citalopram group exhibits decreased excitability. Taken together, these results show that early developmental exposure to SSRIs is sufficient to induce neurodevelopmental effects, however these effects can be complex and vary depending on the SSRI. This may explain some discrepancies across human studies, and further underscores the importance of serotonergic signaling for the developing nervous system.

Fluoxetine Administration During Lactation Impacts the Bone Health of the Dam and the Offspring in Mice

Selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed class of antidepressants during pregnancy and lactation. SSRIs decrease bone mineral density (BMD) across all ages and sexes. Lactation is also characterized by increased bone resorption to mobilize calcium and achieves this via a serotonin-induced hormonal cascade. This serotonin-mediated bone loss is normally restored after weaning but is persistent when an SSRI is administered during the peripartum period. Our lab has previously shown that administration of the SSRI fluoxetine (FLX) during both gestation and lactation results in compromised bone health of the dam, which is characterized by a decreased bone mineral density (BMD). Along with this, we have also shown a decrease in BMD and femoral length in the offspring of the FLX-treated dams at weaning. We hypothesize that FLX usage during lactation only will impact the bone health of the dam as well as the bone health of her offspring due to exposure to FLX via the dam’s milk. Female C57BL/6 mice were randomized to receive the SSRI fluoxetine hydrochloride (20 mg/kg) or saline daily from the beginning of lactation (D0) through the end of lactation (D21), resulting in the following treatments: FLX dams (n=13) and control dams (n=13). The offspring of the treated dams were then harvested at weaning (3 weeks of age). During the peripartal period, the BMD of the dam was monitored via dual x-ray absorptiometry (DEXA). A baseline scan was taken at 6 weeks of age, at the end of pregnancy (E17.5), the beginning of lactation (D2), peak lactation (D10), and at the end of lactation (D21). There was no significant difference in the BMD of the FLX dams compared to the control dams at 6 weeks of age (p=0.9992), E17.5 (p=0.9995), D2 (p>0.9999), or D10 (p>0.9999). However, at D21, the FLX dams had a decreased BMD compared to the control dams (p=0.0493). Along with the decreased BMD of the FLX dams at weaning, there was a significant decrease in femur length in the pups of the FLX dams (p=0.0040). When the pups were separated by sex, the decreased femur length was observed in both the male (p=0.0413) and female (p=0.0047) offspring. These data suggest that fluoxetine use during lactation only results in a decreased BMD of the treated dams, as well as decreased femur length in the exposed offspring in both sexes.

β-sitosterol reduces anxiety and synergizes with established anxiolytic drugs in mice

SummaryAnxiety and stress-related conditions represent a significant health burden in modern society. Unfortunately, most anxiolytic drugs are prone to side effects, limiting their long-term usage. Here, we employ a bioinformatics screen to identify drugs for repurposing as anxiolytics. Comparison of drug-induced gene-expression profiles with the hippocampal transcriptome of an importin α5 mutant mouse model with reduced anxiety identifies the hypocholesterolemic agent β-sitosterol as a promising candidate. β-sitosterol activity is validated by both intraperitoneal and oral application in mice, revealing it as the only clear anxiolytic from five closely related phytosterols. β-sitosterol injection reduces the effects of restraint stress, contextual fear memory, and c-Fos activation in the prefrontal cortex and dentate gyrus. Moreover, synergistic anxiolysis is observed when combining sub-efficacious doses of β-sitosterol with the SSRI fluoxetine. These preclinical findings support further development of β-sitosterol, either as a standalone anxiolytic or in combination with low-dose SSRIs.

Association between antidepressant use and reduced risk of intubation or death in hospitalized patients with COVID-19: results from an observational study.

A prior meta-analysis showed that antidepressant use in major depressive disorder was associated with reduced plasma levels of several pro-inflammatory mediators, which have been associated with severe COVID-19. Recent studies also suggest that severalantidepressants may inhibit acid sphingomyelinase activity, which may prevent the infection of epithelial cells with SARS-CoV-2, and that the SSRI fluoxetine may exert in-vitro antiviral effects on SARS-CoV-2. We examined the potential usefulness of antidepressant use in patients hospitalized for COVID-19 in an observational multicenter retrospective cohort study conducted at AP-HP Greater Paris University hospitals. Of 7230 adults hospitalized for COVID-19, 345 patients (4.8%) received an antidepressant within 48 h of hospital admission. The primary endpoint was a composite of intubation or death. We compared this endpoint between patients who received antidepressants and those who did not in time-to-event analyses adjusted for patient characteristics, clinical and biological markers of disease severity, and other psychotropic medications. The primary analysis was a multivariable Cox model with inverse probability weighting. This analysis showed a significant association between antidepressant use and reduced risk of intubation or death (HR, 0.56; 95% CI, 0.43-0.73, p < 0.001). This association remained significant in multiple sensitivity analyses. Exploratory analyses suggest that this association was also significant for SSRI and non-SSRI antidepressants, and for fluoxetine, paroxetine, escitalopram, venlafaxine, and mirtazapine (all p < 0.05). These results suggest that antidepressant use could be associated with lower risk of death or intubation in patients hospitalized for COVID-19. Double-blind controlled randomized clinical trials of antidepressant medications for COVID-19 are needed.

Reduced Motivation in Perinatal Fluoxetine-Treated Mice: A Hypodopaminergic Phenotype.

Early life is a sensitive period, in which enhanced neural plasticity allows the developing brain to adapt to its environment. This plasticity can also be a risk factor in which maladaptive development can lead to long-lasting behavioral deficits. Here, we test how early-life exposure to the selective-serotonin-reuptake-inhibitor (SSRI), fluoxetine, affects motivation, and dopaminergic signaling in adulthood. We show for the first time that mice exposed to fluoxetine in the early postnatal period exhibit a reduction in effort-related motivation. These mice also show blunted responses to amphetamine and reduced dopaminergic activation in a sucrose reward task. Interestingly, we find that the reduction in motivation can be rescued in the adult by administering bupropion, a dopamine-norepinephrine reuptake inhibitor used as an antidepressant and a smoke cessation aid but not by fluoxetine. Taken together, our studies highlight the effects of early postnatal exposure of fluoxetine on motivation and demonstrate the involvement of the dopaminergic system in this process.SIGNIFICANCE STATEMENT The developmental period is characterized by enhanced plasticity. During this period, environmental factors have the potential to lead to enduring behavioral changes. Here, we show that exposure to the SSRI fluoxetine during a restricted period in early life leads to a reduction in adult motivation. We further show that this reduction is associated with decreased dopaminergic responsivity. Finally, we show that motivational deficits induced by early-life fluoxetine exposure can be rescued by adult administration of bupropion but not by fluoxetine.

Perinatal fluoxetine exposure disrupts the circadian response to a phase-shifting challenge in female rats

RationaleSelective serotonin reuptake inhibitor (SSRI) antidepressants are increasingly prescribed during pregnancy. Changes in serotonergic signaling during human fetal development have been associated with changes in brain development and with changes in affective behavior in adulthood. The suprachiasmatic nucleus (SCN) is known to be modulated by serotonin and it is therefore assumed that SSRIs may affect circadian rhythms. However, effects of perinatal SSRI treatment on circadian system functioning in the offspring are largely unknown.ObjectiveOur aim was to investigate the effects of perinatal exposure to the SSRI fluoxetine (FLX) on circadian behavior, affective behavior, and 5-HT1A receptor sensitivity in female rats. In addition, we studied the expression of clock genes and the 5-HT1A receptor in the SCN, as they are potentially involved in underlying mechanisms contributing to changes in circadian rhythms.ResultsPerinatal FLX exposure shortened the free-running tau in response to the 5-HT1A/7 agonist 8-OH-DPAT. However, FLX exposure did not alter anxiety, stress coping, and 5-HT1A receptor sensitivity. No differences were found in 5-HT1A receptor and clock genes Per1, Per2, Cry1, and Cry2 SCN gene expression.ConclusionsPerinatal FLX exposure altered the response to a phase-shifting challenge in female rats, whether this may pose health risks remains to be investigated.