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PloS One 2022Depression in mammals is known to be associated with poor reproductive capacity. In males, it has been associated with decreased efficiency of spermatogenesis as well as...
Depression in mammals is known to be associated with poor reproductive capacity. In males, it has been associated with decreased efficiency of spermatogenesis as well as the production of spermatozoa of reduced structural and functional integrity. Although antidepressants are effective in correcting depressive states, there is controversy regarding their effectiveness in restoring male reproductive function. Here, using an animal model of depression induced by a forced swim test, we confirmed that depression is accompanied by impaired male reproductive function. We further show that administration of a conventional antidepressant of the serotonin reuptake inhibitor class (paroxetine) impairs male reproductive performance in terms of sperm production and quality when administered to healthy animals. Intriguingly, when paroxetine is administered to "depressed" animals, it resulted in a complete restoration of the animal's ability to produce sperm that appears to be as capable of meeting the parameters evaluated here as those of control animals. The one-carbon cycle (1CC) is one of the most important metabolic cycles that include the methionine and folate cycles and plays a major role in DNA synthesis, amino acids, and also the production of antioxidants. Our results show that depression affects the main components of this cycle and paroxetine on healthy mice increases homocysteine levels, decreases glycine and vitamin B12, while in depressed mice, it increases folate levels and decreases vitamin B12. Thus, paroxetine exerts negative impacts on male reproductive function when administered to healthy animals and it well correlate with the altered sperm parameters and functions of depressed animals, and its mechanism remains to be explored.
Topics: Male; Mice; Animals; Paroxetine; Semen; Models, Animal; Spermatozoa; Vitamin B 12; Folic Acid; Mammals
PubMed: 36480503
DOI: 10.1371/journal.pone.0271217 -
Psychoneuroendocrinology Oct 2021Selective serotonin reuptake inhibitors (SSRI) show high efficacy in treating depression, however during treatment side effects, like for instance sexual dysfunction,...
Selective serotonin reuptake inhibitors (SSRI) show high efficacy in treating depression, however during treatment side effects, like for instance sexual dysfunction, may appear, decreasing compliance. In some cases, this condition will last after drug discontinuation, leading to the so-called post-SSRI sexual dysfunction (PSSD). The etiology of PSSD is still unknown, however a role for neuroactive steroids may be hypothesized. Indeed, these molecules are key physiological regulators of the nervous system, and their alteration has been associated with several neuropathological conditions, including depression. Additionally, neuroactive steroids are also involved in the control of sexual function. Interestingly, sexual dysfunction induced by SSRI treatment has been also observed in animal models. On this basis, we have here evaluated whether a subchronic treatment with paroxetine for two weeks and/or its withdrawal (i.e., a month) may affect the levels of neuroactive steroids in brain areas (i.e., hippocampus, hypothalamus, and cerebral cortex) and/or in plasma and cerebrospinal fluid of male rats. Data obtained indicate that the SSRI treatment alters neuroactive steroid levels and the expression of key enzymes of the steroidogenesis in a brain tissue- and time-dependent manner. Indeed, these observations with the finding that plasma levels of neuroactive steroids are not affected suggest that the effect of paroxetine treatment is directly on neurosteroidogenesis. In particular, a negative impact on the expression of steroidogenic enzymes was observed at the withdrawal. Therefore, it is possible to hypothesize that altered neurosteroidogenesis may also occur in PSSD and consequently it may represent a possible pharmacological target for this disorder.
Topics: Animals; Hippocampus; Male; Neurosteroids; Paroxetine; Rats; Selective Serotonin Reuptake Inhibitors; Sexual Dysfunction, Physiological
PubMed: 34325207
DOI: 10.1016/j.psyneuen.2021.105364 -
International Journal of Molecular... Dec 2023Pathological cardiac remodeling is associated with cardiovascular disease and can lead to heart failure. Nuclear factor-kappa B (NF-κB) is upregulated in the...
Cardioprotective Effects of the GRK2 Inhibitor Paroxetine on Isoproterenol-Induced Cardiac Remodeling by Modulating NF-κB Mediated Prohypertrophic and Profibrotic Gene Expression.
Pathological cardiac remodeling is associated with cardiovascular disease and can lead to heart failure. Nuclear factor-kappa B (NF-κB) is upregulated in the hypertrophic heart. Moreover, the expression of the G-protein-coupled receptor kinase 2 (GRK2) is increased and linked to the progression of heart failure. The inhibitory effects of paroxetine on GRK2 have been established. However, its protective effect on IκBα/NFκB signaling has not been elucidated. This study investigated the cardioprotective effect of paroxetine in an animal model of cardiac hypertrophy (CH), focusing on its effect on GRK2-mediated NF-κB-regulated expression of prohypertrophic and profibrotic genes. Wistar albino rats were administered normal saline, paroxetine, or fluoxetine, followed by isoproterenol to induce CH. The cardioprotective effects of the treatments were determined by assessing cardiac injury, inflammatory biomarker levels, histopathological changes, and hypertrophic and fibrotic genes in cardiomyocytes. Paroxetine pre-treatment significantly decreased the HW/BW ratio ( < 0.001), and the expression of prohypertrophic and profibrotic genes Troponin-I ( < 0.001), BNP ( < 0.01), ( < 0.001), hydroxyproline ( < 0.05), ( < 0.05), and ( < 0.01) as well as inflammatory markers. It also markedly decreased pIκBα, NFκB(p105) subunit expression ( < 0.05) and phosphorylation. The findings suggest that paroxetine prevents pathological cardiac remodeling by inhibiting the GRK2-mediated IκBα/NF-κB signaling pathway.
Topics: Rats; Animals; NF-kappa B; Paroxetine; NF-KappaB Inhibitor alpha; Isoproterenol; G-Protein-Coupled Receptor Kinase 2; Ventricular Remodeling; Myocytes, Cardiac; Cardiomegaly; Heart Failure; Rats, Wistar; Gene Expression
PubMed: 38139099
DOI: 10.3390/ijms242417270 -
Asian Journal of Psychiatry Jun 2021This systematic review aims to assess the efficacy and acceptability of the different types of antidepressants and benzodiazepines for the treatment of panic disorder... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
This systematic review aims to assess the efficacy and acceptability of the different types of antidepressants and benzodiazepines for the treatment of panic disorder (PD) in adult patients.
METHODS
PubMed, Web of Science, EMBASE, MEDLINE, the Cochrane Library, and ClinicalTrials.gov were searched for randomized controlled trials (RCTs) published between 1995 and 2020 on the use of antidepressants and benzodiazepines for the treatment of PD. A systematic review and network meta-analysis were performed.
RESULTS
42 RCTs were included in the network meta-analysis, with a comparison of 11 interventions.Escitalopram (odds ratios OR 1.52, 95 % credible interval CI 1.09-2.10), venlafaxine (OR 1.33, 95 % CI 1.16-1.51) and benzodiazepines (OR 1.50, 95 % CI 1.29-1.75) had greater efficacy and acceptability than the placebo. Imipramine(OR 1.43, 95 % CI 1.15-1.79) was also demonstrated to be efficacious and tolerated but the results were restricted to small sample size. Moreover, paroxetine, sertraline, fluoxetine, citalopram and clomipramine (OR 1.37, 1.36, 1.45, 1.33 and 1.36, respectively) were more efficacious, although the acceptability of paroxetine and sertraline were significantly less tolerated than benzodiazepines. Notably, the efficacy of reboxetine and fluvoxamine were merely as equal as that of the placebo.
OUTCOMES
This is the first systematic review of antidepressants and benzodiazepines for the treatment of PD to use a network analysis. Escitalopram and venlafaxine as well as benzodiazepines may be effective choices as treatments for PD with relatively good acceptability, which still needs to be confirmed byhigh-quality RCTs.
Topics: Adult; Antidepressive Agents; Benzodiazepines; Humans; Network Meta-Analysis; Panic Disorder; Paroxetine
PubMed: 33965693
DOI: 10.1016/j.ajp.2021.102664 -
Psychoneuroendocrinology Sep 2022Paroxetine, a selective serotonin reuptake inhibitor (SSRI), is prescribed to treat psychiatric disorders, although an off-label SSRI use is also for functional...
Paroxetine, a selective serotonin reuptake inhibitor (SSRI), is prescribed to treat psychiatric disorders, although an off-label SSRI use is also for functional gastrointestinal disorders. The mutual correlation between serotonin and peripheral sex steroids has been reported, however little attention to sex steroids synthesized by gut, has been given so far. Indeed, whether SSRIs, may also influence the gut steroid production, immediately after treatment and/or after suspension, is still unclear. The finding that gut possesses steroidogenic capability is of particular relevance, also for the existence of the gut-microbiota-brain axis, where gut microbiota represents a key orchestrator. On this basis, adult male rats were treated daily for two weeks with paroxetine or vehicle and, 24 h after treatment and at 1 month of withdrawal, steroid environment and gut microbiota were evaluated. Results obtained reveal that paroxetine significantly affects steroid levels, only in the colon but not in plasma. In particular, steroid modifications observed immediately after treatment are not overlap with those detected at withdrawal. Additionally, paroxetine treatment and its withdrawal impact gut microbiota populations differently. Altogether, these results suggest a biphasic effect of the drug treatment in the gut both on steroidogenesis and microbiota.
Topics: Animals; Colon; Humans; Male; Microbiota; Paroxetine; Rats; Selective Serotonin Reuptake Inhibitors; Steroids
PubMed: 35700562
DOI: 10.1016/j.psyneuen.2022.105828 -
Journal of Neuroinflammation Feb 2020Astrocytes are the most abundant glial cells in a brain that mediate inflammatory responses and provide trophic support for neurons. We have previously disclosed that...
BACKGROUND
Astrocytes are the most abundant glial cells in a brain that mediate inflammatory responses and provide trophic support for neurons. We have previously disclosed that paroxetine, a common selective serotonin reuptake inhibitor, ameliorates LPS-induced microglia activation. However, it remains elusive for the role of paroxetine in astrocytic responses.
METHODS
Isolated primary astrocytes were pretreated with paroxetine and stimulated with different stimuli, lipopolysaccharide (LPS) or microglia conditioned medium pre-activated with LPS (M/Lps). Inflammatory and neurotrophic responses, underlying mechanisms and the impact on neuronal survival were assessed.
RESULTS
Paroxetine had no impact on LPS-stimulated iNOS, TNF-α, and IL-1β expression, but inhibited M/Lps-induced TNF-α and IL-1β expression in primary astrocytes. Paroxetine suppressed M/Lps- but not LPS-induced activation of NF-κB and had no impact on the activation of MAPKs and STAT3. Incubation with the resulted astrocyte conditioned media caused no change in the viability of SH-SY5Y cells. BDNF and MANF mRNA expressions were upregulated by M/Lps and paroxetine, respectively. However, M/Lps- or LPS-induced extracellular releases of NO, TNF-α, and/or BDNF in astrocytes were in minor amount compared to those by microglia.
CONCLUSIONS
Paroxetine ameliorates the reactive microglia-mediated inflammatory responses in astrocytes partially via inhibition of the NF-κB pathway but has no impact on LPS-stimulated astrocyte activation. While the effects of paroxetine on secondary astrocytic responses are not robust compared to its effect on the innate immune responses of microglia, the results together may implicate a therapeutic potential of paroxetine against neuroinflammation-associated neurological disorders such as Parkinson's disease.
Topics: Animals; Astrocytes; Cell Line; Humans; Inflammation; Interleukin-1beta; Lipopolysaccharides; Mice; Microglia; Nitric Oxide Synthase Type II; Paroxetine; Selective Serotonin Reuptake Inhibitors; Tumor Necrosis Factor-alpha
PubMed: 32024542
DOI: 10.1186/s12974-020-1712-0 -
BMC Urology Jan 2019Paroxetine is one of the selective serotonin reuptake inhibitors (SSRIs) used in the treatment of premature ejaculation (PE). However, this use is not approved in many... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Paroxetine is one of the selective serotonin reuptake inhibitors (SSRIs) used in the treatment of premature ejaculation (PE). However, this use is not approved in many countries. The purpose of this systematic review and meta-analysis is to review the efficacy and safety of paroxetine for PE patients.
METHODS
We searched relevant randomized, controlled trials through May 2018, using PubMed, Embase and Cochrane Central Register. The main endpoint included intra-vaginal ejaculatory latency time (IELT) and side effects in the treatment of PE. Cochrane Collaboration's Revman software, version 5.3, was used for statistical analysis.
RESULTS
Out of 493 unique articles, a total of 19 randomized, controlled trials (RCTs) were reviewed. Quite a few RCTs were considered to have unclear risk of bias because of limited information. Pooled outcomes suggested that paroxetine was more effective than placebo, fluoxetine and escitalopram at increasing IELT (all p < 0.05). However, there existed a high level of heterogeneity in the paroxetine vs. fluoxetine groups and the paroxetine vs. placebo groups. Comparing paroxetine with tramadol, sertraline, phosphodiesterase 5 inhibitors (PDE5Is), local lidocaine gel, behaviour therapy or dapoxetine, we found that the increase in IELT was not statistically significant between groups. Paroxetine combined with tadalafil or behaviour therapy was more efficacious than paroxetine alone (all p < 0.05). Although the side effects in the combination group were more common than in the paroxetine alone group, the most common adverse events, such as nausea, muscle soreness, palpitation and flushing, were mild and tolerable. The main limitations of this systematic review and meta-analysis were the different definitions of PE and short follow-up times.
CONCLUSIONS
According to this systematic review and meta-analysis, paroxetine provided better efficacy than placebo, fluoxetine and escitalopram in the treatment of PE, with well-tolerated side effects. The combination group had better efficacy than the paroxetine alone group.
TRIAL REGISTRATION
This review was reported in agreement with the PRISMA statement and was registered on PROSPERO 2018CRD42018097014 .
Topics: Humans; Male; Paroxetine; Premature Ejaculation; Randomized Controlled Trials as Topic; Selective Serotonin Reuptake Inhibitors; Treatment Outcome
PubMed: 30606186
DOI: 10.1186/s12894-018-0431-7 -
Journal of Oncology Pharmacy Practice :... Jun 2020Intractable and persistent cough is experienced by more than a third of patients with advanced cancer, with a significant negative impact on quality of life....
INTRODUCTION
Intractable and persistent cough is experienced by more than a third of patients with advanced cancer, with a significant negative impact on quality of life. Pharmacological treatment has been of little help in some patients. Limited evidence suggests novel agents such as paroxetine may reduce cough severity. This retrospective study aimed to assess effectiveness and tolerability of paroxetine for the treatment of intractable cough in patients with cancer.
METHODS
Single-centre medical record review of paroxetine use in patients with advanced malignancy and cough treated at an Australia tertiary referral cancer centre between 1 October 2012 and 1 October 2017. Data relating to cough type and severity, response and adverse events were extracted from medical records. Cough type was described as non-productive dry cough, productive chesty cough or cough exhibiting both non-productive and productive features (mixed cough).
RESULTS
Overall, 24/34 patients (71%) experienced a major or moderate reduction in their cough severity after treatment with paroxetine. Nearly half (47%) described a major improvement and a quarter (24%) moderate improvement. Of the 34 patients, nearly half had a lung primary cancer (16/34, 47%) and nearly all (17/18) of those without lung cancer had lung metastases from another primary cancer. Patients with dry cough reported greater benefit from paroxetine. Of the 56% (19/34) of patients with non-productive dry cough, 80% (15/19) reported an improvement in symptoms post paroxetine. The remaining 15 patients, 44% of the group, presented with either a productive chesty cough (9/34, 27%) or mixed cough (6/34, 18%). Of these patients, 60% (9/15) reported an improvement in symptoms. Two thirds of patients were commenced on paroxetine 10 mg (22/34, 65%), with the remainder starting at 20 mg (14/34, 35%).
CONCLUSION
Paroxetine may be an effective, novel, off-label treatment for intractable and persistent cough in patients with advanced cancer.
Topics: Adult; Aged; Aged, 80 and over; Australia; Cough; Female; Humans; Male; Middle Aged; Neoplasms; Paroxetine; Quality of Life; Retrospective Studies
PubMed: 31446865
DOI: 10.1177/1078155219870594 -
Andrologia Sep 2022The primary goal of this systematic review and meta-analysis was to compare the efficacy and safety of fluoxetine with other oral pharmaceuticals in the treatment of... (Meta-Analysis)
Meta-Analysis Review
The primary goal of this systematic review and meta-analysis was to compare the efficacy and safety of fluoxetine with other oral pharmaceuticals in the treatment of premature ejaculation (PE). We searched through databases including CNKI, PubMed, EMBASE and Cochrane to find research published up to 31 March 2022. PROSPERO was used to pre-register this meta-analysis (registration number CRD42022315459). Two separate writers extracted relevant details from all of the papers included in the study. To analyse the quality of literature publishing, we used the Cochrane risk of bias tool. The severity of premature ejaculation was determined using intravaginal ejaculatory latency time (IELT), and the effectiveness and safety of pharmacological interventions were determined using standardized mean difference (SMD) and risk ratio (RR) values with matching 95% confidence level intervals (95% CIs). Our meta-analysis includes a total of ten trials to investigate into the differences in treatment efficacy and safety between fluoxetine and other medicines. The findings revealed that fluoxetine was more effective than placebo in treating PE, whereas sertraline and paroxetine were more effective than fluoxetine (p < 0.05). The side effects of the medications were not significantly different, and they were all acceptable. The results of the sensitivity analysis were unaffected by the removal of any of the articles. There was no evidence of bias in the media. This meta-analysis examined the differences in efficacy and safety between fluoxetine and other oral medications and can be used by clinicians in the treatment of PE.
Topics: Ejaculation; Fluoxetine; Humans; Male; Paroxetine; Premature Ejaculation; Selective Serotonin Reuptake Inhibitors; Sertraline; Treatment Outcome
PubMed: 35760074
DOI: 10.1111/and.14500 -
Journal of Psychopharmacology (Oxford,... Jul 2020Major depression is a common mood disorder and the central sphingolipid system has been identified as a possible drug target of this condition. Here we investigated the...
BACKGROUND
Major depression is a common mood disorder and the central sphingolipid system has been identified as a possible drug target of this condition. Here we investigated the action of antidepressant drugs on sphingolipid levels in rat brain regions, plasma and in cultured mouse macrophages.
METHODS
Two antidepressant drugs were tested: the serotonin reuptake inhibitor paroxetine and the noradrenaline reuptake inhibitor desipramine, either following acute or chronic treatments. Content of sphingosine and ceramide were analysed using LC-MS or HPLC-UV, respectively. This was from samples of brain, plasma and cultured mouse macrophages. Antidepressant-induced effects on mRNA expression for two key genes of the sphingolipid pathway, and , were also measured by using quantitative real-time PCR.
RESULTS
Chronic but not acute administration of paroxetine or desipramine reduced sphingosine levels in the prefrontal cortex and hippocampus (only paroxetine) but not in the striatum. Ceramide levels were also measured in the hippocampus following chronic paroxetine and likewise to sphingosine this treatment reduced its levels. The corresponding collected plasma samples from chronically treated animals did not show any decrease of sphingosine compared to the corresponding controls. Both drugs failed to reduce sphingosine levels from cultured mouse macrophages. The drug-induced decrease of sphingolipids coincided with reduced mRNA expression of two enzymes of the central sphingolipid pathway, i.e. acid sphingomyelinase () and acid ceramidase ().
CONCLUSIONS
This study supports the involvement of brain sphingolipids in the mechanism of action by antidepressant drugs and for the first time highlights their differential effects on brain versus plasma levels.
Topics: Acid Ceramidase; Adrenergic Uptake Inhibitors; Animals; Brain; Depressive Disorder, Major; Desipramine; Disease Models, Animal; Male; Mice; Paroxetine; RAW 264.7 Cells; Rats; Rats, Sprague-Dawley; Selective Serotonin Reuptake Inhibitors; Sphingolipids; Sphingomyelin Phosphodiesterase
PubMed: 32403969
DOI: 10.1177/0269881120915412