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Psychoneuroendocrinology Feb 2022Sexual dysfunction is a common clinical condition due to different causes including the use of selective serotonin reuptake inhibitors (SSRI). Especially, SSRI...
Sexual dysfunction is a common clinical condition due to different causes including the use of selective serotonin reuptake inhibitors (SSRI). Especially, SSRI paroxetine is known to cause numerous types of sexual dysfunction in men. There is growing interest in exercise as a non-pharmacological approach for the treatment of SSRI-induced sexual dysfunction. With these in mind, we investigated the effects of irisin, which is a recently detected exercise-linked hormone, on paroxetine-induced sexual dysfunction in male rats. Our findings showed that circulating irisin levels were lower in paroxetine-induced sexual dysfunction in male rats (20 mg/kg/day for 8 weeks by oral gavage than in vehicle-treated rats). In addition, results from sexual behavioral tests revealed that subcutaneous irisin perfusion (100 ng/kg/day via mini-osmotic pumps for 28 days) ameliorated sexual motivation and copulatory performance in sexually impaired male rats treated with paroxetine. The significantly reduced serum testosterone levels and α1-adrenoceptors (ADRA1A) and tyrosine hydroxylase gene (TH) expression levels in the nucleus accumbens (NAc) in paroxetine-induced sexually dysfunctioning male rats were markedly increased following irisin exposure. Similarly, the expression levels of ADRA1A and TH in the medial preoptic area (mPOA) significantly increased in male rats co-administered with paroxetine and irisin compared to the vehicle-treated male rats. These results demonstrate that irisin may be a therapeutic modality that mimics/supports the beneficial effects of exercise for improving SSRI-associated sexual dysfunction in men through increase in serum testosterone levels and increased expression of α1-adrenoceptors and TH in the NAc and mPOA associated with sexual motivation and copulatory behaviors.
Topics: Animals; Humans; Male; Paroxetine; Rats; Receptors, Adrenergic; Selective Serotonin Reuptake Inhibitors; Sexual Behavior, Animal; Sexual Dysfunction, Physiological; Testosterone
PubMed: 34861466
DOI: 10.1016/j.psyneuen.2021.105597 -
Mayo Clinic Proceedings Jul 2016Antidepressants are commonly prescribed medications in the United States, and there is increasing interest in individualizing treatment selection for more than 20 US... (Review)
Review
Antidepressants are commonly prescribed medications in the United States, and there is increasing interest in individualizing treatment selection for more than 20 US Food and Drug Administration-approved treatments for major depressive disorder. Providing greater precision to pharmacotherapeutic recommendations for individual patients beyond the large-scale clinical trials evidence base can potentially reduce adverse effect toxicity profiles and increase response rates and overall effectiveness. It is increasingly recognized that genetic variation may contribute to this differential risk to benefit ratio and thus provides a unique opportunity to develop pharmacogenetic guidelines for psychiatry. Key studies and concepts that review the rationale for cytochrome P450 2D6 (CYP2D6) and cytochrome P450 2C19 (CYP2C19) genetic testing can be delineated by serum levels, adverse events, and clinical outcome measures (eg, antidepressant response). In this article, we report the evidence that contributed to the implementation of pharmacokinetic pharmacogenetic guidelines for antidepressants primarily metabolized by CYP2D6 and CYP2C19.
Topics: Antidepressive Agents, Second-Generation; Cytochrome P-450 CYP2D6; Cytochrome P-450 Enzyme Inhibitors; Depressive Disorder, Major; Fluoxetine; Humans; Paroxetine; Pharmacogenetics; Practice Guidelines as Topic; Precision Medicine; Prescription Drugs; Venlafaxine Hydrochloride
PubMed: 27289413
DOI: 10.1016/j.mayocp.2016.02.023 -
Scandinavian Journal of Pain Jan 2022To alleviate different pain intensities, morphine administration has been extensively used. However, prolonged administration of morphine leads to a progressive decline...
OBJECTIVES
To alleviate different pain intensities, morphine administration has been extensively used. However, prolonged administration of morphine leads to a progressive decline of its analgesic effect which limits their overall utility. Morphine tolerance is considered as a challenging issue for the treatment of both acute and chronic pain. We conducted this study in rats to investigate the effect of paroxetine on morphine tolerance when used preemptively or after morphine tolerance had developed.
METHODS
Male Wistar rats (weight 250-300 g, n=10) were used to evaluate the effects of paroxetine on tolerance to morphine. In order to induce tolerance, daily intraperitoneal injection of morphine (7 mg/kg) was done. After tolerance induction, a group of animals received intraperitoneal injection of 10 mg/kg paroxetine 30 min prior to each morphine dose. In another trial, to investigate the potential of paroxetine to prevent tolerance to morphine, animals were pretreated with 10 mg/kg paroxetine 30 min before morphine administration. In the control groups, 10 mL/kg of saline was injected. The behavioral test (tail-flick test) was done for all groups.
RESULTS
Our data showed that paroxetine significantly reversed tolerance to morphine when used after tolerance induction (p<0.001). However, administration of paroxetine before occurrence of tolerance had no effect.
CONCLUSIONS
We conclude that paroxetine could decrease tolerance to morphine when used after the occurrence of morphine tolerance, while it was not able to prevent morphine tolerance when administered preemptively.
ETHICAL COMMITTEE NUMBER
IRIB.SBMU.MSP.REC.1394.098.
Topics: Analgesics; Animals; Humans; Immune Tolerance; Male; Morphine; Paroxetine; Rats; Rats, Wistar
PubMed: 34298592
DOI: 10.1515/sjpain-2021-0009 -
The Journal of Steroid Biochemistry and... Dec 2019Serotonin reuptake inhibitors (SRIs) are currently the main molecules prescribed to pregnant women that suffer from depression. Placental cells are exposed to SRIs via...
Serotonin reuptake inhibitors (SRIs) are currently the main molecules prescribed to pregnant women that suffer from depression. Placental cells are exposed to SRIs via maternal blood, and we have previously shown that SRIs alter feto-placental steroidogenesis in an in vitro co-culture model. More specifically, serotonin (5-HT) regulates the estrogen biosynthetic enzyme aromatase (cytochrome P450 19; CYP19), which is disrupted by fluoxetine and its active metabolite norfluoxetine in BeWo choriocarcinoma cells. Based on molecular simulations, the present study illustrates that the SRIs fluoxetine, norfluoxetine, paroxetine, sertraline, citalopram and venlafaxine exhibit binding affinity for the active-site pocket of CYP19, suggesting potential competitive inhibition. Using BeWo cells and primary villous trophoblast cells isolated from normal term placentas, we compared the effects of the SRIs on CYP19 activity. We observed that paroxetine and sertraline induce aromatase activity in BeWo cells, while venlafaxine, fluoxetine, paroxetine and sertraline decrease aromatase activity in primary villous trophoblast. The effects of paroxetine and sertraline in primary villous trophoblasts were observed at the lower doses tested. We also showed that 5-HT and the 5-HT receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) induced CYP19 activity. An increase in phosphorylation of serine and tyrosine and a decrease in threonine phosphorylation of CYP19 was also associated with DOI treatment. Our results contribute to better understanding how 5-HT and SRIs interact with CYP19 and may affect estrogen production. Moreover, this study suggests that alteration of placental 5-HT levels due to depression and/or SRI treatment during pregnancy may be associated with disruption of placental estrogen production.
Topics: Aromatase; Cells, Cultured; Citalopram; Female; Fluoxetine; Humans; Molecular Docking Simulation; Paroxetine; Placenta; Pregnancy; Serotonin; Selective Serotonin Reuptake Inhibitors; Sertraline; Trophoblasts; Venlafaxine Hydrochloride
PubMed: 31509772
DOI: 10.1016/j.jsbmb.2019.105470 -
ELife Jul 2020Antidepressants target the serotonin transporter (SERT) by inhibiting serotonin reuptake. Structural and biochemical studies aiming to understand binding of...
Antidepressants target the serotonin transporter (SERT) by inhibiting serotonin reuptake. Structural and biochemical studies aiming to understand binding of small-molecules to conformationally dynamic transporters like SERT often require thermostabilizing mutations and antibodies to stabilize a specific conformation, leading to questions about relationships of these structures to the bonafide conformation and inhibitor binding poses of wild-type transporter. To address these concerns, we determined the structures of ∆N72/∆C13 and ts2-inactive SERT bound to paroxetine analogues using single-particle cryo-EM and x-ray crystallography, respectively. We synthesized enantiopure analogues of paroxetine containing either bromine or iodine instead of fluorine. We exploited the anomalous scattering of bromine and iodine to define the pose of these inhibitors and investigated inhibitor binding to Asn177 mutants of ts2-active SERT. These studies provide mutually consistent insights into how paroxetine and its analogues bind to the central substrate-binding site of SERT, stabilize the outward-open conformation, and inhibit serotonin transport.
Topics: Cryoelectron Microscopy; Crystallography, X-Ray; Humans; Molecular Structure; Paroxetine; Protein Structure, Tertiary; Serotonin; Serotonin Plasma Membrane Transport Proteins; Selective Serotonin Reuptake Inhibitors
PubMed: 32618269
DOI: 10.7554/eLife.56427 -
Ugeskrift For Laeger Apr 2022Treatment with SSRI have a high frequency of treatment of emergent sexual dysfunction. The mechanism is thought to be through serotoninergic inhibition of the sexual... (Review)
Review
Treatment with SSRI have a high frequency of treatment of emergent sexual dysfunction. The mechanism is thought to be through serotoninergic inhibition of the sexual response. More than 70% of patients treated with sertraline, citalopram or paroxetine experience sexual side effects, while escitalopram and fluvoxamine yield the lowest degree of sexual dysfunction within the group. This review suggests management strategies including dose reduction, change of medication and add-on treatment. A small group of patients experience post-SSRI dysfunction, in which sexual dysfunction persists after treatment termination.
Topics: Citalopram; Humans; Paroxetine; Selective Serotonin Reuptake Inhibitors; Sertraline; Sexual Dysfunction, Physiological
PubMed: 35410653
DOI: No ID Found -
The International Journal of... Apr 2022Venlafaxine is a dual serotonin (5-HT) and norepinephrine reuptake inhibitor. The specific dose at which it begins to efficiently engage the norepinephrine transporter...
BACKGROUND
Venlafaxine is a dual serotonin (5-HT) and norepinephrine reuptake inhibitor. The specific dose at which it begins to efficiently engage the norepinephrine transporter (NET) remained to be determined. Paroxetine is generally considered as a selective 5-HT reuptake inhibitor but exhibits some affinity for NET. Atomoxetine is a NET inhibitor but also has some affinity for the 5-HT reuptake transporter (SERT).
METHODS
This study examined the effects of forced titration of venlafaxine from 75 to 300 mg/d, paroxetine from 20 to 50 mg/d, or atomoxetine from 25 to 80 mg/d in 32 patients with major depressive disorder. Inhibition of SERT was estimated using the depletion of whole-blood 5-HT. Inhibition of NET was assessed using the attenuation of the systolic blood pressure produced by i.v. injections of tyramine.
RESULTS
All 3 medications significantly reduced 5-HT levels at the initiating regimens: venlafaxine and paroxetine by approximately 60% and atomoxetine by 16%. The 3 subsequent regimens of venlafaxine and paroxetine reduced 5-HT levels by over 90%, but the highest dose of atomoxetine only reached a 40% inhibition. Atomoxetine dose dependently inhibited the tyramine pressor response from the lowest dose, venlafaxine from 225 mg/d, and paroxetine left it unaltered throughout.
CONCLUSION
These results confirm that venlafaxine and paroxetine are potent SERT inhibitors over their usual therapeutic range but that venlafaxine starts inhibiting NET only at 225 mg/d, whereas paroxetine remains selective for SERT up to 50 mg/d. Atomoxetine dose dependently inhibits NET from a low dose but does not inhibit SERT to a clinically relevant degree.
Topics: Antidepressive Agents, Second-Generation; Atomoxetine Hydrochloride; Cyclohexanols; Depressive Disorder, Major; Humans; Norepinephrine; Norepinephrine Plasma Membrane Transport Proteins; Paroxetine; Serotonin; Selective Serotonin Reuptake Inhibitors; Tyramine; Venlafaxine Hydrochloride
PubMed: 34958348
DOI: 10.1093/ijnp/pyab086 -
Frontiers in Immunology 2023Up to 40 per cent of people with active inflammatory bowel disease (IBD) also suffer from mood disorders such as anxiety and depression. Notwithstanding, the fundamental...
BACKGROUND
Up to 40 per cent of people with active inflammatory bowel disease (IBD) also suffer from mood disorders such as anxiety and depression. Notwithstanding, the fundamental biological pathways driving depression in IBD remain unknown.
METHODS
We identified 33 core genes that drive depression in IBD patients and performed consensus molecular subtyping with the NMF algorithm in IBD. The CIBERSORT were employed to quantify the immune cells. Metabolic signature was characterized using the "IOBR" R package. The scoring system (D. score) based on PCA. Pre-clinical models are constructed using DSS.
RESULTS
Using transcriptome data from the GEO database of 630 IBD patients, we performed a thorough analysis of the correlation between IBD and depression in this research. Firstly, the samples were separated into two different molecular subtypes (D. cluster1 and D. cluster2) based on their biological signatures. Moreover, the immunological and metabolic differences between them were evaluated, and we discovered that D. cluster2 most closely resembled IBD patients concomitant with depression. We also developed a scoring system to assess the IBD-related depression and predict clinical response to anti-TNF- therapy, with a higher D. score suggesting more inflammation and worse reaction to biological therapies. Ultimately, we also identified through animal experiments an antidepressant, paroxetine, has the added benefit of lowering intestinal inflammation by controlling microorganisms in the digestive tract.
CONCLUSIONS
This study highlights that IBD patients with or without depression show significant variations and antidepressant paroxetine may help reduce intestinal inflammation.
Topics: Humans; Paroxetine; Depression; Tumor Necrosis Factor Inhibitors; Inflammatory Bowel Diseases; Anti-Inflammatory Agents; Antidepressive Agents; Inflammation
PubMed: 36923403
DOI: 10.3389/fimmu.2023.1145070 -
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 -
Cellular Signalling Oct 2017β-adrenergic receptors (βAR) regulate numerous functions throughout the body, however G protein-coupled receptor kinase (GRK)-dependent desensitization of βAR has...
β-adrenergic receptors (βAR) regulate numerous functions throughout the body, however G protein-coupled receptor kinase (GRK)-dependent desensitization of βAR has long been recognized as a maladaptive process in the progression of various disease states. Thus, the development of small molecule inhibitors of GRKs for the study of these processes and as potential therapeutics has been at the forefront of recent research efforts. Via structural and biochemical analyses, the selective serotonin reuptake inhibitor (SSRI) paroxetine was identified as a GRK2 inhibitor that enhances βAR-dependent cardiomyocyte and cardiac contractility and reverses cardiac dysfunction and myocardial βAR expression in mouse models of heart failure. Despite these functional outcomes, consistent with diminished βAR desensitization, the proximal βAR signaling mechanisms sensitive to paroxetine have not been reported. In this study, we aimed to determine whether paroxetine prevents classic βAR desensitization-related signaling mechanisms at a molecular level. Therefore, via immunoblotting, radioligand binding, fluorescence resonance energy transfer (FRET) and microscopy assays, we have performed an assessment of the effect of paroxetine on proximal βAR signaling responses. Indeed, paroxetine treatment inhibited ligand-induced β2AR phosphorylation in a concentration-dependent manner. Additionally, for both β1AR and β2AR, paroxetine decreased ligand-induced βarrestin2 recruitment and subsequent receptor internalization. Thus, paroxetine inhibits βAR desensitization mechanisms consistent with GRK2 inhibition and provides a useful pharmacological tool for studying these proximal GPCR signaling responses.
Topics: Adrenergic beta-Agonists; Cell Line; Endocytosis; Humans; Paroxetine; Phosphorylation; Receptors, Adrenergic, beta; Signal Transduction; beta-Arrestin 2
PubMed: 28711716
DOI: 10.1016/j.cellsig.2017.07.006