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Current Research in Toxicology 2022Selective serotonin reuptake inhibitors (SSRIs), serotonin and noradrenaline reuptake inhibitors (SNRIs), and noradrenergic and specific serotonergic antidepressants...
Selective serotonin reuptake inhibitors (SSRIs), serotonin and noradrenaline reuptake inhibitors (SNRIs), and noradrenergic and specific serotonergic antidepressants (NaSSAs) are broadly used for the treatment of depression. Depression is one of the most common psychiatric disorders in pregnant women and SSRIs are commonly prescribed for depression during pregnancy. The placenta regulates the transport of nutrients and oxygen between the maternal and fetal circulation, and is essential for the survival and growth of the fetus. The present study investigated the effects of antidepressants on human placental BeWo cells. BeWo cell viability was significantly decreased following exposure to sertraline (SSRI), paroxetine (SSRI), fluvoxamine (SSRI), and duloxetine (SNRI), whereas escitalopram (SSRI), venlafaxine (SNRI), and mirtazapine (NaSSA) showed little or no effects. Extracellular lactate dehydrogenase activity was increased by sertraline, paroxetine, fluvoxamine, and duloxetine, indicating toxicity to the cells. Sertraline increased the production of cellular reactive oxygen species (ROS) and decreased the mitochondrial membrane potential. Sertraline decreased the cellular ATP content in a time and concentration-dependent manner. Caspase-3/7 activity and apoptotic cells, detected using the phosphatidylserine-specific fluorescent probe Apotracker Green, were increased by sertraline. Our findings suggest that antidepressants, such as sertraline, paroxetine, fluvoxamine, and duloxetine, induce toxicity in human placental BeWo cells. Sertraline may induce ROS-dependent apoptosis in human placental cells. These results are useful for further studies to determine the optimal dosage of antidepressants for pregnant women.
PubMed: 35602006
DOI: 10.1016/j.crtox.2022.100073 -
International Journal of Women's Health 2022Most women experience vasomotor symptoms (VMS) during their menopausal transition. Menopausal hormone therapy (HT) is the most effective treatment for VMS, but some... (Review)
Review
Most women experience vasomotor symptoms (VMS) during their menopausal transition. Menopausal hormone therapy (HT) is the most effective treatment for VMS, but some women choose not to use HT or have contraindications to using HT. Non-hormonal treatment options should be offered to these symptomatic menopausal women. Multiple large randomized controlled trials have demonstrated statistically significant reductions in hot flash severity and/or frequency with the use of selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs). To date, paroxetine mesylate remains the only non-hormonal treatment that has been approved by the United States Food and Drug Administration (FDA) for the management of moderate to severe postmenopausal vasomotor symptoms. Lower doses are needed to reduce VMS than those used to treat anxiety or depression, which is beneficial since side effects are typically dose dependent. The recommended dosage is 7.5 mg once daily at bedtime. Dose dependent side effects include nausea, fatigue, and dizziness. Knowing potential medication interactions is critical such as with medications that can lead to serotonin syndrome, concomitant use with monoamine oxidase inhibitors and being aware of p450 drug metabolism is essential for patients taking drugs that utilize the CYP2D6 enzyme for metabolism including tamoxifen. This review discusses in detail the available data supporting the use of paroxetine for the treatment of VMS, including side effects and considerations regarding prescribing. A discussion of other emerging treatments is included as well, including estetrol, oxybutynin and neurokinin 3 (NK3) receptor antagonists.
PubMed: 35300283
DOI: 10.2147/IJWH.S282396 -
Neuropharmacology Nov 2022Post-traumatic stress disorder (PTSD) is a disabling psychiatric condition with a critical familiar, personal, and social impact. Patients diagnosed with PTSD show... (Review)
Review
Post-traumatic stress disorder (PTSD) is a disabling psychiatric condition with a critical familiar, personal, and social impact. Patients diagnosed with PTSD show various symptoms, including anxiety, depression, psychotic episodes, and sleep disturbances, complicating their therapeutic management. Only sertraline and paroxetine, two selective serotonin reuptake inhibitors, are approved by different international agencies to treat PTSD. In addition, these drugs are generally combined with psychotherapy to achieve positive results. However, these pharmacological strategies present limited efficacy. Nearly half of the PTSD patients do not experience remission of symptoms, possibly due to the high prevalence of psychiatric comorbidities. Therefore, in clinical practice, other off-label medications are common, even though the effectiveness of these drugs needs to be further investigated. In this line, antipsychotics, antiepileptics, adrenergic blockers, benzodiazepines, and other emerging pharmacological agents have aroused interest as potential therapeutic tools to improve some specific symptoms of PTSD. Thus, this review is focused on the most widely used drugs for the pharmacological treatment of PTSD with a translational approach, including clinical and preclinical studies, to emphasize the need to develop safer and more effective medications.
Topics: Animals; Anxiety Disorders; Paroxetine; Selective Serotonin Reuptake Inhibitors; Sertraline; Stress Disorders, Post-Traumatic
PubMed: 35973598
DOI: 10.1016/j.neuropharm.2022.109211 -
Frontiers in Pharmacology 2024This study aimed to investigate the plasma and breastmilk concentrations for sertraline, citalopram and paroxetine for assessment of the Milk/Plasma (M/P) ratio and...
OBJECTIVES
This study aimed to investigate the plasma and breastmilk concentrations for sertraline, citalopram and paroxetine for assessment of the Milk/Plasma (M/P) ratio and Absolute Infant Dose (AID), and to determine actual infant drug exposure through breastfeeding. Subsequently, informed recommendations will be formulated regarding the advisability of breastfeeding in women undergoing treatment with the three most widely used antidepressants.
METHODS
A pharmacokinetic study in lactating women and their infants using sertraline, citalopram or paroxetine was performed. Paired breastmilk and plasma samples and single point infant plasma samples were collected to determine antidepressant concentrations. An Area Under the Curve (AUC) based approach with the trapezoidal rule was used to calculate M/P ratios and AID for all three antidepressants by combining all measured concentrations for the same dose.
RESULTS
Thirty-seven lactating women and their infants participated in this study. 111 paired breastmilk and plasma samples and 37 single point infant plasma samples were collected. Detectable concentrations of sertraline, citalopram and paroxetine were present in all breastmilk samples. For sertraline and citalopram M/P ratio is above one, indicating higher breastmilk than plasma concentrations, however, drug exposure by breastmilk did not lead to detectable plasma drug levels in any of the 15 infants for sertraline, for nine (out of 13) infants for citalopram and for eight (out of nine) infants for paroxetine.
CONCLUSION
Given the well-known benefits of breastfeeding, our findings support breastfeeding of infants by mothers who are taking sertraline, citalopram or paroxetine is safe. Sertraline and paroxetine are the preferred antidepressants during breastfeeding, reaching mostly undetectable infant drug levels.
PubMed: 38841362
DOI: 10.3389/fphar.2024.1414677 -
Frontiers in Immunology 2022G protein-coupled receptor (GPCR) kinase 2 (GRK2), which phosphorylates agonist-occupied GPCRs to promote their desensitization, has been investigated as an attractive...
G protein-coupled receptor (GPCR) kinase 2 (GRK2), which phosphorylates agonist-occupied GPCRs to promote their desensitization, has been investigated as an attractive therapeutic target for cardiovascular and metabolic diseases. Several GRK2-targeted inhibition strategies have been reported including the use of direct pharmacological inhibitors such as paroxetine (a widely prescribed antidepressant) and its analogs such as compound CCG258747. Cross-linking of high affinity IgE receptor (FcϵRI) on mast cells (MCs) and the resulting degranulation causes anaphylaxis and allergic asthma. Using gene silencing strategy, we recently showed that GRK2 contributes to FcεRI signaling and MC degranulation. The purpose of this study was to determine if the GRK2 inhibitors paroxetine and CCG258747 modulate FcεRI-mediated MC responses and . Utilizing rat basophilic leukemia (RBL-2H3) cells and primary mouse lung MCs (LMCs), we found that paroxetine and CCG258747 inhibit FcϵRI-mediated calcium mobilization and degranulation. Furthermore, intravenous administration of paroxetine and CCG258747 in mice resulted in substantial reduction of IgE-mediated passive cutaneous anaphylaxis. Unlike LMCs, human cutaneous MCs abundantly express a novel GPCR known as MRGPRX2 (mouse; MRGPRB2). We found that in contrast to their inhibitory effects on FcεRI-mediated MC responses, both paroxetine and CCG258747 induce calcium mobilization and degranulation in RBL-2H3 cells stably expressing MRGPRX2 but not in untransfected cells. Furthermore, paroxetine and CCG258747 induced degranulation in peritoneal MCs from Wild-type (WT) mice and caused increased cutaneous vascular permeability , but these responses were substantially reduced in mice. Additionally, upon intradermal injection, paroxetine also induced neutrophil recruitment in WT but not mice. These findings suggest that in addition to their potential therapeutic utility against cardiovascular and metabolic disorders, paroxetine-based GRK2-inhibitors may serve to modulate IgE-mediated anaphylaxis and to enhance cutaneous host defense by harnessing MC's immunomodulatory property through the activation of MRGPRX2/MRGPRB2.
Topics: Rats; Mice; Humans; Animals; Mast Cells; Anaphylaxis; Paroxetine; Receptors, IgE; Calcium; Receptors, G-Protein-Coupled; Immunoglobulin E; Nerve Tissue Proteins; Receptors, Neuropeptide
PubMed: 36275707
DOI: 10.3389/fimmu.2022.1032497 -
Indian Journal of Dermatology 2022Selective serotonin reuptake inhibitors (SSRI) are the most prescribed antidepressant medications for the treatment of depression and other psychiatric disorders due to...
Selective serotonin reuptake inhibitors (SSRI) are the most prescribed antidepressant medications for the treatment of depression and other psychiatric disorders due to their efficacy, tolerability, and safety profile. The dermatological side-effects or cutaneous reactions due to SSRI class of antidepressants is rare. Though there were few case reports of SSRI-induced rash due to fluoxetine, paroxetine, and sertraline, the evidence associated with escitalopram, the highly prescribed antidepressant is comparatively less. The identification and reporting of the drug-related side-effects/adverse drug reactions either serious or non-serious is very important as it will be helpful in understanding, reviewing, and educating the drug-related information before starting medication to the patient.
PubMed: 35656231
DOI: 10.4103/ijd.ijd_1140_20 -
Acta Neuropsychiatrica Aug 2020The aim of this paper was to provide a systematic review and update on the pharmacotherapy of social anxiety disorder (SAD), including the efficacy and tolerability of... (Comparative Study)
Comparative Study
OBJECTIVE
The aim of this paper was to provide a systematic review and update on the pharmacotherapy of social anxiety disorder (SAD), including the efficacy and tolerability of these agents, the ranking of interventions, and the grading of results by quality of evidence.
METHODS
The Common Mental Disorder Controlled Trial Register and two trial registries were searched for randomised controlled trials (RCTs) comparing any pharmacological intervention or placebo in the treatment of SAD. We performed a standard pairwise meta-analysis using a random effects model and carried out a network meta-analysis (NMA) using the statistical package, R. Quality of evidence was also assessed.
RESULTS
We included 67 RCTs in the review and 21 to 45 interventions in the NMA. Paroxetine was most effective in the reduction of symptom severity as compared to placebo. Superior response to treatment was also observed for paroxetine, brofaromine, bromazepam, clonazepam, escitalopram, fluvoxamine, phenelzine, and sertraline. Higher dropout rates were found for fluvoxamine. Brofaromine, escitalopram, fluvoxamine, paroxetine, pregabalin, sertraline, and venlafaxine performed worse in comparison to placebo for the outcome of dropouts due to adverse events. Olanzapine yielded a relatively high rank for treatment efficacy and buspirone the worse rank for dropouts due to any cause.
CONCLUSION
The differences between drugs and placebo were small, apart from a significant reduction in symptom severity and response for paroxetine. We suggest paroxetine as a first-line treatment of SAD, with the consideration of future research on the drug olanzapine as well as brofaromine, bromazepam, clonazepam, escitalopram, fluvoxamine, phenelzine, and sertraline because we observed a response to treatment.
Topics: Adult; Anti-Anxiety Agents; Humans; Network Meta-Analysis; Phobia, Social; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 32039743
DOI: 10.1017/neu.2020.6 -
Andrology Mar 2024Paroxetine, a selective serotonin reuptake inhibitor (SSRI) antidepressant, has caused male sexual dysfunction; however, the paroxetine mechanisms of action in testes...
BACKGROUND
Paroxetine, a selective serotonin reuptake inhibitor (SSRI) antidepressant, has caused male sexual dysfunction; however, the paroxetine mechanisms of action in testes are still unclear.
OBJECTIVES
Paroxetine serotonergic effects in testes were evaluated, focusing on steroidogenesis and the correlation between macrophages population and possible TNF-α-derived oxidative stress. We also verified whether the changes are reversible following treatment interruption.
MATERIALS AND METHODS
Adult rats received paroxetine (PG35 and PG65) or tap water (CG) for 35 days. PG65 was maintained without treatment for 30 more days. Intratesticular testosterone (IT), nitrite, and malondialdehyde concentrations were measured. To confirm serotonergic and estrogenic effects, Htr1b and Esr1 expressions were analyzed. The daily sperm production (DSP), frequency of abnormal seminiferous tubules (ST), SC number, ST area, and Leydig cells nuclear area (LCnu) were evaluated. TUNEL germ cells, M1 (CD68 ), and M2 (Perls ) macrophages were quantified. 17β-HSD7, CYP19A1, NDRG2, oxytocin, TNF-α, and iNOS were evaluated by immunoreactions. Oxytocin and NDRG2 protein levels as well as Tnfa mRNA expression were also analyzed.
RESULTS
The Htr1b downregulation in testes confirmed the paroxetine serotonergic effect. The testicular sections showed abnormal ST frequency, ST atrophy and reduction of DSP, LCnu, SC number and Perls macrophages. TUNEL germ cells and LC were associated with strong NDRG2 immunoexpression. Paroxetine reduced IT levels and 17β-HSD7 immunoexpression in parallel to increased CYP19A1, oxytocin, TNF-α and iNOS. Esr1 and Tnfa overexpression and increased number of CD68 macrophages were also observed together with high nitrite and malondialdehyde levels. Most parameters were not recovered in PG65.
CONCLUSIONS
Paroxetine serotonergic effect impairs LC steroidogenesis, via aromatization, increasing estrogen/testosterone ratio, which in turn upregulate NDRG2, promoting apoptosis, and impairing sperm production. Serotonin-estrogen pathways may be responsible for M2/M1 polarization, Tnfa upregulation, and induction of oxidative stress. The unrecovered testicular changes after treatment discontinuation are due to persistent paroxetine serotonin/estrogen effects.
Topics: Male; Rats; Animals; Testis; Paroxetine; Serotonin; Tumor Necrosis Factor-alpha; Oxytocin; Nitrites; Semen; Testosterone; Estrogens; Macrophages; Malondialdehyde
PubMed: 37675929
DOI: 10.1111/andr.13513 -
Clinical Psychopharmacology and... Aug 2023Restless legs syndrome (RLS) is a chronic progressive movement disorder characterized by abnormal sensations, especially at rest and at night, as the need and urge to...
Restless legs syndrome (RLS) is a chronic progressive movement disorder characterized by abnormal sensations, especially at rest and at night, as the need and urge to move the lower extremity. It has been reported that RLS severity and frequency increase in patients with anxiety and depression. It has been reported that serotonin-noradrenaline reuptake inhibitors such as venlafaxine and selective serotonin reuptake inhibitors such as citalopram, fluoxetine, paroxetine, and sertraline can cause RLS symptoms. No adverse effects of vortioxetine on RLS have been reported in the literature. In this case series, we report the effect of vortioxetine in patients with RLS with symptoms of depression and anxiety. In this case series, the effect of adding vortioxetine to treatment on RLS symptoms is reported in 7 patients (5 female). After the use of vortioxetine, 5 of 7 patients' symptoms regressed without the need to start a separate drug for primary movement disorder. In conclusion, we believe that studies should be conducted to investigate the efficacy of vortioxetine in the treatment of RLS. Therefore, randomized controlled studies are needed to determine the effect and safety of vortioxetine on RLS symptoms.
PubMed: 37424427
DOI: 10.9758/cpn.22.1021 -
Frontiers in Pharmacology 2022To evaluate the efficacy and tolerability of pharmacotherapies for postpartum depression (PPD). We performed a computerized search of MEDLINE (Ovid and PubMed),...
To evaluate the efficacy and tolerability of pharmacotherapies for postpartum depression (PPD). We performed a computerized search of MEDLINE (Ovid and PubMed), Embase, Cochrane Library, Web of Science, and Google Scholar to identify eligible randomized controlled trials (RCTs) before 31 March 2022. We calculated standardized mean differences (SMDs) for continuous outcomes and odds ratios (ORs) for dichotomous outcomes with the random-effects model. The tolerability of antidepressants in terms of early dropouts was investigated. The surface under the cumulative ranking curve (SUCRA) was used for ranking the outcomes. Quality assessment of the included studies was performed using the Cochrane Collaboration's tool. A total of 11 studies with 944 participants were included in this network meta-analysis, involving nine antidepressants. With respect to efficacy, only estradiol and brexanolone were significantly more effective than the placebo ( < 0.05), and the calculated SUCRA indicated that estradiol (94.3%) had the highest probability ranking first for reducing the PPD, followed by paroxetine (64.3%) and zuranolone (58.8%). Regarding tolerability, a greater percentage of patients treated with brexanolone experienced early dropout as compared to those treated with most other antidepressants. Only estradiol and brexanolone showed significantly higher efficacy than the placebo. According to the SUCRA ranking, estradiol, paroxetine, and zuranolone were the three best antidepressants. Concerning acceptability in terms of early dropouts, brexanolone was less well-tolerated than other antidepressants.
PubMed: 36506537
DOI: 10.3389/fphar.2022.950004