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Science Translational Medicine Feb 2021Osteoarthritis (OA) is a debilitating joint disease characterized by progressive cartilage degeneration, with no available disease-modifying therapy. OA is driven by...
Osteoarthritis (OA) is a debilitating joint disease characterized by progressive cartilage degeneration, with no available disease-modifying therapy. OA is driven by pathological chondrocyte hypertrophy (CH), the cellular regulators of which are unknown. We have recently reported the therapeutic efficacy of G protein-coupled receptor kinase 2 (GRK2) inhibition in other diseases by recovering protective G protein-coupled receptor (GPCR) signaling. However, the role of GPCR-GRK2 pathway in OA is unknown. Thus, in a surgical OA mouse model, we performed genetic GRK2 deletion in chondrocytes or pharmacological inhibition with the repurposed U.S. Food and Drug Administration (FDA)-approved antidepressant paroxetine. Both GRK2 deletion and inhibition prevented CH, abated OA progression, and promoted cartilage regeneration. Supporting experiments with cultured human OA cartilage confirmed the ability of paroxetine to mitigate CH and cartilage degradation. Our findings present elevated GRK2 signaling in chondrocytes as a driver of CH in OA and identify paroxetine as a disease-modifying drug for OA treatment.
Topics: Animals; Cartilage; Cartilage, Articular; Chondrocytes; G-Protein-Coupled Receptor Kinase 2; Mice; Osteoarthritis; Paroxetine
PubMed: 33568523
DOI: 10.1126/scitranslmed.aau8491 -
Frontiers in Neuroendocrinology Oct 2022Postpartum depression is a common mental disease in obstetric puerperium. Its etiology is not completely clear, and its clinical manifestations are complex. It has... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Postpartum depression is a common mental disease in obstetric puerperium. Its etiology is not completely clear, and its clinical manifestations are complex. It has serious adverse effects on the body and mind of mothers and infants. Treatment should also follow the principle of individualization. Preliminary studies have shown that traditional chinese medicine prescriptions combined with paroxetine is effective in treating postpartum depression. In order to better determine the therapeutic effect, further exploration was carried out.
HYPOTHESIS
Does the study better evaluate the therapeutic effect and provide data support for clinical promotion?
STUDY DESIGN
The search comes from using the following electronic databases established until January 2022.
STUDY RESULTS
The meta analysis results show that paroxetine combined with traditional chinese medicine prescriptions can reduce the Hamilton Depression Scale (HAMD) score [WMD = -7.35, 95 % CI (-10.84, -3.87), P<0.001] and Edinburgh Postpartum Depression Scale (EPDS) score [WMD = -3.24, 95 % CI (-5.96, -0.53), P < 0.001].And better than paroxetine treatment alone in terms of improving clinical efficacy [RR = 1.22, 95 % CI (1.16, 1.30), P < 0.001].
CONCLUSIONS
Based on the combination of paroxetine and traditional chinese medicine prescriptions in the treatment of postpartum depression, there is a certain clinical effect, and a strong research design and a certain number of RCTs are required at the same time. Future research should clarify the specific composition and composition of traditional Chinese medicine prescriptions.
Topics: Female; Humans; Paroxetine; Depression, Postpartum; Medicine, Chinese Traditional; Randomized Controlled Trials as Topic; Prescriptions; Depression
PubMed: 35926637
DOI: 10.1016/j.yfrne.2022.101019 -
Journal of Pharmacy Practice Dec 2023This brief report describes the case of a 16-year-old girl who was commenced on sertraline for anxiety and depression, and subsequently developed severe and debilitating... (Review)
Review
This brief report describes the case of a 16-year-old girl who was commenced on sertraline for anxiety and depression, and subsequently developed severe and debilitating motor tics. Cessation of sertraline was associated with the resolution of tics; after this, paroxetine was trialled and well tolerated with good response of targeted symptoms and without re-emergence of tics. A narrative literature review yielded a retrospective observational study and eight single case reports on selective serotonin receptor inhibitor-induced motor tics (three in adolescents and five in adults). Tics are not commonly considered as a side-effect of SSRIs. This case report is novel is several aspects: the tics emergence was immediate whereas previous cases were delayed; the tics symptoms were measured and quantified by a validated scale; a dose-response relationship was observed; to our knowledge, our case was the first adolescent female reported; and finally, paroxetine was well-tolerated as a substitute, although it is unclear whether the observed tics-sparing effect is co-incidental, ideocratic or can be replicated.
Topics: Adolescent; Female; Humans; Anxiety; Observational Studies as Topic; Paroxetine; Selective Serotonin Reuptake Inhibitors; Sertraline; Tics; Adult
PubMed: 35943957
DOI: 10.1177/08971900221118015 -
Psychopharmacology Nov 2023Non-invasive home cage monitoring is emerging as a valuable tool to assess the effects of experimental interventions on mouse behaviour. A field in which these...
RATIONALE
Non-invasive home cage monitoring is emerging as a valuable tool to assess the effects of experimental interventions on mouse behaviour. A field in which these techniques may prove useful is the study of repeated selective serotonin reuptake inhibitor (SSRI) treatment and discontinuation. SSRI discontinuation syndrome is an under-researched condition that includes the emergence of sleep disturbances following treatment cessation.
OBJECTIVES
We used passive infrared (PIR) monitoring to investigate changes in activity, sleep, and circadian rhythms during repeated treatment with the SSRI paroxetine and its discontinuation in mice.
METHODS
Male mice received paroxetine (10 mg/kg/day, s.c.) for 12 days, then were swapped to saline injections for a 13 day discontinuation period and compared to mice that received saline injections throughout. Mice were continuously tracked using the Continuous Open Mouse Phenotyping of Activity and Sleep Status (COMPASS) system.
RESULTS
Repeated paroxetine treatment reduced activity and increased behaviourally-defined sleep in the dark phase. These effects recovered to saline-control levels within 24 h of paroxetine cessation, yet there was also evidence of a lengthening of sleep bouts in the dark phase for up to a week following discontinuation.
CONCLUSIONS
This study provides the first example of how continuous non-invasive home cage monitoring can be used to detect objective behavioural changes in activity and sleep during and after drug treatment in mice. These data suggest that effects of paroxetine administration reversed soon after its discontinuation but identified an emergent change in sleep bout duration, which could be used as a biomarker in future preclinical studies to prevent or minimise SSRI discontinuation symptoms.
Topics: Male; Animals; Mice; Paroxetine; Selective Serotonin Reuptake Inhibitors; Sleep; Circadian Rhythm
PubMed: 37584734
DOI: 10.1007/s00213-023-06442-3 -
Pharmaceutical Research Feb 2022The present study aimed to elucidate the transport properties of imipramine and paroxetine, which are the antidepressants, across the blood-brain barrier (BBB) in rats.
PURPOSE
The present study aimed to elucidate the transport properties of imipramine and paroxetine, which are the antidepressants, across the blood-brain barrier (BBB) in rats.
METHODS
In vivo influx and efflux transport of imipramine and paroxetine across the BBB were tested using integration plot analysis and a combination of brain efflux index and brain slice uptake studies, respectively. Conditionally immortalized rat brain capillary endothelial cells, TR-BBB13 cells, were utilized to characterize imipramine and paroxetine transport at the BBB in vitro.
RESULTS
The in vivo influx clearance of [H]imipramine and [H]paroxetine in rats was determined to be 0.322 mL/(min·g brain) and 0.313 mL/(min·g brain), respectively. The efflux clearance of [H]imipramine and [H]paroxetine was 0.380 mL/(min·g brain) and 0.126 mL/(min·g brain), respectively. These results suggest that the net flux of paroxetine, but not imipramine, at the BBB in vivo was dominated by transport to the brain from the circulating blood. The uptake of imipramine and paroxetine by TR-BBB13 cells exhibited time- and temperature-dependence and one-saturable kinetics with a K of 37.6 μM and 89.2 μM, respectively. In vitro uptake analyses of extracellular ion dependency and the effect of substrates/inhibitors for organic cation transporters and transport systems revealed minor contributions to known transporters and transport systems and the difference in transport properties in the BBB between imipramine and paroxetine.
CONCLUSIONS
Our study showed the comprehensive outcomes of imipramine and paroxetine transport at the BBB, implying that molecular mechanism(s) distinct from previously reported transporters and transport systems are involved in the transport.
Topics: Animals; Antidepressive Agents, Second-Generation; Antidepressive Agents, Tricyclic; Biological Transport; Blood-Brain Barrier; Cell Line; Imipramine; Injections, Intravenous; Kinetics; Male; Membrane Transport Proteins; Models, Biological; Paroxetine; Permeability; Rats, Wistar; Rats
PubMed: 35112227
DOI: 10.1007/s11095-022-03179-0 -
Journal of Alzheimer's Disease : JAD 2022Modulation of serotonergic signaling by treatment with selective serotonin reuptake inhibitors (SSRIs) has been suggested to mitigate amyloid-β (Aβ) pathology in...
BACKGROUND
Modulation of serotonergic signaling by treatment with selective serotonin reuptake inhibitors (SSRIs) has been suggested to mitigate amyloid-β (Aβ) pathology in Alzheimer's disease, in addition to exerting an anti-depressant action.
OBJECTIVE
To investigate the efficacy of chronic treatment with the SSRI paroxetine, in mitigating Aβ pathology and Aβ plaque-induced microgliosis in the hippocampus of 18-month-old APPswe/PS1ΔE9 mice.
METHODS
Plaque-bearing APPswe/PS1ΔE9 and wildtype mice were treated with paroxetine per os at a dose of 5 mg/kg/day, from 9 to 18 months of age. The per os treatment was monitored by recording of the body weights and serum paroxetine concentrations, and by assessment of the serotonin transporter occupancy by [3H]DASB-binding in wildtype mice. Additionally, 5,7-dihydroxytryptamine was administered to 9-month-old APPswe/PS1ΔE9 mice, to examine the effect of serotonin depletion on Aβ pathology. Aβ pathology was evaluated by Aβ plaque load estimation and the Aβ42/Aβ40 ratio by ELISA.
RESULTS
Paroxetine treatment led to > 80% serotonin transporter occupancy. The treatment increased the body weight of wildtype mice, but not of APPswe/PS1ΔE9 mice. The treatment had no effect on the Aβ plaque load (p = 0.39), the number and size of plaques, or the Aβ plaque-induced increases in microglial numbers in the dentate gyrus. Three months of serotonin depletion did not significantly impact the Aβ plaque load or Aβ42/Aβ40 ratio in APPswe/PS1ΔE9 mice at 12 months.
CONCLUSION
Our results show that chronic treatment with the SSRI paroxetine does not mitigate Aβ pathology and Aβ plaque-induced microgliosis in the hippocampus of APPswe/PS1ΔE9 mice.
Topics: Alzheimer Disease; Amyloid; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloidosis; Animals; Disease Models, Animal; Humans; Mice; Mice, Transgenic; Paroxetine; Plaque, Amyloid; Presenilin-1; Serotonin; Serotonin Plasma Membrane Transport Proteins; Selective Serotonin Reuptake Inhibitors
PubMed: 35342093
DOI: 10.3233/JAD-220019 -
Human Psychopharmacology Nov 2022Immune dysregulation plays a key role in major depressive disorder (MDD). However, little is known about the complicated involvement of various interleukins in MDD. This...
OBJECTIVES
Immune dysregulation plays a key role in major depressive disorder (MDD). However, little is known about the complicated involvement of various interleukins in MDD. This study was performed to investigate the correlation between plasma interleukin-8 (IL-8) levels and treatment outcome of paroxetine (a selective serotonin reuptake inhibitor) in patients with MDD.
METHODS
A total of 115 hospitalized patients (36 males and 79 females), aged from 18 to 72 years, were enrolled. Plasma levels of IL-8 were measured before treatment initiation (baseline) and at 8 weeks after oral paroxetine treatment. Efficacy of paroxetine was evaluated by use of the Hamilton Depression Rating Scale (HAMD-17). Baseline IL-8 levels were compared between responders and non-responders to paroxetine treatment.
RESULTS
Plasma IL-8 levels decreased significantly after an 8-week antidepressant treatment in responders, in association with a dramatic decrease in HAMD-17 scores. In non-responders, plasma IL-8 levels did not change significantly at 8 weeks after antidepressant treatment. Baseline plasma IL-8 levels were found to be significantly lower in responders than in non-responders, showing a correlation between IL-8 and antidepressant response to paroxetine.
CONCLUSIONS
These results indicate that plasma IL-8 levels were related to treatment outcome of paroxetine, and therefore suggest that IL-8 could be a promising predicator of treatment response in individual patients with MDD.
Topics: Male; Female; Humans; Paroxetine; Depressive Disorder, Major; Interleukin-8; Selective Serotonin Reuptake Inhibitors; Antidepressive Agents; Treatment Outcome
PubMed: 36194639
DOI: 10.1002/hup.2855 -
Journal of Psychopharmacology (Oxford,... Nov 2016The 2002 paper "Does 5-HT restrain panic? A tryptophan depletion study in panic disorder patients recovered on paroxetine" by Bell and colleagues - reprinted in this... (Review)
Review
The 2002 paper "Does 5-HT restrain panic? A tryptophan depletion study in panic disorder patients recovered on paroxetine" by Bell and colleagues - reprinted in this issue of the Journal - reports on a study undertaken in the halcyon days of David Nutt's Psychopharmacology Unit at the University of Bristol, England. In this invited commentary authors of the original work discuss the impact of this paper on the field of acute tryptophan depletion research (especially in the field of clinical anxiety disorders) and the development of disorder-specific anxiogenic provocations over the past decade.
Topics: Anxiety; Anxiety Disorders; Humans; Male; Paroxetine; Serotonin; Tryptophan
PubMed: 27329165
DOI: 10.1177/0269881116655321 -
Cellular and Molecular Neurobiology Oct 2018Ischemic stroke is a debilitating multi-factorial cerebrovascular disorder, representing an area of tremendous unmet medical need. Combination treatment has been...
Ischemic stroke is a debilitating multi-factorial cerebrovascular disorder, representing an area of tremendous unmet medical need. Combination treatment has been proposed as a promising therapeutic approach towards combating ischemic stroke. The present study employs in vitro oxygen glucose deprivation (OGD) model to evaluate the post-ischemic neuroprotective efficacy of Everolimus and Paroxetine, alone and in combination. Post-OGD treatment with Everolimus and Paroxetine, alone or in combination, significantly improved the cell survival (~ 80%) when compared to the cells subjected to ischemic injury alone. The individual neuroprotective doses of Everolimus and Paroxetine were found to be at 6.25 and 25 nM, respectively. Whereas, the synergistic neuroprotective dose for Everolimus:Paroxetine was 2:10 nM, calculated using the Chou-Talalay combination index and other four mathematical models. The synergistic combination dose downregulated neuroinflammatory genes (Tnf-α, Il1b, Nf-κB, and iNos) and upregulated the neuroprotective genes (Bcl-2, Bcl-xl, Hif-1, and Epo). The mitochondrial functioning and ROS neutralizing ability increased with combination treatment. Further, the active role of nitric oxide synthase and calmodulin were revealed while exploring the bio-activity of Everolimus and Paroxetine through network pharmacology. The present study for the first time demonstrates the synergistic post-ischemic neuroprotective efficacy of combination treatment with Everolimus and Paroxetine in vitro. Taken together, these findings clearly suggest that Everolimus in combination with Paroxetine may represent a promising therapeutic strategy for the treatment of ischemic stroke, further supporting the combination treatment strategy for this debilitating disorder.
Topics: Brain Ischemia; Cell Hypoxia; Cells, Cultured; Drug Synergism; Everolimus; Humans; Neurons; Neuroprotection; Neuroprotective Agents; Oxygen; Paroxetine
PubMed: 30062636
DOI: 10.1007/s10571-018-0605-6 -
CNS Drugs Apr 2024Compulsive sexual behavior disorder (CSBD) has recently been recognized as a psychiatric disorder. Pharmacological treatments for CSBD have received little study and... (Review)
Review
Compulsive sexual behavior disorder (CSBD) has recently been recognized as a psychiatric disorder. Pharmacological treatments for CSBD have received little study and thus have limited empirical support. The main objective of the present work is to review existing literature on the efficacy of different drugs on the symptomatology of CSBD, including the subtype of problematic pornography use (PPU). The main pharmacological approaches to treating CSBD have included opioid antagonists (naltrexone and nalmefene), selective serotonin reuptake inhibitors (paroxetine, citalopram, fluoxetine, and sertraline), mood stabilizers (topiramate), tricyclic antidepressants (clomipramine), serotonin antagonist and reuptake inhibitors (nefazodone), and N-acetylcysteine. Since people with CSBD may experience different co-occurring disorders, these should be considered when choosing the best pharmacological treatment. Pharmacological therapy for CSBD/PPU has been suggested as an adjunct to psychological therapies, which, for the moment, have the most empirical evidence. However, to evaluate the efficacy of most of the drugs presented in this narrative review, data to date have only been available from case studies. Thus, empirical support is scant and generalizability of results is limited, highlighting the need for more research in this area.
Topics: Humans; Compulsive Sexual Behavior Disorder; Selective Serotonin Reuptake Inhibitors; Paroxetine; Sertraline; Fluoxetine; Compulsive Behavior
PubMed: 38485889
DOI: 10.1007/s40263-024-01075-2