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Antidepressant and Neuroprotective Effects of 3-Hydroxy Paroxetine, an Analog of Paroxetine in Rats.The International Journal of... Mar 2023Paroxetine (PX) is a widely used antidepressant with side effects such as weakness, dizziness, and trouble sleeping. In search of novel compounds with better efficacy...
BACKGROUND
Paroxetine (PX) is a widely used antidepressant with side effects such as weakness, dizziness, and trouble sleeping. In search of novel compounds with better efficacy and fewer side effects, we synthesized 3HPX, a hydroxylated analog of PX, and compared the 2 in silico for their pharmacokinetic and binding properties and in vivo for their antidepressant and potential neuroprotective effects.
METHODS
In silico studies compared pharmacological properties as well as interactions of PX and 3HPX with the serotonin transporter. In vivo studies utilized an animal model of comorbid depression-Parkinson disease. Adult male Wistar rats were injected (sterotaxically) with lipopolysaccharide in the striatum (unilaterally), followed by 14 days of once-daily injections (i.p.) of 10 mg/kg PX or 3HPX. Animals were tested for motor asymmetry and locomotor activity as well as indices of anhedonia and helplessness using sucrose preference and forced swim tests, respectively. Brains of these animals were collected after the last test, and tyrosine hydroxylase-positive neurons in substantia nigra pars compacta and Iba-1-positive stained microglia in ipsilateral striatum were measured.
RESULTS
In silico findings indicated that 3HPX could bind stronger to serotonin transporter and also have a better clearance and hence less toxicity compared with PX. In vivo results revealed a more effective reversal of immobility in the swim test, substantial increase in tyrosine hydroxylase-positive cells in the substantia nigra pars compacta, and more ramified Iba-1+ cells by 3HPX compared with PX.
CONCLUSION
The findings suggest superior effectiveness of 3HPX as an antidepressant and neuroprotectant compared with PX and hence potential utility in Parkinson disease depression co-morbidity.
Topics: Rats; Male; Animals; Paroxetine; Parkinson Disease; Neuroprotective Agents; Rats, Wistar; Substantia Nigra; Tyrosine 3-Monooxygenase; Serotonin Plasma Membrane Transport Proteins; Antidepressive Agents; Disease Models, Animal
PubMed: 36433759
DOI: 10.1093/ijnp/pyac077 -
MedRxiv : the Preprint Server For... Feb 2023Paroxetine is an older "selective" serotonin reuptake inhibitor (SSRI) that is notable for its lack of selectivity, resulting in a cholinergic adverse-effect profile,...
INTRODUCTION
Paroxetine is an older "selective" serotonin reuptake inhibitor (SSRI) that is notable for its lack of selectivity, resulting in a cholinergic adverse-effect profile, especially among older adults (65+).
METHODS
Paroxetine prescription rates and costs per state were ascertained from the Medicare Specialty Utilization and Payment Data. States' annual prescription rate, corrected per thousand Part D enrollees, outside 95% confidence interval were considered significantly different from the average.
RESULTS
There was a steady decrease in paroxetine prescriptions (-34.52%) and spending (-16.69%) from 2015-2020 but a consistent, five-fold state-level difference. From 2015-2020, Kentucky (194.9, 195.3, 182.7, 165.1, 143.3, 132.5) showed significantly higher prescriptions rates relative to the national average, and Hawaii (42.1, 37.9, 34.3, 31.7, 27.7, 26.6) showed significantly lower prescription rates. North Dakota was often a frequent elevated prescriber of paroxetine (2016: 170.7, 2018: 143.3), relative to the average. Neuropsychiatry and geriatric medicine frequently prescribed the largest amount of paroxetine prescriptions, relative to the number of providers in that specialty, from 2015-2020.
DISCUSSION
Despite the American Geriatrics Society prohibition against paroxetine use in the older adults and many effective treatment alternatives, paroxetine was still commonly used in this population, especially in Kentucky and North Dakota and by neuropsychiatry and geriatric medicine. These findings provide information on the specialty types and states where education and policy reform would likely have the greatest impact on improving adherence to the paroxetine prescription recommendations.
PubMed: 36824839
DOI: 10.1101/2023.02.15.23285973 -
American Journal of Translational... 2022To systematically evaluate the clinical efficacy of acupuncture combined with paroxetine in the treatment of depression. (Review)
Review
OBJECTIVE
To systematically evaluate the clinical efficacy of acupuncture combined with paroxetine in the treatment of depression.
METHODS
The research literature on the treatment of depression with acupuncture and moxibustion combined with paroxetine was collected using keywords in PubMed, Embase, Web of Science, Cochrane Library, CNKI, World Wide Web, Chinese Biomedical Literature and other public publication databases. Collaborative screening of literature was performed according to pre-established inclusion and exclusion criteria. The data in the literature were extracted, the quality of the literature was evaluated, and the RevMan software was used for statistical analysis.
RESULTS
This study finally included 21 research papers involving 1733 clinical patients. The main evaluation indicators for clinical patients were Hamilton Depression Rating Scale (HAMD), total clinical response rate, Rating Scale for Side Effects (SERS) and Treatment Emergent Symptom Scale (TESS). SERS was developed by Asberg. The Chinese version was revised by Zhang Mingyuan (Chairman of the Chinese Medical Association Mental Health Society) et al. The SERS is divided into 14 items, all of which use a 4-point scoring method (none, mild, moderate and severe, respectively). This scale is mainly used to assess the side effects of antidepressants. TESS was compiled by the NIMH of the United States in 1973. It has the most comprehensive items and the widest coverage among the scales of its kind, including not only common adverse symptoms and signs, but also several laboratory test results. Meta-analysis of the above results showed that compared with the control group, the acupuncture combined with paroxetine treatment group showed lower HAMD score (WMD=-4.18 [-5.04, -3.31], P<0.001), higher total response rate (OR=4.01 [3.01, 5.33], P<0.001), lower SERS score (WMD=-2.54 [-4.58, -0.51], P<0.001) and lower TESS score (WMD=-4.39 [-5.15, -3.62], P<0.001), and the differences were statistically significant.
CONCLUSION
The therapeutic effect of acupuncture combined with paroxetine on depression is better than that of conventional drug treatment, and its safety is comparable to that of conventional treatment.
PubMed: 36628233
DOI: No ID Found -
Psychiatria Polska Oct 2019To evaluate harmful interactions between antidepressants and medications used in treatment of cardiovascular disorders.
OBJECTIVES
To evaluate harmful interactions between antidepressants and medications used in treatment of cardiovascular disorders.
METHODS
The analysis of 66 cases of adverse reactions with a clinical picture indicating, to a degree that is probable or certain, that they were the result of the combination of antidepressant with cardiovascular medication.
RESULTS
The most common side effect (n = 25, 37.9%) was bradycardia (and other side effects of beta blockers) as a consequence of addition of metoprolol or propranolol to SSRI or bupropion. In one case combination of fluoxetine with propranolol resulted in cardiac arrest. We observed 8 cases of intensified side effects of amlodipine (swelling of lower limbs, headaches) after its combination with: fluoxetine, sertraline and paroxetine, and occurrence of myalgia, elevated aminotransferase levels, polyuria and hypotension after combination of lercanidipine with some of the SSRIs. We also found i.a. worsening of propafenone tolerance in combination with venlafaxine or bupropion, 2 cases of granulopenia associated with duloxetine-propafenone combination, 2 cases of hemorrhagic complications associated with the combination of vortioxetine-warfarin, 1 case of hyponatremia associated with the combination of vortioxetine and hydrochlorothiazide, as well as antagonizing clonidine's hypotensive effect by mirtazapine, and peripheral thrombosis following the combination of warfarin with trazodone.
CONCLUSIONS
Because of ahigh risk of interactions and related adverse effects, especially in older patients, each decision regarding combination of a particular antidepressant with a medication used in treatment of cardiovascular disorders should be preceded by a detailed analysis of safety and risk-benefit ratio, and also be associated with the search for the safest, alternative combinations of the above-mentioned medications.
Topics: Adult; Adverse Drug Reaction Reporting Systems; Antidepressive Agents; Arrhythmias, Cardiac; Cardiovascular Diseases; Depressive Disorder; Female; Heart Rate; Humans; Male; Middle Aged; Patient Safety; Risk Factors
PubMed: 31955180
DOI: 10.12740/PP/OnlineFirst/96286 -
Aging Oct 2023G protein-coupled receptor kinase-2 (GRK2) is involved in TGF-β1-induced activation of lung fibroblasts, which could give rise to the pathogenesis of pulmonary...
G protein-coupled receptor kinase-2 (GRK2) is involved in TGF-β1-induced activation of lung fibroblasts, which could give rise to the pathogenesis of pulmonary fibrosis. Paroxetine (PRXT) serves as a selective GRK2 inhibitor which is widely used to treat anxiety and depression for several decades. However, whether PRXT could inhibit TGF-β1-induced activation of lung fibroblasts and combat bleomycin-induced pulmonary fibrosis remains unclear. Here, we investigated the effects of PRXT on pulmonary fibrosis in C57/BL6 caused by bleomycin as well as on the activation of murine primary lung fibroblasts stimulated with TGF-β1. The results demonstrated that PRXT markedly improved the pulmonary function and 21-day survival in bleomycin-induced mice. Meanwhile, PRXT significantly decreased collagen deposition, inflammation, and oxidative stress in lung tissues from bleomycin-induced mice. Furthermore, we found that PRXT could inhibit the protein and mRNA expression of GRK2 and Smad3 in lung tissues from bleomycin-induced mice. experiments also PRXT could inhibit cell activation and collagen synthesis in a concentration-dependent manner in TGF-β1-induced lung fibroblasts. In addition, we found that Smad3 overexpression by adenovirus transfection could offset anti-fibrotic and antioxidative effects from PRXT in TGF-β1-induced lung fibroblasts, which showed no effects on the protein expression of GRK2. In conclusion, PRXT mediates the inhibition of GRK2, which further blocks the transcription of Smad3 in TGF-β1-induced lung fibroblasts, providing an attractive therapeutic target for pulmonary fibrosis.
Topics: Mice; Animals; Pulmonary Fibrosis; Bleomycin; Transforming Growth Factor beta1; Paroxetine; Lung; Fibroblasts; Collagen; Mice, Inbred C57BL
PubMed: 37815883
DOI: 10.18632/aging.205092 -
Pharmaceuticals (Basel, Switzerland) Jul 2022Post-traumatic stress disorder (PTSD) occurs after exposure to traumatic events and is characterized by overwhelming fear and anxiety. Disturbances in the... (Review)
Review
Post-traumatic stress disorder (PTSD) occurs after exposure to traumatic events and is characterized by overwhelming fear and anxiety. Disturbances in the hypothalamic-pituitary-adrenal (HPA) axis are involved in the pathogenesis of mood disorders, including anxiety, PTSD, and major depressive disorders. Studies have demonstrated the relationship between the HPA axis response and stress vulnerability, indicating that the HPA axis regulates the immune system, fear memory, and neurotransmission. The selective serotonin reuptake inhibitors (SSRIs), sertraline and paroxetine, are the only drugs that have been approved by the United States Food and Drug Administration for the treatment of PTSD. However, SSRIs require long treatment times and are associated with lower response and remission rates; therefore, additional pharmacological interventions are required. Complementary and alternative medicine therapies ameliorate HPA axis disturbances through regulation of gut dysbiosis, insomnia, chronic stress, and depression. We have described the cellular and molecular mechanisms through which the HPA axis is involved in PTSD pathogenesis and have evaluated the potential of herbal medicines for PTSD treatment. Herbal medicines could comprise a good therapeutic strategy for HPA axis regulation and can simultaneously improve PTSD-related symptoms. Finally, herbal medicines may lead to novel biologically driven approaches for the treatment and prevention of PTSD.
PubMed: 35890196
DOI: 10.3390/ph15070898 -
Parasites & Vectors Jan 2021Serotonin is a phylogenetically ancient molecule that is widely distributed in most metazoans, including flatworms. In addition to its role as a neurotransmitter,...
BACKGROUND
Serotonin is a phylogenetically ancient molecule that is widely distributed in most metazoans, including flatworms. In addition to its role as a neurotransmitter, serotonin acts as a morphogen and regulates developmental processes. Although several studies have focused on the serotonergic nervous system in parasitic flatworms, little is known on the role of serotonin in flatworm development.
METHODS
To study the effects of serotonin on proliferation and development of the cestode Echinococcus multilocularis, we cloned the genes encoding the E. multilocularis serotonin transporter (SERT) and tryptophan hydroxylase (TPH), analyzed gene expression by transcriptome analysis and whole mount in situ hybridization (WMISH) and performed cell culture experiments.
RESULTS
We first characterized orthologues encoding the SERT and TPH, the rate-limiting enzyme in serotonin biosynthesis. WMISH and transcriptomic analyses indicated that the genes for both SERT and TPH are expressed in the parasite nervous system. Long-term treatment of parasite stem cell cultures with serotonin stimulated development towards the parasite metacestode stage. Mature metacestode vesicles treated with serotonin showed increased rates of incorporation of the thymidine analogue 5-ethynyl-2'-deoxyuridine (EdU), indicating stimulated cell proliferation. In contrast, treatment with the selective serotonin reuptake inhibitor paroxetine strongly affected the viability of parasite cells. Paroxetine also caused structural damage in metacestode vesicles, suggesting that serotonin transport is crucial for the integrity of parasite vesicles.
CONCLUSIONS
Our results indicate that serotonin plays an important role in E. multilocularis development and proliferation, providing evidence that the E. multilocularis SERT and TPH are expressed in the nervous system of the protoscolex. Our results further suggest that the E. multilocularis SERT has a secondary role outside the nervous system that is essential for parasite integrity and survival. Since serotonin stimulated E. multilocularis metacestode development and proliferation, serotonin might also contribute to the formation and growth of the parasite in the liver.
Topics: Animals; Cell Proliferation; Echinococcus multilocularis; Gene Expression; Gene Expression Profiling; Helminth Proteins; In Situ Hybridization; Larva; Nervous System; Paroxetine; Serotonin; Serotonin Antagonists; Serotonin Plasma Membrane Transport Proteins; Tryptophan Hydroxylase
PubMed: 33407815
DOI: 10.1186/s13071-020-04533-0 -
Frontiers in Psychiatry 2019Unsuccessfully treated posttraumatic stress disorder (PTSD) is a serious and life-threatening disorder. Two medications, paroxetine hydrochloride and sertraline... (Review)
Review
Unsuccessfully treated posttraumatic stress disorder (PTSD) is a serious and life-threatening disorder. Two medications, paroxetine hydrochloride and sertraline hydrochloride, are approved treatments for PTSD by the Food and Drug Administration (FDA). Analyses of pharmacotherapies for PTSD found only small to moderate effects when compared with placebo. The Multidisciplinary Association for Psychedelic Studies (MAPS) obtained Breakthrough Therapy Designation (BTD) from the FDA for 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for treatment of PTSD on the basis of pooled analyses showing a large effect size for this treatment. This review covers data supporting BTD. In this treatment, MDMA is administered with psychotherapy in up to three monthly 8-h sessions. Participants are prepared for these sessions beforehand, and process material arising from the sessions in follow-up integrative psychotherapy sessions. Comparing data used for the approval of paroxetine and sertraline and pooled data from Phase 2 studies, MAPS demonstrated that MDMA-assisted psychotherapy constitutes a substantial improvement over available pharmacotherapies in terms of safety and efficacy. Studies of MDMA-assisted psychotherapy had lower dropout rates compared to sertraline and paroxetine trials. As MDMA is only administered under direct observation during a limited number of sessions, there is little chance of diversion, accidental or intentional overdose, or withdrawal symptoms upon discontinuation. BTD status has expedited the development of MAPS phase 3 trials occurring worldwide, leading up to a planned submission seeking FDA approval in 2021. www.ClinicalTrials.gov, identifiers NCT00090064, NCT00353938, NCT01958593, NCT01211405, NCT01689740, NCT01793610.
PubMed: 31572236
DOI: 10.3389/fpsyt.2019.00650 -
Progress in Neuro-psychopharmacology &... Jul 2023Post-traumatic stress disorder (PTSD) is a mental disorder that can emerge after an individual experiences a traumatic event such as physical abuse, sexual/relationship... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Post-traumatic stress disorder (PTSD) is a mental disorder that can emerge after an individual experiences a traumatic event such as physical abuse, sexual/relationship violence, combat exposure, witnessing death, or serious injury. This study aimed to identify the most suitable drugs for the management of PTSD based on a network meta-analysis (NMA).
METHODS
Six databases (Ovid Medline, EMBase, CENTRAL, PsycINFO, Ovid Health and Psychosocial Instruments, and Web of Science) were searched from inception to September 6, 2022.
RESULTS
Thirty articles with a total of 5170 participants were included. Compared with placebo, active drugs including olanzapine (SMD = -0.66, 95% CI: -1.19 to -0.13), risperidone (SMD = -0.23, 95% CI: -0.42 to -0.03), quetiapine (SMD = -0.49, 95% CI: -0.93 to -0.04), venlafaxine (SMD = -0.29, 95% CI: -0.42 to -0.16), sertraline (SMD = -0.23, 95% CI: -0.34 to -0.11), paroxetine (SMD = -0.48, 95% CI: -0.60 to -0.36) and fluoxetine (SMD = -0.27, 95% CI: -0.42 to -0.12), significantly reduced the total clinician-administered PTSD scale score.
CONCLUSION
The results of this study support the use of paroxetine, venlafaxine, and quetiapine as first-line treatment for PTSD. In addition, quetiapine is recommended for patients with PTSD affected by symptoms of hyperarousal and re-experience disorder. Clinicians should prescribe medications based on the severity of PTSD symptoms and other conditions to develop the best treatment strategy for this patient population.
Topics: Humans; Stress Disorders, Post-Traumatic; Cognitive Behavioral Therapy; Paroxetine; Quetiapine Fumarate; Venlafaxine Hydrochloride; Network Meta-Analysis
PubMed: 36934999
DOI: 10.1016/j.pnpbp.2023.110754 -
Neural Regeneration Research Jan 2020Given the failure to develop disease-modifying therapies for Alzheimer's disease (AD), strategies aiming at preventing or delaying the onset of the disease are being... (Review)
Review
Given the failure to develop disease-modifying therapies for Alzheimer's disease (AD), strategies aiming at preventing or delaying the onset of the disease are being prioritized. While the debate regarding whether depression is an etiological risk factor or a prodrome of AD rages on, a key determining factor may be the timing of depression onset in older adults. There is increasing evidence that untreated early-onset depression is a risk factor and that late-onset depression may be a catalyst of cognitive decline. Data from animal studies have shown a beneficial impact of selective serotonin reuptake inhibitors on pathophysiological biomarkers of AD including amyloid burden, tau deposits and neurogenesis. In humans, studies focusing on subjects with a prior history of depression also showed a delay in the onset of AD in those treated with most selective serotonin reuptake inhibitors. Paroxetine, which has strong anticholinergic properties, was associated with increased mortality and mixed effects on amyloid and tau deposits in mice, as well as increased odds of developing AD in humans. Although most of the data regarding selective serotonin reuptake inhibitors is promising, findings should be interpreted cautiously because of notable methodological heterogeneity between studies. There is thus a need to conduct large scale randomized controlled trials with long follow up periods to clarify the dose-effect relationship of specific serotonergic antidepressants on AD prevention.
PubMed: 31535641
DOI: 10.4103/1673-5374.264445