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Pharmaceuticals (Basel, Switzerland) Apr 2023G protein-coupled receptor kinase 2 (GRK2) is one of the cytosolic enzymes, and GRK2 translocation induces prostaglandin E2 receptor 4 (EP4) over-desensitization and...
GRK2 Mediates Macrophage Polarization by Regulating EP4-cAMP-pCREB Signaling in Ulcerative Colitis and the Therapeutic Effect of Paroxetine on Mice with DSS-Induced Colitis.
G protein-coupled receptor kinase 2 (GRK2) is one of the cytosolic enzymes, and GRK2 translocation induces prostaglandin E2 receptor 4 (EP4) over-desensitization and reduces the level of cyclic adenosine monophosphate (cAMP) to regulate macrophage polarization. However, the role of GRK2 in the pathophysiology of ulcerative colitis (UC) remains unclear. In this study, we investigated the role of GRK2 in macrophage polarization in UC, using biopsies from patients, a GRK2 heterozygous mouse model with dextran sulfate sodium (DSS)-induced colitis, and THP-1 cells. The results showed that a high level of prostaglandin E2 (PGE2) stimulated the receptor EP4 and enhanced the transmembrane activity of GRK2 in colonic lamina propria mononuclear cells (LPMCs), resulting in a down-regulation of membrane EP4 expression. Then, the suppression of cAMP-cyclic AMP responsive element-binding (CREB) signal inhibited M2 polarization in UC. Paroxetine is acknowledged as one of the selective serotonin reuptake inhibitors (SSRI), which is also considered as a potent GRK2 inhibitor with a high selectivity for GRK2. We found that paroxetine could alleviate symptoms of DSS-induced colitis in mice by regulating GPCR signaling to affect macrophage polarization. Taken together, the current results show that GRK2 may act as a novel therapeutic target in UC by regulating macrophage polarization, and paroxetine as a GRK2 inhibitor may have therapeutic effect on mice with DSS-induced colitis.
PubMed: 37242446
DOI: 10.3390/ph16050664 -
Molecules (Basel, Switzerland) May 2023This study describes the development and validation of a new green and high-throughput microwell spectrophotometric assay (MW-SPA) for the determination of three...
Development and Validation of Green and High-Throughput Microwell Spectrophotometric Assay for the Determination of Selective Serotonin Reuptake Inhibitors in Their Pharmaceutical Dosage Forms.
This study describes the development and validation of a new green and high-throughput microwell spectrophotometric assay (MW-SPA) for the determination of three selective serotonin reuptake inhibitors (SSRIs) in their pharmaceutical dosage forms. These SSRIs are fluoxetine, fluvoxamine, and paroxetine, the most prescribed drugs for the treatment of depression. The proposed assay was based on the formation of orange-colored -substituted naphthoquinone derivatives upon the reaction of SSRIs with 1,2-naphthoquinone-4-sulphonate (NQS) in alkaline media. The assay was conducted in 96-microwell assay plates, and the absorbances of the reaction products were measured by a microplate reader at their maximum absorbance wavelengths. The optimum conditions of the reaction were refined and established. Under these conditions, calibration curves were generated, and linear regression equations were computed. The linear relations between the absorbances and drug concentrations were linear with good correlation coefficients (0.9992-0.9997) in the range of 2-80 µg/mL. The assay limits of detection were in the range of 1.5-4.2 µg/mL. The precision was satisfactory as the values of relative standard deviation did not exceed 1.70%. The accuracy of the assay was ≥98.2%. The proposed MW-SPA was successfully applied to the analysis of the SSRIs in their pharmaceutical dosage forms with acceptable accuracy and precision; the label claims were 99.2-100.5% (±0.96-1.35%). The results of the proposed MW-SPA were compared with those of the official/pre-validated assays by statistical analysis with respect to the accuracy (by -test) and precision (by F-test). No significant differences were found between the calculated and theoretical values of the t- and F-tests at the 95% confidence level, proving similar accuracy and precision in the determination of SSRIs by both assays. The greenness of the proposed assay was confirmed by two metric tools. In addition, the assay is characterized with a high-throughput property which enables the simultaneous analysis of many samples in a short time. Therefore, the assay is a valuable tool for rapid routine application in pharmaceutical quality control units for the determination of the investigated SSRIs.
Topics: Selective Serotonin Reuptake Inhibitors; Spectrophotometry; Fluoxetine; Fluvoxamine; Pharmaceutical Preparations
PubMed: 37241961
DOI: 10.3390/molecules28104221 -
European Review For Medical and... May 2023Premature ejaculation (PE) and erectile dysfunction (ED) are sexual dysfunction diseases affecting males. The phosphodiesterase type 5 (PDE5) inhibitors such as...
OBJECTIVE
Premature ejaculation (PE) and erectile dysfunction (ED) are sexual dysfunction diseases affecting males. The phosphodiesterase type 5 (PDE5) inhibitors such as tadalafil are used to treat ED whereas selective serotonin reuptake inhibitors (SSRIs) are preferred for PE. Most of the patients with ED also suffer from PE simultaneously. The combined drug therapies are commonly preferred as they favor elevated intra-vaginal ejaculation latency time (IELT) scores and improved sexual function. The study aimed to evaluate the efficacy and safety of daily paroxetine and tadalafil combination therapy in patients with PE and ED.
PATIENTS AND METHODS
A total of 81 PE patients with ED were enrolled in the study. Patients were treated with daily paroxetine 20 mg and tadalafil 5 mg for 4 weeks. Pre- and post-treatment IELT, premature ejaculation profile (PEP), and International Index of Erectile Function-Erectile Function (IIEF-EF) scores of the patients were analyzed.
RESULTS
The mean IELT and PEP index scores, and mean IIEF-EF values improved after combination therapy (p<0.001 for each). When lifelong and acquired PE+ED patients were compared, significant improvements were observed in IELT, PEP, and IIEF-EF scores in both groups (p<0.001).
CONCLUSIONS
Even though the treatment methods are different, combined therapies to treat simultaneous PE and ED presence are effective compared to monotherapies. However, there is still no definitive treatment that can cure all subtypes of PE or ED.
Topics: Male; Female; Humans; Erectile Dysfunction; Premature Ejaculation; Paroxetine; Tadalafil; Retrospective Studies; Ejaculation; Phosphodiesterase 5 Inhibitors; Treatment Outcome
PubMed: 37203851
DOI: 10.26355/eurrev_202305_32335 -
Zhejiang Da Xue Xue Bao. Yi Xue Ban =... Aug 2022To evaluate the efficacy and safety of antidepressants in treatment of depression disorder in children and adolescents by network meta-analysis. (Meta-Analysis)
Meta-Analysis
OBJECTIVE
To evaluate the efficacy and safety of antidepressants in treatment of depression disorder in children and adolescents by network meta-analysis.
METHODS
Databases of PubMed, Cochrane Library, EMBASE, Web of Science, PsycINFO, CBM, CNKI and Wanfang Data were searched for randomized controlled trials (RCT) related to antidepressants in treatment of children and adolescents with depression from inception to December 2021. Quality assessment and data extraction from the included RCTs were performed. Statistical analyses of efficacy and tolerability were conducted with Stata 15.1 software. Surface under the cumulative ranking (SUCAR) was used to rank the value of the antidepressants.
RESULTS
A total of 33 RCTs were included in 32 articles, involving 6949 patients. There are 13 antidepressants used in total, including amitriptyline, vilazodone, fluoxetine, selegiline, paroxetine, imipramine, desipramine, sertraline, nortriptyline, escitalopram, citalopram, venlafaxine and duloxetine. The results of network meta-analysis showed that the efficacy of duloxetine ( =1.95, 95% 1.41-2.69), fluoxetine ( =1.73, 95% 1.40-2.14), venlafaxine ( =1.37, 95% 1.04-1.80) and escitalopram ( =1.48, 95% : 1.12-1.95) were significantly higher than that of placebos (all <0.05); the probability cumulative ranks were duloxetine (87.0%), amitriptyline (83.3%), fluoxetine (79.0%), escitalopram (62.7%), etc. The results showed that the intolerability of patients receiving imipramine ( =0.15, 95% 0.08-0.27), sertraline ( =0.33, 95% 0.16-0.71), venlafaxine ( =0.35, 95% 0.17-0.72), duloxetine ( =0.35, 95% 0.17-0.73) and paroxetine ( =0.52, 95% 0.30-0.88) were significantly higher than that of placebos (all <0.05), and the probability cumulative ranks were imipramine (95.7%), sertraline (69.6%), venlafaxine (68.6%), duloxetine (68.2%), etc. Conclusion: Among 13 antidepressants, duloxetine, fluoxetine, escitalopram and venlafaxine are significantly better than placebo in terms of efficacy, but duloxetine and venlafaxine are less well tolerated.
Topics: Adolescent; Child; Humans; Venlafaxine Hydrochloride; Duloxetine Hydrochloride; Fluoxetine; Sertraline; Paroxetine; Amitriptyline; Imipramine; Depression; Escitalopram; Network Meta-Analysis; Depressive Disorder, Major; Antidepressive Agents
PubMed: 37202104
DOI: 10.3724/zdxbyxb-2022-0145 -
Therapeutic Advances in... 2023In patients attempting to discontinue their antidepressant medication, there have been no prospective studies on patterns of withdrawal as a function of the rate of...
BACKGROUND
In patients attempting to discontinue their antidepressant medication, there have been no prospective studies on patterns of withdrawal as a function of the rate of antidepressant reduction during the tapering trajectory, and moderators thereof.
OBJECTIVE
To investigate withdrawal as a function of gradual dose reduction.
DESIGN
Prospective cohort study.
METHODS
The sampling frame consisted of 3956 individuals in the Netherlands who received an antidepressant tapering strip between 19 May 2019 and 22 March 2022 in routine clinical practice. Of these, 608 patients, majorly with previous unsuccessful attempts to stop, provided daily ratings of withdrawal in the context of reducing their antidepressant medications (mostly venlafaxine or paroxetine), using hyperbolic tapering strips offering daily tiny reductions in dose.
RESULTS
Withdrawal in daily-step hyperbolic tapering trajectories was limited, and inverse to the rate of taper. Female sex, younger age, presence of one or more risk factors and faster rate of reduction over shorter tapering trajectories were associated with more withdrawal and differential course over time. Thus, sex and age differences were less marked early in the course of the trajectory, whereas differences associated with risk factors and shorter trajectories tended to peak early in the trajectory. There was evidence that tapering in weekly larger steps (mean per-week dose reduction: 33.4% of previous dose), in comparison with daily tiny steps (mean per-day dose reduction: 4.5% of previous dose or 25.3% per week), was associated with more withdrawal in trajectories of 1, 2 or 3 months, particularly for paroxetine and the group of other (non-paroxetine, non-venlafaxine) antidepressants.
CONCLUSION
Antidepressant hyperbolic tapering is associated with limited, rate-dependent withdrawal that is inverse to the rate of taper. The demonstration of multiple demographic, risk and complex temporal moderators in time series of withdrawal data indicates that antidepressant tapering in clinical practice requires a personalised process of shared decision making over the entire course of the tapering period.
PubMed: 37200818
DOI: 10.1177/20451253231171518 -
Cureus Apr 2023Purpose At present, clinicians typically prescribe antidepressants based on the widely accepted "serotonin hypothesis." This study explores an alternative mechanism,...
Purpose At present, clinicians typically prescribe antidepressants based on the widely accepted "serotonin hypothesis." This study explores an alternative mechanism, the stress mechanism, for selecting antidepressants based on patients' medical history. Methods This study investigated clinicians' prescribing patterns for the 15 most common antidepressants, including amitriptyline, bupropion, citalopram, desvenlafaxine, doxepin, duloxetine, escitalopram, fluoxetine, mirtazapine, nortriptyline, paroxetine, ropinirole, sertraline, trazodone, and Venlafaxine. The least absolute shrinkage and selection operator (LASSO) logistic regression was used to identify factors that affect the remission of depression symptoms after receiving an antidepressant. Results The study found that a wide range of factors influenced the propensity of clinicians to prescribe antidepressants, with the number of predictors ranging from 51 to 206 variables. The prevalence of prescribing an antidepressant ranged from 0.5% for doxepin to 24% for the combination of more than one antidepressant. The area under the receiver operating curves (AROC) ranged from 77.2% for venlafaxine to 90.5% for ropinirole, with an average AROC of 82% for predicting the propensity of medications. A variety of diagnoses and prior medications affected remission, in agreement that the central mechanism for the impact of medications on the brain is through stress reduction. For example, psychotherapy, whether done individually or in a group, whether done for a short or long time, and whether done with evaluation/assessment or not, had an impact on remission. Specifically, teenagers and octogenarians were less likely to benefit from bupropion, citalopram, escitalopram, fluoxetine, and sertraline compared to patients between 40 and 65 years old. The findings of this study suggest that considering a patient's medical history and individual characteristics is crucial for selecting the most effective antidepressant treatment. Conclusions Many studies have raised doubt about the serotonin hypothesis as the central mechanism for depression treatment. The identification of a wide range of predictors for prescribing antidepressants highlights the complexity of depression treatment and the need for individualized approaches that consider patients' comorbidities and previous treatments. The significant impact of comorbidities on the response to treatment makes it improbable that the mechanism of action of antidepressants is solely based on the serotonin hypothesis. It is hard to explain how comorbidities lead to the depletion of serotonin. These findings open up a variety of courses of action for the clinical treatment of depression, each addressing a different source of chronic stress in the brain. Overall, this study contributes to a better understanding of depression treatment and provides valuable insights for clinicians in selecting antidepressants based on patients' medical history.
PubMed: 37168173
DOI: 10.7759/cureus.37117 -
Translational Psychiatry Apr 2023Treatment effect in clinical trials for major depressive disorders (RCT) can be viewed as the resultant of treatment specific and non-specific effects. Baseline... (Randomized Controlled Trial)
Randomized Controlled Trial
Artificial intelligence approach for the analysis of placebo-controlled clinical trials in major depressive disorders accounting for individual propensity to respond to placebo.
Treatment effect in clinical trials for major depressive disorders (RCT) can be viewed as the resultant of treatment specific and non-specific effects. Baseline individual propensity to respond non-specifically to any treatment or intervention can be considered as a major non-specific confounding effect. The greater is the baseline propensity, the lower will be the chance to detect any treatment-specific effect. The statistical methodologies currently applied for analyzing RCTs doesn't account for potential unbalance in the allocation of subjects to treatment arms due to heterogenous distributions of propensity. Hence, the groups to be compared may be imbalanced, and thus incomparable. Propensity weighting methodology was used to reduce baseline imbalances between arms. A randomized, double-blind, placebo controlled, three arms, parallel group, 8-week, fixed-dose study to evaluate efficacy of paroxetine CR 12.5 and 25 mg/day is presented as a cases study. An artificial intelligence model was developed to predict placebo response at week 8 in subjects assigned to placebo arm using changes from screening to baseline of individual Hamilton Depression Rating Scale items. This model was used to predict the probability to respond to placebo in each subject. The inverse of the probability was used as weight in the mixed-effects model applied to assess treatment effect. The analysis with and without propensity weight indicated that the weighted analysis provided an estimate of treatment effect and effect-size about twice larger than the non-weighted analysis. Propensity weighting provides an unbiased strategy to account for heterogeneous and uncontrolled placebo effect making patients' data comparable across treatment arms.
Topics: Humans; Depressive Disorder, Major; Artificial Intelligence; Paroxetine; Double-Blind Method; Treatment Outcome
PubMed: 37120641
DOI: 10.1038/s41398-023-02443-0 -
Neurology and Therapy Apr 2023Patients with depression require thorough clinical assessment, which should include symptom profile, severity and staging, personality factors, antecedent and concurrent...
Patients with depression require thorough clinical assessment, which should include symptom profile, severity and staging, personality factors, antecedent and concurrent psychiatric comorbidity, physical comorbidity, neurocognitive function, exposure to stressors in early life (e.g. trauma) or recently (e.g. bereavement), and protective factors. The presence of anxiety symptoms in a depressed patient is associated with more severe depression, increased suicidality and worse outcomes compared with non-anxious depression. A network meta-analysis of antidepressant treatments found that agomelatine, citalopram, amitriptyline, escitalopram, mirtazapine, paroxetine, venlafaxine and vortioxetine were all significantly more effective than other antidepressants for the treatment of depression, and that agomelatine, citalopram, escitalopram, fluoxetine, sertraline and vortioxetine were better tolerated than other antidepressants. Agomelatine has been shown to have two major effects-relieving depressive symptoms, and supporting symptomatic and functional recovery-and these benefits have been demonstrated in patients with depression as well as in patients with generalised anxiety disorder, including those with more severe symptoms. Agomelatine has also been shown to be efficacious and well tolerated in patients with depression plus concomitant anxiety symptoms. A pooled analysis of data from six agomelatine studies of depression (three placebo-controlled and three with active comparators-fluoxetine, sertraline and venlafaxine) found that agomelatine was significantly more effective than placebo at relieving the anxiety subscore on the Hamilton Depression Rating Scale, and that the difference between agomelatine and placebo was even more marked in the subgroup of patients with severe anxiety symptoms at baseline. Irrespective of the pharmacotherapy used in patients with depression, the likelihoods of response and remission are increased when pharmacotherapy is combined with psychotherapy, with this approach being more effective than either pharmacotherapy or psychotherapy alone. Persistence with treatment is important, and clinicians should therefore encourage patients to keep trying to obtain relief.
PubMed: 37115460
DOI: 10.1007/s40120-023-00470-z -
European Neuropsychopharmacology : the... Jun 2023The World Health Organization has proposed that a search be made for alternatives to vaccines for the prevention and treatment of COVID-19, with one such alternative...
The World Health Organization has proposed that a search be made for alternatives to vaccines for the prevention and treatment of COVID-19, with one such alternative being selective serotonin reuptake inhibitors (SSRIs). This study thus sought to assess: the impact of previous treatment with SSRI antidepressants on the severity of COVID-19 (risk of hospitalisation, admission to an intensive care unit [ICU], and mortality), its influence on susceptibility to SARS-CoV-2 and progression to severe COVID-19. We conducted a population-based multiple case-control study in a region in the north-west of Spain. Data were sourced from electronic health records. Adjusted odds ratios (aORs) and 95%CIs were calculated using multilevel logistic regression. We collected data from a total of 86,602 subjects: 3060 cases PCR+, 26,757 non-hospitalised cases PCR+ and 56,785 controls (without PCR+). Citalopram displayed a statistically significant decrease in the risk of hospitalisation (aOR=0.70; 95% CI 0.49-0.99, p = 0.049) and progression to severe COVID-19 (aOR=0.64; 95% CI 0.43-0.96, p = 0.032). Paroxetine was associated with a statistically significant decrease in risk of mortality (aOR=0.34; 95% CI 0.12 - 0.94, p = 0.039). No class effect was observed for SSRIs overall, nor was any other effect found for the remaining SSRIs. The results of this large-scale, real-world data study indicate that, citalopram, could be a candidate drug for being repurposed as preventive treatment aimed at reducing COVID-19 patients' risk of progressing to severe stages of the disease.
Topics: Humans; Selective Serotonin Reuptake Inhibitors; Citalopram; Case-Control Studies; Drug Repositioning; COVID-19; SARS-CoV-2
PubMed: 37094487
DOI: 10.1016/j.euroneuro.2023.03.011 -
Frontiers in Pharmacology 2023Mental disorders can have a significant impact on patients' life, including economic, social and individual consequences, and psychotropic medication is essential to...
Mental disorders can have a significant impact on patients' life, including economic, social and individual consequences, and psychotropic medication is essential to treat these conditions. Psychotropic drug utilization studies contribute to a clearer picture of the management of these conditions. Data published from Romania on this topic is limited. The present study aims to characterize the utilization patterns of anxiolytics, antidepressants (ADs), and antipsychotics (APs) in Romania during 1998-2018. Drug utilization data were provided by Management Center for Documentation, Information and Marketing (CEGEDIM) Romania and quantitative data for each psychotropic medicine were converted to total defined daily doses (DDDs) and to DDD/1000inhabitants/day (DDD/TID). The total use of medicines in DDD/TID was computed in order to obtain the drug utilization 90% (DU90%) segment. An increasing trend in total utilization of psychotropic medicines in Romania started in 2004. Anxiolytics use was predominant until 2013 and the yearly anxiolytic use over the entire study period remained between 10 and 15 DDD/TID. Diazepam lost popularity over time in detriment of the utilization of other anxiolytic benzodiazepines, such as alprazolam and lorazepam. ADs utilization markedly increased during the study period (the average annual growth rate was 13.66% starting 1999). Selective serotonin reuptake inhibitors (SSRIs) became present on the 2008 DU90% and was the dominant class of ADs, with sertraline being the most prescribed, followed by escitalopram and paroxetine. APs utilization showed an increasing trend from 2003 until 2018. Atypical APs became present on the 2008 DU90%, while typical APs were no longer included in the 2018 DU90%. Among atypical APs, olanzapine was the main agent prescribed, and starting 2010 was followed by quetiapine and risperidone. The uptake of APs long-acting formulations became more evident during the last analyzed years (2015-2018). We observed an increasing utilization of APs and a more prominent increase in ADs utilization in Romania during 1998-2018. The anxiolytic prescribing remained nearly stable during this time. Further research can bring more information on the various factors influencing psychotropic utilization in Romania.
PubMed: 37050903
DOI: 10.3389/fphar.2023.1157231