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Journal of the American Academy of... Apr 2024
Randomized Controlled Trial
Response to John et al's comments of "paroxetine is an effective treatment for refractory erythema of rosacea: Primary results from the prospective rosacea refractory erythema randomized clinical trial".
Topics: Humans; Paroxetine; Prospective Studies; Rosacea; Erythema; Treatment Outcome
PubMed: 38049068
DOI: 10.1016/j.jaad.2023.11.050 -
Journal of Sex Research Dec 2023Compulsive sexual behavior disorder (CSBD) is a burgeoning diagnostic construct. No systematic reviews of CSBD pharmacotherapy interventions have been conducted. We... (Review)
Review
Compulsive sexual behavior disorder (CSBD) is a burgeoning diagnostic construct. No systematic reviews of CSBD pharmacotherapy interventions have been conducted. We addressed this gap using a three-aim approach. We reviewed researchers' theoretical arguments for various pharmacotherapies, outcomes from pharmacotherapy trials, and the generalizability of the extant findings. Our review included = 13 studies, with = 141 participants. An opioid model of reward seeking was the most popular framework, though inconsistently specified. A serotonin model was also documented, though with few details. Naltrexone was the most prominently examined pharmacotherapy and the only medication that reliably demonstrated a therapeutic effect for some (but not all) indicators compared to placebo. Paroxetine and citalopram were also documented in placebo-controlled trials, though their incremental benefit compared to placebo is suspect. Several additional pharmacotherapies have been documented in case series contexts. Across studies, only one female participant was identified. All trials were conducted in developed nations, and race was rarely assessed. We conclude that the case for pharmacotherapy for CSBD is limited and should preferably not occur outside of clinical trial contexts. Naltrexone offers the best evidence for a potential research program, though new theoretically informed approaches are welcome. Finally, we call for additional pharmacotherapy research in women and non-White populations.
PubMed: 38047874
DOI: 10.1080/00224499.2023.2282619 -
Cell Communication and Signaling : CCS Nov 2023In essence, the β adrenergic receptor (βAR) plays an antiproliferative role by increasing the intracellular cyclic 3',5'-adenosine monophosphate (cAMP) concentration...
In essence, the β adrenergic receptor (βAR) plays an antiproliferative role by increasing the intracellular cyclic 3',5'-adenosine monophosphate (cAMP) concentration through G coupling, but interestingly, βAR antagonists are able to effectively inhibit fibroblast-like synoviocytes (FLSs) proliferation, thus ameliorating experimental RA, indicating that the βAR signalling pathway is impaired in RA FLSs via unknown mechanisms. The local epinephrine (Epi) level was found to be much higher in inflammatory joints than in normal joints, and high-level stimulation with Epi or isoproterenol (ISO) directly promoted FLSs proliferation and migration due to impaired βAR signalling and cAMP production. By applying inhibitor of receptor internalization, and small interfering RNA (siRNA) of G and G, and by using fluorescence resonance energy transfer and coimmunoprecipitation assays, a switch in G-G coupling to βAR was observed in inflammatory FLSs as well as in FLSs with chronic ISO stimulation. This G coupling was then revealed to be initiated by G protein coupled receptor kinase 2 (GRK2) but not β-arrestin2 or protein kinase A-mediated phosphorylation of βAR. Inhibiting the activity of GRK2 with the novel GRK2 inhibitor paeoniflorin-6'-O-benzene sulfonate (CP-25), a derivative of paeoniflorin, or the accepted GRK2 inhibitor paroxetine effectively reversed the switch in G-G coupling to βAR during inflammation and restored the intracellular cAMP level in ISO-stimulated FLSs. As expected, CP-25 significantly inhibited the hyperplasia of FLSs in a collagen-induced arthritis (CIA) model (CIA FLSs) and normal FLSs stimulated with ISO and finally ameliorated CIA in rats. Together, our findings revealed the pathological changes in βAR signalling in CIA FLSs, determined the underlying mechanisms and identified the pharmacological target of the GRK2 inhibitor CP-25 in treating CIA. Video Abstract.
Topics: Animals; Rats; Arthritis, Experimental; Cell Proliferation; Cells, Cultured; Epinephrine; Fibroblasts; Inflammation; Isoproterenol; Signal Transduction; Synoviocytes
PubMed: 38037039
DOI: 10.1186/s12964-023-01358-z -
Journal of Neuroimmunology Dec 2023To investigate whether sEH inhibitor AUDA can mitigate postpartum depression (PPD)-like symptoms in the rat model and regulate the AA/NF-κB pathway to suppress the...
OBJECTIVE
To investigate whether sEH inhibitor AUDA can mitigate postpartum depression (PPD)-like symptoms in the rat model and regulate the AA/NF-κB pathway to suppress the inflammatory response in the prefrontal lobes of PPD rats.
METHODS
Five groups of Sprague Dawley rats were used: normal, sham operated, PPD model, AUDA, and paroxetine hydrochloride. During the 21-day treatment period, animals in all groups underwent assessments (open field test, forced swimming test, and sucrose consumption) for depression-like behavior. At the conclusion of the treatment period, animals in all study groups were euthanized and various proteins in the prefrontal lobes were measured.
RESULTS
Depression-like behavior in rats was attenuated by AUDA. In the prefrontal lobes of PPD rats, levels of 5-LOX, COX-2, sEH, IL-1β, IL- 6, p65, p-p65, P-IκBα, NF-κB p65, and GFAP were increased while levels of epoxyeicosatrienoic acids and 5-HT were decreased. AUDA reversed these changes, thus having a similar effect as the classic antidepressant paroxetine hydrochloride.
CONCLUSION
AUDA may constrain AA/NF-κB in the prefrontal cortex of PPD rats, thus inhibiting the inflammatory response and ultimately attenuating postpartum depression-like behavior.
Topics: Animals; Female; Rats; Arachidonic Acids; Depression, Postpartum; NF-kappa B; Paroxetine; Rats, Sprague-Dawley
PubMed: 38029646
DOI: 10.1016/j.jneuroim.2023.578250 -
Menopause (New York, N.Y.) Jan 2024The neurokinin 3 receptor antagonist fezolinetant 45 mg/d significantly reduced frequency/severity of moderate to severe vasomotor symptoms (VMS) of menopause compared... (Meta-Analysis)
Meta-Analysis
Systematic review and network meta-analysis comparing the efficacy of fezolinetant with hormone and nonhormone therapies for treatment of vasomotor symptoms due to menopause.
IMPORTANCE
The neurokinin 3 receptor antagonist fezolinetant 45 mg/d significantly reduced frequency/severity of moderate to severe vasomotor symptoms (VMS) of menopause compared with placebo in two phase 3 randomized controlled trials. Its efficacy relative to available therapies is unknown.
OBJECTIVE
We conducted a systematic review and Bayesian network meta-analysis to compare efficacy with fezolinetant 45 mg and hormone therapy (HT) and non-HT for VMS in postmenopausal women.
EVIDENCE REVIEW
Using OvidSP, we systematically searched multiple databases for phase 3 or 4 randomized controlled trials in postmenopausal women with ≥7 moderate to severe VMS per day or ≥50 VMS per week published/presented in English through June 25, 2021. Mean change in frequency and severity of moderate to severe VMS from baseline to week 12 and proportion of women with ≥75% reduction in VMS frequency at week 12 were assessed using fixed-effect models.
FINDINGS
The network meta-analysis included data from the pooled phase 3 fezolinetant trials plus 23 comparator publications across the outcomes analyzed (frequency, 19 [34 regimens]; severity, 6 [7 regimens]; ≥75% response, 9 [15 regimens]). Changes in VMS frequency did not differ significantly between fezolinetant 45 mg and any of the 27 HT regimens studied. Fezolinetant 45 mg reduced the frequency of moderate to severe VMS events per day significantly more than all non-HTs evaluated: paroxetine 7.5 mg (mean difference [95% credible interval {CrI}], 1.66 [0.63-2.71]), desvenlafaxine 50 to 200 mg (mean differences [95% CrI], 1.12 [0.10-2.13] to 2.16 [0.90-3.40]), and gabapentin ER 1800 mg (mean difference [95% CrI], 1.63 [0.48-2.81]), and significantly more than placebo (mean difference, 2.78 [95% CrI], 1.93-3.62]). Tibolone 2.5 mg (the only HT regimen evaluable for severity) significantly reduced VMS severity compared with fezolinetant 45 mg. Fezolinetant 45 mg significantly reduced VMS severity compared with desvenlafaxine 50 mg and placebo and did not differ significantly from higher desvenlafaxine doses or gabapentin ER 1800 mg. For ≥75% responder rates, fezolinetant 45 mg was less effective than tibolone 2.5 mg (not available in the United States) and conjugated estrogens 0.625 mg/bazedoxifene 20 mg (available only as 0.45 mg/20 mg in the United States), did not differ significantly from other non-HT regimens studied and was superior to desvenlafaxine 50 mg and placebo.
CONCLUSIONS
The only HT regimens that showed significantly greater efficacy than fezolinetant 45 mg on any of the outcomes analyzed are not available in the United States. Fezolinetant 45 mg once daily was statistically significantly more effective than other non-HTs in reducing the frequency of moderate to severe VMS.
RELEVANCE
These findings may inform decision making with regard to the individualized management of bothersome VMS due to menopause.
Topics: Female; Humans; Hot Flashes; Desvenlafaxine Succinate; Network Meta-Analysis; Gabapentin; Bayes Theorem; Menopause; Estrogens, Conjugated (USP)
PubMed: 38016166
DOI: 10.1097/GME.0000000000002281 -
The Cochrane Database of Systematic... Nov 2023A panic attack is a discrete period of fear or anxiety that has a rapid onset and reaches a peak within 10 minutes. The main symptoms involve bodily systems, such as... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
A panic attack is a discrete period of fear or anxiety that has a rapid onset and reaches a peak within 10 minutes. The main symptoms involve bodily systems, such as racing heart, chest pain, sweating, shaking, dizziness, flushing, churning stomach, faintness and breathlessness. Other recognised panic attack symptoms involve fearful cognitions, such as the fear of collapse, going mad or dying, and derealisation (the sensation that the world is unreal). Panic disorder is common in the general population with a prevalence of 1% to 4%. The treatment of panic disorder includes psychological and pharmacological interventions, including antidepressants and benzodiazepines.
OBJECTIVES
To compare, via network meta-analysis, individual drugs (antidepressants and benzodiazepines) or placebo in terms of efficacy and acceptability in the acute treatment of panic disorder, with or without agoraphobia. To rank individual active drugs for panic disorder (antidepressants, benzodiazepines and placebo) according to their effectiveness and acceptability. To rank drug classes for panic disorder (selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), mono-amine oxidase inhibitors (MAOIs) and benzodiazepines (BDZs) and placebo) according to their effectiveness and acceptability. To explore heterogeneity and inconsistency between direct and indirect evidence in a network meta-analysis.
SEARCH METHODS
We searched the Cochrane Common Mental Disorders Specialised Register, CENTRAL, CDSR, MEDLINE, Ovid Embase and PsycINFO to 26 May 2022.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) of people aged 18 years or older of either sex and any ethnicity with clinically diagnosed panic disorder, with or without agoraphobia. We included trials that compared the effectiveness of antidepressants and benzodiazepines with each other or with a placebo.
DATA COLLECTION AND ANALYSIS
Two authors independently screened titles/abstracts and full texts, extracted data and assessed risk of bias. We analysed dichotomous data and continuous data as risk ratios (RRs), mean differences (MD) or standardised mean differences (SMD): response to treatment (i.e. substantial improvement from baseline as defined by the original investigators: dichotomous outcome), total number of dropouts due to any reason (as a proxy measure of treatment acceptability: dichotomous outcome), remission (i.e. satisfactory end state as defined by global judgement of the original investigators: dichotomous outcome), panic symptom scales and global judgement (continuous outcome), frequency of panic attacks (as recorded, for example, by a panic diary; continuous outcome), agoraphobia (dichotomous outcome). We assessed the certainty of evidence using threshold analyses.
MAIN RESULTS
Overall, we included 70 trials in this review. Sample sizes ranged between 5 and 445 participants in each arm, and the total sample size per study ranged from 10 to 1168. Thirty-five studies included sample sizes of over 100 participants. There is evidence from 48 RCTs (N = 10,118) that most medications are more effective in the response outcome than placebo. In particular, diazepam, alprazolam, clonazepam, paroxetine, venlafaxine, clomipramine, fluoxetine and adinazolam showed the strongest effect, with diazepam, alprazolam and clonazepam ranking as the most effective. We found heterogeneity in most of the comparisons, but our threshold analyses suggest that this is unlikely to impact the findings of the network meta-analysis. Results from 64 RCTs (N = 12,310) suggest that most medications are associated with either a reduced or similar risk of dropouts to placebo. Alprazolam and diazepam were associated with a lower dropout rate compared to placebo and were ranked as the most tolerated of all the medications examined. Thirty-two RCTs (N = 8569) were included in the remission outcome. Most medications were more effective than placebo, namely desipramine, fluoxetine, clonazepam, diazepam, fluvoxamine, imipramine, venlafaxine and paroxetine, and their effects were clinically meaningful. Amongst these medications, desipramine and alprazolam were ranked highest. Thirty-five RCTs (N = 8826) are included in the continuous outcome reduction in panic scale scores. Brofaromine, clonazepam and reboxetine had the strongest reductions in panic symptoms compared to placebo, but results were based on either one trial or very small trials. Forty-one RCTs (N = 7853) are included in the frequency of panic attack outcome. Only clonazepam and alprazolam showed a strong reduction in the frequency of panic attacks compared to placebo, and were ranked highest. Twenty-six RCTs (N = 7044) provided data for agoraphobia. The strongest reductions in agoraphobia symptoms were found for citalopram, reboxetine, escitalopram, clomipramine and diazepam, compared to placebo. For the pooled intervention classes, we examined the two primary outcomes (response and dropout). The classes of medication were: SSRIs, SNRIs, TCAs, MAOIs and BDZs. For the response outcome, all classes of medications examined were more effective than placebo. TCAs as a class ranked as the most effective, followed by BDZs and MAOIs. SSRIs as a class ranked fifth on average, while SNRIs were ranked lowest. When we compared classes of medication with each other for the response outcome, we found no difference between classes. Comparisons between MAOIs and TCAs and between BDZs and TCAs also suggested no differences between these medications, but the results were imprecise. For the dropout outcome, BDZs were the only class associated with a lower dropout compared to placebo and were ranked first in terms of tolerability. The other classes did not show any difference in dropouts compared to placebo. In terms of ranking, TCAs are on average second to BDZs, followed by SNRIs, then by SSRIs and lastly by MAOIs. BDZs were associated with lower dropout rates compared to SSRIs, SNRIs and TCAs. The quality of the studies comparing antidepressants with placebo was moderate, while the quality of the studies comparing BDZs with placebo and antidepressants was low.
AUTHORS' CONCLUSIONS
In terms of efficacy, SSRIs, SNRIs (venlafaxine), TCAs, MAOIs and BDZs may be effective, with little difference between classes. However, it is important to note that the reliability of these findings may be limited due to the overall low quality of the studies, with all having unclear or high risk of bias across multiple domains. Within classes, some differences emerged. For example, amongst the SSRIs paroxetine and fluoxetine seem to have stronger evidence of efficacy than sertraline. Benzodiazepines appear to have a small but significant advantage in terms of tolerability (incidence of dropouts) over other classes.
Topics: Adult; Humans; Panic Disorder; Selective Serotonin Reuptake Inhibitors; Paroxetine; Fluoxetine; Venlafaxine Hydrochloride; Serotonin and Noradrenaline Reuptake Inhibitors; Alprazolam; Clomipramine; Reboxetine; Clonazepam; Desipramine; Network Meta-Analysis; Antidepressive Agents; Antidepressive Agents, Tricyclic; Benzodiazepines; Diazepam
PubMed: 38014714
DOI: 10.1002/14651858.CD012729.pub3 -
Pharmaceutics Nov 2023The successful integration of hot-melt extrusion (HME) and fused deposition modelling (FDM) depends on a better understanding of the impact of environmental conditions...
The successful integration of hot-melt extrusion (HME) and fused deposition modelling (FDM) depends on a better understanding of the impact of environmental conditions on the printability of formulations, since they significantly affect the properties of the raw materials, whose control is crucial to enable three-dimensional printing (3DP). Hence, the objective of this work was to investigate the correlation between the environmental settings and the properties of paroxetine (PRX)-loaded filaments, previously produced by HME, which affect printability by FDM. The influence of different drying methods of the physical mixtures (PMs) and HME-filaments (FILs) on the quality and printability of these products was also assessed. The printability of FILs was evaluated in terms of the water content, and the mechanical and thermal properties of the products. Stability studies and physicochemical, thermal, and in vitro dissolution tests were carried out on the 3D-printed tablets. Stability studies demonstrated the high ductility of the PRX loaded FILs, especially under high humidity conditions. Under low humidity storage conditions (11% RH), the FILs became stiffer and were successfully used to feed the FDM printer. Water removal was slow when carried out passively in a controlled atmosphere (desiccator) or accelerated by using active drying methods (heat or microwave). Pre-drying of the PRX/excipients and/or PMs did not show any positive effect on the printability of the FIL. On the contrary, dry heat and, preferably, microwave mediated drying processes were shown to reduce the holding time required for successful FDM printing, enabling on-demand production at the point of care.
PubMed: 38004614
DOI: 10.3390/pharmaceutics15112636 -
Psychopharmacology Nov 2023Social hierarchies are important for individual's well-being, professional and domestic growth, harmony of the society, as well as survival and morbidity. Studies have...
BACKGROUND
Social hierarchies are important for individual's well-being, professional and domestic growth, harmony of the society, as well as survival and morbidity. Studies have revealed sexual dimorphism in the social abilities; however, data is limited on the sex-specific effects of various drugs used to treat psychiatric disorders and social deficits.
OBJECTIVE
The present study aimed at evaluating the sex-dependent effects of Risperidone (antipsychotic that targets D2 dopaminergic, 5HTA serotonergic, and α-adrenergic receptors), Donepezil (a reversible acetylcholinesterase inhibitor), and Paroxetine (a selective serotonin reuptake inhibitor) on social hierarchy in rats under normal and stressed states.
METHODS
8-12 weeks old male and female Wistar rats were divided into sex-wise 4-4 groups, i.e., 1. control group, 2. Risperidone treated group (3 mg/kg/day), 3. Donepezil treated group (5 mg/kg/day), and Paroxetine treated group (10 mg/kg/day). Rats were treated with these drugs in phase I for 21 days in distilled drinking water, followed by a no (drugs) treatment break of 10 days. After the break phase II started with the administration of drugs (same as in phase I) along with tilt-cage stress for 21 days. Home cage activity assessment was performed once a week during both phases (I & II), while tube dominance and resident intruder tests were performed at the end of each phase.
RESULTS
In phase I in both sexes, Risperidone treatment decreased social interaction and motor activity while Paroxetine treatment increased these in both sexes compared to their respective control groups. Social dominance and aggression were reduced after treatment with both of these drugs. In contrast, Donepezil treatment caused an increase in motor activity in females whereas reduced motor activity in males. Furthermore, Donepezil treatment caused reduction in interaction but increased social dominance and aggression were observed in both sexes. In phase II, stress led to an overall decrease in motor activity and social interaction of animals. Treatment with Risperidone, Paroxetine, and Donepezil caused a sex-specific effect on, motor activity, social interaction, and social exploration.
CONCLUSION
These results showed that Risperidone has stronger effects on male social behavior whereas Paroxetine and Donepezil differentially affect social abilities in both sexes during normal and stressed situations.
PubMed: 37994914
DOI: 10.1007/s00213-023-06503-7 -
Georgian Medical News Sep 2023The aim of this study was to evaluate current approaches to the pharmacotherapy of posttraumatic stress disorder. An information search was carried out in the databases...
The aim of this study was to evaluate current approaches to the pharmacotherapy of posttraumatic stress disorder. An information search was carried out in the databases PubMed, Ovid, EMBASE by keywords: "posttraumatic stress disorder", "treatment", and "medications". Search depth 2012-2022 years. From the general data (4877 articles) there were selected 14 articles with the highest degree of relevance. A content analysis of selected articles was carried out with the formation of recommendations for the use of pharmacotherapy in posttraumatic stress disorder. Currently, there are no unified approaches to the pharmacotherapy of posttraumatic stress disorder. Antidepressants (SSRI SNRIs) are primarily considered as first-line drugs, but only sertraline, paroxetine, and fluoxetine are approved by the FDA. But these drugs have a fairly wide range of side effects, including suicidal thoughts. The use of benzodiazepines should be limited as they increase the risk of developing posttraumatic stress disorder. Vortioxetine becomes a very promising option. The most significant benefits of vortioxetine are the significant positive effects of vortioxetine on attention, memory, and executive function. There is some evidence for the use of alpha-1 adrenoceptor antagonists and alpha-2 adrenoceptor agonists in therapy. In insomnia the use of prazosin and trazodone is recommended. Pharmacotherapy of posttraumatic stress disorder requires administration of medications with multimodal action. Currently, there are no unified approaches to the pharmacotherapy of posttraumatic stress disorder. Further randomized clinical trials are necessary for developing effective treatment of posttraumatic stress disorder.
Topics: Humans; Antidepressive Agents; Receptors, Adrenergic; Stress Disorders, Post-Traumatic; Vortioxetine
PubMed: 37991966
DOI: No ID Found -
CNS Neuroscience & Therapeutics Apr 2024Previous research has identified functional impairments within the prefrontal-limbic circuit in individuals with anxiety disorders. However, the link between these...
BACKGROUND
Previous research has identified functional impairments within the prefrontal-limbic circuit in individuals with anxiety disorders. However, the link between these deficiencies, clinical symptoms, and responses to antipsychotic treatment is still not fully understood. This study aimed to investigate abnormal regional activity within the prefrontal-limbic circuit among drug-naive individuals diagnosed with generalized anxiety disorder (GAD) and panic disorder (PD) and to analyze changes following treatment.
METHODS
Resting-state magnetic resonance imaging was performed on a cohort of 118 anxiety disorder patients (64 GAD, 54 PD) and 61 healthy controls (HCs) at baseline. Among them, 52 patients with GAD and 44 patients with PD underwent a 4-week treatment regimen of paroxetine. Fractional amplitude of low-frequency fluctuation (fALFF) measurements and pattern classification techniques were employed to analyze the data in accordance with the human Brainnetome atlas.
RESULTS
Both patients with GAD and PD demonstrated decreased fALFF in the right cHipp subregion of the hippocampus and increased fALFF in specified subregions of the cingulate and orbitofrontal lobe. Notably, patients with PD exhibited significantly higher fALFF in the left A24cd subregion compared to patients with GAD, while other ROI subregions showed no significant variations between the two patient groups. Whole-brain analysis revealed abnormal fALFF in both patient groups, primarily in specific areas of the cingulate and parasingulate gyrus, as well as the inferior and medial orbitofrontal gyrus (OFG). Following a 4-week treatment period, specific subregions in the GAD and PD groups showed a significant decrease in fALFF. Further analysis using support vector regression indicated that fALFF measurements in the right A13 and right A24cd subregions may be predictive of treatment response among anxiety disorder patients.
CONCLUSIONS
Aberrant functional activity in certain subregions of the prefrontal-limbic circuit appears to be linked to the manifestation of anxiety disorders. These findings suggest potential imaging indicators for individual responses to antipsychotic treatment.
Topics: Humans; Antipsychotic Agents; Anxiety Disorders; Brain; Cerebral Cortex; Brain Mapping; Magnetic Resonance Imaging
PubMed: 37990350
DOI: 10.1111/cns.14523