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Journal of Affective Disorders May 2023Desvenlafaxine and duloxetine are selective serotonin and norepinephrine reuptake inhibitors. Their efficacy has not been directly compared using statistical hypotheses.... (Randomized Controlled Trial)
Randomized Controlled Trial
A multicenter, randomized, double-blind, duloxetine-controlled, non-inferiority trial of desvenlafaxine succinate extended-release in patients with major depressive disorder.
BACKGROUND
Desvenlafaxine and duloxetine are selective serotonin and norepinephrine reuptake inhibitors. Their efficacy has not been directly compared using statistical hypotheses. This study evaluated the non-inferiority of desvenlafaxine extended-release (XL) to duloxetine in patients with major depressive disorder (MDD).
METHODS
In this study, 420 adult patients with moderate-to-severe MDD were enrolled and randomly assigned (1:1) to receive 50 mg (once daily [QD]) of desvenlafaxine XL (n = 212) or 60 mg QD of duloxetine (n = 208). The primary endpoint was evaluated using a non-inferiority comparison based on the change from baseline to 8 weeks in the 17-item Hamilton Depression Rating Scale (HAMD) total score. Secondary endpoints and safety were evaluated.
RESULTS
Least-squares mean change in HAM-D total score from baseline to 8 weeks was -15.3 (95% confidence interval [CI]: -17.73, -12.89) in the desvenlafaxine XL group and - 15.9 (95% CI, -18.44, -13.39) in the duloxetine group. The least-squares mean difference was 0.6 (95% CI: -0.48, 1.69), and the upper boundary of 95% CI was less than the non-inferiority margin (2.2). No significant between-treatment differences were found in most secondary efficacy endpoints. The incidence of the most common treatment-emergent adverse events (TEAEs) was lower for desvenlafaxine XL than for duloxetine for nausea (27.2% versus 48.8%) and dizziness (18.0% versus 28.8%).
LIMITATIONS
A short-term non-inferiority study without a placebo arm.
CONCLUSIONS
This study demonstrated that desvenlafaxine XL 50 mg QD was non-inferior to duloxetine 60 mg QD in efficacy in patients with MDD. Desvenlafaxine had a lower incidence of TEAEs than duloxetine did.
Topics: Adult; Humans; Duloxetine Hydrochloride; Depressive Disorder, Major; Desvenlafaxine Succinate; Antidepressive Agents; Double-Blind Method; Treatment Outcome
PubMed: 36813043
DOI: 10.1016/j.jad.2023.02.067 -
The Korean Journal of Internal Medicine Sep 2019About 21% of adults with osteoarthritis (OA) are diagnosed with concomitant depression in addition to chronic pain. Duloxetine, an anti-depressant medication, has been... (Meta-Analysis)
Meta-Analysis
About 21% of adults with osteoarthritis (OA) are diagnosed with concomitant depression in addition to chronic pain. Duloxetine, an anti-depressant medication, has been recently approved for managing Knee OA. We performed a systematic review to ascertain the efficacy and safety of duloxetine for OA. We searched MEDLINE, EMBASE, Web of Science, Google Scholar, and the Cochrane Database from inception to December 2018. Randomized clinical trials (RCTs) assessing the efficacy and/or safety of duloxetine versus placebo in OA patients were included. Data extraction and quality assessment were undertaken by two independent reviewers. Seven RCTs (n = 2,102 participants) met our inclusion criteria, and five RCTs (n = 1,713) were eligible for meta-analysis. The results of our analyses indicate that duloxetine has statistically significant, moderate benefits on pain, function, and quality of life in knee OA patients for up to 13 weeks. Reported incidences of gastrointestinal adverse events were three to four times higher in participants who received duloxetine versus placebo. Duloxetine may be an effective treatment option for individuals with knee OA, but use of the drug is associated with a significantly higher risk of adverse events. Patient preferences and clinicians' judgment must be considered before the initiation of duloxetine.
Topics: Aged; Antirheumatic Agents; Duloxetine Hydrochloride; Female; Humans; Male; Middle Aged; Osteoarthritis, Knee; Quality of Life; Remission Induction; Risk Factors; Treatment Outcome
PubMed: 30871298
DOI: 10.3904/kjim.2018.460 -
Biomedicine & Pharmacotherapy =... Oct 2023Osteoarthritis represents a leading cause of disability with limited treatment options. Furthermore, it is frequently accompanied by cardiovascular and cognitive...
The antidepressant drugs vortioxetine and duloxetine differentially and sex-dependently affect animal well-being, cognitive performance, cardiac redox status and histology in a model of osteoarthritis.
Osteoarthritis represents a leading cause of disability with limited treatment options. Furthermore, it is frequently accompanied by cardiovascular and cognitive disorders, which can be exacerbated by osteoarthritis or drugs used for its treatment. Here, we examined the behavioral and cardiac effects of the novel antidepressant vortioxetine in an osteoarthritis model, and compared them to duloxetine (an established osteoarthritis treatment). Osteoarthritis was induced in male and female rats with an intraarticular sodium-monoiodoacetate injection. Antidepressants were orally administered for 28 days following induction. During this period the acetone, burrowing and novel-object-recognition tests (NORT) were used to assess the effects of antidepressants on pain hypersensitivity (cold allodynia), animal well-being and cognitive performance, respectively. Following behavioral experiments, heart muscles were collected for assessment of redox status/histology. Antidepressant treatment dose-dependently reduced cold allodynia in rats with osteoarthritis. Duloxetine (but not vortioxetine) depressed burrowing behavior in osteoarthritic rats in a dose-related manner. Osteoarthritis induction reduced cognitive performance in NORT, which was dose-dependently alleviated by vortioxetine (duloxetine improved performance only in female rats). Furthermore, duloxetine (but not vortioxetine) increased oxidative stress parameters in the heart muscles of female (but not male) rats and induced histological changes in cardiomyocytes indicative of oxidative damage. Vortioxetine displayed comparable efficacy to duloxetine in reducing pain hypersensitivity. Furthermore, vortioxetine (unlike duloxetine) dose-dependently improved cognitive performance and had no adverse effect on burrowing behavior (animal surrogate of well-being) and cardiac redox status/histology. Our results indicate that vortioxetine could be a potential osteoarthritis treatment (with better characteristics compared to duloxetine).
Topics: Female; Animals; Rats; Duloxetine Hydrochloride; Vortioxetine; Hyperalgesia; Antidepressive Agents; Myocytes, Cardiac; Hypersensitivity; Osteoarthritis; Cognition
PubMed: 37657261
DOI: 10.1016/j.biopha.2023.115360 -
Journal of Analytical Toxicology Oct 2022Duloxetine, known by its brand name, CymbaltaTM, is a selective serotonin and norepinephrine reuptake inhibitor used to treat major depressive disorders. Determination...
Duloxetine, known by its brand name, CymbaltaTM, is a selective serotonin and norepinephrine reuptake inhibitor used to treat major depressive disorders. Determination of patient compliance for duloxetine is typically determined through medication possession ratio (MPR) or plasma concentrations. The purpose of this paper was to characterize normal urinary duloxetine concentrations in patients prescribed duloxetine to monitor patient adherence. Patient data collected from routine screens for duloxetine concentrations in urine were included in this study. Inclusion criteria consisted of patients who were prescribed duloxetine and (i) tested positive for duloxetine, (ii) tested negative for illicit substances and (iii) included creatinine, age and duloxetine dose administered. Of the 5,592 patient urines screened, 2,004 of the results fit into the inclusion criteria. Positive urine concentrations of duloxetine ranged from 50 to 2,722 ng/mL. Duloxetine urine concentrations were normalized to creatinine and dose further characterized by sex, age, body mass index (BMI) and dose in milligrams. Sample distribution included urines collected from 1,487 females and 517 males. The age range of the specimen donors was between 15 and 90 years old with an average age of 52. BMI levels ranged from 13.9 (underweight) to 88.1 (obese), with the average BMI being 33.5. The most common dose of duloxetine prescribed was a daily, oral dose of 60 mg. Analysis of the normalized, transformed creatinine concentrations showed that there was a significant statistical difference (P < 0.05) in the urinary duloxetine concentrations by sex and by dose (mg). Female patients further showed a statistical difference in urinary duloxetine concentration in age groups 18-64 and 64 and older. By characterizing urinary duloxetine concentrations in patients prescribed the medication, normalized distributions of data ranges have been established. These data ranges for urinary duloxetine concentrations can be used to determine patient compliance with duloxetine in routine, clinical samples.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Creatinine; Depressive Disorder, Major; Duloxetine Hydrochloride; Female; Humans; Male; Middle Aged; Norepinephrine; Patient Compliance; Serotonin; Selective Serotonin Reuptake Inhibitors; Thiophenes; Young Adult
PubMed: 35748596
DOI: 10.1093/jat/bkac043 -
Journal of the Peripheral Nervous... Oct 2019Platinum-induced peripheral neurotoxicity (PIPN) is a common side effect of platinum-based chemotherapy that may cause dose reduction and discontinuation, with... (Review)
Review
Platinum-induced peripheral neurotoxicity (PIPN) is a common side effect of platinum-based chemotherapy that may cause dose reduction and discontinuation, with oxaliplatin being more neurotoxic. PIPN includes acute neurotoxicity restricted to oxaliplatin, and chronic non-length-dependent sensory neuronopathy with positive and negative sensory symptoms and neuropathic pain in both upper and lower limbs. Chronic sensory axonal neuropathy manifesting as stocking-and-glove distribution is also frequent. Worsening of neuropathic symptoms after completing the last chemotherapy course may occur. Motor and autonomic involvement is uncommon. Ototoxicity is frequent in children and more commonly to cisplatin. Platinum-based compounds result in more prolonged neuropathic symptoms in comparison to other chemotherapy agents. Patient reported outcomes questionnaires, clinical evaluation and instrumental tools offer complementary information in PIPN. Electrodiagnostic features include diffusely reduced/abolished sensory action potentials, in keeping with a sensory neuronopathy. PIPN is dependent on cumulative dose but there is a large variability in its occurrence. The search for additional risk factors for PIPN has thus far yielded no consistent findings. There are currently no neuroprotective strategies to reduce the risk of PIPN, and symptomatic treatment is limited to duloxetine that was found effective in a single phase III intervention study. This review critically examines the pathogenesis, incidence, risk factors (both clinical and pharmacogenetic), clinical phenotype and management of PIPN.
Topics: Antineoplastic Agents; Cisplatin; Duloxetine Hydrochloride; Humans; Neurotoxicity Syndromes; Organoplatinum Compounds; Oxaliplatin; Peripheral Nervous System Diseases; Serotonin and Noradrenaline Reuptake Inhibitors; Treatment Outcome
PubMed: 31647151
DOI: 10.1111/jns.12335 -
Biomedicine & Pharmacotherapy =... Dec 2023Several studies have reported the association between osteoporosis and major depressive disorder (MDD) as well as the use of antidepressants. However, it remains to be...
BACKGROUND
Several studies have reported the association between osteoporosis and major depressive disorder (MDD) as well as the use of antidepressants. However, it remains to be elucidated whether these associations are related to exposure to antidepressants, a consequence of a disease process, or a combination of both.
METHODS
This study investigates the independent effect of the antidepressant duloxetine hydrochloride (DH) on ovariectomy-induced bone loss in mice. One week after ovariectomy, the treated mice received DH. To explore the mechanism underlying the rescue of bone loss, bone marrow cells were isolated from mouse femurs and tibias, and macrophages extracted from them were induced to become osteoclasts in vitro while being treated with DH. Subsequently, the osteoclasts underwent Bulk RNA-Seq to reveal the involved signaling pathways. The results of the bioinformatic analysis were then validated through in vitro experiments.
RESULTS
The in vivo experiments demonstrated that DH treatment compromised ovariectomy-induced bone loss after 7 weeks. The in vitro experiments suggested that DH treatment attenuated osteoclast differentiation via the MAPKs/NFATc1 signaling pathway.
CONCLUSION
The findings from this study suggest that DH, instead of causing bone mass loss, may assist in alleviating postmenopausal osteoporosis. These results can serve as a reference for the clinical treatment of patients with perimenopausal or postmenopausal depression using antidepressants.
Topics: Humans; Female; Animals; Mice; Osteoclasts; Duloxetine Hydrochloride; Depressive Disorder, Major; Cell Differentiation; Antidepressive Agents; Ovariectomy; Osteogenesis; RANK Ligand
PubMed: 37913736
DOI: 10.1016/j.biopha.2023.115810 -
International Journal of Molecular... May 2023Paclitaxel, a widely used cancer chemotherapeutic agent, has high incidence of neurotoxicity associated with the production of neuropathic pain, for which only...
Paclitaxel, a widely used cancer chemotherapeutic agent, has high incidence of neurotoxicity associated with the production of neuropathic pain, for which only duloxetine has shown significant but moderate analgesic effect. Since statins, classically used to reduce hypercholesterolemia, have shown antinociceptive effect in preclinical studies on neuropathic pain, we studied whether the antinociceptive efficacy of duloxetine could be synergistically potentiated by rosuvastatin in a model of paclitaxel-induced neuropathy in mice. The astrocytic and microglial responses in the spinal cord of paclitaxel-treated mice were also assessed by measuring GFAP and CD11b proteins, respectively. Paclitaxel treatment did not impair motor coordination and balance in rotarod testing. Rosuvastatin, duloxetine, and the rosuvastatin/duloxetine combination (combined at equieffective doses) dose-dependently decreased mechanical allodynia (ED, von Frey testing) and thermal hyperalgesia (ED, hot plate testing) in paclitaxel-treated mice. Isobolographic analysis showed a superadditive interaction for rosuvastatin and duloxetine, as both the ED and ED for the rosuvastatin/duloxetine combination contained only a quarter of each drug compared to the individual drugs. The rosuvastatin/duloxetine combination reversed paclitaxel-induced GFAP overexpression, indicating that such effects might depend in part on astrocyte inactivation. Results suggest that statins could be useful in synergistically enhancing the efficacy of duloxetine in some chemotherapy-induced neuropathic conditions.
Topics: Mice; Animals; Paclitaxel; Duloxetine Hydrochloride; Rosuvastatin Calcium; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Pain Measurement; Neuralgia; Hyperalgesia; Analgesics
PubMed: 37176065
DOI: 10.3390/ijms24098359 -
Current Urology Reports Jul 2024Stress urinary incontinence (SUI) is a commonly observed condition in females, as well as in males who have undergone prostatectomy. Despite the significant progress... (Review)
Review
PURPOSE OF REVIEW
Stress urinary incontinence (SUI) is a commonly observed condition in females, as well as in males who have undergone prostatectomy. Despite the significant progress made in surgical techniques, pharmacotherapy has not yielded substantial outcomes within the clinical domain. This review aims to present a comprehensive overview of the existing pharmacotherapy options for stress urinary incontinence (SUI) and the emerging therapeutic targets in this field.
RECENT FINDINGS
One meta-analysis demonstrated that α-adrenergic medications are more efficacious in improving rather than curing SUI symptoms. One trial showed reduced pad weight gain with PSD-503, a locally administered α-adrenergic receptor agonist. New data show that duloxetine's risk outweighs its benefits. One small-scale trial was found to support the use of locally administered estriol in improving subjective outcomes. Emerging targets include serotonin 5HT agonists, selective inhibitors of norepinephrine uptake, and myostatin inhibitors. Only one of the evaluated drugs, duloxetine, has been approved by some countries. Currently, trials are evaluating novel targets. Systemic adverse effects such as gastrointestinal upset with duloxetine and orthostatic hypotension with α-adrenoceptor agonists have hampered the efficacy of drugs used to treat SUI in women and men.
Topics: Humans; Urinary Incontinence, Stress; Duloxetine Hydrochloride; Female; Male
PubMed: 38727982
DOI: 10.1007/s11934-024-01205-9 -
Molecular Pain 2023Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating, treatment-limiting, side-effect of several classes of chemotherapy drugs. While negatively impacting...
Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating, treatment-limiting, side-effect of several classes of chemotherapy drugs. While negatively impacting oncology patients' quality of life, chemotherapy-induced large-fiber (LF) neuropathy is amongst the least well understood components of CIPN, and one for which there is currently no established therapy. Preliminary clinical observations have led to the suggestion that Duloxetine, which is used for the treatment of pain associated with small-fiber CIPN (SF-CIPN), may be effective against LF-CIPN. In the present experiments we developed a model of LF-CIPN and studied the effect of Duloxetine on LF-CIPN induced by two neurotoxic chemotherapy agents: the proteasome inhibitor, Bortezomib, a first-line treatment of multiple myeloma; and, the anti-microtubule taxane, Paclitaxel, used in the treatment of solid tumors. Since there are currently no models for selective the study of LF-CIPN, our first aim was to establish a pre-clinical model in the rat. LF-CIPN was evaluated with the Current Perception Threshold (CPT) assay, which uses a high frequency (1000 Hz) electrical stimulus protocol that selectively activates large-fiber myelinated afferents. Our second aim was to use this model to test the hypothesis that Duloxetine can prevent LF-CIPN. We report that Bortezomib and Paclitaxel induce elevation of CPT, compatible with loss of large-fiber function, which are prevented by Duloxetine. Our findings support the clinical observation that Duloxetine may be an effective treatment for the large-fiber CIPN. We also suggest that CPT could be used as a biomarker for LF-CIPN in patients receiving neurotoxic chemotherapy.
Topics: Rats; Animals; Paclitaxel; Duloxetine Hydrochloride; Bortezomib; Rats, Sprague-Dawley; Quality of Life; Peripheral Nervous System Diseases; Antineoplastic Agents
PubMed: 37338165
DOI: 10.1177/17448069231185694 -
Acta Crystallographica. Section E,... Apr 2023Duloxetine hydro-chloride (trade name Cymbalta) is marketed as a single enanti-omer ()--methyl-3-(naphthalen-1-yl-oxy)-3-(thio-phen-2-yl)propyl-am-in-ium chloride,...
Duloxetine hydro-chloride (trade name Cymbalta) is marketed as a single enanti-omer ()--methyl-3-(naphthalen-1-yl-oxy)-3-(thio-phen-2-yl)propyl-am-in-ium chloride, CHNOS·Cl, which is twice as effective as the ()-enanti-omer in serotonin uptake. Here, we report the crystal structure of duloxetine hydro-chloride in its racemic form (space group 2), where it shows significant differences in the mol-ecular conformation and packing in its extended structure compared to the previously reported ()-enanti-omer crystal structure. Mol-ecules of this type, comprising aromatic groups with a single side chain terminated in a protonated secondary amine, are commonly found in active anti-depressants. A Cambridge Structural Database survey of mol-ecules with these features reveals a strong correlation between side-chain conformation and the crystal packing: an extended side chain leads to mol-ecules packed into separated layers of hydro-phobic and ionic hydro-philic phases. By comparison, mol-ecules with bent side chains, such as racemic duloxetine hydro-chloride, lead to crystal-packing motifs where an ionic hydro-philic phase is encapsulated within a hydro-phobic shell.
PubMed: 37151834
DOI: 10.1107/S2056989023003353