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Journal of Cancer 2024Brain metastases and lung metastases are major causes of treatment failure and related mortality in melanoma. Fluoxetine hydrochloride (FXT), a widely-used...
Fluoxetine as a Potential Therapeutic Agent for Inhibiting Melanoma Brain and Lung Metastasis: Induction of Apoptosis, G0/G1 Cell Cycle Arrest, and Disruption of Autophagy Flux.
Brain metastases and lung metastases are major causes of treatment failure and related mortality in melanoma. Fluoxetine hydrochloride (FXT), a widely-used antidepressant, has emerged as a potential anticancer agent in preclinical studies. Previous research has shown its potential to inhibit melanoma. However, its efficacy and the underlying mechanisms in melanoma metastasis, especially concerning brain metastases and lung metastases, remain underexplored. This study investigates FXT's inhibitory effects on melanoma growth and metastasis to the lung and brain. Employing a combination of in vitro assays, we demonstrate FXT's potent suppression of melanoma growth through induction of intrinsic apoptosis, disruption of autophagic flux, and cell cycle arrest at the G0/G1 phase. In in vivo mouse models, we found that FXT exhibits strong inhibitory activity against melanoma brain metastases and lung metastases. Our findings provide a foundation for future clinical exploration of FXT as a novel treatment strategy for melanoma, underscoring its ability to target both primary and metastatic lesions.
PubMed: 38911391
DOI: 10.7150/jca.95592 -
Iranian Journal of Basic Medical... 2024In this study, we assessed the impact of luteolin (LUT) on mood disorders (specifically anxiety and depression) induced by sleep deprivation (SD) by regulating pathways...
OBJECTIVES
In this study, we assessed the impact of luteolin (LUT) on mood disorders (specifically anxiety and depression) induced by sleep deprivation (SD) by regulating pathways associated with neuroinflammation.
MATERIALS AND METHODS
Rapid eye movement (REM) SD was employed to induce anxiety and depression in the animal subjects. The animals were treated with PAX (15 mg/kg, positive control) and LUT (10 and 20 mg/kg) for a duration of 21 days. The anxiety and depressive disorders were evaluated using behavioral tests. Following the sacrifice of the animals, hippocampal tissues were stored for molecular investigations.
RESULTS
SD resulted in anxiety, as evidenced by the elevated plus maze test and open field test. Furthermore, the findings from the sucrose performance test, forced swimming test, and tail suspension test confirmed the presence of depressive-like behaviors in the animals. The nuclear factor kappa B (NF-κB) and NLR family pyrin domain containing 3 (NLRP3) inflammasome components, including apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC), NLRP3, and active Caspase-1, were up-regulated in the hippocampus (HC) of the animals subjected to REM SD. However, treatment with LUT demonstrated a significant reversal of the behavioral changes by modulating the NF-κB and NLRP3 inflammasome components in the HC.
CONCLUSION
It can be concluded that LUT demonstrated antidepressant effects via regulation of the NF-κB/NLRP3 inflammasome axis components in the HC.
PubMed: 38911248
DOI: 10.22038/IJBMS.2024.75068.16277 -
Drug Design, Development and Therapy 2024We aimed to evaluate the effect of intravenous esketamine combined with dexmedetomidine as supplemental analgesia in reducing intraoperative visceral pain... (Randomized Controlled Trial)
Randomized Controlled Trial
Esketamine Combined with Dexmedetomidine to reduce Visceral Pain During elective Cesarean Section Under Combined Spinal-Epidural Anesthesia: A double-Blind Randomized Controlled Study.
PURPOSE
We aimed to evaluate the effect of intravenous esketamine combined with dexmedetomidine as supplemental analgesia in reducing intraoperative visceral pain during elective cesarean section under combined spinal-epidural anesthesia (CSEA).
PATIENTS AND METHODS
A total of 269 parturients scheduled for elective cesarean section under CSEA between May 2023 and August 2023 were assessed. The parturients were randomly allocated to receiving either intravenous infusion of 0.3-mg/kg esketamine combined with 0.5-μg/kg dexmedetomidine (group ED, n=76), 0.5-μg/kg dexmedetomidine (group D, n=76), or normal saline (group C, n=76) after umbilical cord clamping. The primary outcome was intraoperative visceral pain. Secondary outcomes included the visual analog scale (VAS) score for pain evaluation and other intraoperative complications.
RESULTS
The incidence of visceral pain was lower in group ED [9 (12.7%)] than in group D [32 (43.8%)] and group C [36 (48.6%), <0.0001]. The VAS score was also lower in group ED when exploring abdominal cavity [0 (0), <0.0001] and suturing the muscle layer [0 (0), =0.036]. The mean arterial pressure was higher in group D [83 (9) mmHg] and group ED [81 (11) mmHg] than in group C [75 (10) mmHg, <0.0001] after solution infusion. The heart rate after infusion of the solution was lower in group D [80 (12) bpm] than in group C [86 (14) bpm] and group ED [85 (12) bpm, = 0.016]. The incidence of transient neurologic or mental symptoms was higher in group ED compared to group C and group D (76.1% vs 18.9% vs 23.3%, <0.0001).
CONCLUSION
During cesarean section, 0.3-mg/kg esketamine combined with 0.5-μg/kg dexmedetomidine can alleviate visceral traction pain and provide stable hemodynamics. Parturients receiving this regimen may experience transient neurologic or mental symptoms that can spontaneously resolve at the end of the surgery.
Topics: Humans; Dexmedetomidine; Ketamine; Double-Blind Method; Cesarean Section; Female; Adult; Visceral Pain; Anesthesia, Spinal; Pregnancy; Anesthesia, Epidural; Drug Therapy, Combination; Elective Surgical Procedures
PubMed: 38911034
DOI: 10.2147/DDDT.S460924 -
Cureus May 2024Sertraline hydrochloride belongs to the selective serotonin reuptake inhibitor class of antidepressants, which can cause respiratory depression, hypotension, malignant...
Sertraline hydrochloride belongs to the selective serotonin reuptake inhibitor class of antidepressants, which can cause respiratory depression, hypotension, malignant vomiting, liver function impairment, and other symptoms when taken in excess. To our knowledge, reports of sertraline hydrochloride overdose causing diabetes insipidus in patients are rare. This report describes a unique case of a 17-year-old female patient who developed diabetes insipidus after a one-time oral intake of 20 sertraline hydrochloride tablets (50 mg/tablet) during the later course of treatment. Her symptoms were effectively relieved after treatment with pituitrin.
PubMed: 38910706
DOI: 10.7759/cureus.60952 -
Scientific Reports Jun 2024Relationship between depressive disorder and autonomic nervous system has been already discussed. Reduced emotional regulation is supposed to be associated with...
Relationship between depressive disorder and autonomic nervous system has been already discussed. Reduced emotional regulation is supposed to be associated with prefrontal hypofunction and subcortical hyperactivity. The aim of this study was to determine the effect of vortioxetine on heart rate variability (HRV), a parameter of cardiac autonomic regulation, in depressed hospitalized paediatric patients and assess the clinical effectiveness of the drug in this population. We performed repeated polysomnography analyses at admission and after a short treatment in hospital (15.2 days on average) and measured various HRV parameters (RRi, pNN50, RMSSD, LF-HRV, HF-HRV) during wakefulness, N3 and REM sleep stages. Out of 27 study subjects, 67% have improved depression symptoms as well as anxiety and subjective sleep quality after short vortioxetine treatment. We have found a significant decrease in parasympathetic parameters pNN50, RMSSD and HF-HRV during N3 sleep phase, though not exclusively among vortioxetine responders. The anticipated increase in cardiovagal regulation after vortioxetine treatment was not demonstrated in this pilot study, possibly due to the drug's multimodal mechanism and impact on the nucleus tractus solitarii, particularly its antagonism on 5HT-3 receptors. Application of selective drugs could further explain the effect of vortioxetine on HRV in depressed patients.
Topics: Humans; Vortioxetine; Heart Rate; Child; Adolescent; Male; Female; Autonomic Nervous System; Antidepressive Agents; Polysomnography; Depression; Pilot Projects
PubMed: 38910177
DOI: 10.1038/s41598-024-65278-9 -
BMJ Open Jun 2024Clinical practice guidelines (CPGs) are essential for standardising patient care based on evidence-based medicine. However, the presence of financial conflicts of...
OBJECTIVE
Clinical practice guidelines (CPGs) are essential for standardising patient care based on evidence-based medicine. However, the presence of financial conflicts of interest (COIs) among CPG authors can undermine their credibility. This study aimed to examine the extent and size of COIs among authors of psychiatry CPGs in Japan.
METHODS
This cross-sectional analysis of disclosed payments from pharmaceutical companies assesses the prevalence and magnitude of personal payments for lecturing, consulting and writing to CPGs for bipolar disorder and major depressive disorder in Japan between 2016 and 2020.
RESULTS
This study found that 93.3% of authors received payments over a 5-year period, with total payments exceeding US$4 million. The median payment per author was US$51 403 (IQR: US$9982-US$111 567), with a notable concentration of payments among a small number of authors, including the CPG chairperson. Despite these extensive financial relationships, only a fraction of authors disclosed their COIs in the CPGs. These large amounts of personal payments were made by pharmaceutical companies manufacturing new antidepressants and sleeping aids listed in the CPGs.
CONCLUSIONS
This study found that more than 93% of authors of CPGs for major depressive disorder and bipolar disorder in Japan received considerable amounts of personal payments from the pharmaceutical industry. The findings highlight deviations from international COI management standards and suggest a need for more stringent COI policies for psychiatry CPGs in Japan.
Topics: Humans; Japan; Depressive Disorder, Major; Cross-Sectional Studies; Drug Industry; Conflict of Interest; Bipolar Disorder; Practice Guidelines as Topic; Disclosure; Authorship
PubMed: 38908845
DOI: 10.1136/bmjopen-2024-086396 -
Trials Jun 2024There are no approved pharmacotherapies for methamphetamine use disorder. Two preliminary phase 2 randomised controlled trials have found mirtazapine, a tetracyclic...
BACKGROUND
There are no approved pharmacotherapies for methamphetamine use disorder. Two preliminary phase 2 randomised controlled trials have found mirtazapine, a tetracyclic antidepressant, to be effective in reducing methamphetamine use. The proposed Tina Trial is the first phase 3 placebo-controlled randomised trial to examine the effectiveness and safety of mirtazapine as an outpatient pharmacotherapy for methamphetamine use disorder.
METHODS
This is a multi-site phase 3 randomised, double-blind, placebo-controlled parallel trial. Participants are randomly allocated (1:1) to receive either mirtazapine (30 mg/day for 12 weeks) or matched placebo, delivered as a take-home medication. The target population is 340 people aged 18-65 years who have moderate to severe methamphetamine use disorder. The trial is being conducted through outpatient alcohol and other drug treatment clinics in Australia. The primary outcome is measured as self-reported days of methamphetamine use in the past 4 weeks at week 12. Secondary outcomes are methamphetamine-negative oral fluid samples, depressive symptoms, sleep quality, HIV risk behaviour and quality of life. Other outcomes include safety (adverse events), tolerability, and health service use. Medication adherence is being monitored using MEMS® Smart Caps fitted to medication bottles.
DISCUSSION
This trial will provide information on the safety and effectiveness of mirtazapine as a pharmacotherapy for methamphetamine use disorder when delivered as an outpatient medication in routine clinical practice. If found to be safe and effective, this trial will support an application for methamphetamine use disorder to be included as a therapeutic indication for the prescription of mirtazapine.
TRIAL REGISTRATION
Australian and New Zealand Clinical Trials Registry ACTRN12622000235707. Registered on February 9, 2022.
Topics: Humans; Mirtazapine; Double-Blind Method; Amphetamine-Related Disorders; Methamphetamine; Adult; Middle Aged; Adolescent; Clinical Trials, Phase III as Topic; Male; Young Adult; Randomized Controlled Trials as Topic; Aged; Female; Treatment Outcome; Multicenter Studies as Topic; Australia; Time Factors; Medication Adherence; Antidepressive Agents, Tricyclic
PubMed: 38907288
DOI: 10.1186/s13063-024-08238-y -
BMC Geriatrics Jun 2024Polypharmacy is a global public health concern. This study aimed to determine the prevalence of polypharmacy and trends in the use of commonly used and potentially...
BACKGROUND
Polypharmacy is a global public health concern. This study aimed to determine the prevalence of polypharmacy and trends in the use of commonly used and potentially inappropriate medications among older Korean patients.
METHODS
Individuals aged ≥ 65 years who were prescribed any medication between 2014 and 2018 were selected from the Korean National Health Information Database. Joinpoint regression analyses were used to determine trends in the age-adjusted polypharmacy rates by age group. The prescription rates of the most commonly used medications and the most commonly used potentially inappropriate medications were analysed by year or age group for patients with polypharmacy using the chi-square and proportion difference tests.
RESULTS
This study included 1,849,968 patients, 661,206 (35.7%) of whom had polypharmacy. Age-adjusted polypharmacy rates increased significantly between 2014 and 2018 (P = 0.046). Among patients with polypharmacy, the most commonly prescribed medications were aspirin (100 mg), atorvastatin, metformin, glimepiride, and rosuvastatin. The most commonly prescribed and potentially inappropriate medications were alprazolam, diazepam, amitriptyline, zolpidem, and dimenhydrinate. There was a significant decrease in the prescription rates for each of these drugs in 2018 compared with 2014 among patients with polypharmacy (all P < 0.001), whereas there was a significant increase in alprazolam prescription among patients aged ≥ 85 years when analysed by age group (P < 0.001).
CONCLUSIONS
This study revealed an increasing prevalence of polypharmacy among older adults. Additionally, it highlighted that the utilisation of commonly prescribed potentially inappropriate medications, such as benzodiazepines and tricyclic antidepressants, has remained persistent, particularly among patients aged ≥ 85 years who practiced polypharmacy. These findings provide evidence-based guidance for the development of robust polypharmacy management strategies to ensure medication safety among older adults.
Topics: Humans; Aged; Republic of Korea; Polypharmacy; Male; Female; Potentially Inappropriate Medication List; Aged, 80 and over; Inappropriate Prescribing
PubMed: 38907201
DOI: 10.1186/s12877-024-05141-8 -
Translational Psychiatry Jun 2024Major depressive disorder (MDD) is the leading cause of disability worldwide, yet treatment selection still proceeds via "trial and error". Given the varied presentation...
Major depressive disorder (MDD) is the leading cause of disability worldwide, yet treatment selection still proceeds via "trial and error". Given the varied presentation of MDD and heterogeneity of treatment response, the use of machine learning to understand complex, non-linear relationships in data may be key for treatment personalization. Well-organized, structured data from clinical trials with standardized outcome measures is useful for training machine learning models; however, combining data across trials poses numerous challenges. There is also persistent concern that machine learning models can propagate harmful biases. We have created a methodology for organizing and preprocessing depression clinical trial data such that transformed variables harmonized across disparate datasets can be used as input for feature selection. Using Bayesian optimization, we identified an optimal multi-layer dense neural network that used data from 21 clinical and sociodemographic features as input in order to perform differential treatment benefit prediction. With this combined dataset of 5032 individuals and 6 drugs, we created a differential treatment benefit prediction model. Our model generalized well to the held-out test set and produced similar accuracy metrics in the test and validation set with an AUC of 0.7 when predicting binary remission. To address the potential for bias propagation, we used a bias testing performance metric to evaluate the model for harmful biases related to ethnicity, age, or sex. We present a full pipeline from data preprocessing to model validation that was employed to create the first differential treatment benefit prediction model for MDD containing 6 treatment options.
Topics: Humans; Depressive Disorder, Major; Machine Learning; Bayes Theorem; Clinical Trials as Topic; Female; Male; Antidepressive Agents; Adult; Middle Aged; Neural Networks, Computer
PubMed: 38906883
DOI: 10.1038/s41398-024-02970-4 -
The Lancet. Digital Health Jul 2024Despite the availability of effective treatments, most depressive disorders remain undetected and untreated. Internet-based depression screening combined with automated... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Despite the availability of effective treatments, most depressive disorders remain undetected and untreated. Internet-based depression screening combined with automated feedback of screening results could reach people with depression and lead to evidence-based care. We aimed to test the efficacy of two versions of automated feedback after internet-based screening on depression severity compared with no feedback.
METHODS
DISCOVER was an observer-masked, three-armed, randomised controlled trial in Germany. We recruited individuals (aged ≥18 years) who were undiagnosed with depression and screened positive for depression on an internet-based self-report depression rating scale (Patient Health Questionnaire-9 [PHQ-9] ≥10 points). Participants were randomly assigned 1:1:1 to automatically receive no feedback, non-tailored feedback, or tailored feedback on the depression screening result. Randomisation was stratified by depression severity (moderate: PHQ-9 score 10-14 points; severe: PHQ-9 score ≥15 points). Participants could not be masked but were kept unaware of trial hypotheses to minimise expectancy bias. The non-tailored feedback included the depression screening result, a recommendation to seek professional diagnostic advice, and brief general information about depression and its treatment. The tailored feedback included the same basic information but individually framed according to the participants' symptom profiles, treatment preferences, causal symptom attributions, health insurance, and local residence. Research staff were masked to group allocation and outcome assessment as these were done using online questionnaires. The primary outcome was change in depression severity, defined as change in PHQ-9 score 6 months after random assignment. Analyses were conducted following the intention-to-treat principle for participants with at least one follow-up visit. This trial was registered at ClinicalTrials.gov, NCT04633096.
FINDINGS
Between Jan 12, 2021, and Jan 31, 2022, 4878 individuals completed the internet-based screening. Of these, 1178 (24%) screened positive for depression (mean age 37·1 [SD 14·2] years; 824 [70%] woman, 344 [29%] men, and 10 [1%] other gender identity). 6 months after random assignment, depression severity decreased by 3·4 PHQ-9 points in the no feedback group (95% CI 2·9-4·0; within-group d 0·67; 325 participants), by 3·5 points in the non-tailored feedback group (3·0-4·0; within-group d 0·74; 319 participants), and by 3·7 points in the tailored feedback group (3·2-4·3; within-group d 0·71; 321 participants), with no significant differences among the three groups (p=0·72). The number of participants seeking help for depression or initiating psychotherapy or antidepressant treatment did not differ among study groups. The results remained consistent when adjusted for fulfilling the DSM-5-based criteria for major depressive disorder or subjective belief of having a depressive disorder. Negative effects were reported by less than 1% of the total sample 6 months after random assignment.
INTERPRETATION
Automated feedback following internet-based depression screening did not reduce depression severity or prompt sufficient depression care in individuals previously undiagnosed with but affected by depression.
FUNDING
German Research Foundation.
Topics: Humans; Male; Female; Germany; Adult; Internet; Middle Aged; Depression; Mass Screening; Feedback; Depressive Disorder; Surveys and Questionnaires
PubMed: 38906611
DOI: 10.1016/S2589-7500(24)00070-0