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Heliyon May 2024To investigate whether SJF functions in similar manner as the key substance in the inflammatory process, soluble epoxide hydrolase (sEH) inhibitor, to inhibit the...
AIM
To investigate whether SJF functions in similar manner as the key substance in the inflammatory process, soluble epoxide hydrolase (sEH) inhibitor, to inhibit the arachidonic acid metabolic pathway and nuclear factor kappa-B(NF-κB) signal path in the hippocampi of postpartum depression rats.
METHODS
The rats were subcutaneous injected estradiol benzoate and progesterone to build PPD rat model. SJF, paroxetine hydrochloride and sEH inhibitor (AUDA) were used to treat PPD rats for 3 weeks. Then the morphological changes of hippocampi and various proteins were observed after that behavioral test were conducted in all 36 SD rats in six group: SJF, paroxetine, AUDA, PPD, sham and normal group.
RESULTS
Weight, results of sucrose preference, upright times, total and center squares crossing decreased significantly (P < 0.01), whereas immobility time increased (P < 0.01). Results above were reversed in animals that in the SJF, paroxetine and AUDA groups. Hippocampal neurons in PPD rats partially degenerated with narrowed nuclei, increased autophagy and mitochondria bound to lysosomes were visible while the autophagy of hippocampal neurons in the paroxetine and AUDA group decreased, with a small amount of lysosomes. sEH, COX-2, 5-LOX, TNF-α, IL-1, IL-6, NF-κB p65, and Cor increased in hippocampi of PPD rats while EETs and 5-HT decreased. Protein expressions of Ibal, GFAP, p-IκBα, p65, and p-p65(S536)increased in PPD animals. Those changes were reversed by SJF, paroxetine and AUDA. Gene expressions of TNF-α, IL-1β, IL-6, 5-LOX, COX-2 and p65 increased in PPD rats and the changes of expression in these genes were reversed by paroxetine and AUDA. SJF reversed the gene expression changes of COX-2, TNF-α, and IL-1β.
CONCLUSION
SJF may have an analogous effect as sEH inhibitor to relieve depressive symptoms by suppressing inflammatory signaling pathways in hippocampi of PPD rats, which involves AA metabolic pathway and NF-κB signal pathway.
PubMed: 38726147
DOI: 10.1016/j.heliyon.2024.e29978 -
BMC Psychiatry Sep 2023Appropriate medication is very important for pilots with acute stress disorder. Improper medication can not only affect the physical and mental health of the pilots but...
BACKGROUND
Appropriate medication is very important for pilots with acute stress disorder. Improper medication can not only affect the physical and mental health of the pilots but can also endanger flight safety. Hence, we aimed to quickly and effectively relieve symptoms and restore cognitive function by forming a consensus of Chinese experts on the pharmacological treatment of acute stress disorder in pilots using the Delphi method.
METHODS
Relevant literature was searched to enumerate the current status of pharmacological treatment of acute stress disorder in pilots, followed by two rounds of expert consultation and discussion according to the listed status of the survey using the Delphi method. A descriptive statistical method was used to analyze the basic information, authority coefficients, concentration of opinions, and survey items of the experts to develop a consensus on the pharmacological treatment of acute stress disorder in pilots.
RESULTS
A total of 16 experts in psychiatry, pharmacology, and aerospace medicine from different provinces and cities across China were invited for consultation. The recovery rate of the two rounds of consultation was 100%, and the expert authority coefficients were 0.897 and 0.906, respectively. Kendall's coefficient of concordance of indicators at all levels was 0.564-0.594 (p < 0.01). Based on the number of votes received, alprazolam tablets (16), eszopiclone tablets (15), and lorazepam tablets (14) were recommended for the treatment of excitatory psychomotor symptoms of acute stress disorder; paroxetine tablets (15) and sertraline tablets (15) were available for psychomotor depressive symptoms; olanzapine tablets (15), olanzapine orally disintegrating tablets (14), and quetiapine fumarate tablets (14) were selected for psychotic symptoms.
CONCLUSIONS
This study formed a consensus on rapid and effective pharmacological treatment for different symptoms of acute stress disorder pilots, which provides a reference for clinical treatment.
Topics: Humans; Consensus; Delphi Technique; East Asian People; Olanzapine; Stress Disorders, Traumatic, Acute; Pilots
PubMed: 37684592
DOI: 10.1186/s12888-023-05145-5 -
Frontiers in Psychiatry 2023Vasomotor symptoms, or hot flashes, are among the most common complaints for menopausal and postmenopausal women. As an alternative to hormone replacement therapy,...
INTRODUCTION
Vasomotor symptoms, or hot flashes, are among the most common complaints for menopausal and postmenopausal women. As an alternative to hormone replacement therapy, paroxetine mesylate became the only non-hormonal treatment approved by the U.S. Food and Drug Administration (FDA), despite limited evidence for its efficacy. More specifically, there is uncertainty around paroxetine's unique benefit and the magnitude of the placebo response in clinical trials of paroxetine.
METHODS
Relevant databases were searched to identify randomized clinical trials examining the efficacy of paroxetine to treat hot flashes. The primary outcomes of interest were hot flash frequency and hot flash severity scores. Data was extracted from the published results, and risk of bias assessments were conducted.
RESULTS
Six randomized clinical trials that included a total of 1,486 women were coded and analyzed. The results demonstrated that 79% of the mean treatment response for hot flash frequency is accounted for by a placebo response, resulting in a mean true drug effect of 21% at most. Additionally, 68% of the mean treatment response for hot flash severity is accounted for by a placebo response, resulting in a maximum true drug effect of 32%.
DISCUSSION
The results herein call into question the actual efficacy of the only FDA approved, non-hormonal treatment for hot flashes by demonstrating that a placebo response accounts for the majority of treatment responses for reductions in both hot flash frequency and severity. The findings provide evidence to reevaluate the use of paroxetine to treat postmenopausal hot flashes and emphasize the importance of considering effective, alternative treatments for vasomotor symptoms.
PubMed: 37599891
DOI: 10.3389/fpsyt.2023.1204163 -
Cureus Dec 2023Symptoms caused by a selective serotonin reuptake inhibitor (SSRI) overdose are often mild and can be managed with supportive care and close monitoring, even when...
Symptoms caused by a selective serotonin reuptake inhibitor (SSRI) overdose are often mild and can be managed with supportive care and close monitoring, even when complicated by serotonin syndrome. There are limited pharmacokinetic data regarding massive overdoses of paroxetine, and the severity of an SSRI overdose is likely to be underestimated. We describe a fatal case of severe serotonin syndrome and acute respiratory distress syndrome (ARDS) following an overdose of controlled-release paroxetine. A 53-year-old male with depression presented with altered consciousness. He had ingested controlled-release paroxetine along with other medications. On arrival, he had ocular flutter and myoclonus, and blood examinations revealed acute kidney injury and rhabdomyolysis, which suggested serotonin syndrome. Computed tomography (CT) showed pharmacobezoars in the esophagus and stomach. Symptoms of serotonin syndrome and hypotension persisted despite administration of high doses of vasopressors with endotracheal intubation. We performed endoscopic decontamination to remove pharmacobezoars from the stomach. Finally, he developed severe ARDS and died due to respiratory failure on day 23. Sequential serum concentrations of paroxetine were 5.38 µg/mL at admission and 3.21 µg/mL on day 7, both above lethal levels. This case highlights the potential for fatal complications and prolonged toxicity in the case of a massive overdose of controlled-release paroxetine. We should recognize that such an overdose may be life-threatening and should consider aggressive interventions including endoscopic decontamination. A better understanding of the pharmacokinetics of a massive SSRI overdose would be helpful for optimal management.
PubMed: 38229825
DOI: 10.7759/cureus.50691 -
MDM Policy & Practice 2024Global climate change is resulting in dramatic increases in wildfires. Individuals exposed to wildfires experience a high burden of posttraumatic stress disorder...
UNLABELLED
Global climate change is resulting in dramatic increases in wildfires. Individuals exposed to wildfires experience a high burden of posttraumatic stress disorder (PTSD), and the cost-effectiveness of the treatment options to address PTSD from wildfires has not been studied. The objective of this study was to conduct a cost-utility analysis comparing screening followed by treatment with paroxetine or trauma-focused cognitive behavioral therapy (TF-CBT) versus no screening in Canadian adult wildfire evacuees. Using a Markov model, quality-adjusted life-years (QALYs) and costs were evaluated over a 5-y time horizon using health care and societal perspectives. All costs and utilities in the model were discounted at 1.5%. Probabilistic and deterministic sensitivity analyses examined the uncertainty in the incremental net monetary benefit (INMB) under a willingness-to-pay threshold of $50,000. From a societal perspective, no screening (NMB = $177,641) was dominated by screening followed by treatment with paroxetine (NMB = $180,733) and TF-CBT (NMB = $181,787), with TF-CBT having the highest likelihood of being cost-effective at a willingness-to-pay threshold of $50,000 per QALY (probability = 0.649). The initial prevalence of PTSD, probability of acceptance of treatment, and costs of productivity had the largest impact on the INMB of both paroxetine or TF-CBT versus no screening. Neither intervention was cost-effective at a willingness-to-pay threshold of $50,000 per QALY from a health care perspective. Screening followed by treatment with paroxetine or TF-CBT compared with no screening was found to be cost-saving while providing additional QALYs in wildfire evacuees. Governments should consider funding screening programs for PTSD followed by treatment with TF-CBT for wildfire evacuees.
HIGHLIGHTS
Two prior studies examined the cost-effectiveness of screening followed by treatment for PTSD among individuals exposed to other disaster-type events (i.e., terrorist attack and Hurricane Sandy) and found screening followed by treatment (i.e., cognitive behavioral therapy [CBT]) to be highly cost-effective.Among wildfire evacuees, screening followed by treatment with paroxetine or trauma-focused (TF)-CBT provides additional quality-adjusted life-years (QALYs) and is cost-saving from a societal perspective. TF-CBT was the treatment option found most likely to be cost-effective.Neither treatment option was cost-effective at a willingness-to-pay threshold of $50,000 per QALY from a health care perspective.Screening programs for PTSD should be considered for wildfire evacuees, and individuals diagnosed with PTSD could be prescribed either TF-CBT or paroxetine depending on their preference and resources availability.
PubMed: 38904072
DOI: 10.1177/23814683241260423 -
Journal of Psychiatry & Neuroscience :... 2023Impaired functional connectivity between the bilateral hemispheres may serve as the neural substrate for anxiety and depressive disorders, yet its role in comorbid...
BACKGROUND
Impaired functional connectivity between the bilateral hemispheres may serve as the neural substrate for anxiety and depressive disorders, yet its role in comorbid generalized anxiety disorder (GAD) and depression, as well as the effect of treatment on this connectivity, remains unclear. We sought to examine functional connectivity between homotopic regions of the 2 hemispheres (voxel-mirrored homotopic connectivity [VMHC]) among people with GAD with and without comorbid depression at baseline and after a 4-week paroxetine treatment.
METHODS
Drug-naïve patients with GAD, with or without comorbid depression and healthy controls underwent functional magnetic resonance imaging and clinical assessments at baseline and after treatment. We compared VMHC and seed-based functional connectivity across the 3 groups. We performed correlation analysis and support vector regression (SVR) to examine the intrinsic relationships between VMHC and symptoms.
RESULTS
Both patient groups ( = 40 with GAD only, = 58 with GAD and depression) showed decreased VMHC in the precuneus, posterior cingulate cortex and lingual gyrus compared with healthy controls ( = 54). Moreover, they showed decreased VMHC in different brain regions compared with healthy controls. However, we did not observe any significant differences between the 2 patient groups. Seeds from abnormal VMHC clusters in patient groups had decreased functional connectivity. Voxel-mirrored homotopic connectivity in the precuneus, posterior cingulate cortex and lingual gyrus was negatively correlated with cognitive impairment among patients with GAD only and among all patients. The SVR analysis based on abnormal VMHC showed significant positive correlations ( < 0.0001) between predicted and actual treatment responses. However, we did not observe significant differences in VMHC or functional connectivity after treatment.
LIMITATIONS
A notable dropout rate and intergroup somatic symptom variations may have biased the results.
CONCLUSION
Patients with GAD with or without comorbid depression exhibited shared and distinct abnormal VMHC patterns, which might be linked to their cognitive deficits. These patterns have the potential to serve as prognostic biomarkers for GAD. ClinicalTrials.gov NCT03894085.
Topics: Humans; Magnetic Resonance Imaging; Depression; Brain Mapping; Follow-Up Studies; Anxiety Disorders; Anxiety; Cognitive Dysfunction
PubMed: 37935477
DOI: 10.1503/jpn.230091 -
Cureus Mar 2024Neuroleptic malignant syndrome (NMS) is a severe reaction to antipsychotic medications characterized by fever, muscle rigidity, altered mental status, and autonomic...
Neuroleptic malignant syndrome (NMS) is a severe reaction to antipsychotic medications characterized by fever, muscle rigidity, altered mental status, and autonomic dysfunction. Here, we describe the case of a 58-year-old female who presented with altered mental status two days after open reduction and internal fixation of the hip. A rapid response team was called when the patient appeared agitated with increased respiratory demand. After being intubated and moved to the ICU, she became febrile and rigid. A preliminary diagnosis of metabolic encephalopathy of unknown origin was made. Before being transported to the ICU, the patient was given multiple haloperidol doses in addition to her continued at-home medication, paroxetine, for major depressive disorder. The differential diagnosis included a workup for NMS, serotonin syndrome, and infectious processes. Once NMS was determined as the most likely etiology, all antipsychotic and serotonergic medications were discontinued. Then dantrolene and amantadine were administered, which resulted in clinically significant improvement. This case report demonstrates the importance of early identification of and intervention for NMS.
PubMed: 38686249
DOI: 10.7759/cureus.57276 -
Biochemical Pharmacology May 2024Treatment of major depressive disorder remains a major unmet clinical need. Given the advantages of intranasal administration for targeted brain delivery, the present...
Treatment of major depressive disorder remains a major unmet clinical need. Given the advantages of intranasal administration for targeted brain delivery, the present study aimed at investigating the pharmacokinetics of paroxetine, after its intranasal instillation and assessing its potential therapeutic effect on female and male mice subjected to unpredictable chronic mild stress (UCMS) protocol. IN administration revealed direct nose-to-brain paroxetine delivery but dose- and sex-dependent differences. Pharmacokinetics was nonlinear and paroxetine concentrations were consistently higher in plasma and brain of male mice. Additionally, UCMS decreased animal preference for sucrose in both male and female mice following acute (p < 0.01) and chronic stress (p < 0.05), suggesting anhedonia. Both male and female mice exhibited depressive-like behavior in the forced swimming test. UCMS females displayed a significantly longer immobility time and shorter climbing time than the control group (p < 0.05), while no differences were found between male mice. Two weeks of paroxetine intranasal administration reduced immobility time and lengthened climbing and swimming time, approaching values similar to those observed in the healthy control group. The therapeutic effect was stronger on female mice. Importantly, melatonin plasma levels were significantly decreased in female mice following UCMS (p < 0.05), while males exhibited heightened corticosterone levels. On the other hand, treatment with IN paroxetine significantly increased corticosterone and melatonin levels in both sexes compared to healthy mice (p < 0.05). Intranasal paroxetine delivery undoubtedly ameliorated the behavioral despair, characteristic of depressive-like animals. Despite its efficiency in male and female mice subjected to UCMS, females were more prone to this novel therapeutic strategy.
Topics: Female; Mice; Male; Animals; Paroxetine; Depressive Disorder, Major; Administration, Intranasal; Sex Characteristics; Corticosterone; Melatonin; Depression; Disease Models, Animal; Stress, Psychological
PubMed: 38556027
DOI: 10.1016/j.bcp.2024.116184 -
Clinical Pharmacokinetics Dec 2023Ulotaront is a novel psychotropic agent with agonist activity at trace amine-associated receptor 1 (TAAR1) and 5-hydroxytryptamine type 1A (5-HT) receptors in phase III...
BACKGROUND
Ulotaront is a novel psychotropic agent with agonist activity at trace amine-associated receptor 1 (TAAR1) and 5-hydroxytryptamine type 1A (5-HT) receptors in phase III clinical development for the treatment of schizophrenia.
OBJECTIVE
This study aimed to investigate the effect of paroxetine, a strong cytochrome P450 (CYP) 2D6 inhibitor, on ulotaront pharmacokinetics (PK) in healthy volunteers.
METHODS
Subjects received a single oral dose of 25 mg ulotaront on Day 1 and an oral dose of 20 mg paroxetine once daily from Days 5 to 10 to achieve steady-state plasma paroxetine levels. On Day 11, subjects received another single oral dose of 25 mg ulotaront, with continued daily oral dosing of 20 mg paroxetine from Days 11 to 14. All 24 subjects were CYP2D6 normal metabolizers.
RESULTS
Coadministration of paroxetine increased ulotaront maximum observed plasma concentration (C) and area under the plasma concentration-time curve from time zero to infinity (AUC) by 31% and 72%, respectively, and decreased ulotaront apparent clearance (CL/F) by approximately 42%. While coadministration of paroxetine increased AUC of active but minor metabolite SEP-363854 by 32%, it had no effect on SEP-363854 C, or on SEP-363854 to the ulotaront AUC from time zero to the last quantifiable concentration (AUC) ratio. Based on the acceptable adverse event profile of ulotaront across previous phase II studies, the increase in ulotaront exposure is unlikely to be clinically meaningful.
CONCLUSIONS
Weak drug-drug interactions were observed between ulotaront and the strong CYP2D6 inhibitor paroxetine; however, dose adjustment as a precondition when ulotaront is coadministered with strong CYP2D6 inhibitors or administered to CYP2D6 poor metabolizers should not be necessary.
Topics: Humans; Cytochrome P-450 CYP2D6; Paroxetine; Healthy Volunteers; Cytochrome P-450 CYP2D6 Inhibitors; Drug Interactions; Enzyme Inhibitors; Area Under Curve
PubMed: 37882999
DOI: 10.1007/s40262-023-01317-4 -
Scientific Reports Oct 2023The aim of this study was to investigate the clinical characteristics, psychological status, sleep quality, and quality of life of patients with functional anorectal...
The aim of this study was to investigate the clinical characteristics, psychological status, sleep quality, and quality of life of patients with functional anorectal pain (FAP). The study also assessed the treatment efficacy of paroxetine in alleviating FAP symptoms. A retrospective comparative study of forty-three patients with FAP who were first treated with an anal plug compound glycolate suppository versus paroxetine combined with anal plug compound glycolate suppository between November 2021 and August 2022. Pain, quality of life, depression, anxiety and sleep quality were assessed before and after treatment by the Chinese version of the Short-Form McGill Pain Questionnaire-2 (SF-MPQ-2), Health-related quality of life scale (The 12-Item Short-Form Health Survey, SF-12), 17-item Hamilton Depression Rating Scale (HDRS), 14-item Hamilton Anxiety Scale (HAMA), and Pittsburgh Sleep Quality Index (PSQI). A total of 46.5% of patients with FAP were found to have anxiety symptoms (HAMA ≥ 7), 37.2% of patients with FAP were found to have depressive symptoms (HDRS ≥ 8). A total of 32.6% of patients with FAP had sleep disorders (PSQI > 10). Within 1 week after drug withdrawal, the short-term efficacy rate of oral paroxetine was 95.5%. After treatment, the symptom pain score (VAS) and sleep score were lower than those before treatment (P < 0.01). In the areas of vitality (VT), Social Functioning (SF), and Mental Health (MH), the difference between the pre-treatment and 8 weeks posttreatment scores of the study group and the control group was statistically significant (P < 0.05). FAP patients have obvious symptoms of anxiety and depression, and the incidence of sleep disturbance is prevalent. Paroxetine, a typical serotonin reuptake inhibitor (SSRI), was able to alleviate depression, anxiety, and pain symptoms in FAP, which might have clinical application prospects.
Topics: Humans; Paroxetine; Retrospective Studies; Quality of Life; Treatment Outcome; Pelvic Pain; Glycolates
PubMed: 37865675
DOI: 10.1038/s41598-023-45401-y