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BioRxiv : the Preprint Server For... Nov 2023Recently, the FDA approved microdosing ketamine for treatment resistant depression. Traditional antidepressants, like serotonin selective reuptake inhibitors (SSRIs),...
Recently, the FDA approved microdosing ketamine for treatment resistant depression. Traditional antidepressants, like serotonin selective reuptake inhibitors (SSRIs), block serotonin reuptake, but it is not clear if ketamine blocks serotonin reuptake. Here, we tested the effects of feeding ketamine and SSRIs to larvae, which has a similar serotonin system to mammals, and is a good model to track depression behaviors, such as locomotion and feeding. Fast-scan cyclic voltammetry (FSCV) was used to measure optogenetically-stimulated serotonin changes, and locomotion tracking software and blue dye feeding to monitor behavior. We fed larvae various doses (1-100 mM) of antidepressants for 24 hours and found that 1 mM ketamine did not affect serotonin, but increased locomotion and feeding. Low doses (≤ 10 mM) of escitalopram and fluoxetine inhibited dSERT and also increased feeding and locomotion behaviors. At 100 mM, ketamine inhibited dSERT and increased serotonin concentrations, but decreased locomotion and feeding due to its anesthetic properties. Since microdosing ketamine causes behavioral effects, we also investigated behavior changes with low doses of other NMDA receptor antagonists and 5-HT agonists, which are other possible sites for ketamine action. NMDA receptor antagonism increased feeding, while serotonin receptor agonism increased locomotion, which could explain these effects with ketamine. Ultimately, this work shows that is a good model to discern antidepressant mechanisms, and that ketamine does not work on dSERT like SSRIs at microdoses, but affects behavior with other mechanisms.
PubMed: 37986873
DOI: 10.1101/2023.11.07.566121 -
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 -
Brain Sciences Sep 2023Social behavior is a complex term which involves different interactions between various individuals of a community. It is controlled by different neurotransmitter...
Social behavior is a complex term which involves different interactions between various individuals of a community. It is controlled by different neurotransmitter systems in a sexually dimorphic way. Certain environmental factors, like stress, cause various neurological disorders with associated social abnormalities in a sexually dimorphic way. Multiple drugs are used in clinical settings to treat behavioral disorders. However, the sexually dimorphic effects of these drugs, particularly on social behavior, still need to be studied. The present study was designed to investigate the sex-dependent effects of Risperidone, Donepezil, and Paroxetine in 8-12 weeks old male and female rats under normal and stressed conditions. There were four male and four female groups, i.e., control group (no drug treatment), Risperidone (3 mg/kg/day) treated group, Donepezil (5 mg/kg/day) treated group, and Paroxetine (10 mg/kg/day) treated group. Each group received its respective drug during phase 1 for 21 days, followed by a 10-day break with no drug treatment. After the break, same groups received the same drugs along with tilt-cage stress for an additional 21 days during phase 2. A social preference and novelty test was performed at the end of both phases (1 and 2). During phase 1, Risperidone treatment caused impaired social behavior and reduced locomotion in the male group only, compared to its control group. Donepezil treatment caused a reduction in social interaction, while Paroxetine treatment caused increased social interaction and locomotion in a sex-dependent manner. During phase 2, social novelty was affected in both male and female stress groups. Treatment with drugs along with stress showed differential sex-dependent effects. The study showed a predominant effect of Risperidone on males while there were differential effects of Donepezil and Paroxetine on both sexes. This study has paved the way for the development of more targeted and effective neuromodulatory drugs for use against various psychiatric and social deficits.
PubMed: 37891747
DOI: 10.3390/brainsci13101378 -
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 -
Drug Metabolism and Disposition: the... Oct 2023Atomoxetine is a cytochrome P450 (P450) 2D6 probe substrate and an approved medicine for attention-deficit/hyperactivity disorder. In this humanized-liver mouse study,...
Atomoxetine is a cytochrome P450 (P450) 2D6 probe substrate and an approved medicine for attention-deficit/hyperactivity disorder. In this humanized-liver mouse study, interactions between atomoxetine and the P450 2D6 probe drug paroxetine were observed. Human physiologically based pharmacokinetic (PBPK) models were established by scaling up humanized-liver mouse data obtained in the absence or presence of paroxetine. These models could explain the drug monitoring results of atomoxetine and its primary 4-hydroxylated and -demethylated metabolites in Japanese children aged 8-14 years and could be used to help establish the correct dosage and for the evaluation of clinical outcomes. The results of simple PBPK models (using input parameters that reflected the subjects' small body size and normal or reduced P450 2D6-dependent clearance) were in general agreement with one-point measured plasma concentrations of atomoxetine and its 4-hydroxylated and -demethylated metabolites in 13 pediatric participants. Unexpectedly high hepatic exposure, possibly in intermediate-metabolizer patients harboring or alleles might in part explain the adverse effects of atomoxetine prescribed alone recorded in a Japanese adverse-event database. The steady-state, one-point drug monitoring data from the participants indicated extensive biotransformation of atomoxetine to 4-hydroxyatomoxetine under individually prescribed doses of atomoxetine. These results also suggest that a relatively narrow range of 4-hydroxyatomoxetine and -desmethylatomoxetine concentration ratios in spot urine and/or plasma samples from pediatric patients could be a simple semiquantitative determinant factor for P450 2D6 intermediate metabolizers, compared with the wide range of concentrations of the two primary metabolites and substrate in extensive metabolizers. Validated simple pharmacokinetic models are able to predict steady-state plasma concentrations of the approved medicine atomoxetine and its primary metabolites in the majority of pediatric patients. The package insert advises careful dose escalation, especially for poor metabolizers; however, no simple way exists to determine P450 2D6 phenotypes. A relatively narrow range ratio of 4-hydroxyatomoxetine and -desmethylatomoxetine in spot urine/plasma samples could be a simple semi-quantitative determinant factor for P450 2D6 intermediate metabolizers to optimize or confirm the correct dosage.
PubMed: 37879849
DOI: 10.1124/dmd.123.001481 -
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 -
Frontiers in Pharmacology 2023We aimed to systematically evaluate the prevalence and clinical characteristics of adverse events associated with the adaptogens and antidepressant drug interactions in...
We aimed to systematically evaluate the prevalence and clinical characteristics of adverse events associated with the adaptogens and antidepressant drug interactions in a retrospective chart review. A total of 1,816 reports of adverse events were evaluated. Cases were included in the analysis if the pharmacoepidemiological analysis showed the presence of a high probability of a causal relationship between an adaptogen and antidepressant interaction and the occurrence of adverse events. The following data were extracted from the reports: age, sex, antidepressant, plant products containing adaptogens, other concomitant medications, and clinical consequences of the interactions and their possible mechanisms. Adaptogens were involved in 9% of adverse events associated with the concomitant use of antidepressants and other preparations. We identified 30 reports in which side effects presented a causal relationship with the use of antidepressants and adaptogens. Here, we present the list of adaptogens with the corresponding antidepressants and the side effects caused by their interactions: : reboxetine (testicle pain and ejaculatory dysfunctions), sertraline (severe diarrhea), escitalopram (myalgia, epigastric pain, nausea, vomiting, restless legs syndrome, and severe cough), and paroxetine (generalized myalgia, ophthalmalgia, and ocular hypertension); : duloxetine (upper gastrointestinal bleeding), paroxetine (epistaxis), sertraline (vaginal hemorrhage), and agomelatine (irritability, agitation, headache, and dizziness); : bupropion (arthralgia and thrombocytopenia), amitriptyline (delirium), and fluoxetine (dysuria); : citalopram (generalized pruritus), escitalopram (galactorrhea), and trazodone (psoriasis relapse); : mianserin (arrhythmias), mirtazapine (edema of lower limbs and myalgia), and fluoxetine (gynecomastia); : mianserin (restless legs syndrome), paroxetine (gynecomastia and mastalgia), and venlafaxine (hyponatremia); : agomelatine (back pain and hyperhidrosis) and moclobemide (myocardial infarction); : duloxetine (back pain); : sertraline (upper gastrointestinal bleeding); : mianserin (restless legs syndrome); and : bupropion (seizures). Clinicians should monitor the adverse events associated with the concomitant use of adaptogens and antidepressant drugs in patients with mental disorders. Aggregation of side effects and pharmacokinetic interactions (inhibition of CYP and p-glycoprotein) between those medicines may result in clinically significant adverse events.
PubMed: 37829299
DOI: 10.3389/fphar.2023.1271776 -
Aging Oct 2023G protein-coupled receptor kinase-2 (GRK2) is involved in TGF-β1-induced activation of lung fibroblasts, which could give rise to the pathogenesis of pulmonary...
G protein-coupled receptor kinase-2 (GRK2) is involved in TGF-β1-induced activation of lung fibroblasts, which could give rise to the pathogenesis of pulmonary fibrosis. Paroxetine (PRXT) serves as a selective GRK2 inhibitor which is widely used to treat anxiety and depression for several decades. However, whether PRXT could inhibit TGF-β1-induced activation of lung fibroblasts and combat bleomycin-induced pulmonary fibrosis remains unclear. Here, we investigated the effects of PRXT on pulmonary fibrosis in C57/BL6 caused by bleomycin as well as on the activation of murine primary lung fibroblasts stimulated with TGF-β1. The results demonstrated that PRXT markedly improved the pulmonary function and 21-day survival in bleomycin-induced mice. Meanwhile, PRXT significantly decreased collagen deposition, inflammation, and oxidative stress in lung tissues from bleomycin-induced mice. Furthermore, we found that PRXT could inhibit the protein and mRNA expression of GRK2 and Smad3 in lung tissues from bleomycin-induced mice. experiments also PRXT could inhibit cell activation and collagen synthesis in a concentration-dependent manner in TGF-β1-induced lung fibroblasts. In addition, we found that Smad3 overexpression by adenovirus transfection could offset anti-fibrotic and antioxidative effects from PRXT in TGF-β1-induced lung fibroblasts, which showed no effects on the protein expression of GRK2. In conclusion, PRXT mediates the inhibition of GRK2, which further blocks the transcription of Smad3 in TGF-β1-induced lung fibroblasts, providing an attractive therapeutic target for pulmonary fibrosis.
Topics: Mice; Animals; Pulmonary Fibrosis; Bleomycin; Transforming Growth Factor beta1; Paroxetine; Lung; Fibroblasts; Collagen; Mice, Inbred C57BL
PubMed: 37815883
DOI: 10.18632/aging.205092 -
Frontiers in Neuroscience 2023Lifelong premature ejaculation (PE) in men lacks an adequate on-demand pharmacological treatment. Although selective serotonin reuptake inhibitors (SSRIs) are used for...
Lifelong premature ejaculation (PE) in men lacks an adequate on-demand pharmacological treatment. Although selective serotonin reuptake inhibitors (SSRIs) are used for PE they only work after chronic treatment, or if used on-demand, less adequately than chronic SSRI treatment. It has been shown that the addition of a behaviorally silent 5-HT-receptor antagonist to an SSRI can generate acute inhibitory effects on male rat sexual behavior. Atlas987 is a selective 5-HT-receptor antagonist with equal potency to displace agonist and antagonist binding to pre- and post-synaptic 5-HT receptors in rat and human brain. To investigate whether Atlas987 together with the SSRI paroxetine, a combination called Enduro, induces acute inhibitory effects on male rat sexual behavior, we tested Enduro in Wistar rats in a dose-dependent manner. We first tested the 5-HT receptor antagonist Atlas987 in 8-OH-DPAT induced serotonergic behavior in rats. Second, we tested Enduro in a dose-dependent manner in male sexual behavior. Third, we tested the effective time window of Enduro's action, and lastly, we measured the plasma levels of Atlas987 and paroxetine over an 8-h period. Results showed that Enduro acutely and dose-dependently reduced the number of ejaculations and increased the ejaculation latencies. The behavioral pattern induced reflected a specific effect on sexual behavior excluding non-specific effects like sedation or sensoric-motoric disturbances. The time-window of activity of Enduro showed that this sexual inhibitory activity was at least found in a 1-4 h' time window after administration. Plasma levels showed that in this time frame both Atlas987 and paroxetine are present. In conclusion, in rats, Enduro is successful in acutely inhibiting sexual behavior. These results may be therapeutically attractive as "on demand" treatment for life-long premature ejaculation in men.
PubMed: 37781259
DOI: 10.3389/fnins.2023.1224959 -
Medicine Sep 2023Anti-amphiphysin antibodies are uncommonly detected in paraneoplastic neurologic syndromes (PNS), especially in patients with small cell lung cancer. Here, we report the...
RATIONALE
Anti-amphiphysin antibodies are uncommonly detected in paraneoplastic neurologic syndromes (PNS), especially in patients with small cell lung cancer. Here, we report the first case of anti-amphiphysin antibody-associated PNS with pruritus and dysphagia as the first complaints.
PATIENT CONCERNS
The patient was a 58-year-old man who sought medical advice with a chief complaint of dysphagia and the lung occupancy. We found that he had developed progressive pruritus several months ago.
DIAGNOSES
In the outer basal segment of the right lung lower lobe, PET-CT revealed small occupancies with hypermetabolism. Later, the pathology showed small cell lung cancer. And anti-amphiphysin antibodies were detected in serum. Above all, the patient's symptoms improved significantly after antitumor treatment. Even neither of the 2 cranial enhancement MRIs showed any meaningful imaging signs, the above evidence could confirm the diagnosis of PNS.
INTERVENTIONS
The chemotherapy regimen was etoposide 0.1g d1-3+cisplatin 40 mg d1-3 (q3w). Paroxetine 20 mg/day was given to relieve the itching.
OUTCOMES
After the treatment, the Watian water swallowing test dropped from grade 5 to grade 1, the intense itching also became tolerable.
LESSONS
Clinicians should consider diagnoses other than anxiety states or esophageal cancer in a patient with pruritus and dysphagia, such as PNS.
Topics: Male; Humans; Middle Aged; Small Cell Lung Carcinoma; Positron Emission Tomography Computed Tomography; Deglutition Disorders; Autoantibodies; Encephalitis; Paraneoplastic Syndromes, Nervous System; Lung Neoplasms; Brain Stem; Pruritus
PubMed: 37773812
DOI: 10.1097/MD.0000000000035325