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Renal [alpha]2-adrenoceptors have been reported to play a role in the regulation of urinary output, renin secretion, and water and sodium excretion in the kidneys. However, the distribution of [alpha]2-adrenoceptor subtypes in the kidneys remains unclear. In this study, we aimed to investigate the localization of [alpha]2-adrenoceptor subtypes in rat kidneys using 8-week-old Sprague-Dawley rats. Immunofluorescence imaging revealed that both [alpha]2A- and [alpha]2B-adrenoceptors were expressed in the basolateral, but not apical, membrane of the epithelial cells of the proximal tubules. We also found that [alpha]2A- and [alpha]2B-adrenoceptors were not expressed in the glomeruli, collecting ducts, or the descending limb of the loop of Henle and vasa recta. In contrast, [alpha]2C-adrenoceptors were found to be localized in the glomeruli and lumen of the cortical and medullary collecting ducts. These results suggest that noradrenaline may act on the basement membrane of the proximal tubules through [alpha]2A- and [alpha]2B-adrenoceptors. Moreover, noradrenaline may be involved in the regulation of glomerular filtration and proteinuria through the induction of morphological changes in mesangial cells and podocytes via [alpha]2C-adrenoceptors. In the collecting ducts, urinary noradrenaline may regulate morphological changes of the microvilli through [alpha]2C-adrenoceptors. Our findings provide an immunohistochemical basis for understanding the cellular targets of [alpha]2-adrenergic regulation in the kidneys. This may be used to devise therapeutic strategies targeting [alpha]2-adrenoceptors.

This was a double-blind, randomized, phase 2 study of adults (18–64 years) with DSM−5 diagnosis of major depressive disorder (MDD), with moderate-to-severe episode severity (Montgomery–Åsberg Depression Rating Scale [MADRS] ≥25) despite an adequate course with ongoing antidepressant for ≥6 weeks to ≤12 months. Following a double-blind placebo lead-in period (up to 3 weeks), participants were randomized to receive once daily aticaprant 10 mg or continue placebo, added to their ongoing treatment, for 6 weeks. Of 184 participants enrolled, 169 were included in safety analyses (aticaprant n  = 85, placebo n  = 84) and 166 in full intent-to-treat (fITT) efficacy analyses; 121 placebo lead-in non-responders (<30% reduction in MADRS total score) in fITT were included in enriched ITT (eITT) analyses. Improvement (least squares mean difference [upper limit 1-sided 80% CI] versus placebo) in MADRS total score at week 6 for aticaprant was significant versus placebo (eITT: −2.1 [−1.09], 1-sided p  = 0.044; effect size (ES) 0.23; fITT −3.1 [2.21], 1-sided p  = 0.002; ES 0.36). The between-group difference was larger among participants with Snaith–Hamilton Pleasure Scale (SHAPS) score greater/equal to versus less than baseline median SHAPS. The most common treatment-emergent adverse events reported for aticaprant (versus placebo) were headache (11.8% versus 7.1%), diarrhea (8.2% versus 2.4%), nasopharyngitis (5.9% versus 2.4%), and pruritus (5.9% versus 0%). One participant (1.2%) in each arm discontinued treatment due to an adverse event. In this study of participants with MDD and inadequate response to SSRI/SNRI, adjunctive treatment with aticaprant significantly reduced depressive symptoms versus placebo, without resulting in significant safety signals, supporting further investigation in larger trials.

In this randomized trial, esketamine nasal spray plus an SSRI or SNRI was superior to quetiapine plus an SSRI or SNRI with respect to remission at week 8 in patients with treatment-resistant depression.

Successful recovery from stress is integral for adaptive responding to the environment. At a cellular level, this involves (slow genomic) actions of cortisol, which alter or reverse rapid effects of noradrenaline and cortisol associated with acute stress. At the network scale, stress recovery is less well understood but assumed to involve changes within salience-, executive control-, and default mode networks. To date, few studies have investigated this phase and directly tested these assumptions. Here, we present results from a double-blind, placebo-controlled, between-group paradigm (N = 165 healthy males) administering 10 mg oral yohimbine and/or 10 mg oral hydrocortisone two hours prior to resting state scanning. We found no changes in within-network connectivity of the three networks, both after single and combined drug administration. We further report the results of Bayesian parameter inference to provide evidence for the null hypothesis. Our results contrast with previous findings, which may be attributable to systematic differences between paradigms, highlighting the need to isolate paradigm-specific effects from those related to stress.

Background In general, traditional antidepressants often have limited efficacy in patients with major depressive disorder (MDD). Agomelatine, as an antidepressant with a different mechanism of action, might have adjunctive effects on traditional antidepressants. This study aimed to investigate the augmentation effect of agomelatine versus placebo in treating MDD patients who failed to respond to selective serotonin reuptake inhibitors (SSRIs) and serotonin-noradrenaline reuptake inhibitors (SNRIs). Methods This is an 8-week, multi-centred, double-blinded, randomized, and placebo-controlled trial. Participants diagnosed with MDD and demonstrated inadequate response to SSRI or SNRI lasting at least 2 weeks were randomly allocated to receive either agomelatine or placebo in conjunction with SSRIs or SNRIs. The 17 items of the Hamilton Depression Scale (HAMD-17) were employed to assess depression severity. The primary outcome is the total score of HAMD-17 at week 8. Secondary outcomes included HAMD-17 scores at weeks 2 and 4 and clinical remission and response over 8 weeks. Adverse events (AEs) reported in both groups were recorded. A linear mixed model was established for both primary and secondary outcomes. Results A total of 123 eligible participants were included, among which 60 were randomized into the agomelatine group, and 63 were randomized into the placebo group. The between-group difference in HAMD-17 score reduction from baseline to week 8 was not significant (difference = − 0.12, 95% CI = − 3.94 to 3.70,  P  = 0.90; Cohen’s d  = 0.022). In addition, we did not observe significant differences between the two treatment groups for secondary outcomes, including response remission, and AEs. Conclusions This study did not obtain significant findings in favour of the augmentation effect of agomelation for MDD patients. However, agomelatine was generally well tolerated and demonstrated a favourable safety profile when used in combination with SSRIs and SNRIs. Trial registration. This trial is registered at ClinicalTrials.gov ( https://clinicaltrials.gov ), the registration number is NCT 04589143.

Chronic stress-induced depression is a common hallmark of many psychiatric disorders with high morbidity rate. Stress-induced dysregulation of noradrenergic system has been implicated in the pathogenesis of depression. Lack of monoamine in the brain has been believed to be the main causative factor behind pathophysiology of major depressive disorder (MDD) and several antidepressants functions by increasing the monoamine level at the synapses in the brain. However, it is undetermined whether the noradrenergic receptor stimulation is critical for the therapeutic effect of antidepressant. Contrary to noradrenergic receptor stimulation, it has been suggested that the desensitization of β-adrenoceptor is involved in the therapeutic effect of antidepressant. In addition, enhanced noradrenaline (NA) release is central response to stress and thought to be a risk factor for the development of MDD. Moreover, fast acting antidepressant suppresses the hyperactivation of noradrenergic neurons in locus coeruleus (LC). However, it is unclear how they alter the firing activity of LC neurons. These inconsistent reports about antidepressant effect of NA-reuptake inhibitors (NRIs) and enhanced release of NA as a stress response complicate our understanding about the pathophysiology of MDD. In this review, we will discuss the role of NA in pathophysiology of stress and the mechanism of therapeutic effect of NA in MDD. We will also discuss the possible contributions of each subtype of noradrenergic receptors on LC neurons, hypothalamic-pituitary-adrenal axis (HPA-axis) and brain derived neurotrophic factor-induced hippocampal neurogenesis during stress and therapeutic effect of NRIs in MDD.

ObjectiveOne of the complications of chemotherapy is peripheral neuropathy. Various studies have shown that potent norepinephrine and serotonin reuptake inhibitors such as gabapentin, venlafaxine and duloxetine have therapeutic effects on neuropathy. The aim of this study was to compare the effects of venlafaxine vs. duloxetine on chemotherapy-induced peripheral neuropathy.MethodsIn this clinical trial, cancer patients who were suffering from chemotherapy-induced peripheral neuropathy comprised the study population. They were randomly assigned to three pharmacotherapy groups including venlafaxine, duloxetine and placebo. Cranial, sensory, motor neuropathies as well as neuropathic pain were evaluated on day 1, week 2, and week 4 after enrollment.ResultsGrade of cranial, motor, sensory and neuropathic pain decreased significantly in venlafaxine and duloxetine groups. This reduction was more considerable in duloxetine group compared to venlafaxine group (P < 0.05).ConclusionDuloxetine seems to be more effective than venlafaxine in decreasing the symptoms of chemotherapy-induced peripheral neuropathy. Duloxetine was more effective than venlafaxine in decreasing motor neuropathy and neuropathic pain grade.

Purpose Previous pilot data suggested that venlafaxine could prevent acute and chronic oxaliplatin-related neuropathy. The purpose of this randomized, placebo-controlled, double-blinded pilot study was to obtain additional data to support conducting a phase III trial to test the use of venlafaxine to prevent oxaliplatin neurotoxicity. Methods Fifty patients, scheduled to undergo oxaliplatin-based therapy (FOLFOX) for stages II–III (67 %) or stage IV (33 %) colon cancer, were randomized to receive venlafaxine extended release (37.5 mg) or placebo, twice daily, through their last dose of oxaliplatin and then titrated off. Neurotoxicity was evaluated via several patient- and physician-reported measures, including the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Chemotherapy-Induced Peripheral Neuropathy 20 (EORTC QLQ-CIPN20) instrument. Results Baseline patient characteristics were equivalent for the two arms, with a median age of 60 years. There was a trend toward benefit for the venlafaxine arm, when evaluated by the oxaliplatin-specific neuropathy scale and by acute neuropathy measures of throat discomfort and discomfort swallowing cold liquids, the latter only for the first two oxaliplatin doses. These trends were outweighed by a lack of any such trends in all other measurements including the following: (1) the CIPN20 sensory subscale ( P  = 0.55, primary endpoint), physician-completed NCI CTCAE assessment, or cumulative administered oxaliplatin doses (median 716 vs 631 mg for placebo and venlafaxine, respectively, P  = 0.34). Conclusions The present study neither supports the use of venlafaxine for preventing oxaliplatin-induced neuropathy in clinical practice nor the initiation of a phase III trial to investigate venlafaxine in this setting.

Anxiety, obsessive-compulsive, and stress-related disorders frequently co-occur, and patients often present symptoms of several domains. Treatment involves the use of selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs), but data on comparative efficacy and acceptability are lacking. We aimed to compare the efficacy of SSRIs, SNRIs, and placebo in multiple symptom domains in patients with these diagnoses over the lifespan through a 3-level network meta-analysis. We searched for published and unpublished randomized controlled trials that aimed to assess the efficacy of SSRIs or SNRIs in participants (adults and children) with diagnosis of any anxiety, obsessive-compulsive, or stress-related disorder in MEDLINE, PsycINFO, Embase, and Cochrane Library from inception to 23 April 2015, with an update on 11 November 2020. We supplemented electronic database searches with manual searches for published and unpublished randomized controlled trials registered in publicly accessible clinical trial registries and pharmaceutical companies' databases. No restriction was made regarding comorbidities with any other mental disorder, participants' age and sex, blinding of participants and researchers, date of publication, or study language. The primary outcome was the aggregate measure of internalizing symptoms of these disorders. Secondary outcomes included specific symptom domains and treatment discontinuation rate. We estimated standardized mean differences (SMDs) with 3-level network meta-analysis with random slopes by study for medication and assessment instrument. Risk of bias appraisal was performed using the Cochrane Collaboration's risk of bias tool. This study was registered in PROSPERO (CRD42017069090). We analyzed 469 outcome measures from 135 studies (n = 30,245). All medications were more effective than placebo for the aggregate measure of internalizing symptoms (SMD -0.56, 95% CI -0.62 to -0.51, p < 0.001), for all symptom domains, and in patients from all diagnostic categories. We also found significant results when restricting to the most used assessment instrument for each diagnosis; nevertheless, this restriction led to exclusion of 72.71% of outcome measures. Pairwise comparisons revealed only small differences between medications in efficacy and acceptability. Limitations include the moderate heterogeneity found in most outcomes and the moderate risk of bias identified in most of the trials. In this study, we observed that all SSRIs and SNRIs were effective for multiple symptom domains, and in patients from all included diagnostic categories. We found minimal differences between medications concerning efficacy and acceptability. This three-level network meta-analysis contributes to an ongoing discussion about the true benefit of antidepressants with robust evidence, considering the significantly larger quantity of data and higher statistical power when compared to previous studies. The 3-level approach allowed us to properly assess the efficacy of these medications on internalizing psychopathology, avoiding potential biases related to the exclusion of information due to distinct assessment instruments, and to explore the multilevel structure of transdiagnostic efficacy.