Opioid Receptor μ-1 and Ketamine Effects in a Suicidal Depression Trial: A Post Hoc Exploration.
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SUBMITTER: Grunebaum MF
PROVIDER: S-EPMC7347432 | biostudies-literature | 2020 Jul/Aug
REPOSITORIES: biostudies-literature
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Opioid Receptor μ-1 and Ketamine Effects in a Suicidal Depression Trial: A Post Hoc Exploration.
Grunebaum Michael F MF Galfalvy Hanga C HC Liu Jun J Huang Yung-Yu YY Marcott Stephen S Burke Ainsley K AK Mann J John JJ
Journal of clinical psychopharmacology 20200701 4
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Project description:Synthetic opioids are increasingly challenging to combat the opioid epidemic and act primarily at opioid receptors, chiefly the G protein-coupled receptor (GPCR) μ-opioid receptor (MOR), which signals through G protein-dependent and β-arrestin pathways. Using a bioluminescence resonance energy transfer (BRET) system, we investigate GPCR-signaling profiles by synthetic nitazenes, which are known to cause overdose and death due to respiratory depression. We show that isotonitazene and its metabolite, N-desethyl isotonitazene, are very potent MOR-selective superagonists, surpassing both DAMGO G protein and β-arrestin recruitment activity, which are properties distinct from other conventional opioids. Both isotonitazene and N-desethyl isotonitazene show high potency in mouse analgesia tail-flick assays, but N-desethyl isotonitazene shows longer-lasting respiratory depression compared to fentanyl. Overall, our results suggest that potent MOR-selective superagonists may be a pharmacological property predictive of prolonged respiratory depression resulting in fatal consequences and should be examined for future opioid analgesics.
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Project description:Modern antiretroviral therapies have provided HIV-1 infected patients longer lifespans and better quality of life. However, several neurological complications are now being seen in these patients due to HIV-1 associated injury of neurons by infected microglia and astrocytes. In addition, these effects can be further exacerbated with opiate use and abuse. One possible mechanism for such potentiation effects of opiates is the interaction of the mu opioid receptor (MOR) with the chemokine receptor CCR5 (CCR5), a known HIV-1 co-receptor, to form MOR-CCR5 heterodimer. In an attempt to understand this putative interaction and its relevance to neuroAIDS, we designed and synthesized a series of bivalent ligands targeting the putative CCR5-MOR heterodimer. To understand how these bivalent ligands may interact with the heterodimer, biological studies including calcium mobilization inhibition, binding affinity, HIV-1 invasion, and cell fusion assays were applied. In particular, HIV-1 infection assays using human peripheral blood mononuclear cells, macrophages, and astrocytes revealed a notable synergy in activity for one particular bivalent ligand. Further, a molecular model of the putative CCR5-MOR heterodimer was constructed, docked with the bivalent ligand, and molecular dynamics simulations of the complex was performed in a membrane-water system to help understand the biological observation.
| S-EPMC5112769 | biostudies-literature
Project description:Introduction Diabetes and depression may present concurrently, and clinical pharmacists are well equipped to manage these conditions. Clinical pharmacists were grant funded to implement a diabetes-focused randomized controlled trial in a Federally Qualified Health Center. The objective of this analysis is to evaluate if glycemic control and depressive symptoms improve for patients with diabetes and depression with additional management from clinical pharmacists compared with those receiving the standard of care. Methods This is a post hoc subgroup analysis of a diabetes-focused randomized controlled trial. Pharmacists enrolled patients with type 2 diabetes mellitus (T2DM) and a glycated hemoglobin (A1C) greater than 8% and randomly assigned them to 1 of 2 cohorts, one managed by the primary care provider alone and one with additional care from the pharmacist. Pharmacists completed encounters with patients who have T2DM with or without depression to comprehensively optimize pharmacotherapy while tracking glycemic and depressive outcomes throughout the study. Results A1C improved from baseline to 6 months in patients with depressive symptoms who received additional care from pharmacists by −2.4 percentage points (SD, 2.41) compared with a −0.1 percentage point (SD, 1.78) reduction in the control arm (P .0081), and there was no change in depressive symptoms. Discussion Patients with T2DM and depressive symptoms experienced better diabetes outcomes with additional pharmacist management compared with a similar cohort of patients with depressive symptoms, managed independently by primary care providers. These patients with diabetes and comorbid depression received a higher level of engagement and care from the pharmacists, which led to more therapeutic interventions.
| S-EPMC9987260 | biostudies-literature
Project description:Major depressive disorder is associated with lowered mood, anxiety, anhedonia, sleep problems, and cognitive impairments. Many of these functions are regulated by μ-opioid receptor (MOR) system. Preclinical, in vivo, and post-mortem studies have however yielded inconclusive results regarding the role of the MOR in depression and anxiety. Moreover, it is not known whether alterations in MOR are already present in subclinical depression and anxiety. In a large-scale retrospective cross-sectional study we pooled data from 135 (113 males and 22 females) healthy subjects whose brain's MOR availability was measured with positron emission tomography (PET) using an agonist radioligand [11C]carfentanil that has high affinity for MORs. Depressive and anxious symptomology was addressed with BDI-II and STAI-X questionnaires, respectively. Both anxiety and depression scores in the subclinical range were negatively associated with MOR availability in cortical and subcortical areas, notably in amygdala, hippocampus, ventral striatum, and orbitofrontal and cingulate cortices. We conclude that dysregulated MOR availability is involved in altered mood and pathophysiology of depression and anxiety disorders.
| S-EPMC7608336 | biostudies-literature
Project description:ObjectiveStudies demonstrate rapid antidepressant and anti-suicidal ideation effects of subanesthetic ketamine. The specific subcomponents of depression that are most closely tied to reduction of suicidal ideation with ketamine treatment are less explored.MethodsExploratory, post hoc analysis of data from a randomized clinical trial of ketamine vs midazolam in patients with major depressive disorder (MDD) and clinically significant suicidal ideation examined changes in factor analysis-derived symptom clusters from standard measures of depression (Hamilton Depression Rating Scale, HDRS; Beck Depression Inventory, BDI) and mood disturbance (Profile of Mood States, POMS), and their relationship to severity of suicidal ideation (Beck Scale for Suicidal Ideation; SSI). Ratings obtained before and one day after blinded intravenous infusion were decomposed into component factors or published subscales. Treatment effects on factors/subscales were compared between drugs, correlations with changes in suicidal ideation were tested, and stepwise regression was used to derive predictors of change in SSI.ResultsFactor scores for HDRS Psychic Depression, HDRS Anxiety, BDI Subjective Depression, POMS Depression and POMS Fatigue improved more with ketamine than midazolam. Stepwise regression showed across both drugs that improvement in HDRS Psychic Depression, POMS Depression, and HDRS Anxiety predicted 51.6% of the variance in reduction of suicidal ideation.LimitationsSecondary analysis of clinical trial data.ConclusionsKetamine's rapid effects on suicidal ideation appear to be mostly a function of its effects on core mood and anxiety symptoms of MDD, with comparatively little contribution from neurovegetative symptoms with the potential exception of vigor/fatigue.Trial registrationData used in this secondary analysis came from ClinicalTrials.gov identifier: NCT01700829.
| S-EPMC8828686 | biostudies-literature
Project description:To evaluate suicidal thoughts in relationship to depressive symptom severity and reasons for living in patients hospitalized for major depressive disorder (MDD). A post hoc analysis was conducted of a randomized, double-blind, parallel-group trial involving hospitalized patients with MDD (DSM-IV criteria) who received duloxetine 60 mg once daily or duloxetine 60 mg twice daily for 8 weeks. After 4 weeks, the dose for nonresponders receiving 60 mg once daily could be increased to 60 mg twice daily (double-blind). The study was conducted between February 9, 2007, and August 26, 2008 at 43 centers in 4 countries across Europe and South Africa. Suicidal thoughts were assessed with Montgomery-Asberg Depression Rating Scale (MADRS) item 10, depression severity was assessed with the 6-item Hamilton Depression Rating Scale and the Clinical Global Impressions-Severity of Illness scale, and protective factors were assessed with the patient-rated Reasons for Living Inventory (RFL) assessing 6 domains. Descriptive statistics, correlation, and linear regression analysis were performed. At baseline, patients (N = 336) had varying severity of suicidal thoughts: 18% had a score ≥ 4. The proportion of patients with a score ≥ 4 decreased to 7% at week 1 and 1% at week 8 of treatment. The RFL scores at baseline were lower in patients with higher baseline suicidal thoughts and increased significantly during treatment (P < .0001). A regression model revealed that only 16% of variance in baseline total RFL score is explained by the different MADRS items. Eight patients had suicidal behavior or ideation recorded as an adverse event during the study; no consistent pattern was found in the different psychometric scores either at baseline or at the visit preceding the suicidal behavior/ideation. Suicidality rapidly decreased in hospitalized patients with severe depression treated with duloxetine. The RFL scores were low at baseline but increased during treatment, suggesting that they are at least partially state rather than trait variables. Since RFL scores are lower in depressed inpatients, these scores lose the predictive value that they have in a general population sample. ClinicalTrials.gov identifier: NCT00422162.
| S-EPMC4195637 | biostudies-literature
Project description:ObjectivePharmacotherapy to rapidly relieve suicidal ideation in depression may reduce suicide risk. Rapid reduction in suicidal thoughts after ketamine treatment has mostly been studied in patients with low levels of suicidal ideation. The authors tested the acute effect of adjunctive subanesthetic intravenous ketamine on clinically significant suicidal ideation in patients with major depressive disorder.MethodIn a randomized clinical trial, adults (N=80) with current major depressive disorder and a score ≥4 on the Scale for Suicidal Ideation (SSI), of whom 54% (N=43) were taking antidepressant medication, were randomly assigned to receive ketamine or midazolam infusion. The primary outcome measure was SSI score 24 hours after infusion (at day 1).ResultsThe reduction in SSI score at day 1 was 4.96 points greater for the ketamine group compared with the midazolam group (95% CI=2.33, 7.59; Cohen's d=0.75). The proportion of responders (defined as having a reduction ≥50% in SSI score) at day 1 was 55% for the ketamine group and 30% for the midazolam group (odds ratio=2.85, 95% CI=1.14, 7.15; number needed to treat=4.0). Improvement in the Profile of Mood States depression subscale was greater at day 1 for the ketamine group compared with the midazolam group (estimate=7.65, 95% CI=1.36, 13.94), and this effect mediated 33.6% of ketamine's effect on SSI score. Side effects were short-lived, and clinical improvement was maintained for up to 6 weeks with additional optimized standard pharmacotherapy in an uncontrolled follow-up.ConclusionsAdjunctive ketamine demonstrated a greater reduction in clinically significant suicidal ideation in depressed patients within 24 hours compared with midazolam, partially independently of antidepressant effect.
| S-EPMC5880701 | biostudies-literature
Project description:BackgroundThe endogenous opioid system is thought to play a role in the placebo antidepressant response. A recent trial comparing the rapid antidepressant effects of ketamine versus placebo in surgical patients, some of whom were on chronic opioid therapy, revealed a substantial placebo effect. This finding provided an opportunity to test the hypothesis that opioid agonist exposure interacts with placebo antidepressant responses.MethodsThis post hoc analysis utilized data from a previously reported randomized, anesthesia-blinded, placebo-controlled trial of intravenous ketamine in depressed patients undergoing routine surgery. Mixed-effects models were used to determine whether baseline opioid use influenced antidepressant responses to the trial interventions, as measured by the Montgomery-Åsberg Depression Rating Scale (MADRS) over 1 to 14 days post-treatment.ResultsIn the placebo arm, baseline opioid use was associated with a 10-point increase (95% CI: 0.81-19.4) in MADRS scores across all post-treatment time points, indicating worse depression in this subgroup. In an alternative model using percent change in MADRS scores, the difference between opioid users and non-users was 38.4% (95% CI: 8.59-68.2), with opioid users experiencing less improvement. For ketamine-treated participants, baseline opioid use did not significantly impact MADRS scores or the percent change in MADRS scores. Pain intensity was not a significant predictor of MADRS outcomes, and the correlation between post-treatment MADRS scores and pain intensity was negligible (R=0.12).LimitationsThis analysis was unregistered and conducted on a small sample; the findings need to be confirmed by prospective controlled studies.ConclusionsOpioid use at baseline attenuated the placebo antidepressant response independently of pain in depressed patients who received the study treatment under general anesthesia for routine surgery. The antidepressant response was preserved in opioid users who received intravenous ketamine.
| S-EPMC11469457 | biostudies-literature
Project description:Preliminary evidence suggests intravenous ketamine has rapid effects on suicidal cognition, making it an attractive candidate for depressed patients at imminent risk of suicide. In the first randomized controlled trial of ketamine using an anesthetic control condition, we tested ketamine's acute effects on explicit suicidal cognition and a performance-based index of implicit suicidal cognition (Implicit Association Test; IAT) previously linked to suicidal behavior.Symptomatic patients with treatment-resistant unipolar major depression (inadequate response to ?3 antidepressants) were assessed using a composite index of explicit suicidal ideation (Beck Scale for Suicidal Ideation, Montgomery-Asberg Rating Scale suicide item, Quick Inventory of Depressive Symptoms suicide item) and the IAT to assess suicidality implicitly. Measures were taken at baseline and 24 hr following a single subanesthetic dose of ketamine (n = 36) or midazolam (n = 21), a psychoactive placebo agent selected for its similar, rapid anesthetic effects. Twenty four hours postinfusion, explicit suicidal cognition was significantly reduced in the ketamine but not the midazolam group.Fifty three percent of ketamine-treated patients scored zero on all three explicit suicide measures at 24 hr, compared with 24% of the midazolam group (?(2) = 4.6; P = .03). Implicit associations between self- and escape-related words were reduced following ketamine (P = .01; d = .58) but not midazolam (P = .68; d = .09). Ketamine-specific decreases in explicit suicidal cognition were largest in patients with elevated suicidal cognition at baseline, and were mediated by decreases in nonsuicide-related depressive symptoms.Intravenous ketamine produces rapid reductions in suicidal cognition over and above active placebo. Further study is warranted to test ketamine's antisuicidal effects in higher-risk samples.
| S-EPMC4112410 | biostudies-literature
Project description:we derived, validated, and applied a novel MOR-specific Cre mouse line, inserting a T2A cleavable peptide sequence and the Cre coding sequence into the MOR 3’UTR. Importantly, this line shows specificity and fidelity of MOR expression throughout the brain and with respect to function, there were no differences in behavioral responses to morphine when compared to wild type mice, nor are there any alterations in Oprm1 gene expression or receptor density. To assess Cre recombinase activity, MOR-Cre mice were crossed with the floxed GFP-reporters, RosaLSLSun1-sfGFP or RosaLSL-GFP-L10a. The latter allowed for cell type specific RNA sequencing via TRAP (Translating Ribosome Affinity Purification) of striatal MOR+ neurons following opioid withdrawal.
2023-01-01 | GSE218564 | GEO