ABSTRACT
BACKGROUND AND OBJECTIVES: Esmethadone (dextromethadone; d-methadone; S-methadone (+)-methadone; REL-1017) is a low potency N-methyl-D-aspartate (NMDA) receptor channel blocker that showed a rapid and sustained adjunctive antidepressant effects in patients with major depressive disorder with inadequate response to ongoing serotonergic antidepressant treatment. Previous studies indicated that esmethadone is partially excreted by the kidney (53.9% of the dose) and by the liver (39.1% of the dose). METHODS: Here we studied the pharmacokinetics and safety of esmethadone after a single oral dose of 25 mg in subjects with different stages of kidney and liver impairment. RESULTS: In subjects with a mild and moderate decrease in glomerular fraction rate (GFR), esmethadone Cmax and AUC0-inf values did not differ compared with healthy subjects. In patients with severe renal impairment, the ratios of Cmax and AUC0-inf values compared with healthy subjects were above 100% (138.22-176.85%) and, while modest, these increases reached statistical significance. In subjects with end stage renal disease (ESRD) undergoing intermittent hemodialysis (IHD), Cmax and AUC0-inf values were not statistically different compared with healthy subjects. IHD did not modified plasma total esmethadone concentrations in blood exiting versus entering the dialyzer. Dose adjustment is not warranted in subjects with mild-to-moderate impaired renal function. Dose reduction may be considered for select patients with severe renal disfunction. In subjects with mild-or-moderate hepatic impairment, Cmax and AUC0-inf were approximately 20-30% lower compared with healthy controls. The drug free fraction increased with the severity of hepatic impairment, from 5.4% in healthy controls to 8.3% in subjects with moderate hepatic impairment. CONCLUSION: Mild and moderate hepatic impairment has a minimal to modest impact on exposure to total or unbound esmethadone and dose adjustments are not warranted in subjects with mild and moderate hepatic impairment. Administration of esmethadone was well tolerated in healthy adult subjects, in subjects with mild or moderate hepatic impairment, and in subjects with mild moderate or severe renal impairment, including patients with ESRF undergoing dialysis.
Subject(s)
Methadone , Renal Insufficiency, Chronic , Humans , Male , Female , Middle Aged , Adult , Methadone/pharmacokinetics , Methadone/administration & dosage , Methadone/adverse effects , Renal Insufficiency, Chronic/therapy , Liver Diseases , Aged , Area Under Curve , Young Adult , Administration, Oral , Glomerular Filtration Rate/drug effectsABSTRACT
Currently, there are few pharmacotherapy options for clinicians treating post-traumatic stress disorder (PTSD), and antidepressants are usually the medication of choice. This meta-analysis aimed to review the efficacy of antidepressants in the acute treatment of PTSD in adults while investigating the contribution of study design and placebo response to the findings of these studies. Randomized, double-blind, placebo-controlled clinical trials that compared antidepressants with placebo for acute treatment of PTSD were selected. Standardized mean difference (SMD) in change in Clinician-Administered PTSD Scale scores were pooled after examining for heterogeneity. A random-effects meta-analysis was performed. Twenty-nine antidepressant-placebo comparisons, involving 4575 subjects, were analyzed. The SMD among all studies was 0.25, a small to medium effect size, lower than that in studies of antidepressants in adult major depressive disorder. The SMDs for low and high mean placebo responses, were 0.27 and 0.22, respectively. The overall SMD for paroxetine studies was in the moderate range (0.43) and that for sertraline studies was in the small range (0.12). Our findings suggest that antidepressants have modest efficacy in alleviating PTSD symptoms. Patient-level meta-analyses are required to further explore the potential clinical relevance of sertraline for PTSD.
ABSTRACT
Objective: To test esmethadone (REL-1017) as adjunctive treatment in patients with major depressive disorder (MDD) and inadequate response to standard antidepressants.Methods: In this phase 3, double-blind, placebo-controlled trial, outpatients with MDD (DSM-5) were randomized to daily oral esmethadone (75 mg on day 1, followed by 25 mg daily on days 2 through 28) or placebo between December 2020 and December 2022. The primary efficacy measure was change from baseline (CFB) to day 28 in the Montgomery-Asberg Depression Rating Scale (MADRS) score. The intent-to-treat (ITT) population included all randomized participants. The per-protocol (PP) population included completers without major protocol deviations impacting assessment. Post hoc analyses included participants with severe depression (baseline MADRS score ≥35).Results: For the ITT analysis (n = 227), mean CFB was 15.1 (SD 11.3) for esmethadone (n = 113) and 12.9 (SD 10.4) for placebo (n = 114), with a mean difference (MD) of 2.3, which was not statistically significant (P = .154; Cohen effect size [ES] = 0.21). Remission rates were 22.1% and 13.2% (P = .076), and response rates were 39.8% and 27.2% (P = .044) with esmethadone and placebo, respectively. For the PP analysis (n = 198), mean CFB was 15.6 (SD 11.2) for esmethadone (n = 101) and 12.5 (SD 9.9) for placebo (n = 97), with an MD of 3.1 (P = .051; ES =0.29). In post hoc analyses of patients with baseline MADRS ≥35 in the ITT population (n = 112), MD was 6.9; P = .0059; ES = 0.57, and for the PP population (n = 98), MD was 7.9; P = .0015; ES = 0.69. Adverse events (AEs) were predominantly mild or moderate and transient, with no significant differences between groups.Conclusions: The primary end point was not met. Esmethadone showed stronger efficacy in PP than in ITT analyses, with the discrepancy not attributable to AEs impacting treatment adherence. Significant efficacy occurred in post hoc analyses of patients with severe depression. Esmethadone was well tolerated, consistent with prior studies.Trial Registration: ClinicalTrials.gov identifier: NCT04688164.
Subject(s)
Antidepressive Agents , Depressive Disorder, Major , Humans , Depressive Disorder, Major/drug therapy , Male , Adult , Female , Double-Blind Method , Middle Aged , Antidepressive Agents/adverse effects , Antidepressive Agents/administration & dosage , Antidepressive Agents/therapeutic use , Depressive Disorder, Treatment-Resistant/drug therapy , Treatment Outcome , Drug Therapy, CombinationABSTRACT
BACKGROUND: Wernicke encephalopathy (WE) is an acute and potentially fatal neuropsychiatric disorder resulting from thiamine deficiency: its etiology and clinical presentation can be heterogeneous and arduously recognized, especially in children and adolescents. CASE PRESENTATION: An 8-year-old girl arrived to the emergency room with ataxic gait, nystagmus, and mental confusion after a 10-day history of repeated severe vomiting; her recent clinical history was characterized by restricted nutrition due to a choking phobia, which caused substantial weight loss. Brain magnetic resonance imaging revealed a bilaterally increased T2 signal in the medial areas of the thalami and cerebral periaqueductal region. Diagnosis of WE based on clinical and neuroradiological findings was established and confirmed after labwork showing low serum thiamine. Following psychiatric evaluation, the patient was also diagnosed with avoidance-restrictive food intake disorder (ARFID), which required starting cognitive behavioral therapy and introducing aripiprazole. The patient displayed improvement of the radiological findings after one month and complete resolution of her neurological symptoms and signs. CONCLUSIONS: Eating disorders like ARFID might forerun acute signs of WE; this possibility should be considered even in pediatric patients, especially when atypical neurological pictures or feeding issues come out.
ABSTRACT
Objective: The relationship between the duration of major depressive disorder (MDD) and therapeutic response to standard antidepressant treatment (SAT) is unknown. N-methyl-D-aspartate receptor uncompetitive antagonists are emerging drugs for MDD. We investigated whether the antidepressant effect of esmethadone (REL-1017) could be related to the duration of depression.Methods: We analyzed data from a Phase 2a study of adjunctive treatment with esmethadone in MDD patients (DSM-5) with inadequate response to ongoing SAT (May 2018-August 2019). Patients were randomized to treatment with esmethadone 25 mg, esmethadone 50 mg, or placebo for 7 days, followed by an observation period (Days 7-14). Duration of depression was derived from 2 measures: (1) time from onset (TFO), calculated as the difference in years between age at trial enrollment and age at the onset of the first major depressive episode (MDE), and (2) TFO index, calculated by computing the years of illness duration (number of years from the beginning of MDD), divided by age and multiplied by 100. First, bivariate correlations between TFO and change from baseline (CFB) were calculated by Spearman ρ. Linear mixed-model analyses were also conducted.Results: A total of 62 patients participated in the trial. The median values of time from MDD onset for the 62 patients were 11 years (absolute value) and 22% (percentage of life-years). Duration of depression was significantly correlated with Montgomery-Asberg Depression Rating Scale (MADRS) CFB on Day 14, even when controlling for the effect of current depression severity (MADRS baseline). In the linear mixed-model analyses, we found a significant effect of duration on reduction in MADRS score from T0 to subsequent assessments (P < .05). Number of previous MDEs and effect of esmethadone 50 mg when compared to 25 mg were not significant.Conclusion: Esmethadone 25 and 50 mg were more effective in reducing MADRS scores in patients with shorter time from first MDE onset.Trial Registration: ClinicalTrials.gov identifier: NCT03051256.
Subject(s)
Antidepressive Agents , Depressive Disorder, Major , Humans , Depressive Disorder, Major/drug therapy , Male , Female , Adult , Middle Aged , Antidepressive Agents/therapeutic use , Antidepressive Agents/administration & dosage , Antidepressive Agents/adverse effects , Time Factors , Treatment Outcome , Double-Blind MethodABSTRACT
OBJECTIVE: To identify childhood psychopathological features that predict the onset of adolescent Bipolar (BD) versus Unipolar Major Depressive Disorder (UD) during adolescence. METHOD: We analyzed clinical data from 495 juveniles diagnosed with DSM-5 UD (n = 359), and BD (n = 136), using bivariate analysis and multivariate logistic regression model. RESULTS: BD subjects exhibited earlier onset of any psychiatric feature compared to UD. Antecedents associated with later BD were: oppositional defiant > specific phobias > ADHD > obsessive compulsive (OCD). Antecedents selectively associated with later UD were: social anxiety and separation anxiety. Factors significantly and independently associated with later BD diagnosis were: [a] emotional dysregulation at onset of the mood disorder; [b] first depressive episode with mixed features; [c] antecedent ADHD; [d] antecedent OCD, and [e] antecedent oppositional-defiance. CONCLUSION: Identifying developmental differences in BD and UD symptoms can aid clinicians in early identification and treatment planning for bipolar disorder in youth.
Subject(s)
Attention Deficit Disorder with Hyperactivity , Bipolar Disorder , Depressive Disorder, Major , Humans , Adolescent , Child , Depressive Disorder, Major/diagnosis , Depressive Disorder, Major/epidemiology , Depressive Disorder, Major/complications , Bipolar Disorder/diagnosis , Bipolar Disorder/epidemiology , Attention Deficit Disorder with Hyperactivity/complications , Diagnostic and Statistical Manual of Mental Disorders , FearABSTRACT
BACKGROUND AND OBJECTIVE: Esmethadone (dextromethadone; d-methadone; S-methadone (+)-methadone; REL-1017) is the opioid inactive dextro-isomer of racemic methadone. Esmethadone is a low potency N-methyl-D-aspartate (NMDA) receptor channel blocker with higher affinity for GluN2D subtypes. Esmethadone showed robust, rapid, and sustained antidepressant effects in patients with major depressive disorder (MDD) with inadequate response to ongoing serotonergic antidepressant treatment. METHODS: Here we described the results of in vitro and phase 1 clinical trials aimed at investigating the esmethadone metabolism and possible drug-drug interactions. RESULTS: Esmethadone is primarily metabolized to EDDP (2-ethylene-1,5-dimethyl-3,3-diphenylpyrrolidine) by multiple enzymes, including CYP3A4/5 and CYP2B6. In vitro studies showed that esmethadone inhibits CYP2D6 with IC50 of 9.6 µM and is an inducer of CYP3A4/5. The clinical relevance of the inhibition of CYP2D6 and the induction of CYP3A4 were investigated by co-administering esmethadone and dextromethorphan (a substrate for CYP2D6) or midazolam (a substrate for CYP3A4) in healthy volunteers. The administration of esmethadone at the dosage of 75 mg (which is the loading dose administered to patients in MDD clinical trials) significantly increased the exposure (AUC) of both dextromethorphan and its metabolite dextrorphan by 2.71 and 3.11-fold, respectively. Esmethadone did not modify the pharmacokinetic profile of midazolam, while it increased Cmax and AUC of its metabolite 1'-hydroxymidazolam by 2.4- and 3.8-fold, respectively. A second study evaluated the effect of the CYP3A4 inhibitor cobicistat on the pharmacokinetics of esmethadone. Cobicistat slightly increase (+32%) the total exposure (AUC0-inf) of esmethadone. CONCLUSIONS: In summary, esmethadone demonstrated a negligible effect on CYP3A4 induction and its metabolism was not meaningfully affected by strong CYP3A4 inhibitors while it increased exposure of CYP2D6-metabolized drugs.
ABSTRACT
Introduction: Suicidal attempts (SAs) in youth have been increasing during the last decades. Methods: We studied consultations, SA, and suicidal ideation (SI) in a pediatric emergency department (ED). Results: From 1 January 2011 to 31 May 2022, 606,159 patients accessed the ED, 8,397 of who had a child psychiatry consultation (CPC). CPCs increased significantly by 11 times in the last decade (155 in 2011 vs. 1,824 in 2021, p < 0.001); CPCs for SA increased significantly by 33 times, from 6 in 2011 to 200 in 2021 (3.9% of total CPC vs. 11%, p < 0.001). While total CPCs increased constantly during the entire period (annual percent change (APC) of 21.7 from 2011 to 2021 in a 0 joinpoint model), CPCs for SA increased significantly from 2011 to 2016, were approximately stable from 2016 to 2020, and then had a peak in 2021 after the COVID-19 pandemic (APC from 2011 to 2016 of 64.1, APC of 1.2 from 2016 to 2020, and APC of 230 after 2020 in a 2-joinpoint model). Discussion: Total CPCs in ED as well as evaluation for SA and SI increased significantly during the last decade. CPCs for SA had an additional increase after the COVID-19 pandemic. This picture warrants timely and efficient improvements in emergency settings and mental health resources.
ABSTRACT
Access to the emergency department (ED) for acute psychiatric problems, especially for suicide attempts (SA), has increased in the last decade. This increase has exceptionally accelerated after the COVID-19 pandemic. The aim of this project was to study the increase in acute psychiatric care demand of children and adolescents in the short and medium term after the pandemic, in relation to public health measures and in comparison with a pre pandemic reference period. We retrospectively studied 5445 child psychiatric (CP) consultations requested for any reason and for suicide attempt (SA), suicidal ideation (SI) and non-suicidal self-injury (NSSI) in a pediatric ED during three different pandemic periods in Italy (from March 2020 to May 2022) and compared them to a pre-pandemic reference period (from January 2018 to February 2020). Monthly CP consultations for any reason increased significantly by 2.2 times from 70.9 in 2018 to 157 in 2022 (p < 0.001). During the pandemic, monthly CP consultations for any reason increased significantly from 75/month in the first lockdown to 153/month in the second lockdown, remaining stable in the following year. CP consultations for SA increased significantly from 5/month in the first lockdown to 16/month in the second. Consultations for SI increased gradually but significantly from the pre-pandemic period to the end of the pandemic. Juveniles evaluated for SA during the pandemic vs. pre-pandemic more frequently attempted suicide by self-poisoning and less frequently by precipitation, and they were more likely to be diagnosed with a major depressive disorder. CP consultations for any reason and for suicide attempts significantly increased in the decade before the pandemic and peaked in the second lockdown period in Italy.
ABSTRACT
Esmethadone (REL-1017) is the opioid-inactive dextro-isomer of methadone and a low-affinity, low-potency uncompetitive NMDA receptor antagonist. In a Phase 2, randomized, double-blind, placebo-controlled trial, esmethadone showed rapid, robust, and sustained antidepressant effects. Two studies were conducted to evaluate the abuse potential of esmethadone. Each study utilized a randomized, double-blind, active-, and placebo-controlled crossover design to assess esmethadone compared with oxycodone (Oxycodone Study) or ketamine (Ketamine Study) in healthy recreational drug users. Esmethadone 25 mg (proposed therapeutic daily dose), 75 mg (loading dose), and 150 mg (Maximum Tolerated Dose) were evaluated in each study. Positive controls were oral oxycodone 40 mg and intravenous ketamine 0.5 mg/kg infused over 40 min. The Ketamine study included oral dextromethorphan 300 mg as an exploratory comparator. The primary endpoint was maximum effect (Emax) for Drug Liking, assessed using a bipolar 100-point visual analog scale (VAS). A total of 47 and 51 participants completed the Oxycodone Study and the Ketamine Study, respectively (Completer Population). In both studies, esmethadone doses ranging from therapeutic (25 mg) to 6 times therapeutic (150 mg) had a meaningful and statistically significantly (p < 0.001) lower Drug Liking VAS Emax compared with the positive control. Results were consistent for all secondary endpoints in both studies. In both studies, all doses of esmethadone were statistically equivalent to placebo on Drug Liking VAS Emax (p < 0.05). In the Ketamine Study, Drug Liking VAS Emax scores for esmethadone at all tested doses were significantly lower vs. dextromethorphan (p < 0.05) (exploratory endpoint). These studies indicate no meaningful abuse potential for esmethadone at all tested doses.
Subject(s)
Illicit Drugs , Ketamine , Humans , Oxycodone , Receptors, N-Methyl-D-Aspartate , Dextromethorphan/adverse effects , Ketamine/adverse effects , Analgesics, Opioid/adverse effects , Cross-Over Studies , Double-Blind MethodABSTRACT
This review article presents select recent studies that form the basis for the development of esmethadone into a potential new drug. Esmethadone is a promising member of the pharmacological class of uncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonists that have shown efficacy for major depressive disorder (MDD) and other diseases and disorders, such as Alzheimer's dementia and pseudobulbar affect. The other drugs in the novel class of NMDAR antagonists with therapeutic uses that are discussed for comparative purposes in this review are esketamine, ketamine, dextromethorphan, and memantine. We present in silico, in vitro, in vivo, and clinical data for esmethadone and other uncompetitive NMDAR antagonists that may advance our understanding of the role of these receptors in neural plasticity in health and disease. The efficacy of NMDAR antagonists as rapid antidepressants may advance our understanding of the neurobiology of MDD and other neuropsychiatric diseases and disorders.
Subject(s)
Alzheimer Disease , Depressive Disorder, Major , Humans , Excitatory Amino Acid Antagonists/pharmacology , Depressive Disorder, Major/drug therapy , Memantine/pharmacology , Memantine/therapeutic use , Antidepressive Agents/pharmacology , Antidepressive Agents/therapeutic use , Alzheimer Disease/drug therapyABSTRACT
BACKGROUND: Children with Attention Deficit Hyperactivity Disorder (ADHD) having a history of adverse childhood experiences (ACEs) could be very difficult to treat with standard psychotherapeutic approaches. Some children diagnosed with ADHD may have Post-Traumatic Stress Disorder (PTSD) or have had experienced a significant traumatic event. Trauma and PTSD could exacerbate ADHD core symptoms and be a risk factor of poor outcome response. OBJECTIVE: to report for the first time the history of a patient with ADHD and ACE successfully treated with an EMDR approach. CONCLUSION: EMDR could be a promising treatment for ADHD children with a history of traumatic experiences in addition to pharmacological treatments.
ABSTRACT
Objective: Improvement of cognitive function in patients with major depressive disorder (MDD) is an important treatment outcome. REL-1017 (esmethadone HCl) is a novel N-methyl-d-aspartate receptor (NMDAR) channel blocker and a potentially rapidly acting antidepressant. The objective of this study was to define the effects of REL-1017 on subjective cognitive measures in patients with MDD.Methods: Post hoc analysis was conducted of subjective cognitive measures from the Montgomery-Asberg Depression Rating Scale (MADRS) and the Symptoms of Depression Questionnaire (SDQ) from a randomized, double-blind, placebo-controlled, Phase 2a study. The study, designed to assess the safety, tolerability, and efficacy of 2 dosages (25 mg and 50 mg) of REL-1017 as an adjunctive treatment in patients with MDD unresponsive to standard antidepressants, included 62 patients. We analyzed subjective cognitive measures derived from the MADRS and SDQ scales at baseline and up to day 14, 7 days after the last dose of study drug. We developed 2 composite indexes that included subjective cognitive measures selected from the MADRS and SDQ.Results: The subanalysis of single measures and the 2 composite indexes derived from the MADRS and SDQ measures showed clinically meaningful and statistically significant improvements in cognitive function (P < .05).Conclusions: In a Phase 2a clinical trial, REL-1017 improved subjective measures of cognitive impairment, in addition to improving total MADRS and SDQ scores. These results need to be confirmed in larger and longer studies in MDD that include objective measures of cognitive function. Phase 3 studies of REL-1017 for MDD are currently underway.Clinical Trials Registration: ClinicalTrials.gov identifier: NCT03051256.
Subject(s)
Depressive Disorder, Major , Humans , Depressive Disorder, Major/drug therapy , Antidepressive Agents/therapeutic use , Treatment Outcome , Depression , Cognition , Double-Blind MethodABSTRACT
This article presents a mechanism of action hypothesis to explain the rapid antidepressant effects of esmethadone (REL-1017) and other uncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonists and presents a corresponding mechanism of disease hypothesis for major depressive disorder (MDD). Esmethadone and other uncompetitive NMDAR antagonists may restore physiological neural plasticity in animal models of depressive-like behavior and in patients with MDD via preferential tonic block of pathologically hyperactive GluN2D subtypes. Tonic Ca2+ currents via GluN2D subtypes regulate the homeostatic availability of synaptic proteins. MDD and depressive behaviors may be determined by reduced homeostatic availability of synaptic proteins, due to upregulated tonic Ca2+ currents through GluN2D subtypes. The preferential activity of low-potency NMDAR antagonists for GluN2D subtypes may explain their rapid antidepressant effects in the absence of dissociative side effects.
Subject(s)
Depressive Disorder, Major , Animals , Depressive Disorder, Major/drug therapy , Receptors, N-Methyl-D-Aspartate/metabolism , Antidepressive Agents/pharmacology , Antidepressive Agents/therapeutic use , Neuronal Plasticity , Cell CommunicationABSTRACT
Objective: The purpose of this study was to examine the effects of REL-1017 (esmethadone), a novel N-methyl-d-aspartate receptor (NMDAR) channel blocker, in patients with major depressive disorder who failed to benefit from one to three standard antidepressant treatments in their current major depressive episode. Methods: A 7-day phase 2 multicenter randomized double-blind placebo-controlled trial, comprising three arms, was conducted to assess the safety, tolerability, pharmacokinetics, and efficacy of two dosages of REL-1017 (25 mg or 50 mg orally once a day). Patients were randomly assigned in a 1:1:1 ratio to placebo (N=22), REL-1017 25 mg/day (N=19), or REL-1017 50 mg/day (N=21). Safety scales included the 4-item Positive Symptom Rating Scale for psychotomimetic symptoms, the Clinician-Administered Dissociative States Scale for dissociative symptoms, the Clinical Opiate Withdrawal Scale for withdrawal signs and symptoms, and the Columbia-Suicide Severity Rating Scale for suicidality. The primary efficacy endpoint was the Montgomery-Åsberg Depression Scale (MADRS) score. All 62 randomly assigned patients were included in the full analysis set population analysis. Results: Patients experienced mild or moderate transient adverse events and no evidence of dissociative or psychotomimetic effects, opioid effects, or withdrawal signs and symptoms. The improvement in MADRS score shown on day 4 in both of the REL-1017 dosage groups was sustained through day 7 (last dose) and day 14 (7 days after the last dose), with effect sizes from 0.7 to 1.0. Conclusions: This trial showed favorable safety, tolerability, and pharmacokinetic profiles and suggests that REL-1017 may have rapid and sustained antidepressant effects compared with placebo in patients with inadequate responses to antidepressant treatments. These results will need confirmation in larger and longer trials.