Trials / Recruiting

RecruitingNCT06511908

Investigation of the Antidepressant Effects of (2R,6R)-HNK, an Enhancer of Synaptic Glutamate Release, in Treatment-Resistant Depression

An Investigation of the Antidepressant Effects of (2R,6R)-HNK, an Enhancer of Synaptic Glutamate Release, in Treatment-Resistant Depression

Status: Recruiting
Phase: Phase 2
Study type: Interventional
Enrollment: 50 (estimated)

Sponsor: National Institute of Mental Health (NIMH) · NIH
Sex: All
Age: 18 Years – 70 Years
Healthy volunteers: Not accepted

Summary

Background: Major depressive disorder (MDD) is a serious mental illness that can put people at risk of self-harm and death. Many drugs are used to treat MDD, but it can take a long time for them to be effective. Researchers want to know if a faster-acting drug, (2R,6R)-hydroxynorketamine (HNK), can better treat the symptoms of MDD. Objective: To test a study drug (HNK) in people with MDD. Eligibility: People aged 18 to 70 years with MDD. They must have had a screening assessment under protocol 01-M-0254. Design: Participants will be tapered off their current MDD drugs over 2 to 5 weeks. They will stay off of the drugs for up to 2 weeks prior to starting the study medication and procedures. They will have a physical exam with blood tests. They will have tests of their heart function, mood, and thinking. They will answer questions about their symptoms. They may choose to have imaging scans and scans of their brain activity. HNK is given through a tube attached to a needle inserted into a vein. Participants will receive infusions on this schedule: They will receive 4 infusions over 2 weeks. They will stay in the clinical center overnight after each infusion or for the duration of the study. They will receive no drugs for 2 to 3 weeks. They will have 4 more infusions over 2 weeks, with overnight stays after each or for the duration of the study. One set of 4 infusions will be the HNK. The other set of 4 infusions will be a placebo. A placebo looks just like the real drug but contains no medicine. Participants will not know when they are getting the HNK or placebo. ...

Detailed description

Study Description This is a randomized, double-blind, placebo-controlled, crossover, single-site study. This experimental study will assess the efficacy and safety of two weeks of 0.25 to 2.0 mg/kg (2R,6R)-hydroxynorketamine (HNK), an enhancer of synaptic glutamate release. The study may be conducted on an inpatient or outpatient basis. Objectives Primary Objective The primary objective is to evaluate the ability of (2R,6R)-HNK, an enhancer of synaptic glutamate release, to improve overall depressive symptomatology in participants with major depressive disorder (MDD). The efficacy of a two-week course of (2R,6R)-HNK will be compared to two weeks of saline placebo in a crossover study. Montgomery-Asberg Depression Rating Scale (MADRS) score will serve as the main outcome measure. Secondary Objectives 1. To evaluate the antidepressant efficacy of (2R,6R)-HNK at days 0 (230 min), 1, 2, 3, 4, 7, 8, 10, 11, and 12 compared to placebo in a crossover study, as assessed by change from baseline on MADRS total scores. 2. To determine whether (2R,6R)-HNK demonstrates superior antidepressant efficacy compared to placebo in a crossover study, as assessed by the proportion of participants in remission (defined as MADRS total score \<=10). 3. To determine whether antidepressant response to (2R,6R)-HNK is superior to response to placebo in a crossover study, as assessed by the proportion of participants achieving response (defined as a \>=50% reduction from baseline in MADRS total score). 4. To evaluate the antisuicidal ideation effects of (2R,6R)-HNK at days 0 (230 min), 1, 2, 3, 4, 7, 8, 10, 11, and 12 compared to placebo in a crossover study, as assessed by change from baseline on item 10 (suicidality) of the MADRS, the Columbia Suicide Severity Rating Scale (C-SSRS), and the Scale for Suicide Ideation (SSI). 5. To investigate the effects of (2R,6R)-HNK on mood, anxiety, and anhedonia symptoms at days 0 (230 min), 1, 2, 3, 4, 7, 8, 10, 11, and 12 compared to placebo in a crossover study, as assessed by change from baseline on the Beck Depression Inventory Second Edition (BDI-II), Hamilton Depression Rating Scale (HDRS), Hamilton Anxiety Rating Scale (HAM-A), Positive and Negative Affect Schedule (PANAS), Snaith-Hamilton Pleasure Scale (SHAPS), and the Temporal Experience of Pleasure Scale (TEPS), as well as change from baseline on various cognitive tasks (Auditory, Somatosensory, and Visual Evoked Fields Task, Monetary Incentive Delay (MID) task, Hariri Hamer task, and Probabilistic Reward Task (PRT)). 6. To assess the safety and tolerability of a two-week course of (2R,6R)-HNK compared to placebo in a crossover study by incidence of adverse events (AEs) and total scores on the Clinician Administered Dissociative States Scale (CADSS), Young Mania Rating Scale (YMRS), Brief Psychiatric Rating Scale (BPRS), vital signs, changes in clinical laboratory evaluations, and electrocardiograms (ECGs). 7. To assess the analgesic efficacy of (2R,6R)-HNK compared to placebo on days -1, 1, 4, 8, and 11, as assessed by pain measures during quantitative sensory testing and brain-based biomarkers for pain measured with fMRI on day 4 and day 11. Endpoints Endpoints Primary Endpoint Effect of drug on the MADRS total score at day 12. Secondary Endpoints * Proportion of subjects in remission (defined as MADRS total score \<=10) at days 0 (230 min), 1, 2, 3, 4, 7, 8, 10, 11, and 12. * Proportion of subjects with response (defined as \>=50% reduction from baseline in MADRS total score) at days 0 (230 min), 1, 2, 3, 4, 7, 8, 10, 11, and 12. * Effect of drug on MADRS total scores at days 0 (230 min), 1, 2, 3, 4, 7, 8, 10, 11, and 12. * Effect of drug on HDRS, BDI-II, BPRS, CADSS, C-SSRS, HAM-A, PANAS, SHAPS, SSI, TEPS, and YMRS total scores, and the MADRS item 10 (suicidality) at days 0 (230 min), 1, 2, 3, 4, 7, 8, 10, 11 and 12. * Effect of drug on the Auditory, Somatosensory, and Visual Evoked Fields Task, MID task, Hariri Hamer task, and PRT. * Incidence and nature of adverse events; vital signs; weight and body mass index (BMI) changes; physical examination changes; clinical laboratory evaluations; ECG. * Effect of drug on acute pain measures derived from Quantitative Sensory Testing (QST) at days -1, 1, 4, 8, and 11. Surrogate Markers of Drug Effect, Target Engagement, and Antidepressant Response * Change in magnetoencephalography (MEG) spectral power (gamma power). * Change in brain glutamate levels using magnetic resonance spectroscopy (MRS). * Change in resting and task-based functional connectivity in functional magnetic resonance imaging (fMRI). * Change in peripheral biomarkers. * Change in brain-based biomarkers for pain.

Conditions

Interventions

Type	Name	Description
DRUG	(2R,6R)-hydroxynorketamine (0.25 to 2.0 mg/kg)	Arm 1 and 2 Experimental Intervention
DRUG	Placebo	Arm 1 and 2 Control Intervention

Timeline

Start date: 2024-11-06
Primary completion: 2027-07-01
Completion: 2027-07-01
First posted: 2024-07-22
Last updated: 2026-04-16

Locations

1 site across 1 country: United States

Regulatory

FDA-regulated drug study

Source: ClinicalTrials.gov record NCT06511908. Inclusion in this directory is not an endorsement.