Investigation of the Antidepressant Effects of (2R,6R)-HNK, an Enhancer of Synaptic Glutamate Release, in Treatment-Resistant Depression
- Conditions
- SuicideDepressive Disorder, Treatment-ResistantMolecular Mechanisms of Pharmacological ActionNeurotransmitter AgentsExcitatory Amino Acid AgentsKetaminePhysiological Effects of DrugsDepressive Disorder, MajorMental DisordersMood Disorders
- Interventions
- Drug: (2R,6R)-hydroxynorketamine (0.25 to 2.0 mg/kg)Drug: Placebo
- Registration Number
- NCT06511908
- Lead Sponsor
- National Institute of Mental Health (NIMH)
- Brief 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.
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- 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).
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.
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.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 50
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- CROSSOVER
- Arm && Interventions
Group Intervention Description 1 (2R,6R)-hydroxynorketamine (0.25 to 2.0 mg/kg) Individuals in Arm 1 will receive double-blinded (2R,6R)-HNK infusions four times over two weeks during Test Session 1 and daily double-blinded placebo infusions four times over two weeks during Test Session 2. The starting dose will be 0.25 mg/kg and the treatment target for all participants will be 2.0 mg/kg. If response criteria is not met by the morning of the next infusion, the dose may be increased. Doses will be decreased if tolerability issues arise. 1 Placebo Individuals in Arm 1 will receive double-blinded (2R,6R)-HNK infusions four times over two weeks during Test Session 1 and daily double-blinded placebo infusions four times over two weeks during Test Session 2. The starting dose will be 0.25 mg/kg and the treatment target for all participants will be 2.0 mg/kg. If response criteria is not met by the morning of the next infusion, the dose may be increased. Doses will be decreased if tolerability issues arise. 2 (2R,6R)-hydroxynorketamine (0.25 to 2.0 mg/kg) Individuals in Arm 2 will receive double-blinded placebo infusions four times over two weeks during Test Session 2 and double-blinded (2R,6R)-HNK infusions four times over two weeks during Test Session 1. The starting dose will be 0.25 mg/kg and the treatment target for all participants will be 2.0 mg/kg. If response criteria is not met by the morning of the next infusion, the dose may be increased. Doses will be decreased if tolerability issues arise. 2 Placebo Individuals in Arm 2 will receive double-blinded placebo infusions four times over two weeks during Test Session 2 and double-blinded (2R,6R)-HNK infusions four times over two weeks during Test Session 1. The starting dose will be 0.25 mg/kg and the treatment target for all participants will be 2.0 mg/kg. If response criteria is not met by the morning of the next infusion, the dose may be increased. Doses will be decreased if tolerability issues arise.
- Primary Outcome Measures
Name Time Method Change from baseline on Montgomery-Asberg Depression Rating Scale total scores Baseline, Day 12 Clinical rating scale of depression
- Secondary Outcome Measures
Name Time Method Proportion of participants in remission (defined as Montgomery-Asberg Depression Rating Scale total score =10) Baseline, 230 min post-drug, and Days 1, 2, 3, 4, 7, 8, 10, 11, and 12, per Test Session. Clinical rating scale of depression
Change from baseline on item 10 (suicidality) of the Montgomery-Asberg Depression Rating Scale and total score on the Columbia Suicide Severity Rating Scale and the Scale for Suicide Ideation. Baseline, 230 min post-drug, and Days 1, 2, 3, 4, 7, 8, 10, 11, and 12, per Test Session. Clinical rating scales of depression and suicidality
Change from baseline on the Hamilton Depression Rating Scale, Hamilton Anxiety Rating Scale, Positive and Negative Affect Schedule, Snaith-Hamilton Pleasure Scale, Temporal Experience of Pleasure Scale, and cognitive tasks. Baseline, 230 min post-drug, and Days 1, 2, 3, 4, 7, 8, 10, 11, and 12, per Test Session. Clinical rating scales of mood, anxiety, and anhedonia
Incidence of AEs and total scores using the Clinician Administered Dissociative States Scale, Young Mania Rating Scale, Brief Psychiatric Rating Scale, vital signs, changes in clinical laboratory evaluations, and electrocardiograms. Baseline, 230 min post-drug, and Days 1, 2, 3, 4, 7, 8, 10, 11, and 12, per Test Session. Measures and evaluations assess various aspects of clinical condition, adverse events, and mood and anxiety symptomology
Change from baseline on Montgomery-Asberg Depression Rating Scale total scores Baseline, 230 min post-drug, and Days 1, 2, 3, 4, 7, 8, 10, 11, and 12, per Test Session. Clinical rating scale of depression
Proportion of participants achieving response (defined as a >/=50% reduction from baseline in Montgomery-Asberg Depression Rating Scale total score) Baseline, 230 min post-drug, and Days 1, 2, 3, 4, 7, 8, 10, 11, and 12, per Test Session. Clinical rating scale of depression
Trial Locations
- Locations (1)
National Institutes of Health Clinical Center
🇺🇸Bethesda, Maryland, United States