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

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.