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

NCT06511908 | Recruiting Phase 2 FDA Drug

• 2 other identifiers: 10001602001602-M
• Study Type: interventional
• Target: 50
• Locations: 1 country
• Sites: 1

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. ...

Conditions

Excitatory Amino Acid Agents; Depressive Disorder, Major; Depressive Disorder; Depression; Mental Disorders; Mood Disorders; Behavioral Symptoms; Suicide; Ketamine; Neurotransmitter Agents; Depressive Disorder, Treatment-Resistant; Molecular Mechanisms of Pharmacological Action; Physiological Effects of Drugs

Keywords

Major Depressive Disorder; Ketamine; Biomarkers; Neuropharmacology; Magnetic Resonance Imaging; Magnetoencephalography; Neurobiology; Glutamate; Hydroxynorketamine

Outcome Measures

Primary Outcomes (1)

• Change from baseline on Montgomery-Asberg Depression Rating Scale total scores

  Clinical rating scale of depression

  Baseline, Day 12

Secondary Outcomes (8)

• 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.

• 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.

• 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.

• 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.

• 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.

Study Arms (2)

1

EXPERIMENTAL

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.

Drug: (2R,6R)-hydroxynorketamine (0.25 to 2.0 mg/kg); Drug: Placebo

2

EXPERIMENTAL

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.

Drug: (2R,6R)-hydroxynorketamine (0.25 to 2.0 mg/kg); Drug: Placebo

Interventions

(2R,6R)-hydroxynorketamine (0.25 to 2.0 mg/kg) DRUG

Arm 1 and 2 Experimental Intervention

1; 2

Placebo DRUG

Arm 1 and 2 Control Intervention

1; 2

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• In order to be eligible to participate in this study, an individual must meet all of the following criteria:
• Ability of participant to understand and willingness to sign a written informed consent document. To verify this, participants must score \>= 80% on the consent quiz.
• Stated willingness to comply with all study procedures and availability for the duration of the study.
• to 70 years of age.
• All participants must have undergone a screening assessment under protocol 01-M-0254.
• Participants must fulfill DSM-IV or DSM-5 criteria for MDD, single episode or recurrent without psychotic features, based on clinical assessment and confirmed by a structured diagnostic interview (SCID-P). Participants must be experiencing a current major depressive episode lasting at least two weeks.
• Participants must have an initial score of \>= 20 on the MADRS and a YMRS score of \<12 within one week of study entry and upon entry into Phase II.
• Ability to take intravenous medication and be willing to adhere to the (2R,6R)-HNK regimen.
• Participants must have a current or past history of lack of response to at least one adequate antidepressant trial (may be from the same chemical class), with at least one in the current major depressive episode, operationally defined using the modified Antidepressant Treatment History Form (ATHF); non-response to an adequate trial of ECT or TMS would count as an adequate antidepressant trial.
• For individuals of reproductive potential: use of highly effective contraception starting at the time of enrollment and agreement to use such a method during study participation and for an additional four weeks after the end of Study Phase II.
• For males of reproductive potential: use of condoms or other methods from the time of enrollment to ensure effective contraception with partner, and for an additional 90 days after the end of Phase II.
• Agreement to adhere to Lifestyle Considerations throughout study duration.
• Medically healthy, or with stable, treated, chronic medical conditions (provided any medications are not excluded)

You may not qualify if:

• An individual who meets any of the following criteria will be excluded from participation in this study:
• Current use of disallowed concomitant medications or transcranial magnetic stimulation (TMS) two weeks prior to the start of Phase II.
• Treatment with a reversible monoamine oxidase inhibitor (MAOI) four weeks prior to the start of Phase II.
• Treatment with fluoxetine, aripiprazole, or brexpiprazole five weeks prior to the start of Phase II.
• Treatment with clozapine or electroconvulsive therapy (ECT) four weeks prior to the start of Phase II.
• Ongoing treatment with moderate or strong CYP3A4/5 inhibitors or inducers
• Lifetime history of deep brain stimulation.
• Previous antidepressant non-response to ketamine or esketamine (full course).
• No structured psychotherapy will be permitted during the total duration of the study. Participants unable or unwilling to stop psychotherapy will be unable to participate in the study.
• Pregnancy or lactation.
• Current psychotic features or a diagnosis of schizophrenia or any other psychotic disorder as defined in the DSM-IV or DSM-5.
• Participants with a DSM-IV or DSM-5 Axis II diagnosis of borderline or antisocial personality disorder.
• Participants with a history of head injury that resulted in loss of consciousness exceeding five minutes (for the imaging component of the study).
• No serious, unstable medical illnesses including but not limited to the following body systems and organs or those that in the judgment of the Principal Investigator pose a risk to the participant's ability to safely participate in the study: Hepatic diseases (e.g. active viral hepatitis infection or cirrhosis of the liver, any liver disease with Child-Pugh score \>=5), cardiovascular disease (including ischemic heart disease, coronary artery disease, congestive heart failure, poorly controlled hypertension due to risk of further blood pressure elevation and increase in demand on cardiac function from study drug), renal/urologic (e.g chronic kidney disease or acute kidney injury, history of bladder dysfunction due to theoretical risk of ketamine-induced cystitis, moderate to severe renal impairment of any etiology), endocrinologic (including uncontrolled diabetes due to association with progressive abnormality of the microvasculature and nervous system), or neurologic disease (e.g. elevated intraocular pressure or history of or presence of diseases that are associated with elevated intracranial pressure).
• Participants with unstable clinical hyperthyroidism or hypothyroidism.

Sponsors & Collaborators

• National Institute of Mental Health (NIMH): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

RECRUITING

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Suicide; Depressive Disorder, Treatment-Resistant; Depressive Disorder, Major; Depressive Disorder; Depression; Mental Disorders; Mood Disorders; Behavioral Symptoms

Interventions

6-hydroxynorketamine

Condition Hierarchy (Ancestors)

Self-Injurious Behavior; Behavior

Study Officials

• Carlos A Zarate, M.D.

  National Institute of Mental Health (NIMH)

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Solaleh Azimipour

CONTACT

(877) 646-3644; solaleh.azimipour@nih.gov

Carlos A Zarate, M.D.

CONTACT

(301) 326-5836; zaratec@mail.nih.gov

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 19, 2024
• First Posted: July 22, 2024
• Study Start: November 6, 2024
• Primary Completion (Estimated): July 1, 2027
• Study Completion (Estimated): July 1, 2027
• Last Updated: April 16, 2026

Record last verified: 2026-04-13

Data Sharing

• IPD Sharing: Will share
• Shared Documents: SAP
• Time Frame: Starting within 1 year of completion of the study.
• Access Criteria: Branch Chief will review requests and access will need to be approved by the NIMH/DIRP SD and OCD NIMH and the NIH IRB.

Locations

US (1)