Actively Recruiting
An Investigation of the Antidepressant Effects of (2R,6R)-HNK, an Enhancer of Synaptic Glutamate Release, in Treatment-Resistant Depression
Led by National Institute of Mental Health (NIMH) · Updated on 2026-04-16
50
Participants Needed
1
Research Sites
N/A
Total Duration
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AI-Summary
What this Trial Is About
This research aims to evaluate the antidepressant effects of (2R,6R)-hydroxynorketamine (HNK) in adults aged 18 to 70 years with major depressive disorder (MDD) who have not responded well to previous treatments. The study compares the impact of HNK to a placebo on depressive symptoms, including mood, anxiety, and suicidal thoughts, using various rating scales and brain imaging techniques. It is a randomized, double-blind, placebo-controlled, crossover study conducted by the National Institute of Mental Health (NIMH). Participants will first taper off their current depression medications over 2 to 5 weeks and remain off these drugs for up to 2 weeks before starting study treatments. They will receive intravenous infusions of HNK or placebo four times over two weeks during each of two test sessions, with overnight stays at the clinical center after each infusion or for the study duration. The dose of HNK may be adjusted between 0.25 mg/kg and 2.0 mg/kg based on response and tolerability. After the first set of infusions and a drug-free period, participants will receive the alternate treatment for the second test session. Throughout the study, participants will undergo physical exams, blood tests, heart monitoring, mood and cognitive assessments, and symptom questionnaires. Optional brain imaging and activity scans may be performed. Researchers will track changes in depression severity using the Montgomery-Asberg Depression Rating Scale (MADRS) and other mood and anxiety measures. Safety and side effects will be carefully monitored through clinical evaluations, laboratory tests, and vital sign checks. The study is expected to continue until July 2027.
CONDITIONS
Brief Title
Investigation of the Antidepressant Effects of (2R,6R)-HNK, an Enhancer of Synaptic Glutamate Release, in Treatment-Resistant Depression
Who Can Participate
Eligibility Criteria
You may qualify if you...
- Ability to understand and sign informed consent, scoring at least 80% on a consent quiz
- Willingness to comply with all study procedures and be available for the study duration
- Age between 18 and 70 years
- Completion of screening assessment under protocol 01-M-0254
- Diagnosis of major depressive disorder (single or recurrent episode) without psychotic features, currently experiencing a major depressive episode lasting at least two weeks
- Initial score of 20 or higher on the Montgomery-Asberg Depression Rating Scale (MADRS) and less than 12 on the Young Mania Rating Scale (YMRS) within one week before study entry
- Ability and willingness to receive intravenous medication and follow the (2R,6R)-HNK regimen
- History of inadequate response to at least one antidepressant trial during the current episode
- For individuals of reproductive potential, agreement to use effective contraception during the study and for a specified period after
- Medically healthy or with stable, treated chronic conditions
You will not qualify if you...
- Use of disallowed medications or transcranial magnetic stimulation (TMS) within two weeks before study start
- Use of reversible MAO inhibitors within four weeks before study start
- Use of fluoxetine, aripiprazole, or brexpiprazole within five weeks before study start
- Use of clozapine or electroconvulsive therapy (ECT) within four weeks before study start
- Ongoing treatment with moderate or strong CYP3A4/5 inhibitors or inducers
- History of deep brain stimulation
- Previous lack of response to ketamine or esketamine treatment
- Ongoing psychotherapy during the study
- Pregnancy or breastfeeding
- Current psychotic features or diagnosis of schizophrenia or other psychotic disorders
- Recent substance or alcohol use disorders, except for caffeine, nicotine, or cannabis under strict conditions
- Diagnosis of borderline or antisocial personality disorder
- History of significant head injury with prolonged unconsciousness
- Serious or unstable medical illnesses affecting liver, heart, kidney, endocrine, or neurological function
- Unstable thyroid conditions
- Seizure history without clear resolution
- Abnormal laboratory test results beyond specified limits
- Moderate to severe kidney impairment
- High suicide or homicide risk
- Positive HIV test
- Contraindications to magnetic resonance spectroscopy (MRS) imaging
- COVID-19 or suspected infection
- Inability to read and understand English
AI-Screening
AI-Powered Screening
Complete this quick 3-step screening to check your eligibility
Your Study Journey
Duration - 2 to 4 weeks
Participants are screened for eligibility to participate in the trial.
1 screening and enrollment visit
Duration - Two weeks per treatment session
Participants receive double-blinded infusions of either (2R,6R)-hydroxynorketamine or placebo four times over two weeks during each test session in a crossover design. Dose adjustments may occur based on response and tolerability.
Four infusion visits per treatment session over two weeks
Duration - Up to 12 days per treatment session
Participants are assessed for antidepressant efficacy, safety, and various symptom evaluations at multiple time points during and after each treatment session.
Multiple assessment visits on days 0 (230 min post-infusion), 1, 2, 3, 4, 7, 8, 10, 11, and 12 per treatment session
Trial Site Locations
Total: 1 location
1
National Institutes of Health Clinical Center
Bethesda, Maryland, United States, 20892
Actively Recruiting
Research Team
S
Solaleh Azimipour
C
Carlos A Zarate, M.D.
How is the study designed?
Study Type
INTERVENTIONAL
Masking
TRIPLE
Allocation
RANDOMIZED
Model
CROSSOVER
Primary Purpose
TREATMENT
Number of Arms
2
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