Actively Recruiting
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
138 weeks
Total Duration
On this page
AI-Summary
What this Trial Is About
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
Official 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 the consent quiz
- Willingness to comply with all study procedures and be available for the study duration
- Age between 18 and 70 years
- Completion of a screening assessment under protocol 01-M-0254
- Diagnosis of major depressive disorder (single episode or recurrent without psychotic features) with current episode lasting at least two weeks
- Initial Montgomery-Asberg Depression Rating Scale score of 20 or higher and Young Mania Rating Scale score below 12 within one week of study entry
- Ability and willingness to receive intravenous medication and follow the (2R,6R)-HNK treatment plan
- History of non-response to at least one adequate antidepressant treatment during current episode
- Use of highly effective contraception for individuals of reproductive potential during and four weeks after study Phase II
- Use of condoms or other effective contraception methods for males with reproductive potential during and 90 days after Phase II
- Agreement to follow lifestyle considerations during the study
- Medically healthy or with stable, treated chronic medical conditions
You will not qualify if you...
- Use of disallowed medications or transcranial magnetic stimulation within two weeks before Phase II
- Treatment with reversible monoamine oxidase inhibitors within four weeks before Phase II
- Treatment with fluoxetine, aripiprazole, or brexpiprazole within five weeks before Phase II
- Treatment with clozapine or electroconvulsive therapy within four weeks before Phase II
- Ongoing treatment with moderate or strong CYP3A4/5 inhibitors or inducers
- History of deep brain stimulation
- Previous non-response to ketamine or esketamine treatments
- Current psychotherapy during the study or inability to stop psychotherapy
- Pregnancy or breastfeeding
- Current psychotic symptoms or diagnosis of schizophrenia or other psychotic disorder
- Recent history (within three months) of substance or alcohol abuse or dependence except caffeine, nicotine, or cannabis; daily cannabis use or inability to abstain during study
- Diagnosis of borderline or antisocial personality disorder
- History of head injury causing loss of consciousness over five minutes (for imaging)
- Serious or unstable medical illnesses affecting liver, heart, kidneys, endocrine, or nervous system
- Unstable thyroid conditions
- History of seizures without clear resolved cause
- Abnormal laboratory test results beyond specified limits
- Moderate to severe kidney impairment
- Current serious suicidal or homicidal risk
- Positive HIV test
- Contraindications to magnetic resonance spectroscopy such as metal implants or claustrophobia
- COVID-19 infection or suspected infection
- Inability to read and understand English as required for study assessments
AI-Screening
AI-Powered Screening
Complete this quick 3-step screening to check your eligibility
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
CONTACT
C
Carlos A Zarate, M.D.
CONTACT
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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