Clinical TrialTreatment-Resistant Depression (TRD)PlaceboPlaceboRecruiting

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

Randomized, double-blind, placebo-controlled crossover Phase II trial (n=50) testing IV (2R,6R)-HNK infusions (0.25→2.0 mg/kg, up to four infusions over 2 weeks) versus saline placebo in treatment-resistant MDD.

Target Enrollment
50 participants
Study Type
Phase II interventional
Design
Randomized, triple Blind

Detailed Description

This single-site, randomized, double-blind, placebo-controlled crossover study evaluates the antidepressant efficacy and safety of (2R,6R)-hydroxynorketamine (HNK) in adults with treatment-resistant major depressive disorder.

Participants receive four IV infusions over two weeks of HNK (starting 0.25 mg/kg with a target of 2.0 mg/kg, with escalation rules) in one treatment period and four matched saline placebo infusions in the other; periods are crossed over.

Primary outcome is change in MADRS total score at day 12; secondary outcomes include remission and response rates, suicidality measures (C-SSRS, SSI, MADRS item 10), mood/anxiety scales, cognitive tasks and neuroimaging/MRS markers of glutamate and MEG/fMRI measures.

Study Protocol

Preparation

sessions

Dosing

8 sessions

Integration

sessions

Study Arms & Interventions

HNK → Placebo

experimental

Participants receive double-blinded (2R,6R)-HNK infusions four times over two weeks during Test Session 1 and saline placebo infusions four times over two weeks during Test Session 2 (crossover). Starting dose 0.25 mg/kg with target 2.0 mg/kg; dose may be increased if response criteria not met.

Interventions

  • Compound0.25 - 2 mg/kg
    via IV• four infusions over 2 weeks• 4 doses total

    (2R,6R)-HNK intravenous infusions, starting 0.25 mg/kg with escalation up to 2.0 mg/kg per protocol; dose adjustments for tolerability.

  • Placebo
    via IV• four infusions over 2 weeks• 4 doses total

    Saline placebo infusions, double-blinded.

Placebo → HNK

experimental

Crossover opposite sequence: placebo infusions in Test Session 1 and (2R,6R)-HNK infusions in Test Session 2; identical dosing schedule and escalation rules.

Interventions

  • Placebo
    via IV• four infusions over 2 weeks• 4 doses total

    Saline placebo infusions, double-blinded.

  • Compound0.25 - 2 mg/kg
    via IV• four infusions over 2 weeks• 4 doses total

    (2R,6R)-HNK intravenous infusions, starting 0.25 mg/kg with escalation up to 2.0 mg/kg per protocol.

Participants

Ages
18 – 70
Sexes
Male & Female

Inclusion Criteria

  • 1. Ability to understand and willingness to sign informed consent (score ≥80% on consent quiz).
  • 2. Willingness to comply with study procedures and availability for study duration.
  • 3. 18 to 70 years of age.
  • 4. Undergone screening assessment under protocol 01-M-0254.
  • 5. DSM-IV or DSM-5 criteria for MDD, single episode or recurrent without psychotic features, confirmed by structured interview (SCID-P); current major depressive episode ≥2 weeks.
  • 6. Initial MADRS ≥20 and YMRS <12 within one week of study entry and upon entry into Phase II.
  • 7. Ability to take IV medication and willingness to adhere to (2R,6R)-HNK regimen.
  • 8. History of lack of response to at least one adequate antidepressant trial (may include same class), with at least one in current episode; non-response to adequate ECT or TMS counts as adequate trial.
  • 9. For individuals of reproductive potential: use of highly effective contraception during participation and for 4 weeks after Phase II.
  • 10. For males of reproductive potential: use of condoms or other effective contraception during participation and for 90 days after Phase II.
  • 11. Agreement to adhere to lifestyle considerations throughout study.
  • 12. Medically healthy or stable treated chronic medical conditions (provided medications are not excluded).

Exclusion Criteria

  • 1. Current use of disallowed concomitant medications or TMS within 2 weeks prior to Phase II.
  • 2. Treatment with reversible MAOI within 4 weeks prior to Phase II.
  • 3. Treatment with fluoxetine, aripiprazole, or brexpiprazole within 5 weeks prior to Phase II.
  • 4. Treatment with clozapine or ECT within 4 weeks prior to Phase II.
  • 5. Lifetime history of deep brain stimulation.
  • 6. Previous antidepressant non-response to ketamine or esketamine (full course).
  • 7. No structured psychotherapy permitted during study; inability or unwillingness to stop psychotherapy excludes participation.
  • 8. Pregnancy or lactation.
  • 9. Current psychotic features or diagnosis of schizophrenia or other psychotic disorder.
  • 10. DSM-IV substance or alcohol abuse/dependence or DSM-5 SUD (except caffeine, nicotine, cannabis) within preceding 3 months; recent illicit drug use; positive urine drug test (except prescribed benzodiazepines or stimulants) excludes participation.
  • 11. DSM-IV/DSM-5 Axis II borderline or antisocial personality disorder.
  • 12. History of head injury with loss of consciousness >5 minutes (for imaging component).
  • 13. Serious unstable medical illnesses (hepatic, cardiovascular, renal, endocrine, neurologic) that in PI judgment pose risk.
  • 14. Unstable clinical hyperthyroidism or hypothyroidism.
  • 15. History of seizures without clear/resolved etiology.
  • 16. Clinically significant abnormal labs (Alk Phos >150 U/L; ALT >55 U/L; AST >34 U/L; TB >1.2 mg/dL; DB >0.5 mg/dL; 25-hydroxyvitamin D <20 ng/mL; Folate <2 ng/mL; B12 <200 pg/mL).
  • 17. Current serious suicidal or homicidal risk as judged by PI.
  • 18. Positive HIV test.
  • 19. Contraindications to MRS (metal in body, claustrophobia, etc.).
  • 20. Current or suspected COVID-19.
  • 21. Current NIMH employee/staff or immediate family member.
  • 22. Inability to read and understand English.

Study Details

Locations

National Institutes of Health Clinical Center — Bethesda, Maryland, United States

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