Investigation of the Antidepressant Effects of... — Clinical Trial Details

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.

Participants

Ages

18 – 70

Sexes

Male & Female

BMI

Psychosis History

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.

Company

Product

Legal

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

Detailed Description

Study Protocol

Preparation

Locations

Dosing

Integration

Study Arms & Interventions

HNK → Placebo

Interventions

Placebo → HNK

Interventions

Participants

Inclusion Criteria

Exclusion Criteria

Study Details

Study Team

Sponsors & Collaborators