RECRUITING

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

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Study Overview

This clinical trial focuses on testing the efficacy of different digital interventions to promote re-engagement in cancer-related long-term follow-up care for adolescent and young adult (AYA) survivors of childhood cancer.

Description

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. ...

Official Title

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

Quick Facts

Study Start:2024-11-06

Study Completion:2027-07-01

Study Type:Not specified

Phase:Not Applicable

Enrollment:Not specified

Status:RECRUITING

Study ID

NCT06511908

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Ages Eligible for Study:18 Years to 70 Years

Sexes Eligible for Study:ALL

Accepts Healthy Volunteers:No

Standard Ages:ADULT, OLDER_ADULT

Inclusion Criteria	Exclusion Criteria
1. 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. 2. Stated willingness to comply with all study procedures and availability for the duration of the study. 3. 18 to 70 years of age. 4. All participants must have undergone a screening assessment under protocol 01-M-0254. 5. 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. 6. 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. 7. Ability to take intravenous medication and be willing to adhere to the (2R,6R)-HNK regimen. 8. 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) (152); non-response to an adequate trial of ECT or TMS would count as an adequate antidepressant trial. 9. 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. 10. 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. 11. Agreement to adhere to Lifestyle Considerations throughout study duration. 12. Medically healthy, or with stable, treated, chronic medical conditions (provided any medications are not excluded)	1. Current use of disallowed concomitant medications or transcranial magnetic stimulation (TMS) two weeks prior to the start of Phase II. 2. Treatment with a reversible monoamine oxidase inhibitor (MAOI) four weeks prior to the start of Phase II. 3. Treatment with fluoxetine, aripiprazole, or brexpiprazole five weeks prior to the start of Phase II. 4. Treatment with clozapine or electroconvulsive therapy (ECT) four weeks prior to the start of Phase II. 5. Lifetime history of deep brain stimulation. 6. Previous antidepressant non-response to ketamine or esketamine (full course). 7. 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. 8. Pregnancy or lactation. 9. Current psychotic features or a diagnosis of schizophrenia or any other psychotic disorder as defined in the DSM-IV or DSM-5. 10. Participants with a history of DSM-IV substance or alcohol abuse or dependence, or DSM-5 substance use disorder (except for caffeine, nicotine, or cannabis), or moderate to severe alcohol use disorder, within the preceding three months. In addition, participants who are currently using drugs (except for caffeine, nicotine, or cannabis) must not have used illicit substances or known drugs of abuse in the two weeks prior to screen and must have a negative drug urine test (except for prescribed benzodiazepines or stimulants) prior to starting Phase II. Cannabis use is exclusionary if the use is daily, or if participants are unable to abstain during the study, or if function of daily life is impaired by use as determined by a clinician. Due to the interactions between cannabis and SSRIs, frequent cannabis use during previous antidepressant treatment will result in that treatment being considered a failed trial for eligibility purposes. 11. Participants with a DSM-IV or DSM-5 Axis II diagnosis of borderline or antisocial personality disorder. 12. Participants with a history of head injury that resulted in loss of consciousness exceeding five minutes (for the imaging component of the study). 13. 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), 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), 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). 14. Participants with unstable clinical hyperthyroidism or hypothyroidism. 15. Participants with one or more seizures without a clear and resolved etiology. 16. Clinically significant abnormal laboratory tests specifically defined by: * Alkaline phosphatase (Alk Phos) \> 150 U/L * Alanine aminotransferase (ALT) \> 55 U/L * Aspartate aminotransferase (AST) \> 34 U/L * Total bilirubin (TB) \> 1.2 mg/dL * Direct bilirubin (DB) \> 0.5 mg/dL * 25-hydroxyvitamin D \< 20 ng/mL * Folate \< 2ng/mL * Vitamin B12 \< 200 pg/mL 17. Participants who, in the Principal Investigator s judgment, pose a current serious suicidal or homicidal risk. 18. Positive HIV test. 19. Contraindications to MRS (metal in body, claustrophobia, etc. for imaging) 20. Weight \>119 kg. 21. Participants with COVID-19 or suspected COVID-19 22. A current NIMH employee/staff or their immediate family member. 23. Inability to read and understand English. Non- English speakers will not be eligible as most of the required monitoring and rating instruments are not validated in languages other than English.

Inclusion Criteria

Exclusion Criteria

1. 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.
2. Stated willingness to comply with all study procedures and availability for the duration of the study.
3. 18 to 70 years of age.
4. All participants must have undergone a screening assessment under protocol 01-M-0254.
5. 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.
6. 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.
7. Ability to take intravenous medication and be willing to adhere to the (2R,6R)-HNK regimen.
8. 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) (152); non-response to an adequate trial of ECT or TMS would count as an adequate antidepressant trial.
9. 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.
10. 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.
11. Agreement to adhere to Lifestyle Considerations throughout study duration.
12. Medically healthy, or with stable, treated, chronic medical conditions (provided any medications are not excluded)

1. Current use of disallowed concomitant medications or transcranial magnetic stimulation (TMS) two weeks prior to the start of Phase II.
2. Treatment with a reversible monoamine oxidase inhibitor (MAOI) four weeks prior to the start of Phase II.
3. Treatment with fluoxetine, aripiprazole, or brexpiprazole five weeks prior to the start of Phase II.
4. Treatment with clozapine or electroconvulsive therapy (ECT) four weeks prior to the start of Phase II.
5. Lifetime history of deep brain stimulation.
6. Previous antidepressant non-response to ketamine or esketamine (full course).
7. 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.
8. Pregnancy or lactation.
9. Current psychotic features or a diagnosis of schizophrenia or any other psychotic disorder as defined in the DSM-IV or DSM-5.
10. Participants with a history of DSM-IV substance or alcohol abuse or dependence, or DSM-5 substance use disorder (except for caffeine, nicotine, or cannabis), or moderate to severe alcohol use disorder, within the preceding three months. In addition, participants who are currently using drugs (except for caffeine, nicotine, or cannabis) must not have used illicit substances or known drugs of abuse in the two weeks prior to screen and must have a negative drug urine test (except for prescribed benzodiazepines or stimulants) prior to starting Phase II. Cannabis use is exclusionary if the use is daily, or if participants are unable to abstain during the study, or if function of daily life is impaired by use as determined by a clinician. Due to the interactions between cannabis and SSRIs, frequent cannabis use during previous antidepressant treatment will result in that treatment being considered a failed trial for eligibility purposes.
11. Participants with a DSM-IV or DSM-5 Axis II diagnosis of borderline or antisocial personality disorder.
12. Participants with a history of head injury that resulted in loss of consciousness exceeding five minutes (for the imaging component of the study).
13. 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), 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), 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).
14. Participants with unstable clinical hyperthyroidism or hypothyroidism.
15. Participants with one or more seizures without a clear and resolved etiology.
16. Clinically significant abnormal laboratory tests specifically defined by:
* Alkaline phosphatase (Alk Phos) \> 150 U/L
* Alanine aminotransferase (ALT) \> 55 U/L
* Aspartate aminotransferase (AST) \> 34 U/L
* Total bilirubin (TB) \> 1.2 mg/dL
* Direct bilirubin (DB) \> 0.5 mg/dL
* 25-hydroxyvitamin D \< 20 ng/mL
* Folate \< 2ng/mL
* Vitamin B12 \< 200 pg/mL
17. Participants who, in the Principal Investigator s judgment, pose a current serious suicidal or homicidal risk.
18. Positive HIV test.
19. Contraindications to MRS (metal in body, claustrophobia, etc. for imaging)
20. Weight \>119 kg.
21. Participants with COVID-19 or suspected COVID-19
22. A current NIMH employee/staff or their immediate family member.
23. Inability to read and understand English. Non- English speakers will not be eligible as most of the required monitoring and rating instruments are not validated in languages other than English.

Contacts and Locations

Study Contact

Ebtehal Al Shami

CONTACT

(301) 675-4450

ebtehal.alshami@nih.gov

Carlos A Zarate, M.D.

CONTACT

(301) 326-5836

zaratec@mail.nih.gov

Principal Investigator

Carlos A Zarate, M.D.

PRINCIPAL_INVESTIGATOR

National Institute of Mental Health (NIMH)

Study Locations (Sites)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892

United States

Collaborators and Investigators

Sponsor: National Institute of Mental Health (NIMH)

Carlos A Zarate, M.D., PRINCIPAL_INVESTIGATOR, National Institute of Mental Health (NIMH)

Study Record Dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates

Study Start Date2024-11-06

Study Completion Date2027-07-01

Study Record Updates