Major DepressionPhase 2NCT02484456
Antidepressant Effects of the Glycine Receptor Antagonist AV-101 (4-chlorokynurenine) in Major Depressive Disorder
A Phase 2 study testing AV 101 (4-Chlorokynurenine) in people with Major Depression, run by National Institute of Mental Health (NIMH) at 1 site in United States.
Trial summary
Background: Drugs and talk therapy help treat depression, but these treatments usually take quite a bit of time to work. Ketamine is a fast-acting antidepressant, but it has side effects like unusual dreams and experiences. The drug AV-101 may have the same antidepressant effects but fewer side effects. Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- Major Depression
- What is being tested?
- AV 101 (4-Chlorokynurenine)
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 22 participants
- Where
- 1 siteUnited States
- Study dates
- 14 Oct 2015to 3 Dec 2019
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 18 to 65 years of age.
- Subjects must have a level of understanding sufficient to agree to all required tests and examinations, sign an informed consent document and verify understanding. To verify this, subjects must score greater than or equal to 80% on the consent quiz.
- Subjects must fulfill Diagnostic and Statistical Manual (DSM)-IV or DSM-V criteria for MDD, single episode or recurrent without psychotic features, based on clinical assessment and confirmed by a structured diagnostic interview (SCID-P). Subjects must be experiencing a current major depressive episode of at least 4 weeks duration.
- Subjects must have an initial score of at least 18 on the HDRS at screening and at baseline of study phase I.
- Subjects must have a current or past history of lack of response to one adequate antidepressant trial (may be from the same chemical class) operationally defined using the modified-Antidepressant Treatment History Form (ATHF).
Who cannot join
- Current psychotic features or a diagnosis of schizophrenia or any other psychotic disorder as defined in the DSM-IV or DSM-V.
- Subjects with a history of DSM-IV drug or alcohol dependency or abuse (or alcohol use disorder per DSM-V),except for caffeine or nicotine dependence within the preceding 3 months.
- Head injury that results in loss of consciousness exceeding 5 minutes (for the imaging component of the study).
- Subjects with a DSM IV or DSM-V Axis II diagnosis of borderline or antisocial personality disorder.
- Pregnant or nursing women or women of child bearing potential not using at least 1 medically accepted means of contraception from the time of enrollment in the study until 1 month after completion of the second phase. Examples of medically accepted means of contraception include oral, injectable, or implant birth control, condom, diaphragm with spermicide, intrauterine devices (IUD), tubal ligation, abstinence or partner with vasectomy. .
- Serious, unstable illnesses including hepatic, renal, gastroenterologic, respiratory, cardiovascular (including ischemic heart disease), endocrinologic, neurologic, immunologic, or hematologic disease.
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- Subjects with clinical hyperthyroidism or hypothyroidism.
- Subjects with one or more seizures without a clear and resolved etiology.
- Clinically significant abnormal laboratory tests.
- Treatment with a reversible monoamine oxidase inhibitor (MAOI) within 4 weeks of study phase II.
- Treatment with fluoxetine or aripiprazole within 5 weeks of study phase II.
- Treatment with any other disallowed concomitant medication or TMS 14 days before randomization.
- Treatment with clozapine or electroconvulsive therapy (ECT) within 1 month of randomization.
- Lifetime history of deep brain stimulation.
- Subjects who, in the Principal Investigator's judgment, pose a current serious suicidal or homicidal risk.
- Positive HIV test
- Contraindications to MRS (metal in body, claustrophobia, etc for imaging)
- No structured psychotherapy will be permitted during the total duration of the study. Subjects unable or unwilling to stop psychotherapy will be unable to participate in the study.
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, 20892
About this study
Official title: An Investigation of the Antidepressant Effects of the Glycine Receptor Antagonist AV 101 (4-chlorokynurenine) in Major Depressive Disorder
Background:
- Drugs and talk therapy help treat depression, but these treatments usually take quite a bit of time to work. Ketamine is a fast-acting antidepressant, but it has side effects like unusual dreams and experiences. The drug AV-101 may have the same antidepressant effects but fewer side effects. Researchers want to see if it is effective and safe for people with major depressive disorder.
Read more
Objective:
- To see if the drug, AV-101 is safe and if it treats symptoms of major depressive disorder.
Eligibility:
- Adults ages 18-65 with major depression without psychotic features.
Design:
- Participants will be screened under a separate protocol.
- Participants will stay in the hospital for 12-14 weeks.
- Phase 1 (2-7 weeks): participants will stop taking their medicines then not take any for 2 weeks. They will have several scans and other procedures.
- Phase 2 (6-7 weeks): 2 weeks each of study drug and placebo once a day, with 2 weeks of no drugs in between.
- Participants will have:
- Physical exams
- Interviews
- Frequent blood collection. A needle will place a small plastic tube in the arm. Some blood samples will be taken through this tube.
- 2 spinal taps (optional). The back will be numbed. A needle will insert a catheter between back bones. That will be left in for up to 30 hours. Spinal fluid will be collected through it.
- 5 scans. Participants will lie in a machine with a magnetic field. The machine takes pictures of the brain and brain chemicals.
- At the end of the study, participants will have medical evaluation, questions, and blood tests. Some may continue treatment at the clinic.
Read the detailed description
Objective
Modulation of the NMDA receptor (NMDAR) complex or other components of glutamatergic signaling is likely involved in improvement of depressive symptoms and related constructs/dimensions of observable behavior and neurobiological measures. Current standard monoaminergic pharmacological approaches for major depressive disorder (MDD) have proven to be only modestly effective during acute depressive episodes. We have systematically tested different glutamatergic modulators in patients with mood disorders in order to develop improved therapeutics. We found that the NMDAR antagonist ketamine produces rapid antidepressant effects in patients with treatment-resistant depression (in MDD and Bipolar Disorder). However, despite being highly efficacious, the proof of concept ketamine produces psychotomimetic effects.
In the present protocol, we aim to evaluate a new glutamate-mediated mechanism associated with antidepressant efficacy by targeting the glycine receptor within the NMDA receptor. Targeting the glycine co-agonist site of the (NMDA) receptor may bypass potential adverse effects that occur with ketamine without affecting the robust efficacy observed. This may then result in the glutamate surge that has been associated with the rapid acting antidepressant effects of ketamine.
The present Phase 2 proof-of-concept study is designed to evaluate the antidepressant effects of AV 101 (L-4-chlorokynurenine or 4-Cl- KYN) in MDD; this is a synthetic compound which is enzymatically converted into the selective glycine/NMDAR antagonist 7-chlorokynurenine (7-Cl-KYNA) after crossing the blood brain barrier (BBB) and then reaching brain glial cells. In animal models of depression, 4-Cl-KYNA (AV 101) induced acute and prolonged antidepressant-like effects without exhibiting ketamine-like side effects as determined by the drug discrimination, conditioned place preference, and pre-pulse inhibition tests.
We will also evaluate the neurobiological mechanisms involved in the antidepressant response to AV 101. We expect that this effect may modulate glutamate transmission and reverse the clinical symptoms of depression. The demonstration that a glycine-antagonist produces antidepressant effects without psychotomimetic side effects would support the therapeutic relevance of the glycine site of the NMDAR and could direct the development of novel drug targets for the treatment of depression.
Study Population
Twenty-five individuals with treatment-resistant major depressive disorder (MDD) will be included.
Design
Male and female patients, ages 18 to 65 years, with a diagnosis of MDD, currently in an episode of major depression, will be recruited for this study. This study will consist of a randomized, double-blind crossover administration of either the glycine receptor antagonist AV 101 (1,080 or 1,440 mg/day given orally) or placebo for 2 weeks. The study will assess the efficacy in improving overall depressive symptomatology and tolerability of AV 101 in treatment-resistant MDD. Other aims of the study include: 1) determining whether changes in brain neurochemicals (e.g. glutamate) and peripheral biomarkers obtained via MRS and cerebrospinal fluid (CSF) correlate with antidepressant response (decrease in Hamilton Depression Rating Scale (HDRS) total scores) to AV 101 in patients with treatment-resistant MDD, and 2) examine other potential biomarkers of response.
Outcome Measures
Primary: Hamilton Rating Scale (HDRS) total score.
Secondary: Proportion of subjects achieving remission (HDRS less than or greater than 7) and response (greater than or equal to 50% reduction from baseline in HDRS total score); change from baseline in Hamilton Anxiety Rating Scale (HAM-A), Montgomery-Asberg Depression Rating Scale (MADRS), and the Columbia Suicide Severity Rating Scale (C-SSRS) total scores. Surrogate biomarkers of drug effect/response include: changes in prefrontal glutamate levels measured with 7T H-MRS.
- Conditions
- Major Depression
- Being tested
- AV 101 (4-Chlorokynurenine), Placebo Comparator
- Keywords
- Major Depression, Glycine Receptor Antagonist, 4-chlorokynurenine, Treatment Resistant, Glutamatergic System
- Medical subject headings
- Depressive Disorder, Major
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AV 101 (4-Chlorokynurenine)Drug
Also called 4-Cl-KYN
L-4-chlorokynurenine (4-Cl-KYN) was developed as a prodrug that is rapidly converted in vivo to its active metabolite 7-chlorokynurenic acid (7-Cl-KYNA), a well-characterized N-Methyl-D-aspartate receptor (NMDAR) antagonist at the glycine site.
Placebo ComparatorOther
Placebo
| Study group | Role | What they receive |
|---|---|---|
| AV 101 (4-chlorokynurenine), then Placebo | Experimental | After a two-week drug-free period, participants received daily oral dose of AV 101 (4-chlorokynurenine) monotherapy 1,080mg/day for seven days, then dose increased to AV 101 1,440mg/day for next seven days followed by a two-week washout period; then crossover to placebo phase with daily dose of placebo pill for two weeks. Receives: Drug: AV 101 (4-Chlorokynurenine); Other: Placebo Comparator |
| Placebo, then AV 101 (4-chlorokynurenine) | Experimental | After a two-week drug-free period, participants received daily dose of placebo pill for two weeks followed by two-week washout period; then crossover to AV 101 treatment phase with daily oral dose of AV 101 (4-chlorokynurenine) monotherapy 1,080mg/day for seven days, then dose increased to AV 101 1,440mg/day for next seven days. Receives: Drug: AV 101 (4-Chlorokynurenine); Other: Placebo Comparator |
What is being measured
The primary outcome is the main question the study is designed to answer.
Model Adjusted Means for Hamilton Depression Rating Score
The Hamilton Depression Rating scale is a 17-item global measure of depressive symptoms on a 5-point scale ranging from 0 = not present to 4 = severe (full score values = 0,1,2,3,4). Some items rated on a scale of 0-2 (0, 1, 2) with 0 = not present to 2 = more severe. Total scores are a sum of the individual items. The maximum total score being 52 on the 17-point scale, and the minimum score being 0.Total scores of 0-7 are considered as being normal, 8-16 suggest mild depression, 17-23 moderate depression and scores over 24 are indicative of severe depression.
Measured: Post Dose Day 0
Model Adjusted Means for Hamilton Depression Rating Score
The Hamilton Depression Rating scale is a 17-item global measure of depressive symptoms on a 5-point scale ranging from 0 = not present to 4 = severe (full score values = 0,1,2,3,4). Some items rated on a scale of 0-2 (0, 1, 2) with 0 = not present to 2 = more severe. Total scores are a sum of the individual items. The maximum total score being 52 on the 17-point scale, and the minimum score being 0.Total scores of 0-7 are considered as being normal, 8-16 suggest mild depression, 17-23 moderate depression and scores over 24 are indicative of severe depression.
Measured: Post Dose Day 1
Model Adjusted Means for Hamilton Depression Rating Score
The Hamilton Depression Rating scale is a 17-item global measure of depressive symptoms on a 5-point scale ranging from 0 = not present to 4 = severe (full score values = 0,1,2,3,4). Some items rated on a scale of 0-2 (0, 1, 2) with 0 = not present to 2 = more severe. Total scores are a sum of the individual items. The maximum total score being 52 on the 17-point scale, and the minimum score being 0.Total scores of 0-7 are considered as being normal, 8-16 suggest mild depression, 17-23 moderate depression and scores over 24 are indicative of severe depression.
Measured: Post Dose Day 2
Model Adjusted Means for Hamilton Depression Rating Score
The Hamilton Depression Rating scale is a 17-item global measure of depressive symptoms on a 5-point scale ranging from 0 = not present to 4 = severe (full score values = 0,1,2,3,4). Some items rated on a scale of 0-2 (0, 1, 2) with 0 = not present to 2 = more severe. Total scores are a sum of the individual items. The maximum total score being 52 on the 17-point scale, and the minimum score being 0.Total scores of 0-7 are considered as being normal, 8-16 suggest mild depression, 17-23 moderate depression and scores over 24 are indicative of severe depression.
Measured: Post Dose Day 3
Model Adjusted Means for Hamilton Depression Rating Score
The Hamilton Depression Rating scale is a 17-item global measure of depressive symptoms on a 5-point scale ranging from 0 = not present to 4 = severe (full score values = 0,1,2,3,4). Some items rated on a scale of 0-2 (0, 1, 2) with 0 = not present to 2 = more severe. Total scores are a sum of the individual items. The maximum total score being 52 on the 17-point scale, and the minimum score being 0.Total scores of 0-7 are considered as being normal, 8-16 suggest mild depression, 17-23 moderate depression and scores over 24 are indicative of severe depression.
Measured: Post Dose Day 7
Model Adjusted Means for Hamilton Depression Rating Score
The Hamilton Depression Rating scale is a 17-item global measure of depressive symptoms on a 5-point scale ranging from 0 = not present to 4 = severe (full score values = 0,1,2,3,4). Some items rated on a scale of 0-2 (0, 1, 2) with 0 = not present to 2 = more severe. Total scores are a sum of the individual items. The maximum total score being 52 on the 17-point scale, and the minimum score being 0.Total scores of 0-7 are considered as being normal, 8-16 suggest mild depression, 17-23 moderate depression and scores over 24 are indicative of severe depression.
Measured: Post Dose Day 13
Secondary outcomes (18)
Model Adjusted Means for Beck Depression Score
The Beck Depression Inventory (BDI) is a 21-item measure of depression with each question on a 4-point scale ranging from 0=minimal to 3 = more severe (full list score values = 0,1,2,3). Total scores are a sum of individual items. The minimal depression = 0-13, mild depression = 14-19, moderate depression = 20-28, and severe depression = 29-63. The maximum score being 63 and the minimum possible score = 0.
Measured: Post Dose Day 0
Model Adjusted Means for Beck Depression Score
The Beck Depression Inventory (BDI) is a 21-item measure of depression with each question on a 4-point scale ranging from 0=minimal to 3 = more severe (full list score values = 0,1,2,3). Total scores are a sum of individual items. The minimal depression = 0-13, mild depression = 14-19, moderate depression = 20-28, and severe depression = 29-63. The maximum score being 63 and the minimum possible score = 0.
Measured: Post Dose Day 1
Model Adjusted Means for Beck Depression Score
The Beck Depression Inventory (BDI) is a 21-item measure of depression with each question on a 4-point scale ranging from 0=minimal to 3 = more severe (full list score values = 0,1,2,3). Total scores are a sum of individual items. The minimal depression = 0-13, mild depression = 14-19, moderate depression = 20-28, and severe depression = 29-63. The maximum score being 63 and the minimum possible score = 0.
Measured: Post Dose Day 2
Model Adjusted Means for Beck Depression Score
The Beck Depression Inventory (BDI) is a 21-item measure of depression with each question on a 4-point scale ranging from 0=minimal to 3 = more severe (full list score values = 0,1,2,3). Total scores are a sum of individual items. The minimal depression = 0-13, mild depression = 14-19, moderate depression = 20-28, and severe depression = 29-63. The maximum score being 63 and the minimum possible score = 0.
Measured: Post Dose Day 3
Model Adjusted Means for Beck Depression Score
The Beck Depression Inventory (BDI) is a 21-item measure of depression with each question on a 4-point scale ranging from 0=minimal to 3 = more severe (full list score values = 0,1,2,3). Total scores are a sum of individual items. The minimal depression = 0-13, mild depression = 14-19, moderate depression = 20-28, and severe depression = 29-63. The maximum score being 63 and the minimum possible score = 0.
Measured: Post Dose Day 7
Model Adjusted Means for Beck Depression Score
The Beck Depression Inventory (BDI) is a 21-item measure of depression with each question on a 4-point scale ranging from 0=minimal to 3 = more severe (full list score values = 0,1,2,3). Total scores are a sum of individual items. The minimal depression = 0-13, mild depression = 14-19, moderate depression = 20-28, and severe depression = 29-63. The maximum score being 63 and the minimum possible score = 0.
Measured: Post Dose Day 13
Model Adjusted Means for Hamilton Anxiety Rating Score
The Hamilton Anxiety Rating Scale (HAM-A) is a 14-item global measure of anxiety symptoms. Each item is scored on a scale of 0 (not present) to 4 (severe) (full score list = 0,1,2,3,4), with a total score range of 0-56 (0 = minimum score and 56 = maximum), where <17 indicates mild severity, 18-24 mild to moderate severity and 25-30 moderate to severe. Total scores are a sum of individual items.
Measured: Post Dose Day 0
Model Adjusted Means for Hamilton Anxiety Rating Score
The Hamilton Anxiety Rating Scale (HAM-A) is a 14-item global measure of anxiety symptoms. Each item is scored on a scale of 0 (not present) to 4 (severe) (full score list = 0,1,2,3,4), with a total score range of 0-56 (0 = minimum score and 56 = maximum), where <17 indicates mild severity, 18-24 mild to moderate severity and 25-30 moderate to severe. Total scores are a sum of individual items.
Measured: Post Dose Day 1
Model Adjusted Means for Hamilton Anxiety Rating Score
The Hamilton Anxiety Rating Scale (HAM-A) is a 14-item global measure of anxiety symptoms. Each item is scored on a scale of 0 (not present) to 4 (severe) (full score list = 0,1,2,3,4), with a total score range of 0-56 (0 = minimum score and 56 = maximum), where <17 indicates mild severity, 18-24 mild to moderate severity and 25-30 moderate to severe. Total scores are a sum of individual items.
Measured: Post Dose Day 2
Model Adjusted Means for Hamilton Anxiety Rating Score
The Hamilton Anxiety Rating Scale (HAM-A) is a 14-item global measure of anxiety symptoms. Each item is scored on a scale of 0 (not present) to 4 (severe) (full score list = 0,1,2,3,4), with a total score range of 0-56 (0 = minimum score and 56 = maximum), where <17 indicates mild severity, 18-24 mild to moderate severity and 25-30 moderate to severe. Total scores are a sum of individual items.
Measured: Post Dose Day 3
Model Adjusted Means for Hamilton Anxiety Rating Score
The Hamilton Anxiety Rating Scale (HAM-A) is a 14-item global measure of anxiety symptoms. Each item is scored on a scale of 0 (not present) to 4 (severe) (full score list = 0,1,2,3,4), with a total score range of 0-56 (0 = minimum score and 56 = maximum), where <17 indicates mild severity, 18-24 mild to moderate severity and 25-30 moderate to severe. Total scores are a sum of individual items.
Measured: Post Dose Day 7
Model Adjusted Means for Hamilton Anxiety Rating Score
The Hamilton Anxiety Rating Scale (HAM-A) is a 14-item global measure of anxiety symptoms. Each item is scored on a scale of 0 (not present) to 4 (severe) (full score list = 0,1,2,3,4), with a total score range of 0-56 (0 = minimum score and 56 = maximum), where <17 indicates mild severity, 18-24 mild to moderate severity and 25-30 moderate to severe. Total scores are a sum of individual items.
Measured: Post Dose Day 13
Model Adjusted Means for Montgomery-Asberg Depression Rating Score
The Montgomery-Asberg Depression Rating Scale (MADRS) is a 10-item global measure evaluating core symptoms of depression. Questions concern how the patient has felt over the past week. Each item is rated on a scale from 0 to 6, with 0 being "normal/not present" and 6 being "extreme" (full score list = 0,1,2,3,4,5,6). Maximum score = 60, minimum score = 0. Total scores are a sum of the individual items.
Measured: Post Dose Day 0
Model Adjusted Means for Montgomery-Asberg Depression Rating Score
The Montgomery-Asberg Depression Rating Scale (MADRS) is a 10-item global measure evaluating core symptoms of depression. Questions concern how the patient has felt over the past week. Each item is rated on a scale from 0 to 6, with 0 being "normal/not present" and 6 being "extreme" (full score list = 0,1,2,3,4,5,6). Maximum score = 60, minimum score = 0. Total scores are a sum of the individual items.
Measured: Post Dose Day 1
Model Adjusted Means for Montgomery-Asberg Depression Rating Score
The Montgomery-Asberg Depression Rating Scale (MADRS) is a 10-item global measure evaluating core symptoms of depression. Questions concern how the patient has felt over the past week. Each item is rated on a scale from 0 to 6, with 0 being "normal/not present" and 6 being "extreme" (full score list = 0,1,2,3,4,5,6). Maximum score = 60, minimum score = 0. Total scores are a sum of the individual items.
Measured: Post Dose Day 2
Model Adjusted Means for Montgomery-Asberg Depression Rating Score
The Montgomery-Asberg Depression Rating Scale (MADRS) is a 10-item global measure evaluating core symptoms of depression. Questions concern how the patient has felt over the past week. Each item is rated on a scale from 0 to 6, with 0 being "normal/not present" and 6 being "extreme" (full score list = 0,1,2,3,4,5,6). Maximum score = 60, minimum score = 0. Total scores are a sum of the individual items.
Measured: Post Dose Day 3
Model Adjusted Means for Montgomery-Asberg Depression Rating Score
The Montgomery-Asberg Depression Rating Scale (MADRS) is a 10-item global measure evaluating core symptoms of depression. Questions concern how the patient has felt over the past week. Each item is rated on a scale from 0 to 6, with 0 being "normal/not present" and 6 being "extreme" (full score list = 0,1,2,3,4,5,6). Maximum score = 60, minimum score = 0. Total scores are a sum of the individual items.
Measured: Post Dose Day 7
Model Adjusted Means for Montgomery-Asberg Depression Rating Score
The Montgomery-Asberg Depression Rating Scale (MADRS) is a 10-item global measure evaluating core symptoms of depression. Questions concern how the patient has felt over the past week. Each item is rated on a scale from 0 to 6, with 0 being "normal/not present" and 6 being "extreme" (full score list = 0,1,2,3,4,5,6). Maximum score = 60, minimum score = 0. Total scores are a sum of the individual items.
Measured: Post Dose Day 13
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted29 Jun 2015 (estimated)
- Study start14 Oct 2015
- Primary completion21 Feb 2019
- Study completion3 Dec 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (6)Papers the sponsor has linked to this study.
- Other trials for Major DepressionStudies of the same condition, open and under way.
- More trials run by National Institute of Mental Health (NIMH)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 22 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Institute of Mental Health (NIMH)
- Sponsor type
- US National Institutes of Health
- Responsible party
- Sponsor
- Investigators
- Carlos A Zarate, M.D., Principal investigator, National Institute of Mental Health (NIMH)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02484456
- Sponsor's protocol ID
- 150151
- Other IDs
- 15-M-0151
- Status last verified
- 3 Dec 2019
- First submitted
- 26 Jun 2015
- Last updated
- 11 Apr 2022
- Results posted
- Yes, on ClinicalTrials.gov
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Publications
Jones GH, Gilbert JR, Johnston JN, Akula N, Schulmann A, Arakelian M, Peng S, Yuan P, Winful EA, Yavi M, Quintanilla B, Elkahloun A, Moaddel R, Henter ID, Greenstein D, Machado-Vieira R, Bartley CM, Kadriu B, Amit M, Rezvani K, Kvarta MD, McMahon FJ, Zarate CA Jr. Convergent neuroimmune signaling underlying rapid antidepressant response to ketamine and psychedelics. Mol Psychiatry. 2026 Jul 28. doi: 10.1038/s41380-026-03777-z. Online ahead of print.
PubMed 42521762Johnston JN, Jones GH, Peng S, Yuan P, Yavi M, Kadriu B, Henter ID, Quintanilla B, Elkahloun A, Moaddel R, Schulmann A, Akula N, Kvarta MD, McMahon FJ, Zarate CA Jr. Time-dependent effects of rapid-acting antidepressants in iPSC-derived neurons from treatment-resistant depression and healthy volunteers. Mol Psychiatry. 2026 Jul 24. doi: 10.1038/s41380-026-03768-0. Online ahead of print.
PubMed 42498781Gorka A, Evans J, Kvarta M, Ballard E, Zarate C. Major depressive disorder is associated with reduced intrinsic connectivity between the bed nucleus of the stria terminalis and ventral striatum. J Psychiatry Neurosci. 2026 Jan 1;51:1-7. doi: 10.1139/jpn-2025-0160.
PubMed 42171126Johnston J, Jones G, Peng S, Yuan P, Yavi M, Kadriu B, Henter I, Quintanilla B, Elkahloun AG, Moaddel R, Schulmann A, Akula N, Kvarta M, McMahon F, Zarate C. Time-Dependent Effects of Rapid-Acting Antidepressants in iPSC-Derived Neurons from Treatment-Resistant Depression and Healthy Volunteers. Res Sq [Preprint]. 2026 Feb 12:rs.3.rs-8733841. doi: 10.21203/rs.3.rs-8733841/v1.
PubMed 41743330Johnston JN, Yuan P, Kadriu B, Akula N, Quintanilla B, Peng S, Jones GH, Schulmann A, Yavi M, Henter ID, McMahon FJ, Kalynchuk LE, Zarate CA Jr, Caruncho HJ. Response of iPSC-derived neurons from individuals with treatment-resistant depression to (2 R,6 R)-hydroxynorketamine and reelin: an exploratory study. Transl Psychiatry. 2025 Nov 18;15(1):524. doi: 10.1038/s41398-025-03724-6.
PubMed 41257792Park LT, Kadriu B, Gould TD, Zanos P, Greenstein D, Evans JW, Yuan P, Farmer CA, Oppenheimer M, George JM, Adeojo LW, Snodgrass HR, Smith MA, Henter ID, Machado-Vieira R, Mannes AJ, Zarate CA. A Randomized Trial of the N-Methyl-d-Aspartate Receptor Glycine Site Antagonist Prodrug 4-Chlorokynurenine in Treatment-Resistant Depression. Int J Neuropsychopharmacol. 2020 Jul 29;23(7):417-425. doi: 10.1093/ijnp/pyaa025.
PubMed 32236521
Study at a glance
From the registry record, last updated by the sponsor on 11 Apr 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- An Investigation of the Antidepressant Effects of the Glycine Receptor Antagonist AV 101 (4-chlorokynurenine) in Major Depressive Disorder
- ClinicalTrials.gov ID
- NCT02484456
- Acronym / sponsor ID
- 150151
- Conditions
- Major Depression
- Keywords
- Major Depression, Glycine Receptor Antagonist, 4-chlorokynurenine, Treatment Resistant, Glutamatergic System
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 22 participants (actual)
- Lead sponsor
- National Institute of Mental Health (NIMH)US National Institutes of Health
- Study start
- 14 Oct 2015 (actual)
- Primary completion
- 21 Feb 2019 (actual)
- Study completion
- 3 Dec 2019 (actual)
- First posted
- 29 Jun 2015 (estimated)
- Results
- Posted 2 Mar 2022
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Background:
- Drugs and talk therapy help treat depression, but these treatments usually take quite a bit of time to work. Ketamine is a fast-acting antidepressant, but it has side effects like unusual dreams and experiences. The drug AV-101 may have the same antidepressant effects but fewer side effects. Researchers want to see if it is effective and safe for people with major depressive disorder.
Objective:
- To see if the drug, AV-101 is safe and if it treats symptoms of major depressive disorder.
Eligibility:
- Adults ages 18-65 with major depression without psychotic features.
Design:
- Participants will be screened under a separate protocol.
- Participants will stay in the hospital for 12-14 weeks.
- Phase 1 (2-7 weeks): participants will stop taking their medicines then not take any for 2 weeks. They will have several scans and other procedures.
- Phase 2 (6-7 weeks): 2 weeks each of study drug and placebo once a day, with 2 weeks of no drugs in between.
- Participants will have:
- Physical exams
- Interviews
- Frequent blood collection. A needle will place a small plastic tube in the arm. Some blood samples will be taken through this tube.
- 2 spinal taps (optional). The back will be numbed. A needle will insert a catheter between back bones. That will be left in for up to 30 hours. Spinal fluid will be collected through it.
- 5 scans. Participants will lie in a machine with a magnetic field. The machine takes pictures of the brain and brain chemicals.
- At the end of the study, participants will have medical evaluation, questions, and blood tests. Some may continue treatment at the clinic.
Detailed description
Objective
Modulation of the NMDA receptor (NMDAR) complex or other components of glutamatergic signaling is likely involved in improvement of depressive symptoms and related constructs/dimensions of observable behavior and neurobiological measures. Current standard monoaminergic pharmacological approaches for major depressive disorder (MDD) have proven to be only modestly effective during acute depressive episodes. We have systematically tested different glutamatergic modulators in patients with mood disorders in order to develop improved therapeutics. We found that the NMDAR antagonist ketamine produces rapid antidepressant effects in patients with treatment-resistant depression (in MDD and Bipolar Disorder). However, despite being highly efficacious, the proof of concept ketamine produces psychotomimetic effects.
In the present protocol, we aim to evaluate a new glutamate-mediated mechanism associated with antidepressant efficacy by targeting the glycine receptor within the NMDA receptor. Targeting the glycine co-agonist site of the (NMDA) receptor may bypass potential adverse effects that occur with ketamine without affecting the robust efficacy observed. This may then result in the glutamate surge that has been associated with the rapid acting antidepressant effects of ketamine.
The present Phase 2 proof-of-concept study is designed to evaluate the antidepressant effects of AV 101 (L-4-chlorokynurenine or 4-Cl- KYN) in MDD; this is a synthetic compound which is enzymatically converted into the selective glycine/NMDAR antagonist 7-chlorokynurenine (7-Cl-KYNA) after crossing the blood brain barrier (BBB) and then reaching brain glial cells. In animal models of depression, 4-Cl-KYNA (AV 101) induced acute and prolonged antidepressant-like effects without exhibiting ketamine-like side effects as determined by the drug discrimination, conditioned place preference, and pre-pulse inhibition tests.
We will also evaluate the neurobiological mechanisms involved in the antidepressant response to AV 101. We expect that this effect may modulate glutamate transmission and reverse the clinical symptoms of depression. The demonstration that a glycine-antagonist produces antidepressant effects without psychotomimetic side effects would support the therapeutic relevance of the glycine site of the NMDAR and could direct the development of novel drug targets for the treatment of depression.
Study Population
Twenty-five individuals with treatment-resistant major depressive disorder (MDD) will be included.
Design
Male and female patients, ages 18 to 65 years, with a diagnosis of MDD, currently in an episode of major depression, will be recruited for this study. This study will consist of a randomized, double-blind crossover administration of either the glycine receptor antagonist AV 101 (1,080 or 1,440 mg/day given orally) or placebo for 2 weeks. The study will assess the efficacy in improving overall depressive symptomatology and tolerability of AV 101 in treatment-resistant MDD. Other aims of the study include: 1) determining whether changes in brain neurochemicals (e.g. glutamate) and peripheral biomarkers obtained via MRS and cerebrospinal fluid (CSF) correlate with antidepressant response (decrease in Hamilton Depression Rating Scale (HDRS) total scores) to AV 101 in patients with treatment-resistant MDD, and 2) examine other potential biomarkers of response.
Outcome Measures
Primary: Hamilton Rating Scale (HDRS) total score.
Secondary: Proportion of subjects achieving remission (HDRS less than or greater than 7) and response (greater than or equal to 50% reduction from baseline in HDRS total score); change from baseline in Hamilton Anxiety Rating Scale (HAM-A), Montgomery-Asberg Depression Rating Scale (MADRS), and the Columbia Suicide Severity Rating Scale (C-SSRS) total scores. Surrogate biomarkers of drug effect/response include: changes in prefrontal glutamate levels measured with 7T H-MRS.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Double blind (participant, investigator)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| AV 101 (4-chlorokynurenine), then Placebo | Experimental | Drug: AV 101 (4-Chlorokynurenine), Other: Placebo ComparatorAfter a two-week drug-free period, participants received daily oral dose of AV 101 (4-chlorokynurenine) monotherapy 1,080mg/day for seven days, then dose increased to AV 101 1,440mg/day for next seven days followed by a two-week washout period; then crossover to placebo phase with daily dose of placebo pill for two weeks. |
| Placebo, then AV 101 (4-chlorokynurenine) | Experimental | Drug: AV 101 (4-Chlorokynurenine), Other: Placebo ComparatorAfter a two-week drug-free period, participants received daily dose of placebo pill for two weeks followed by two-week washout period; then crossover to AV 101 treatment phase with daily oral dose of AV 101 (4-chlorokynurenine) monotherapy 1,080mg/day for seven days, then dose increased to AV 101 1,440mg/day for next seven days. |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- 18 to 65 years of age.
- Subjects must have a level of understanding sufficient to agree to all required tests and examinations, sign an informed consent document and verify understanding. To verify this, subjects must score greater than or equal to 80% on the consent quiz.
- Subjects must fulfill Diagnostic and Statistical Manual (DSM)-IV or DSM-V criteria for MDD, single episode or recurrent without psychotic features, based on clinical assessment and confirmed by a structured diagnostic interview (SCID-P). Subjects must be experiencing a current major depressive episode of at least 4 weeks duration.
- Subjects must have an initial score of at least 18 on the HDRS at screening and at baseline of study phase I.
- Subjects must have a current or past history of lack of response to one adequate antidepressant trial (may be from the same chemical class) operationally defined using the modified-Antidepressant Treatment History Form (ATHF).
Key exclusion criteria (18 listed)
- Current psychotic features or a diagnosis of schizophrenia or any other psychotic disorder as defined in the DSM-IV or DSM-V.
- Subjects with a history of DSM-IV drug or alcohol dependency or abuse (or alcohol use disorder per DSM-V),except for caffeine or nicotine dependence within the preceding 3 months.
- Head injury that results in loss of consciousness exceeding 5 minutes (for the imaging component of the study).
- Subjects with a DSM IV or DSM-V Axis II diagnosis of borderline or antisocial personality disorder.
- Pregnant or nursing women or women of child bearing potential not using at least 1 medically accepted means of contraception from the time of enrollment in the study until 1 month after completion of the second phase. Examples of medically accepted means of contraception include oral, injectable, or implant birth control, condom, diaphragm with spermicide, intrauterine devices (IUD), tubal ligation, abstinence or partner with vasectomy. .
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| AV 101 (4-Chlorokynurenine)Also: 4-Cl-KYNL-4-chlorokynurenine (4-Cl-KYN) was developed as a prodrug that is rapidly converted in vivo to its active metabolite 7-chlorokynurenic acid (7-Cl-KYNA), a well-characterized N-Methyl-D-aspartate receptor (NMDAR) antagonist at the glycine site. | Drug | AV 101 (4-chlorokynurenine), then Placebo, Placebo, then AV 101 (4-chlorokynurenine) |
| Placebo ComparatorPlacebo | Other | AV 101 (4-chlorokynurenine), then Placebo, Placebo, then AV 101 (4-chlorokynurenine) |
Primary outcome
Model Adjusted Means for Hamilton Depression Rating Score
Time frame: Post Dose Day 0
The Hamilton Depression Rating scale is a 17-item global measure of depressive symptoms on a 5-point scale ranging from 0 = not present to 4 = severe (full score values = 0,1,2,3,4). Some items rated on a scale of 0-2 (0, 1, 2) with 0 = not present to 2 = more severe. Total scores are a sum of the individual items. The maximum total score being 52 on the 17-point scale, and the minimum score being 0.Total scores of 0-7 are considered as being normal, 8-16 suggest mild depression, 17-23 moderate depression and scores over 24 are indicative of severe depression.
Model Adjusted Means for Hamilton Depression Rating Score
Time frame: Post Dose Day 1
The Hamilton Depression Rating scale is a 17-item global measure of depressive symptoms on a 5-point scale ranging from 0 = not present to 4 = severe (full score values = 0,1,2,3,4). Some items rated on a scale of 0-2 (0, 1, 2) with 0 = not present to 2 = more severe. Total scores are a sum of the individual items. The maximum total score being 52 on the 17-point scale, and the minimum score being 0.Total scores of 0-7 are considered as being normal, 8-16 suggest mild depression, 17-23 moderate depression and scores over 24 are indicative of severe depression.
Model Adjusted Means for Hamilton Depression Rating Score
Time frame: Post Dose Day 2
The Hamilton Depression Rating scale is a 17-item global measure of depressive symptoms on a 5-point scale ranging from 0 = not present to 4 = severe (full score values = 0,1,2,3,4). Some items rated on a scale of 0-2 (0, 1, 2) with 0 = not present to 2 = more severe. Total scores are a sum of the individual items. The maximum total score being 52 on the 17-point scale, and the minimum score being 0.Total scores of 0-7 are considered as being normal, 8-16 suggest mild depression, 17-23 moderate depression and scores over 24 are indicative of severe depression.
Model Adjusted Means for Hamilton Depression Rating Score
Time frame: Post Dose Day 3
The Hamilton Depression Rating scale is a 17-item global measure of depressive symptoms on a 5-point scale ranging from 0 = not present to 4 = severe (full score values = 0,1,2,3,4). Some items rated on a scale of 0-2 (0, 1, 2) with 0 = not present to 2 = more severe. Total scores are a sum of the individual items. The maximum total score being 52 on the 17-point scale, and the minimum score being 0.Total scores of 0-7 are considered as being normal, 8-16 suggest mild depression, 17-23 moderate depression and scores over 24 are indicative of severe depression.
Model Adjusted Means for Hamilton Depression Rating Score
Time frame: Post Dose Day 7
The Hamilton Depression Rating scale is a 17-item global measure of depressive symptoms on a 5-point scale ranging from 0 = not present to 4 = severe (full score values = 0,1,2,3,4). Some items rated on a scale of 0-2 (0, 1, 2) with 0 = not present to 2 = more severe. Total scores are a sum of the individual items. The maximum total score being 52 on the 17-point scale, and the minimum score being 0.Total scores of 0-7 are considered as being normal, 8-16 suggest mild depression, 17-23 moderate depression and scores over 24 are indicative of severe depression.
Model Adjusted Means for Hamilton Depression Rating Score
Time frame: Post Dose Day 13
The Hamilton Depression Rating scale is a 17-item global measure of depressive symptoms on a 5-point scale ranging from 0 = not present to 4 = severe (full score values = 0,1,2,3,4). Some items rated on a scale of 0-2 (0, 1, 2) with 0 = not present to 2 = more severe. Total scores are a sum of the individual items. The maximum total score being 52 on the 17-point scale, and the minimum score being 0.Total scores of 0-7 are considered as being normal, 8-16 suggest mild depression, 17-23 moderate depression and scores over 24 are indicative of severe depression.
18 secondary outcomes
Model Adjusted Means for Beck Depression Score
Time frame: Post Dose Day 0
Model Adjusted Means for Beck Depression Score
Time frame: Post Dose Day 1
Model Adjusted Means for Beck Depression Score
Time frame: Post Dose Day 2
Model Adjusted Means for Beck Depression Score
Time frame: Post Dose Day 3
Model Adjusted Means for Beck Depression Score
Time frame: Post Dose Day 7
Model Adjusted Means for Beck Depression Score
Time frame: Post Dose Day 13
Model Adjusted Means for Hamilton Anxiety Rating Score
Time frame: Post Dose Day 0
Model Adjusted Means for Hamilton Anxiety Rating Score
Time frame: Post Dose Day 1
Model Adjusted Means for Hamilton Anxiety Rating Score
Time frame: Post Dose Day 2
Model Adjusted Means for Hamilton Anxiety Rating Score
Time frame: Post Dose Day 3
Model Adjusted Means for Hamilton Anxiety Rating Score
Time frame: Post Dose Day 7
Model Adjusted Means for Hamilton Anxiety Rating Score
Time frame: Post Dose Day 13
Model Adjusted Means for Montgomery-Asberg Depression Rating Score
Time frame: Post Dose Day 0
Model Adjusted Means for Montgomery-Asberg Depression Rating Score
Time frame: Post Dose Day 1
Model Adjusted Means for Montgomery-Asberg Depression Rating Score
Time frame: Post Dose Day 2
Model Adjusted Means for Montgomery-Asberg Depression Rating Score
Time frame: Post Dose Day 3
Model Adjusted Means for Montgomery-Asberg Depression Rating Score
Time frame: Post Dose Day 7
Model Adjusted Means for Montgomery-Asberg Depression Rating Score
Time frame: Post Dose Day 13
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 11 Apr 2022.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 42521762Jones GH, Gilbert JR, Johnston JN, Akula N, Schulmann A, Arakelian M, Peng S, Yuan P, Winful EA, Yavi M, Quintanilla B, Elkahloun A, Moaddel R, Henter ID, Greenstein D, Machado-Vieira R, Bartley CM, Kadriu B, Amit M, Rezvani K, Kvarta MD, McMahon FJ, Zarate CA Jr. Convergent neuroimmune signaling underlying rapid antidepressant response to ketamine and psychedelics. Mol Psychiatry. 2026 Jul 28. doi: 10.1038/s41380-026-03777-z. Online ahead of print.
- Derived from this study: PubMed 42498781Johnston JN, Jones GH, Peng S, Yuan P, Yavi M, Kadriu B, Henter ID, Quintanilla B, Elkahloun A, Moaddel R, Schulmann A, Akula N, Kvarta MD, McMahon FJ, Zarate CA Jr. Time-dependent effects of rapid-acting antidepressants in iPSC-derived neurons from treatment-resistant depression and healthy volunteers. Mol Psychiatry. 2026 Jul 24. doi: 10.1038/s41380-026-03768-0. Online ahead of print.
- Derived from this study: PubMed 42171126Gorka A, Evans J, Kvarta M, Ballard E, Zarate C. Major depressive disorder is associated with reduced intrinsic connectivity between the bed nucleus of the stria terminalis and ventral striatum. J Psychiatry Neurosci. 2026 Jan 1;51:1-7. doi: 10.1139/jpn-2025-0160.
- Derived from this study: PubMed 41743330Johnston J, Jones G, Peng S, Yuan P, Yavi M, Kadriu B, Henter I, Quintanilla B, Elkahloun AG, Moaddel R, Schulmann A, Akula N, Kvarta M, McMahon F, Zarate C. Time-Dependent Effects of Rapid-Acting Antidepressants in iPSC-Derived Neurons from Treatment-Resistant Depression and Healthy Volunteers. Res Sq [Preprint]. 2026 Feb 12:rs.3.rs-8733841. doi: 10.21203/rs.3.rs-8733841/v1.
- Derived from this study: PubMed 41257792Johnston JN, Yuan P, Kadriu B, Akula N, Quintanilla B, Peng S, Jones GH, Schulmann A, Yavi M, Henter ID, McMahon FJ, Kalynchuk LE, Zarate CA Jr, Caruncho HJ. Response of iPSC-derived neurons from individuals with treatment-resistant depression to (2 R,6 R)-hydroxynorketamine and reelin: an exploratory study. Transl Psychiatry. 2025 Nov 18;15(1):524. doi: 10.1038/s41398-025-03724-6.
- Derived from this study: PubMed 32236521Park LT, Kadriu B, Gould TD, Zanos P, Greenstein D, Evans JW, Yuan P, Farmer CA, Oppenheimer M, George JM, Adeojo LW, Snodgrass HR, Smith MA, Henter ID, Machado-Vieira R, Mannes AJ, Zarate CA. A Randomized Trial of the N-Methyl-d-Aspartate Receptor Glycine Site Antagonist Prodrug 4-Chlorokynurenine in Treatment-Resistant Depression. Int J Neuropsychopharmacol. 2020 Jul 29;23(7):417-425. doi: 10.1093/ijnp/pyaa025.
- NIH Clinical Center Detailed Web PageLink provided by the sponsor.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Carlos A Zarate, M.D. principal investigator
National Institute of Mental Health (NIMH)
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing AV 101 (4-Chlorokynurenine) in people with Major Depression, run by National Institute of Mental Health (NIMH) at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 18 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 11 Apr 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 2 Mar 2022). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Model Adjusted Means for Hamilton Depression Rating Score (time frame: Post Dose Day 0). The study lists 6 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02484456, which also lists 6 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 11 Apr 2022.