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| ID | Type | Description | Link |
|---|---|---|---|
| 15-M-0151 |
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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:
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 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. |
|
| 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| AV 101 (4-Chlorokynurenine) | Drug | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | 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. | 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. | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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. |
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EXCLUSION CRITERIA:
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| Name | Affiliation | Role |
|---|---|---|
| Carlos A Zarate, M.D. | National Institute of Mental Health (NIMH) | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| National Institutes of Health Clinical Center, 9000 Rockville Pike | Bethesda | Maryland | 20892 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 42171126 | Derived | Gorka 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. | |
| 41743330 | Derived | Johnston 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. |
| Label | URL |
|---|---|
| NIH Clinical Center Detailed Web Page | View source |
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22 participants signed consent. 3 participants withdrew before start of treatment leaving 19 participants starting.
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| ID | Title | Description |
|---|---|---|
| FG000 | AV 101 (4-chlorokynurenine), Then Placebo | 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. |
| FG001 | Placebo, Then AV 101 (4-chlorokynurenine) | 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 (4-chlorokynurenine) treatment phase with daily oral dose of AV 101 monotherapy 1,080mg/day for seven days, then dose increased to AV 101 1,440mg/day for next seven days. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| First Treatment Period: Week 1 |
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| First Treatment Period: Week 2 |
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| Washout Period |
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| Second Treatment Period: Week 1 |
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| Second Treatment Period: Week 2 |
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| ID | Title | Description |
|---|---|---|
| BG000 | AV 101 (4-chlorokynurenine), Then Placebo | 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. |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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. | The primary analysis compared active drug condition with placebo condition. Using within subject data (each person serving as their own control), we estimated means for drug, placebo and their difference at each time point. If outcome data were missing subsequent to a participant dropping out, their available data was included in the model. | Posted | Mean | Standard Error | score on a scale | Post Dose Day 0 |
|
3 months
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | AV 101 (4-chlorokynurenine) 1,080 mg for 1 Week | Daily oral dose of AV 101 (4-chlorokynurenine) monotherapy 1,080mg/day for seven days |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Cerebrospinal fluid leakage | Injury, poisoning and procedural complications | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Chest pain | Cardiac disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Zarate, Carlos | National Institute of Mental Health | +1 301 451 0861 | zaratec@mail.nih.gov |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | May 15, 2018 | May 1, 2020 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D003865 | Depressive Disorder, Major |
| ID | Term |
|---|---|
| D003866 | Depressive Disorder |
| D019964 | Mood Disorders |
| D001523 | Mental Disorders |
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| ID | Term |
|---|---|
| C027883 | 4-chlorokynurenine |
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| Placebo Comparator | Other | Placebo |
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| 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. | 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. | Post Dose Day 13 |
| 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | Post Dose Day 13 |
| 41257792 | Derived | Johnston 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. |
| 32236521 | Derived | Park 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. |
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| BG001 |
| Placebo, Then AV 101 (4-chlorokynurenine) |
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 (4-chlorokynurenine) treatment phase with daily oral dose of AV 101 monotherapy 1,080mg/day for seven days, then dose increased to AV 101 1,440mg/day for next seven days. |
| BG002 | Total | Total of all reporting groups |
| Participants |
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| Sex: Female, Male | Count of Participants | Participants |
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| Ethnicity (NIH/OMB) | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| AV 101 (4-chlorokynurenine) |
Participants received daily oral dose of AV 101 monotherapy 1,080mg/day for seven days, then 1,440mg/day for next seven days. |
| OG001 | Placebo | Participants received a daily oral dose of placebo pills for 2 weeks. |
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| Primary | 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. | The primary analysis compared active drug condition with placebo condition. Using within subject data (each person serving as their own control), we estimated means for drug, placebo and their difference at each time point. If outcome data were missing subsequent to a participant dropping out, their available data was included in the model. | Posted | Mean | Standard Error | score on a scale | Post Dose Day 1 |
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| Primary | 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. | The primary analysis compared active drug condition with placebo condition. Using within subject data (each person serving as their own control), we estimated means for drug, placebo and their difference at each time point. If outcome data were missing subsequent to a participant dropping out, their available data was included in the model. | Posted | Mean | Standard Error | score on a scale | Post Dose Day 2 |
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| Primary | 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. | The primary analysis compared active drug condition with placebo condition. Using within subject data (each person serving as their own control), we estimated means for drug, placebo and their difference at each time point. If outcome data were missing subsequent to a participant dropping out, their available data was included in the model. | Posted | Mean | Standard Error | score on a scale | Post Dose Day 3 |
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| Primary | 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. | The primary analysis compared active drug condition with placebo condition. Using within subject data (each person serving as their own control), we estimated means for drug, placebo and their difference at each time point. If outcome data were missing subsequent to a participant dropping out, their available data was included in the model. | Posted | Mean | Standard Error | score on a scale | Post Dose Day 7 |
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| Primary | 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. | The primary analysis compared active drug condition with placebo condition. Using within subject data (each person serving as their own control), we estimated means for drug, placebo and their difference at each time point. If outcome data were missing subsequent to a participant dropping out, their available data was included in the model. | Posted | Mean | Standard Error | score on a scale | Post Dose Day 13 |
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| Secondary | 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. | The primary analysis compared active drug condition with placebo condition. Using within subject data (each person serving as their own control), we estimated means for drug, placebo and their difference at each time point. If outcome data were missing subsequent to a participant dropping out, their available data was included in the model. | Posted | Mean | Standard Error | score on a scale | Post Dose Day 0 |
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| Secondary | 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. | The primary analysis compared active drug condition with placebo condition. Using within subject data (each person serving as their own control), we estimated means for drug, placebo and their difference at each time point. If outcome data were missing subsequent to a participant dropping out, their available data was included in the model. | Posted | Mean | Standard Error | score on a scale | Post Dose Day 1 |
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| Secondary | 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. | The primary analysis compared active drug condition with placebo condition. Using within subject data (each person serving as their own control), we estimated means for drug, placebo and their difference at each time point. If outcome data were missing subsequent to a participant dropping out, their available data was included in the model. | Posted | Mean | Standard Error | score on a scale | Post Dose Day 2 |
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| Secondary | 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. | The primary analysis compared active drug condition with placebo condition. Using within subject data (each person serving as their own control), we estimated means for drug, placebo and their difference at each time point. If outcome data were missing subsequent to a participant dropping out, their available data was included in the model. | Posted | Mean | Standard Error | score on a scale | Post Dose Day 3 |
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| Secondary | 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. | The primary analysis compared active drug condition with placebo condition. Using within subject data (each person serving as their own control), we estimated means for drug, placebo and their difference at each time point. If outcome data were missing subsequent to a participant dropping out, their available data was included in the model. | Posted | Mean | Standard Error | score on a scale | Post Dose Day 7 |
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| Secondary | 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. | The primary analysis compared active drug condition with placebo condition. Using within subject data (each person serving as their own control), we estimated means for drug, placebo and their difference at each time point. If outcome data were missing subsequent to a participant dropping out, their available data was included in the model. | Posted | Mean | Standard Error | score on a scale | Post Dose Day 13 |
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| Secondary | 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. | The primary analysis compared active drug condition with placebo condition. Using within subject data (each person serving as their own control), we estimated means for drug, placebo and their difference at each time point. If outcome data were missing subsequent to a participant dropping out, their available data was included in the model. | Posted | Mean | Standard Error | score on a scale | Post Dose Day 0 |
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| Secondary | 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. | The primary analysis compared active drug condition with placebo condition. Using within subject data (each person serving as their own control), we estimated means for drug, placebo and their difference at each time point. If outcome data were missing subsequent to a participant dropping out, their available data was included in the model. | Posted | Mean | Standard Error | score on a scale | Post Dose Day 1 |
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| Secondary | 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. | The primary analysis compared active drug condition with placebo condition. Using within subject data (each person serving as their own control), we estimated means for drug, placebo and their difference at each time point. If outcome data were missing subsequent to a participant dropping out, their available data was included in the model. | Posted | Mean | Standard Error | score on a scale | Post Dose Day 2 |
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| Secondary | 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. | The primary analysis compared active drug condition with placebo condition. Using within subject data (each person serving as their own control), we estimated means for drug, placebo and their difference at each time point. If outcome data were missing subsequent to a participant dropping out, their available data was included in the model. | Posted | Mean | Standard Error | score on a scale | Post Dose Day 3 |
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| Secondary | 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. | The primary analysis compared active drug condition with placebo condition. Using within subject data (each person serving as their own control), we estimated means for drug, placebo and their difference at each time point. If outcome data were missing subsequent to a participant dropping out, their available data was included in the model. | Posted | Mean | Standard Error | score on a scale | Post Dose Day 7 |
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| Secondary | 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. | The primary analysis compared active drug condition with placebo condition. Using within subject data (each person serving as their own control), we estimated means for drug, placebo and their difference at each time point. If outcome data were missing subsequent to a participant dropping out, their available data was included in the model. | Posted | Mean | Standard Error | score on a scale | Post Dose Day 13 |
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| Secondary | 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. | The primary analysis compared active drug condition with placebo condition. Using within subject data (each person serving as their own control), we estimated means for drug, placebo and their difference at each time point. If outcome data were missing subsequent to a participant dropping out, their available data was included in the model. | Posted | Mean | Standard Error | score on a scale | Post Dose Day 0 |
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| Secondary | 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. | The primary analysis compared active drug condition with placebo condition. Using within subject data (each person serving as their own control), we estimated means for drug, placebo and their difference at each time point. If outcome data were missing subsequent to a participant dropping out, their available data was included in the model. | Posted | Mean | Standard Error | score on a scale | Post Dose Day 1 |
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| Secondary | 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. | The primary analysis compared active drug condition with placebo condition. Using within subject data (each person serving as their own control), we estimated means for drug, placebo and their difference at each time point. If outcome data were missing subsequent to a participant dropping out, their available data was included in the model. | Posted | Mean | Standard Error | score on a scale | Post Dose Day 2 |
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| Secondary | 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. | The primary analysis compared active drug condition with placebo condition. Using within subject data (each person serving as their own control), we estimated means for drug, placebo and their difference at each time point. If outcome data were missing subsequent to a participant dropping out, their available data was included in the model. | Posted | Mean | Standard Error | score on a scale | Post Dose Day 3 |
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| Secondary | 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. | The primary analysis compared active drug condition with placebo condition. Using within subject data (each person serving as their own control), we estimated means for drug, placebo and their difference at each time point. If outcome data were missing subsequent to a participant dropping out, their available data was included in the model. | Posted | Mean | Standard Error | score on a scale | Post Dose Day 7 |
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| Secondary | 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. | The primary analysis compared active drug condition with placebo condition. Using within subject data (each person serving as their own control), we estimated means for drug, placebo and their difference at each time point. If outcome data were missing subsequent to a participant dropping out, their available data was included in the model. | Posted | Mean | Standard Error | score on a scale | Post Dose Day 13 |
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| 0 |
| 19 |
| 1 |
| 19 |
| 9 |
| 19 |
| EG001 | AV 101 (4-chlorokynurenine) 1,440 mg for 1 Week | Daily oral dose of AV 101 (4-chlorokynurenine) monotherapy 1,440 mg/day for seven days | 0 | 19 | 1 | 19 | 7 | 19 |
| EG002 | Placebo 2 Weeks | Daily dose of placebo pill for two weeks | 0 | 19 | 0 | 19 | 6 | 19 |
| Pulmonary embolism | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
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| Speech disorder | Nervous system disorders | Systematic Assessment |
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| Eye irritation | Eye disorders | Systematic Assessment |
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| Vision blurred | Eye disorders | Systematic Assessment |
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| Abdominal discomfort | Gastrointestinal disorders | Systematic Assessment |
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| Diarrhoea | Gastrointestinal disorders | Systematic Assessment |
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| Nausea | Gastrointestinal disorders | Systematic Assessment |
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| Cold sweat | General disorders | Systematic Assessment |
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| Decreased appetite | General disorders | Systematic Assessment |
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| Fatigue | General disorders | Systematic Assessment |
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| Irritability | General disorders | Systematic Assessment |
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| Pyrexia | General disorders | Systematic Assessment |
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| Musculoskeletal pain | Musculoskeletal and connective tissue disorders | Systematic Assessment |
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| Advanced sleep phase | Nervous system disorders | Systematic Assessment |
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| Headache | Nervous system disorders | Systematic Assessment |
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| Insomnia | Nervous system disorders | Systematic Assessment |
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| Memory impairment | Nervous system disorders | Systematic Assessment |
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| Motor dysfunction | Nervous system disorders | Systematic Assessment |
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| Peripheral sensory neuropathy | Nervous system disorders | Systematic Assessment |
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| Sedation | Nervous system disorders | Systematic Assessment |
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| Sensory loss | Nervous system disorders | Systematic Assessment |
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| Sleep phase rhythm disturbance | Nervous system disorders | Systematic Assessment |
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| Tremor | Nervous system disorders | Systematic Assessment |
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| Skin irritation | Skin and subcutaneous tissue disorders | Systematic Assessment |
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| Influenza | Infections and infestations | Systematic Assessment |
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| Pain in jaw | Musculoskeletal and connective tissue disorders | Systematic Assessment |
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| Pharyngitis | Gastrointestinal disorders | Systematic Assessment |
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| Reflux gastritis | Gastrointestinal disorders | Systematic Assessment |
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| Asthenia | General disorders | Systematic Assessment |
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Not provided
Not provided