Antidepressant Effects of the Glycine Receptor Antagonist AV-101 (4-chlorokynurenine) in Major Depressive Disorder

Phase 2

Completed

Conditions: Major Depression

Interventions: Drug: AV 101 (4-Chlorokynurenine)
Other: Placebo Comparator

Registration Number: NCT02484456

Lead Sponsor: National Institute of Mental Health (NIMH)

Brief 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. 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 22

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Placebo, then AV 101 (4-chlorokynurenine)	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 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.
Placebo, then AV 101 (4-chlorokynurenine)	Placebo Comparator	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.
AV 101 (4-chlorokynurenine), then Placebo	AV 101 (4-Chlorokynurenine)	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.
AV 101 (4-chlorokynurenine), then Placebo	Placebo Comparator	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.

Primary Outcome Measures

Name	Time	Method
Model Adjusted Means for Hamilton Depression Rating Score	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.

Secondary Outcome Measures

Name	Time	Method
Model Adjusted Means for Beck Depression Score	Post Dose Day 13	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.
Model Adjusted Means for Hamilton Anxiety Rating Score	Post Dose Day 13	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.
Model Adjusted Means for Montgomery-Asberg Depression Rating Score	Post Dose Day 13	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.