Antidepressant Effects of the Glycine Receptor Antagonist AV-101 (4-chlorokynurenine) in Major Depressive Disorder
| Status: | Recruiting |
|---|---|
| Conditions: | Depression, Depression, Major Depression Disorder (MDD) |
| Therapuetic Areas: | Psychiatry / Psychology, Pulmonary / Respiratory Diseases |
| Healthy: | No |
| Age Range: | 18 - 65 |
| Updated: | 3/14/2019 |
| Start Date: | June 19, 2015 |
| End Date: | December 31, 2019 |
| Contact: | Libby Jolkovsky |
| Email: | jolkovsl@mail.nih.gov |
| Phone: | (877) 646-3644 |
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.
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.
- 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.
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-chlorokynurine
(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.
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-chlorokynurine
(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.
- INCLUSION CRITERIA:
- 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 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).
EXCLUSION CRITERIA:
- 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.
- 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 aripirazole 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.
We found this trial at
1
site
9000 Rockville Pike
Bethesda, Maryland 20892
Bethesda, Maryland 20892
Phone: 800-411-1222
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