Antidepressant Effects of the Glycine Receptor Antagonist AV-101 (4-chlorokynurenine) in Major Depressive Disorder
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|ClinicalTrials.gov Identifier: NCT02484456|
Recruitment Status : Recruiting
First Posted : June 29, 2015
Last Update Posted : May 30, 2018
- 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.
- To see if the drug, AV-101 is safe and if it treats symptoms of major depressive disorder.
- Adults ages 18-65 with major depression without psychotic features.
- 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
- 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.
|Condition or disease||Intervention/treatment||Phase|
|Major Depression||Drug: AV 101 (4-Chlorokynurenine) Other: Placebo||Phase 2|
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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.
Twenty-five individuals with treatment-resistant major depressive disorder (MDD) will be included.
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.
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 Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||25 participants|
|Intervention Model:||Crossover Assignment|
|Masking:||Double (Participant, Investigator)|
|Official Title:||An Investigation of the Antidepressant Effects of the Glycine Receptor Antagonist AV 101 (4-chlorokynurenine) in Major Depressive Disorder|
|Study Start Date :||June 19, 2015|
|Estimated Primary Completion Date :||December 31, 2019|
|Estimated Study Completion Date :||December 31, 2019|
Placebo Comparator: Test Session 2
2 weeks of single daily dose of placebo pill
Experimental: Test Session 1
2 weeks of 1,080 or 1,440 mg/day (single daily dose) of study drug
Drug: AV 101 (4-Chlorokynurenine)
Glycine Receptor Antagonist
- Change from baseline in the Hamilton Depression Rating scale total score. [ Time Frame: Multiple timepoints ]
- Change from baseline in BPRS, CADSS, C-SSRS, HAM-A, HDRS, MADRS, PANAS, SHAPS, SSI, TEPS, YMRS total scores. [ Time Frame: Multiple ]
- Change from baseline in the C-SSRS total score. [ Time Frame: Multiple ]
- Proportion of subjects with response (defined as greater than or equal to 50% reduction from baseline in HDRS total score [ Time Frame: Multiple ]
- Proportion of subjects in remission (defined as HDRS total score less than or equal to 7 [ Time Frame: End of test sessions ]
- Incidence and nature of adverse events; vital signs; weight and body mass index (BMI) changes; physical examination changes; clinical laboratory evaluations; ECG. [ Time Frame: Multiple ]
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02484456
|Contact: Libby Jolkovsky||(877) firstname.lastname@example.org|
|United States, Maryland|
|National Institutes of Health Clinical Center, 9000 Rockville Pike||Recruiting|
|Bethesda, Maryland, United States, 20892|
|Contact: For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR) 800-411-1222 ext TTY8664111010 email@example.com|
|Principal Investigator:||Carlos A Zarate, M.D.||National Institute of Mental Health (NIMH)|