Antidepressant Effects of TS-161 in Treatment-Resistant Depression
- Conditions
- Major Depressive DisorderTreatment-Resistant DepressionDepression
- Interventions
- Other: PlaceboDrug: TS-161 (50 - 100 mg)
- Registration Number
- NCT04821271
- Lead Sponsor
- National Institute of Mental Health (NIMH)
- Brief Summary
Background:
Major depressive disorder (MDD) is a common, chronic mental illness. It can take weeks to months for antidepressants to work. Researchers want to test a new drug that might act more rapidly.
Objective:
To see if TS-161 will improve symptoms of depression in people with MDD.
Eligibility:
Adults ages 18-65 with MDD without psychotic features.
Design:
Participants will be screened under a separate protocol. They will have blood tests. They will complete surveys about their symptoms.
Participants will have an inpatient visit at NIH. Participation may last 12-16 weeks.
During the first phase of the study, participants will be tapered off their psychiatric medicines. For 2 weeks they will have a drug-free period.
During Phase II participants will take TS-161 or placebo. They will take TS-161 for 3 weeks and placebo for 3 weeks. In between the 3-week time period, they will have 2-3 weeks where they will be drug free. Participants will also have the following tests during this time:
* Interviews
* Physical exams
* Psychological tests and surveys about their symptoms
* Blood draws and urine samples
* They may complete tests of mood and thinking
* MRI (Magnetic resonance imaging): Participants will lie in a machine that takes pictures of their brain.
* Functional MRIs: They will perform tasks displayed on a computer screen inside the MRI scanner
* MEG (magnetoencephalography): Participants will lie down and do tasks of memory, attention, and thinking. A cone lowered on their head will record brain activity.
* Electrocardiograms to record the heart s electrical activity. Electrodes will be placed on the skin....
- Detailed Description
OBJECTIVE
Modulation of glutamatergic signaling is implicated in improvement of depressive symptoms and related constructs/dimensions of observable behavior and neurobiological measures with treatment. Current standard monoaminergic pharmacological approaches for major depressive disorder (MDD) have proven to be only modestly effective during acute major depressive episodes (MDEs). We have systematically tested different glutamatergic modulators in subjects with mood disorders in order to develop improved therapeutics. We found that the N-methyl-D-aspartate receptor (NMDAR) antagonist, ketamine, produces rapid antidepressant effects in patients with treatment-resistant depression (TRD in MDD, Bipolar Disorder) and in suicidal ideation. However, despite being highly efficacious, ketamine produces psychotomimetic effects and has the risk of abuse. The antidepressant effects of mGlu2/3 receptor antagonists are worthy of pursuit, since the antidepressant profile in preclinical assays as well as the synaptic/neural cellular and molecular mechanisms involved in their actions are comparable to those of ketamine, but without the side effects and abuse potential of ketamine.
In the present protocol, we aim to evaluate a new glutamate-mediated mechanism associated with antidepressant efficacy by targeting the mGlu2/3 receptor with a potent and selective antagonist. Targeting the mGlu2/3 receptor with an antagonist is anticipated to, and similar to ketamine, result via pre-synaptic mechanisms in a "glutamate surge" with subsequent alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) activation and gamma power increases but without potential adverse effects that occur with ketamine.
The present Phase 2 proof-of-concept (POC) study is designed to evaluate in subjects with MDD, the antidepressant effects of TS-161, the prodrug of a potent and selective mGlu2/3 receptor antagonist TP0178894 that crosses the blood brain barrier (BBB). In animal model assays of antidepressant efficacy, TS-161 induced acute and prolonged antidepressant-like effects without exhibiting ketamine-like side effects as determined by the lack of increase in locomotor activity or abuse potential.
We will also evaluate the putative neurobiological mechanisms involved in the antidepressant response to TS-161. We expect that this effect may modulate glutamate transmission and reverse the clinical symptoms of depression. The demonstration that an mGlu2/3 receptor antagonist produces antidepressant effects without psychotomimetic side effects would support the therapeutic relevance of the mGlu2/3 receptor 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 consented.
DESIGN
Male and female subjects, 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 mGlu2/3 receptor antagonist prodrug TS-161 (50 to 100 mg/day given orally) or placebo for 3 weeks. The study will assess the efficacy in improving overall depressive symptomatology and tolerability of TS-161 in treatment-resistant MDD. Other aims of the study include determining whether changes in gamma power obtained via magnetoencephalography (MEG), brain neurochemicals (e.g. glutamate) obtained via magnetic resonance spectroscopy (MRS), and peripheral measures correlate with drug effects and/or antidepressant response to TS-161 in subjects with treatment-resistant MDD.
OUTCOME MEASURES
Primary: Montgomery-Asberg Depression Rating Scale (MADRS) total score.
Secondary: Proportion of subjects achieving remission (MADRS\<=10) and response (\>=50% reduction from baseline in MADRS total score); change from baseline on the Hamilton Rating Scale (HDRS), change from baseline in Hamilton Anxiety Rating Scale (HAM-A), and the Columbia Suicide Severity Rating Scale (C-SSRS) total scores. Surrogate biomarkers of drug effect/response include: changes in gamma power measured with MEG, changes in prefrontal glutamate levels measured with 7T 1H-MRS, resting and task based functional connectivity with fMRI, neurocognitive functioning, and changes in peripheral biological indices (neurotrophic factors, cell cycle/signal transduction regulators, neuroinflammatory, neuroendocrinological measures, and metabolomic and proteomic measures).
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 11
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- CROSSOVER
- Arm && Interventions
Group Intervention Description 2 Placebo Individuals in Arm 2 will receive daily double-blinded placebo for three weeks during Test Session 1 and daily double-blinded TS-161 for three weeks during Test Session 2. 1 Placebo Individuals in Arm 1 will receive daily double-blinded TS-161 for three weeks during Test Session 1 and daily double-blinded placebo for three weeks during Test Session 2. 1 TS-161 (50 - 100 mg) Individuals in Arm 1 will receive daily double-blinded TS-161 for three weeks during Test Session 1 and daily double-blinded placebo for three weeks during Test Session 2. 2 TS-161 (50 - 100 mg) Individuals in Arm 2 will receive daily double-blinded placebo for three weeks during Test Session 1 and daily double-blinded TS-161 for three weeks during Test Session 2.
- Primary Outcome Measures
Name Time Method Change from baseline on Montgomery-Asberg Depression Rating Scale (MADRS) total scores Baseline, Day 21 Clinical rating scale of depression
- Secondary Outcome Measures
Name Time Method Proportion of participants achieving response (defined as a >/=50% reduction from baseline in MADRS total score). Baseline, 230 min post-drug, and Days 1, 2, 3, 7, 14, and 21, per Test Session. Clinical rating scale of depression
Gamma power measured via MEG Baseline, 120 min post-dose, Day 21 Measurement of glutamate and glutamine levels
Change from baseline on MADRS total scores Baseline, 230 min post-drug, and Days 1, 2, 3, 7, and 14, per Test Session. Clinical rating scale of depression
Proportion of participants in remission (defined as MADRS total score =10) Baseline, 230 min post-drug, and Days 1, 2, 3, 7, 14, and 21, per Test Session. Clinical rating scale of depression
Incidence of AEs and total scores using the Clinician Administered Dissociative States Scale (CADSS), Young Mania Rating Scale (YMRS), the Brief Psychiatric Rating Scale (BPRS), vital signs, changes in clinical laboratory evaluations, and ECGs. At specific timepoints within each treatment condition indicated in the protocol. Measures and evaluations assess various aspects of clinical condition, adverse events, and mood and anxiety symptomology
Changes in activity in the frontolimbic circuitry Baseline, 240 min post-dose, Day 21 fMRI is used to measure frontolimbic circuitry
Change from baseline on the HDRS, HAM-A, the PANAS, Snaith Hamilton Pleasure Scale (SHAPS), and the Temporal Experience of Pleasure Scale (TEPS) scales. Baseline, 230 min post-drug, and Days 1, 2, 3, 7, 14, and 21, per Test Session. Clinical rating scales of mood, anxiety, and anhedonia.
Change from baseline on item 10 (suicidality) of the MADRS and total score on the C-SSRS, and the Scale for Suicidal Ideation (SSI). Baseline, 230 min post-drug, and Days 1, 2, 3, 7, 14, and 21, per Test Session. Clinical assessments of suicidality
[1]H-MRS correlates with changes in MADRS score Baseline, 240 min post-drug, Day 21, per Test Session MADRS: Clinical rating scale of depression; MRS: Measurement of glutamate and glutamine levels
Trial Locations
- Locations (1)
National Institutes of Health Clinical Center
🇺🇸Bethesda, Maryland, United States