Antidepressant Effects of TS-161 in Treatment-Resistant Depression

Sponsor

National Institute of Mental Health (NIMH) (NIH)

Overall Status

Recruiting

CT.gov ID

NCT04821271

Collaborator

Taisho Pharmaceutical Co., Ltd. (Industry)

Enrollment

Location

Arms

23.8

Anticipated Duration (Months)

1.1

Patients Per Site Per Month

Study Details

Study Description

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....

Condition or Disease	Intervention/Treatment	Phase
Major Depressive Disorder Treatment-Resistant Depression Depression	Other: Placebo Drug: TS-161 (50 - 100 mg)	Phase 2

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).

Study Design

Study Type:

Interventional

Anticipated Enrollment :

25 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Masking:

Triple (Participant, Care Provider, Investigator)

Primary Purpose:

Treatment

Official Title:

An Investigation of the Antidepressant Effects of the mGlu2/3 Receptor Antagonist TS-161 in Treatment-Resistant Depression

Actual Study Start Date :

Jun 10, 2021

Anticipated Primary Completion Date :

Jun 3, 2023

Anticipated Study Completion Date :

Jun 3, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1 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.	Other: Placebo Arm 1 and 2 Control Intervention Drug: TS-161 (50 - 100 mg) Arm 1 and 2 Experimental Intervention
Experimental: 2 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.	Other: Placebo Arm 1 and 2 Control Intervention Drug: TS-161 (50 - 100 mg) Arm 1 and 2 Experimental Intervention

Arm

Intervention/Treatment

Experimental: 1

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.

Other: Placebo

Arm 1 and 2 Control Intervention

Drug: TS-161 (50 - 100 mg)

Arm 1 and 2 Experimental Intervention

Experimental: 2

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.

Other: Placebo

Arm 1 and 2 Control Intervention

Drug: TS-161 (50 - 100 mg)

Arm 1 and 2 Experimental Intervention

Outcome Measures

Primary Outcome Measures

Change from baseline on Montgomery-Asberg Depression Rating Scale (MADRS) total scores [Baseline, Day 21]
Clinical rating scale of depression

Secondary Outcome Measures

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
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
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
Gamma power measured via MEG [Baseline, 120 min post-dose, Day 21]
Measurement of glutamate and glutamine levels
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 MADRS total scores [Baseline, 230 min post-drug, and Days 1, 2, 3, 7, and 14, per Test Session.]
Clinical rating scale of depression
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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 65 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

INCLUSION CRITERIA:

Participants may be eligible for this study if they:

Are able to understand the study and can provide your own consent.
Are willing to undergo all study procedures and are available for the duration of the study.
Are aged 18 to 65.
Have major depressive disorder.
Have a current episode of depression lasting at least 4 weeks.
Ability to take oral medication.
Have not responded to at least one antidepressant.
For females of reproductive potential: use of contraception while in the study and for an additional 4 weeks after stopping the study drug.
For males of reproductive potential: use of condoms or other types of birth control with partner while in the study and for an additional 3 months after stopping the study drug.
Agree to be hospitalized at the NIH Clinical Center.
Abstain from alcohol and drug use while in the study.

EXCLUSION CRITERIA:

Participants may not be eligible for this study if they:

Are taking any medications that might make it unsafe for you to receive TS-161 or might interfere with our study results.
Have been treated with a reversible monoamine oxidase inhibitor (such as phenelzine (Nardil) and tranylcypromine (Parnate)), clozapine, or electroconvulsive therapy (ECT) less than 4 weeks before Phase II.
Have been treated with fluoxetine, aripiprazole, or brexpiprazole less than 5 weeks before Phase II.
Have ever undergone deep brain stimulation.
Have taken ketamine or esketamine for the treatment of depression but did not respond.
Are unwilling to stop undergoing one-on-one psychotherapy for the duration of the study.
Are pregnant or plan to become pregnant in the next 12 to 16 weeks while in the study, or are breast-feeding.
Have schizophrenia or any other psychotic disorder.
Had significant drug or alcohol dependence or abuse in the past 3 months (except for nicotine or caffeine), or are currently using illicit substances.
Have been diagnosed with borderline or antisocial personality disorder.
Had a head injury that caused a loss of consciousness for more than 5 minutes (for the brain imaging).
Have a medical illness that might make your participation unsafe, such as heart (including coronary artery disease, atherosclerotic ischemic stroke, and atrial fibrillation), liver, respiratory, blood, immune, or kidney disease or a seizure disorder, based on our evaluation.
Have abnormal results on blood and urine tests we will do.
Have significant suicidal or homicidal thoughts.
Have a positive HIV test.
For brain imaging: Have metal in your body which would make having an MRI scan unsafe, such as pacemakers, stimulators, pumps, aneurysm clips, metallic prostheses, artificial heart valves, cochlear implants or shrapnel fragments, or if you were a welder or metal worker, since you may have small metal fragments in the eye.
Weigh over 245 lbs and cannot fit into the MRI scanner.
Have a positive, or suspected positive, COVID-19 test.
Are an NIMH staff member or an immediate family member of an NIMH staff member.