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Antidepressant Effects of TS-161 in Treatment-Resistant Depression

Primary Purpose

Major Depressive Disorder, Treatment-Resistant Depression, Depression

Status
Recruiting
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Placebo
TS-161 (50 - 100 mg)
Sponsored by
National Institute of Mental Health (NIMH)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Major Depressive Disorder focused on measuring Biomarker, Neurobiology, Glutamate, Magnetoencephalography, Magnetic Resonance Spectroscopy

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers
  • INCLUSION CRITERIA:

Participants may be eligible for this study if they:

  1. Are able to understand the study and can provide your own consent.
  2. Are willing to undergo all study procedures and are available for the duration of the study.
  3. Are aged 18 to 65.
  4. Have major depressive disorder.
  5. Have a current episode of depression lasting at least 4 weeks.
  6. Ability to take oral medication.
  7. Have not responded to at least one antidepressant.
  8. For females of reproductive potential: use of contraception while in the study and for an additional 4 weeks after stopping the study drug.
  9. 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.
  10. Agree to be hospitalized at the NIH Clinical Center.
  11. Abstain from alcohol and drug use while in the study.

EXCLUSION CRITERIA:

Participants may not be eligible for this study if they:

  1. Are taking any medications that might make it unsafe for you to receive TS-161 or might interfere with our study results.
  2. 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.
  3. Have been treated with fluoxetine, aripiprazole, or brexpiprazole less than 5 weeks before Phase II.
  4. Have ever undergone deep brain stimulation.
  5. Have taken ketamine or esketamine for the treatment of depression but did not respond.
  6. Are unwilling to stop undergoing one-on-one psychotherapy for the duration of the study.
  7. Are pregnant or plan to become pregnant in the next 12 to 16 weeks while in the study, or are breast-feeding.
  8. Have schizophrenia or any other psychotic disorder.
  9. Had significant drug or alcohol dependence or abuse in the past 3 months (except for nicotine or caffeine), or are currently using illicit substances.
  10. Have been diagnosed with borderline or antisocial personality disorder.
  11. Had a head injury that caused a loss of consciousness for more than 5 minutes (for the brain imaging).
  12. 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.
  13. Have abnormal results on blood and urine tests we will do.
  14. Have significant suicidal or homicidal thoughts.
  15. Have a positive HIV test.
  16. 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.
  17. Weigh over 245 lbs and cannot fit into the MRI scanner.
  18. Have a positive, or suspected positive, COVID-19 test.
  19. Are an NIMH staff member or an immediate family member of an NIMH staff member.

Sites / Locations

  • National Institutes of Health Clinical CenterRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

1

2

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

Change from baseline on Montgomery-Asberg Depression Rating Scale (MADRS) total scores
Clinical rating scale of depression

Secondary Outcome Measures

Proportion of participants in remission (defined as MADRS total score =10)
Clinical rating scale of depression
Proportion of participants achieving response (defined as a >/=50% reduction from baseline in MADRS total score).
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.
Measures and evaluations assess various aspects of clinical condition, adverse events, and mood and anxiety symptomology
Gamma power measured via MEG
Measurement of glutamate and glutamine levels
Changes in activity in the frontolimbic circuitry
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.
Clinical rating scales of mood, anxiety, and anhedonia.
Change from baseline on MADRS total scores
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).
Clinical assessments of suicidality
[1]H-MRS correlates with changes in MADRS score
MADRS: Clinical rating scale of depression; MRS: Measurement of glutamate and glutamine levels

Full Information

First Posted
February 27, 2021
Last Updated
September 2, 2023
Sponsor
National Institute of Mental Health (NIMH)
Collaborators
Taisho Pharmaceutical Co., Ltd.
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1. Study Identification

Unique Protocol Identification Number
NCT04821271
Brief Title
Antidepressant Effects of TS-161 in Treatment-Resistant Depression
Official Title
An Investigation of the Antidepressant Effects of the mGlu2/3 Receptor Antagonist TS-161 in Treatment-Resistant Depression
Study Type
Interventional

2. Study Status

Record Verification Date
August 30, 2023
Overall Recruitment Status
Recruiting
Study Start Date
June 10, 2021 (Actual)
Primary Completion Date
June 3, 2024 (Anticipated)
Study Completion Date
June 3, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Institute of Mental Health (NIMH)
Collaborators
Taisho Pharmaceutical Co., Ltd.

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No

5. 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....
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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Major Depressive Disorder, Treatment-Resistant Depression, Depression
Keywords
Biomarker, Neurobiology, Glutamate, Magnetoencephalography, Magnetic Resonance Spectroscopy

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Crossover Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
25 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
1
Arm Type
Experimental
Arm Description
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.
Arm Title
2
Arm Type
Experimental
Arm Description
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.
Intervention Type
Other
Intervention Name(s)
Placebo
Intervention Description
Arm 1 and 2 Control Intervention
Intervention Type
Drug
Intervention Name(s)
TS-161 (50 - 100 mg)
Intervention Description
Arm 1 and 2 Experimental Intervention
Primary Outcome Measure Information:
Title
Change from baseline on Montgomery-Asberg Depression Rating Scale (MADRS) total scores
Description
Clinical rating scale of depression
Time Frame
Baseline, Day 21
Secondary Outcome Measure Information:
Title
Proportion of participants in remission (defined as MADRS total score =10)
Description
Clinical rating scale of depression
Time Frame
Baseline, 230 min post-drug, and Days 1, 2, 3, 7, 14, and 21, per Test Session.
Title
Proportion of participants achieving response (defined as a >/=50% reduction from baseline in MADRS total score).
Description
Clinical rating scale of depression
Time Frame
Baseline, 230 min post-drug, and Days 1, 2, 3, 7, 14, and 21, per Test Session.
Title
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.
Description
Measures and evaluations assess various aspects of clinical condition, adverse events, and mood and anxiety symptomology
Time Frame
At specific timepoints within each treatment condition indicated in the protocol.
Title
Gamma power measured via MEG
Description
Measurement of glutamate and glutamine levels
Time Frame
Baseline, 120 min post-dose, Day 21
Title
Changes in activity in the frontolimbic circuitry
Description
fMRI is used to measure frontolimbic circuitry
Time Frame
Baseline, 240 min post-dose, Day 21
Title
Change from baseline on the HDRS, HAM-A, the PANAS, Snaith Hamilton Pleasure Scale (SHAPS), and the Temporal Experience of Pleasure Scale (TEPS) scales.
Description
Clinical rating scales of mood, anxiety, and anhedonia.
Time Frame
Baseline, 230 min post-drug, and Days 1, 2, 3, 7, 14, and 21, per Test Session.
Title
Change from baseline on MADRS total scores
Description
Clinical rating scale of depression
Time Frame
Baseline, 230 min post-drug, and Days 1, 2, 3, 7, and 14, per Test Session.
Title
Change from baseline on item 10 (suicidality) of the MADRS and total score on the C-SSRS, and the Scale for Suicidal Ideation (SSI).
Description
Clinical assessments of suicidality
Time Frame
Baseline, 230 min post-drug, and Days 1, 2, 3, 7, 14, and 21, per Test Session.
Title
[1]H-MRS correlates with changes in MADRS score
Description
MADRS: Clinical rating scale of depression; MRS: Measurement of glutamate and glutamine levels
Time Frame
Baseline, 240 min post-drug, Day 21, per Test Session

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Carlos A Zarate, M.D.
Phone
(877) 646-3644
Email
moodresearch@mail.nih.gov
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Carlos A Zarate, M.D.
Organizational Affiliation
National Institute of Mental Health (NIMH)
Official's Role
Principal Investigator
Facility Information:
Facility Name
National Institutes of Health Clinical Center
City
Bethesda
State/Province
Maryland
ZIP/Postal Code
20892
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR)
Phone
800-411-1222
Ext
TTY8664111010
Email
prpl@cc.nih.gov

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
.Clinical and demographic and biomarker participant data collected during the trial, after deidentification.
IPD Sharing Time Frame
Starting within 1 year of completion of the study.
IPD Sharing Access Criteria
Branch Chief will review requests and access will need to be approved by the NIMH/DIRP SD and OCD NIMH and the NIH IRB.
Links:
URL
https://clinicalstudies.info.nih.gov/cgi/detail.cgi?A_000101-M.html
Description
NIH Clinical Center Detailed Web Page

Learn more about this trial

Antidepressant Effects of TS-161 in Treatment-Resistant Depression

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