UMIN-CTR Clinical Trial
| Unique ID issued by UMIN | UMIN000055331 |
|---|---|
| Receipt number | R000063234 |
| Scientific Title | Core Molecular and Neural Mechanisms of Treatment-Resistant Depression (TRD) & Novel Treatment: Combining clinical trials, animal experiments, gene and family follow-up research |
| Date of disclosure of the study information | 2024/08/25 |
| Last modified on | 2024/08/25 21:44:33 |
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Basic information
Public title
Core Molecular and Neural Mechanisms of Treatment-Resistant Depression (TRD) & Novel Treatment: Combining clinical trials, animal experiments, gene and family follow-up research
Acronym
CMNM-TRD & NT: CCT, AE, GFFR
Scientific Title
Core Molecular and Neural Mechanisms of Treatment-Resistant Depression (TRD) & Novel Treatment: Combining clinical trials, animal experiments, gene and family follow-up research
Scientific Title:Acronym
CMNM-TRD & NT: CCT, AE, GFFR
Region
| Asia(except Japan) |
Condition
Condition
1.Understand the molecular mechanisms of Treatment-Resistant Depression (TRD) and the associated prefrontal cortex-related brain networks.
2.Investigate the effects of novel glutamatergic treatments and core molecular mechanisms by administering low doses of Ketamine or S-Ketamine (Esketamine) +/- GABA-A agonists in TRD patients.
3.Study the heritability and polygenic risks associated with Treatment-Resistant Depression (TRD).
Classification by specialty
| Psychiatry |
Classification by malignancy
Others
Genomic information
YES
Objectives
Narrative objectives1
Owing to the high prevalence of treatment-resistant depression (TRD) patients and the dilemma in treating these patients, we aim to find the underlying mechanisms and novel treatments for them. Growing studies indicate that neurobiological factors significantly contribute to TRD, with glutamate and GABA, rather than monoamines, potentially being key to TRD. Additionally, the DLPFC (dorsolateral PFC) is critically involved in TRD, but its role remains largely unknown. Therefore, our central hypothesis is that the underlying molecular mechanisms of TRD involve decreased GABA-B receptor-mediated inhibition (or in combination with GABA-A receptor-mediated inhibition), leading to decreased glutamate receptor-mediated pyramidal neuronal function (which may be accompanied by decreased phosphorylated ERK), which in turn leads to further suppression of GABA-B receptor-mediated inhibition. To test this hypothesis, we divided the experiment into three parts: a study on brain function in TRD, a study on the treatment of TRD cases using low-dose Ketamine and S-Ketamine (Esketamine), and a study on genes associated with TRD.
Basic objectives2
Others
Basic objectives -Others
Focuses on exploring the underlying molecular mechanisms of TRD, particularly in relation to PFC-related networks. Glutamate and GABA are recognized as key players in the core antidepressant mechanisms, with the DLPFC identified as a critical region in the pathophysiology of TRD. Our specific objective is to investigate whether the impairment of GABA-B receptors and/or GABA-A mediated inhibition in the DLPFC is more pronounced in TRD and how this contributes to its pathophysiology. To achieve this, we will employ a novel methodology combining human studies.
Trial characteristics_1
Trial characteristics_2
Developmental phase
Assessment
Primary outcomes
According to three different conditions, we divided the whole study into three parts, each with a corresponding primary outcome.
1. Compare the differences in functional connectivity, brain glucose metabolism activity, and brain wave patterns between patients with Treatment-Resistant Depression and other subjects in prefrontal cortex-related brain regions.
2. Compare the differences in antidepressant effects both between and within groups treated with novel glutamatergic drugs.
3. Identify the SNP loci associated with Treatment-Resistant Depression and use Polygenic Risk Scoring (PRS) to predict the risk of siblings developing Treatment-Resistant Depression
Key secondary outcomes
Base
Study type
Interventional
Study design
Basic design
Cross-over
Randomization
Randomized
Randomization unit
Individual
Blinding
Double blind -all involved are blinded
Control
Placebo
Stratification
Dynamic allocation
Institution consideration
Blocking
Concealment
Intervention
No. of arms
2
Purpose of intervention
Treatment
Type of intervention
| Medicine |
Interventions/Control_1
In the first and second years, the Ketamine study will be conducted, followed by the Esketamine study in the third and fourth years.
Ketamine Group: A total of 48 participants will be enrolled and randomly assigned in a 1:1 ratio to the following two parts:
1.For the first session, after an intramuscular injection of 0.045 mg/kg of Midazolam, an intravenous infusion of 0.5 mg/kg of Ketamine will be administered 30 minutes later. Two weeks later, for the second session, after an intramuscular injection of saline (placebo), an intravenous infusion of 0.5 mg/kg of Ketamine will be administered 30 minutes later.
2.For the first session, after an intramuscular injection of saline (placebo), an intravenous infusion of 0.5 mg/kg of Ketamine will be administered 30 minutes later. Two weeks later, for the second session, after an intramuscular injection of 0.045 mg/kg of Midazolam, an intravenous infusion of 0.5 mg/kg of Ketamine will be administered 30 minutes later.
Interventions/Control_2
Esketamine Group: A total of 48 participants will be enrolled and randomly assigned in a 1:1 ratio to the following two parts:
1.For the first session, after an intramuscular injection of 0.045 mg/kg of Midazolam, a nasal spray of 84 mg of Esketamine will be administered 30 minutes later. Two weeks later, for the second session, after an intramuscular injection of saline (placebo), a nasal spray of 84 mg of Esketamine will be administered 30 minutes later.
2.For the first session, after an intramuscular injection of saline (placebo), a nasal spray of 84 mg of Esketamine will be administered 30 minutes later. Two weeks later, for the second session, after an intramuscular injection of 0.045 mg/kg of Midazolam, a nasal spray of 84 mg of Esketamine will be administered 30 minutes later.
Interventions/Control_3
Interventions/Control_4
Interventions/Control_5
Interventions/Control_6
Interventions/Control_7
Interventions/Control_8
Interventions/Control_9
Interventions/Control_10
Eligibility
Age-lower limit
| 21 | years-old | <= |
Age-upper limit
| 75 | years-old | >= |
Gender
Male and Female
Key inclusion criteria
Treatment-Resistant Depression (TRD): Must have a well-documented history confirming that the patient has not responded to at least two different antidepressants (including Selective Serotonin Reuptake Inhibitors, SSRIs) at adequate doses and treatment durations. Depression severity is assessed with the 17-item Hamilton Depression Rating Scale (HDRS-17), with a score of 18 or above, and the Clinical Global Impression-Severity (CGI-S) scale with a score of 4 or above.
Key exclusion criteria
1.Previously met the DSM-IV criteria for Bipolar Disorder, Schizophrenia, or Dementia.
2.History of major medical or surgical illnesses or neurological disorders; or currently has physical conditions that the investigator deems unsuitable for this treatment (e.g., severe hypertension, severe cardiovascular disease, severe liver or kidney dysfunction, or other physical abnormalities that the investigator considers unsuitable for this treatment).
3.History of alcohol and drug abuse.
4.Presence of metallic implants or other implants that may interfere with EEG signals.
5.Substance dependence or abuse within the past six months (e.g., cocaine, cannabis, opioids, ketamine, MDMA).
6.Current use of NMDA receptor antagonist medications (e.g., Amantadine, Rimantadine, Lamotrigine, Memantine, Dextromethorphan).
7.Pregnant subjects.
8.Other conditions that prevent cooperation, such as being deemed unsuitable after screening or refusal to sign the informed consent form.
9.Previously underwent Ketamine treatment with no antidepressant effect.
10.Exclusion of subjects with strong suicidal ideation within the past week, as indicated by a score of 4 on the third item of the Hamilton Depression Rating Scale (suicidality).
Target sample size
96
Research contact person
Name of lead principal investigator
| 1st name | Cheng-Ta |
| Middle name | |
| Last name | Li |
Organization
Taipei Veterans General Hospital, Taiwan
Division name
Department of Psychiatry
Zip code
112
Address
No.201, Sec. 2, Shih-Pai Road, Beitou district, Taipei, Taiwan
TEL
+88628757027
on5083@msn.com
Public contact
Name of contact person
| 1st name | Cheng-Ta |
| Middle name | |
| Last name | Li |
Organization
Taipei Veterans General Hospital, Taiwan
Division name
Department of Psychiatry
Zip code
112
Address
No.201, Sec. 2, Shih-Pai Road, Beitou district, Taipei, Taiwan
TEL
+88628757027
Homepage URL
on5083@msn.com
Sponsor or person
Institute
Grant of Taipei Veterans General Hospital, Taiwan
Institute
Department
Personal name
Funding Source
Organization
Taipei Veterans General Hospital, Taiwan
Organization
Division
Category of Funding Organization
Outside Japan
Nationality of Funding Organization
Other related organizations
Co-sponsor
Name of secondary funder(s)
IRB Contact (For public release)
Organization
Institutional Review Board, Taipei Veterans General Hospital, Taipei, Taiwan
Address
NO.201, SEC. 2, SHIPAI RD, Taipei City, Taiwan
Tel
886-2-2875-7384
irbopinion@vghtpe.gov.tw
Secondary IDs
Secondary IDs
NO
Study ID_1
Org. issuing International ID_1
Study ID_2
Org. issuing International ID_2
IND to MHLW
Institutions
Institutions
Other administrative information
Date of disclosure of the study information
| 2024 | Year | 08 | Month | 25 | Day |
Related information
URL releasing protocol
Publication of results
Unpublished
Result
URL related to results and publications
Number of participants that the trial has enrolled
Results
Results date posted
Results Delayed
Results Delay Reason
Date of the first journal publication of results
Baseline Characteristics
Participant flow
Adverse events
Outcome measures
Plan to share IPD
IPD sharing Plan description
Progress
Recruitment status
Enrolling by invitation
Date of protocol fixation
| 2022 | Year | 09 | Month | 01 | Day |
Date of IRB
| 2022 | Year | 03 | Month | 18 | Day |
Anticipated trial start date
| 2022 | Year | 09 | Month | 01 | Day |
Last follow-up date
| 2025 | Year | 08 | Month | 31 | Day |
Date of closure to data entry
Date trial data considered complete
Date analysis concluded
Other
Other related information
Management information
Registered date
| 2024 | Year | 08 | Month | 25 | Day |
Last modified on
| 2024 | Year | 08 | Month | 25 | Day |
Link to view the page
Value
https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000063234
