R01MH129371
Project Grant
Overview
Grant Description
AMPA receptor components of the antidepressant response to ketamine in humans - project summary
Treatment resistant depression (TRD) is a major cause of distress and disability. The discovery of the antidepressant effects of ketamine, an N-methyl-D-aspartate glutamate receptor (NMDAR) antagonist, has brought new hope to TRD patients. The search for the biological bases underlying the antidepressant effects of ketamine is a key priority.
Preclinical studies suggest that, in the subcallosal cortex (SCC), ketamine activates cortical circuits, increasing glutamate release, stimulating A-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid glutamate receptors (AMPAR), and engaging downstream neuroplasticity mechanisms. In animal models of depression, AMPAR blockade prevents the antidepressant effects of ketamine. However, it is unclear whether this applies to humans with TRD.
With the availability of the first FDA-approved AMPAR antagonist, perampanel, we can now test this hypothesis.
Aim 1 evaluates whether perampanel pretreatment prevents the reduction in depression symptoms produced by ketamine in TRD patients.
Aim 2 tests whether perampanel pretreatment augments ketamine-related increases in SCC resting state functional connectivity.
Aim 3 assesses whether perampanel blocks ketamine-associated increases in SCC cerebral metabolic rate of oxygen relative to the pre-ketamine baseline. These metabolic increases may subserve restoring synaptic connectivity in TRD patients.
Together, these aims would provide an important test of a central hypothesis related to the mechanism underlying the therapeutic effects of ketamine and could inform efforts to develop alternatives to ketamine as a treatment for TRD.
Treatment resistant depression (TRD) is a major cause of distress and disability. The discovery of the antidepressant effects of ketamine, an N-methyl-D-aspartate glutamate receptor (NMDAR) antagonist, has brought new hope to TRD patients. The search for the biological bases underlying the antidepressant effects of ketamine is a key priority.
Preclinical studies suggest that, in the subcallosal cortex (SCC), ketamine activates cortical circuits, increasing glutamate release, stimulating A-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid glutamate receptors (AMPAR), and engaging downstream neuroplasticity mechanisms. In animal models of depression, AMPAR blockade prevents the antidepressant effects of ketamine. However, it is unclear whether this applies to humans with TRD.
With the availability of the first FDA-approved AMPAR antagonist, perampanel, we can now test this hypothesis.
Aim 1 evaluates whether perampanel pretreatment prevents the reduction in depression symptoms produced by ketamine in TRD patients.
Aim 2 tests whether perampanel pretreatment augments ketamine-related increases in SCC resting state functional connectivity.
Aim 3 assesses whether perampanel blocks ketamine-associated increases in SCC cerebral metabolic rate of oxygen relative to the pre-ketamine baseline. These metabolic increases may subserve restoring synaptic connectivity in TRD patients.
Together, these aims would provide an important test of a central hypothesis related to the mechanism underlying the therapeutic effects of ketamine and could inform efforts to develop alternatives to ketamine as a treatment for TRD.
Awardee
Funding Goals
NOT APPLICABLE
Grant Program (CFDA)
Awarding / Funding Agency
Place of Performance
New Haven,
Connecticut
065208043
United States
Geographic Scope
Single Zip Code
Related Opportunity
Analysis Notes
Amendment Since initial award the total obligations have increased 299% from $837,441 to $3,342,174.
Yale Univ was awarded
AMPAR Antagonist Perampanel in Ketamine-Resistant Depression Treatment
Project Grant R01MH129371
worth $3,342,174
from the National Institute of Mental Health in July 2023 with work to be completed primarily in New Haven Connecticut United States.
The grant
has a duration of 4 years 9 months and
was awarded through assistance program 93.242 Mental Health Research Grants.
The Project Grant was awarded through grant opportunity Research Project Grant (Parent R01 Clinical Trial Required).
Status
(Ongoing)
Last Modified 7/6/26
Period of Performance
7/3/23
Start Date
4/30/28
End Date
Funding Split
$3.3M
Federal Obligation
$0.0
Non-Federal Obligation
$3.3M
Total Obligated
Activity Timeline
Transaction History
Modifications to R01MH129371
Additional Detail
Award ID FAIN
R01MH129371
SAI Number
R01MH129371-2790327306
Award ID URI
SAI UNAVAILABLE
Awardee Classifications
Private Institution Of Higher Education
Awarding Office
75N700 NIH National Institute of Mental Health
Funding Office
75N700 NIH National Institute of Mental Health
Awardee UEI
FL6GV84CKN57
Awardee CAGE
4B992
Performance District
CT-03
Senators
Richard Blumenthal
Christopher Murphy
Christopher Murphy
Budget Funding
| Federal Account | Budget Subfunction | Object Class | Total | Percentage |
|---|---|---|---|---|
| National Institute of Mental Health, National Institutes of Health, Health and Human Services (075-0892) | Health research and training | Grants, subsidies, and contributions (41.0) | $837,441 | 100% |
Modified: 7/6/26