# AMPA Receptor Components of the Antidepressant Response to Ketamine in Humans

> **NIH NIH R01** · YALE UNIVERSITY · 2023 · $837,441

## Abstract

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 α-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.

## Key facts

- **NIH application ID:** 10734845
- **Project number:** 1R01MH129371-01A1
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** NAOMI R DRIESEN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $837,441
- **Award type:** 1
- **Project period:** 2023-07-03 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10734845

## Citation

> US National Institutes of Health, RePORTER application 10734845, AMPA Receptor Components of the Antidepressant Response to Ketamine in Humans (1R01MH129371-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10734845. Licensed CC0.

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