# Leveraging Rapid-Acting Antidepressants for Personalized Response

> **NIH NIH F30** · YALE UNIVERSITY · 2022 · $31,637

## Abstract

PROJECT SUMMARY
 At least 1 in 10 people experience debilitating depression in their life, representing major personal, social,
and economic burden. In light of this it is troubling that current treatments for depression have been inadequate.
A standard first-line antidepressant, for example, is often beneficial but can take weeks to reach an effective
dose and will still fail in over half of patients. A key challenge is that while the clinical presentation of depression
is heterogeneous across patients—likely due to distinct brain circuit and system-level disruptions underlying their
symptoms—current medications are not personalized to one’s specific needs. Recently, compounds with fast-
acting antidepressant properties have emerged as potential revolutionizing therapies. One such compound is
ketamine, primarily an NMDA receptor antagonist, which at low dose relieves an array of depressive symptoms
with rapid onset and sustained response. The therapeutic promise of ketamine led to recent clinical approvals
for treatment-resistant depression and acute suicidal ideation. Still, similar to conventional treatments, rapid-
acting antidepressants are not effective for all patients nor targeted to one’s specific symptoms. Thus, a critical
opportunity to extend and enhance the beneficial actions of ketamine will be addressed here.
 Several studies now link the behavioral actions of ketamine to the growth of new synapses on frontal cortical
pyramidal neurons, but it is unknown which input pathways benefit from this increase in connectivity. The input
specificity of ketamine’s plasticity actions is crucial because distinct afferents to frontal cortex are thought to
underlie discrete behavioral impairments, such as deficits in reward processing that commonly follow chronic
stress. Aim 1 will uncover ketamine’s typical plasticity actions on various inputs to frontal cortex using in vivo
optical imaging in the mouse. Next, ketamine-induced synaptic plasticity will be augmented by stimulating one
specific pathway during drug administration. Aim 2 will harness this approach to modify a corticocortical pathway
with hypothesized relevance to reward-guided behavior. Specifically, an instrumental sucrose preference task
recently developed in-house uses principles of reinforcement learning to reveal deficits in reward processing
following chronic social defeat. With this paradigm, input-specific stimulation of retrosplenial cortex inputs to
medial frontal cortex will be added to ketamine treatment and to improve the rescue of stress-induced deficits in
reward sensitivity. Together, this work will reveal if the neural and behavioral actions of rapid antidepressants
can be individualized, fueling the critical insights needed to adapt these emerging therapies to best serve patients.

## Key facts

- **NIH application ID:** 10490846
- **Project number:** 5F30MH129085-02
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Neil Savalia
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $31,637
- **Award type:** 5
- **Project period:** 2021-09-16 → 2024-09-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10490846

## Citation

> US National Institutes of Health, RePORTER application 10490846, Leveraging Rapid-Acting Antidepressants for Personalized Response (5F30MH129085-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10490846. Licensed CC0.

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