# Determining the efficacy of psychedelic agents reversing depression-relevant amotivated behaviors with concomittant EEG biomarkers.

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2024 · $237,000

## Abstract

Project Summary
Major depressive disorder (MDD) is a common and burdensome psychiatric disorder. Unfortunately, current
depression treatments suffer from numerous weaknesses, including treatment-resistance in a large proportion
of patients. Several factors likely contribute to the limitations of current MDD pharmacotherapies, including the
heterogeneous nature of depression symptoms and the fact that most conventional treatments were
discovered serendipitously rather than by targeting the underlying mechanisms of the disorder. One reason
why targeted treatments have not been developed for MDD is the lack of translation between the depression-
relevant behaviors quantifiable in humans relative to those used to model MDD. Unfortunately, many
behavioral models used to test new medications for MDD are often based on phenomena will limited relevance
to those seen in humans, meaning that treatments targeting those behaviors often have limited clinical efficacy.
As an alternative to those existing models, specific tests quantify impairments exhibited by people with
depression that are also available for testing in rodents. Here, we propose an approach that leverages the
clinical sensitivities of behavioral and electroencephalographic (EEG) assessments to better evaluate the
putative impact of depression-relevant manipulations. Given the heterogeneous origins of MDD, Aim 1 will
test whether three distinct manipulations known to induce depression-relevant behaviors (chronic
corticosterone treatment, a short-active winter-like photoperiod, and acute treatment with the
acetylcholinesterase inhibitor physostigmine) are capable of inducing depression-relevant states in mice,
using cross-species behavioral readouts affected in people with MDD, the probabilistic reversal learning and
progressive ratio breakpoint tasks. Because depression can also alter neurological processes independent of
its behavioral impacts, Aim 2 will test whether the same three manipulations have effects on specific
behavioral-associated neural processes that are known to be impacted in MDD that can be directly
tested in rodents (Reward Positivity and parietal alpha power). Finally, to test the ability of these models to
detect novel treatment efficacy, Aim 3 will determine the impact on these models of classical psychedelic
drugs such as psilocybin (currently undergoing human trials for MDD) that produce long-lasting symptom
reductions after acute administration. To disentangle the potential therapeutic-like effects of psychedelics from
their intoxicating properties, the psychedelics will be tested at doses equivalent to high and low (micro)doses in
humans. Overall, we will develop translational depression-relevant models that target specific domains of
performance impacted in people and assessable in mice, potentially enabling the discovery and development
of new, mechanistically-targeted treatments for MDD. Given our use of psychedelics in current clinical trials
and use of these EEG-...

## Key facts

- **NIH application ID:** 10799340
- **Project number:** 1R21MH135378-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** ADAM L. Halberstadt
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $237,000
- **Award type:** 1
- **Project period:** 2024-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10799340

## Citation

> US National Institutes of Health, RePORTER application 10799340, Determining the efficacy of psychedelic agents reversing depression-relevant amotivated behaviors with concomittant EEG biomarkers. (1R21MH135378-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10799340. Licensed CC0.

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