# Evaluation of Bioenergetic Supplements in Treatment-Resistant Depression, Cognitive Dysfunction and Anxiety

> **NIH NIH R01** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2024 · $444,903

## Abstract

Major depressive disorder (MDD) and anxiety are linked to brain deficits in the bioenergetic molecules creatine
(CR) and acetyl-L carnitine (ALC), nutritional supplements which show potential as antidepressants. MDD and
anxiety are often comorbid, and affect 20% of US adults. Moreover, cognitive dysfunction contributes markedly
to MDD-linked functional disability. Classical antidepressants such as selective serotonin reuptake inhibitors
(SSRIs) are ineffective in ~50% of patients, and mostly do not improve cognitive symptoms. Unlike classical
antidepressants, bioenergetic compounds show promise for improving multiple aspects of MDD symptomology,
including cognitive function and comorbid anxiety. We now plan to explore the bioenergetic compounds CR,
cyclocreatine (CyCR, a CR analog) and ALC as therapeutics in a model for treatment resistant depression (TRD).
We established a sex-based animal model to study etiology of the high rates of MDD and anxiety in people at
altitude (hypobaric hypoxia). At moderate altitude (4500ft), rats of both sexes exhibit symptoms of depression,
anxiety and cognitive dysfunction vs. those at sea level, and a sustained lack of response to most SSRIs. Hypo-
baric hypoxia induces brain bioenergetic deficits, and CR, CyCR and ALC can reduce the deficit to show sex-
based antidepressant-like or anxiolytic-like efficacy in this model. Brain bioenergetic deficits are directly linked
to MDD, but can further promote onset of MDD by causing inflammation and oxidative stress. Hypoxia-inducible
transcription factors (HIFs) interact with the oxidative stress system to mediate cellular response to hypoxia, and
CR can alter HIF activation. Our central hypothesis is that bioenergetic compounds will improve status of de-
pression, anxiety and cognitive function by reducing inflammation and oxidative stress at altitude. In Aim 1, we
will identify impact of CR, CyCR and ALC vs. SSRI on behavioral symptoms. Efficacy in reducing symptoms of
depression (in forced swim, sucrose preference tests), anxiety (e.g., marble burying, elevated T-maze tests) and
cognitive dysfunction (e.g., novelty object, radial arm tests) will be tested. In Aim 2, we will study the mode of
action by which bioenergetic compounds reduce MDD-linked biomarkers. The impact of CR, CyCR and ALC on
biomarkers of inflammation (e.g., the nonspecific inflammatory marker CRF, inflammatory cytokines TNFα, IL6,
IL1β), HIF1a activation and oxidative stress (e.g., reactive oxygen species, antioxidants) will be assessed. In
Aim 3, we will test molecular mechanisms via which bioenergetic compounds protect against TRD. In our model,
bioenergetic drugs may protect against TRD by activating HIFs. CR and ALC can also activate mTOR, PI3K or
NfκB pathways. We will now use inhibitors of the signaling pathways likely involved (HIF1a, mTOR, PI3K, NfκB)
to block behavioral and biomarker impacts of bioenergetic drugs. Data from studies in this model will further be
confirmed using the chronic ...

## Key facts

- **NIH application ID:** 10883449
- **Project number:** 1R01AT012359-01A1
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Shami Kanekar
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $444,903
- **Award type:** 1
- **Project period:** 2024-08-16 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10883449

## Citation

> US National Institutes of Health, RePORTER application 10883449, Evaluation of Bioenergetic Supplements in Treatment-Resistant Depression, Cognitive Dysfunction and Anxiety (1R01AT012359-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10883449. Licensed CC0.

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