# Reducing Hippocampal Hyperactivity and Improving Cognition in Schizophrenia

> **NIH VA I01** · VA EASTERN COLORADO HEALTH CARE SYSTEM · 2022 · —

## Abstract

Schizophrenia is a leading cause of disability for Veterans. Due to the lack of an effective
treatment, Veterans with schizophrenia suffer a myriad of cognitive impairments, including deficits in
attention, memory, and processing speed. As a result, patients struggle on the job, in relationships, and in
day-to-day activities, contributing to an overall poor quality of life.
 New treatments for cognitive dysfunction in schizophrenia clearly are needed. A potentially
powerful approach for developing and evaluating novel therapeutics is to combine
behavioral/neurocognitive outcome measures with functional imaging of a drug's effects on a
neurobiological marker. A topic of current great interest in schizophrenia research is the finding that
patients show increased activity of the hippocampus, particularly at “rest” or in other similar conditions of
low cognitive load. This increased activity has been hypothesized to prevent further recruitment of the
region as task demands increase, contributing to cognitive dysfunction. Furthermore, recently published
work has demonstrated that cognitive performance in schizophrenia is negatively correlated with resting
hippocampal activity. It follows that a drug treatment capable of reducing resting hippocampal activity may
improve cognition in patients.
 Recent findings have demonstrated that low doses of the anti-epileptic drug levetiracetam (LEV)
reduce hippocampal hyperactivity and improve performance on a memory task in patients with mild
cognitive impairment. LEV also reduces hippocampal hyperactivity in mouse models of Alzheimer's
disease, an effect also recently shown in a mouse model of schizophrenia. Unlike other anti-epileptics,
LEV improves cognition in epilepsy patients. The drug is well tolerated at doses several fold higher than
that used to demonstrate its effects on the hippocampus. As such, it is possible that low-dose LEV may be
a useful strategy for reducing hippocampal hyperactivity and improving cognition in schizophrenia.
 A thorough investigation of the hypothesis that LEV will reduce hippocampal hyperactivity and
improve cognition in Veterans with schizophrenia is proposed. In the first Aim, functional magnetic
resonance imaging will be used to determine the lowest dose at which LEV engages the biological target
of interest, hippocampal hyperactivity. This Aim will use a 2-week open-label crossover design to examine
the effects of two low doses of LEV (125 mg b.i.d. and [62.5] mg b.i.d.) on resting hippocampal activity in
schizophrenia. The second Aim will then use the dose optimized in Aim 1 in a 4-week placebo-controlled,
double-blind, randomized, parallel design to assess the cognitive effects of LEV, utilizing the Repeatable
Battery for the Assessment of Neurological Status (RBANS). The relationship between LEV effects on
hippocampal activity and its effects on cognitive performance also will be examined.
 This project will use a novel approach to investigate the efficacy of a potentia...

## Key facts

- **NIH application ID:** 10295165
- **Project number:** 5I01CX001414-05
- **Recipient organization:** VA EASTERN COLORADO HEALTH CARE SYSTEM
- **Principal Investigator:** JASON R TREGELLAS
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2017-10-01 → 2023-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10295165

## Citation

> US National Institutes of Health, RePORTER application 10295165, Reducing Hippocampal Hyperactivity and Improving Cognition in Schizophrenia (5I01CX001414-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10295165. Licensed CC0.

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