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Modulation of hippocampal activity in schizophrenia with levetiracetam: a randomized, double-blind, cross-over, placebo-controlled trial

Neuropsychopharmacology volume 49, pages 681–689 (2024)Cite this article

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Abstract

Hippocampal hyperactivity is a novel pharmacological target in the treatment of schizophrenia. We hypothesized that levetiracetam (LEV), a drug binding to the synaptic vesicle glycoprotein 2 A, normalizes hippocampal activity in persons with schizophrenia and can be measured using neuroimaging methods. Thirty healthy control participants and 30 patients with schizophrenia (28 treated with antipsychotic drugs), were randomly assigned to a double-blind, cross-over trial to receive a single administration of 500 mg oral LEV or placebo during two study visits. At each visit, we assessed hippocampal function using resting state fractional amplitude of low frequency fluctuations (fALFF), cerebral blood flow (CBF) with arterial spin labeling, and hippocampal blood-oxygen-level-dependent (BOLD) signal during a scene processing task. After placebo treatment, we found significant elevations in hippocampal fALFF in patients with schizophrenia, consistent with hippocampal hyperactivity. Additionally, hippocampal fALFF in patients with schizophrenia after LEV treatment did not significantly differ from healthy control participants receiving placebo, suggesting that LEV may normalize hippocampal hyperactivity. In contrast to our fALFF findings, we did not detect significant group differences or an effect of LEV treatment on hippocampal CBF. In the context of no significant group difference in BOLD signal, we found that hippocampal recruitment during scene processing is enhanced by LEV more significantly in schizophrenia. We conclude that pharmacological modulation of hippocampal hyperactivity in schizophrenia can be studied with some neuroimaging methods, but not others. Additional studies in different cohorts, employing alternate neuroimaging methods and study designs, are needed to establish levetiracetam as a treatment for schizophrenia.

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Fig. 1: Study design.
Fig. 2: Hippocampal fALFF, but not rCBF or BOLD PSC, is increased in schizophrenia.
Fig. 3: LEV enhances recruitment in scene processing in schizophrenia.
Fig. 4: Hippocampal activity does not differ between patients treated with LEV and controls treated with placebo.

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Funding

Funding

Research reported in this publication was supported by the Charlotte and Donald Test Fund, the Vanderbilt Psychiatric Genotype/Phenotype Project, the National Institute of Mental Health (NIMH) grants R01-MH70560 (SH) and F30-MH125507 (MJR), the National Institute of General Medical Sciences (NIGMS) grant T32-GM007347, and the Vanderbilt Institute for Clinical and Translational Research (through grant UL1-TR000445 from the National Center for Research Resources/NIH).

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Authors and Affiliations

  1. Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, TN, USA

    Maxwell J. Roeske, Maureen McHugo, Kristan Armstrong, Suzanne Avery & Stephan Heckers

  2. Vanderbilt University Institute of Imaging Sciences, Nashville, TN, USA

    Baxter Rogers

  3. Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA

    Manus Donahue

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Contributions

Study concept, design, and acquisition of funding: MJR and SH. Participant recruitment: MJR, KA, and SH. Acquisition and processing of data: MJR, MM, BR, MD, and SH. Statistical analyses and interpretation of data: MJR, MM, SA, MD, SH. Drafting of manuscript: MJR and SH. Critical revision of manuscript: MJR, MM, BR, KA, SA, MD, SH. Study supervision: SH. All authors read and approve the manuscript and vouch for the adherence of the trial to the protocol, the accuracy of the data and analyses, and reporting of adverse events.

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Correspondence to Maxwell J. Roeske.

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Roeske, M.J., McHugo, M., Rogers, B. et al. Modulation of hippocampal activity in schizophrenia with levetiracetam: a randomized, double-blind, cross-over, placebo-controlled trial. Neuropsychopharmacol. 49, 681–689 (2024). https://doi.org/10.1038/s41386-023-01730-0

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  • DOI: https://doi.org/10.1038/s41386-023-01730-0

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