Reducing Hippocampal Hyperactivity and Improving Cognition in Schizophrenia

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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 potential new pharmacologic target in schizophrenia. The project also will evaluate hippocampal hyperactivity as a biomarker in schizophrenia by examining its ability to predict treatment response. Understanding the cognitive and neurobiological effects of LEV will provide an early indication of whether LEV can be repurposed to enhance cognitive function in Veterans with schizophrenia.