Investigating the Effect of a Single-dose of Levetiracetam on Brain Function, Chemistry and Cognitive Performance in Psychosis Risk (LEVHIPPRO)


King's College London


Not yet enrolling




Drug: Placebo
Drug: Levetiracetam

Study type


Funder types



223486/Z/21/Z (Other Grant/Funding Number)

Details and patient eligibility


Background Psychosis is a mental health condition that affects around 3 in 100 people in their lifetime. Most treatments for psychosis target a brain chemical called dopamine but they don't work for everyone and don't address many of the symptoms. People with psychosis and people at risk of developing psychosis show differences in a part of the brain called the hippocampus, such as smaller size and increased activity. This hyperactivity may be associated with cognitive difficulties (thinking and memory). The basis of this hippocampal hyperactivity is thought to be a deficit in excitation and inhibition of brain cells. Excitation causes brain cells to send signals more frequently, and inhibition causes cells to send signals less frequently. A balance between these signals is important for the brain, including the hippocampus, to function properly. Approach Levetiracetam is a medication that is widely used to treat epilepsy and which helps balance excitation-inhibition in the brain. We will use brain imaging, using Magnetic Resonance Imaging (MRI), to test if levetiracetam can help reduce hippocampal hyperactivity, alter connectivity and change levels of brain chemicals in people who are at risk of developing psychosis. Participants (18-40 years), identified as at risk of psychosis through the Outreach and Support in South London (OASIS) teams, will attend an initial visit at the Institute of Psychiatry, Psychology \& Neuroscience. This will involve questions about experiences and feelings, assessment of thinking and memory, and a blood test. They will then attend two scanning visits at the Centre for Neuroimaging Sciences, during which they will take capsules of either levetiracetam or placebo (in a randomised order) before having a 60 mins MRI scan. The MRI scan will look at blood flow to the hippocampus, resting activity, activity during a cognitive task and levels of brain chemicals. Funded by the Wellcome Trust and conducted by King's College London researchers, the study spans 2-3 months per participant. Impact Our study will provide important evidence about how levetiracetam affects brain function, and how this relates to cognition. This knowledge may lead to innovative approaches for understanding and treating psychosis early.

Full description

Can the acute administration of levetiracetam modulate hippocampal rCBF, resting-state fMRI connectivity, cognitive performance and cortical glutamatergic levels in CHR individuals? Study Design: Investigators will address the above research question using a randomised, double-blind, placebo-paired, within-subject crossover design on 36 participants at CHR for psychosis. The study will enrich the CHR sample and reduce heterogeneity by selecting patients who present with positive symptoms (score 3-5 on Clinical Assessment of At Risk Mental State (CAARMS) unusual thought content or non-bizarre ideas subscales), as known proxy measures of hippocampal dysfunction (Allen et al., 2018a; Modinos et al., 2018; Tregellas et al., 2014). Previous rCBF studies including our own (Allen et al., 2016, 2018a; Percie du Sert et al., 2023) have robustly demonstrated hippocampal hyperactivity in CHR individuals compared to healthy controls. Nevertheless, the presence of hippocampal dysfunction in our CHR group will be established by comparing the MRI data for CHR under placebo condition with that of healthy controls from independent studies conducted by the supervisory team which used the same scanner and imaging modalities. Sample: 36 subjects at CHR of psychosis Methodology: All participants will undergo: Screening visit Scanning Visit 1 (under placebo/levetiracetam) Scanning Visit 2 (under levetiracetam/placebo) SCREENING VISIT: The screening visit will last approximately 2 hours and will be conducted at the the Institute of Psychiatry, Psychology & Neuroscience (IoPPN) by a qualified study researcher. All subjects that undergo screening are logged into a screening log associated with the study by the study researcher, to which only authorized members of the research team can access. - Procedures involved in the screening visit: Consent / capacity assessment Sociodemographic information, including medical, family, substance use history (including history of current pregnancy and breast feeding) Brief assessment of inclusion/exclusion criteria - including MRI safety questionnaire Blood sampling Clinical assessment (see below) Cognitive assessment (see below) Clinical assessment: Psychopathology will be assessed using the CAARMS. Anxiety and mood will be assessed using the Hamilton Anxiety and Depression Rating Scale (HAM-A/D). Social functioning, disability, adjustment, and interactions, and emotional empathy will be assessed using the Social and Occupational Functioning Scale (SOFAS, Global Functioning Social and Role, GF-S/R) Cognitive assessment: Wechsler Adult Intelligence Scale (WAIS-III) short version (Current IQ) National Adult Reading Test (NART) (Premorbid IQ) Pattern separation task Cambridge Neuropsychological Test Automated Battery (CANTAB)- specific battery used for previous multi-site study PSYSCAN Study drug / placebo: The study drug (500mg levetiracetam) and placebo (75mg ascorbic acid) capsules will be encapsulated, stored and dispensed by the South London and Maudsley (SLaM) NHS Foundation Trust Pharmacy. Levetiracetam / placebo capsules will be dispensed in visually identical capsules for blinding purposes. SCANNING VISITS MRI scans will take place at the Centre for Neuroimaging Sciences, IoPPN. Scanning visit 1 and 2 will be identical, the only difference being the administration of either placebo or levetiracetam. Schedule: 90 min Arrive at the centre 80 min ID, neuroimaging consent and pre-scan checklist. During waiting subject given pre-scan self-report measures to complete. Basic physical examination (weight, height, blood pressure, and standard systems exam). Urine sample for urine drug screen and urine pregnancy test. 60 min Dose of levetiracetam or placebo administered. 10 min Pattern separation task. T = 0 MRI scan 60 min End scan. Subject escorted to recovery room. Subject provided with snack and refreshment. 70 min Post-scan monitoring. MRI imaging: Neuroimaging data will be acquired using an MRI scanner at the Centre for Neuroimaging Sciences, IoPPN. Each scanning session will involve 1 hour waiting time prior to scanning to allow for the drug to exert its effects, followed by 60 minutes of scanning: Scene processing task. Glutamate and GABA Magnetic Resonance Spectroscopy (MRS) Resting-State fMRI Arterial Spin Labelling (ASL) Structural MRI Drug / Placebo Administration: An oral dose of levetiracetam (500 mg) or placebo (75mg ascorbic acid) will be given 1 h before the beginning of the neuroimaging acquisition. This time interval is chosen because levetiracetam has peak plasma concentration (Cmax) 1 - 1.5 hours after administration. It is rapidly and almost completely absorbed following oral administration with >95% bioavailability. Half of the sample will be given placebo in the first experimental session and levetiracetam in the second experimental session, and the other half will be given levetiracetam in the first experimental session. Timing of Assessments: Scanning visit 1 must be completed within three months of the screening visit. The timing of scanning visit 2 is relative to scanning visit 1. This will result in a comparable study completion period between participants. Scanning visit 2 occurs 3 weeks +/- 1 week after scanning visit 1, to allow for complete washout. Levetiracetam has a half life of 6-8 hours in healthy adults. Duration of study: The study will take 24 - 36 months. Each participant will be enrolled in the study for approximately 3 months from recruitment to completion of the study (screening visit + scanning visit 1 + scanning visit 2), although note that participants will only be required to attend for a few hours for each visit. Sample size and power calculation: Investigators will aim to recruit 36 CHR participants to allow for potential drop out rate of 20%, aiming for at least 29 subjects with both scans complete. There are no existing studies of rCBF or other fMRI changes with levetiracetam in CHR individuals. Studies with levetiracetam administration in participants Mild Cognitive Impairment (MCI) (n= 17) have shown that levetiracetam significantly reduced mean task-based hippocampal BOLD-fMRI activation (t = 2.537, p = 0.022) to a level that no longer significantly differed from controls (n=22)(Bakker et al., 2012). A recent study completed by the Modinos group (unpublished data) has shown that acute diazepam administration in 24 CHR individuals significantly reduced rCBF in the right (t=-4.30, FDR-corrected p<0.001) and left hippocampus (t=-2.69, FDR-corrected p=0.015). Multiple studies have demonstrated significantly higher hippocampal rCBF for CHR individuals compared to healthy controls (Allen et al., 2016, 2018b). Allen et al (2018) showed an effect size of 0.62 for increased rCBF in the hippocampal region of interest (ROI) in CHR compared to controls (Allen et al., 2016, 2018a). Based on this, a sample size of 29 subjects will have at least 0.90 power (alpha= 0.05, two-tailed paired t-test) to detect a significant change in rCBF. These estimates are conservative as this study benefits from a within-subject crossover design, which will reduce variability and confounding, and enrichment of the sample to reduce inter-subject variability. Image Analysis and Statistics To determine whether the baseline findings in CHR-P individuals are abnormal, investigators will compare the MRI data for CHR-P under placebo condition with that of healthy controls from previous studies conducted by the study team which used the same scanner and imaging modalities (apart from the scene processing task). Investigators will use one-way ANOVAs, controlling for confounding variables (age, sex) as covariates of no interest in the design. Hypothesis 1. Levetiracetam (vs placebo) will decrease hippocampal rCBF in people at CHR-P of psychosis. rCBF data will be pre-processed using the Automatic Software for ASL Processing (ASAP) 2.0 toolbox51. Differences in hippocampal rCBF between levetiracetam and placebo conditions will be tested using a hippocampal ROI approach, via a paired t-test (p<0.05 family-wise error corrected). Hypothesis 2. Levetiracetam (vs placebo) will improve hippocampal resting-state functional connectivity. Resting-state fMRI data will be analysed using a seed-based approach for the hippocampus in the CONN-fMRI Functional Connectivity toolbox52. Differences between levetiracetam and placebo will be tested using paired t-tests. Dynamic connectivity will be analysed using edge-centric analysis in Matlab53. The frequency and amplitude of co-fluctuation peaks for levetiracetam vs placebo will be compared using paired t-tests (p<0.05 family-wise error corrected). The Amplitude of Low-Frequency Fluctuation (ALFF) analysis will be performed using the current recommended methodology. The ALFF data for levetiracetam vs placebo will be compared using paired t-tests (p<0.05 family-wise error corrected). Hypothesis 3. Levetiracetam (vs placebo) will improve hippocampal fMRI activation during a scene processing task and performance on a pattern separation task. The scene processing fMRI task first level analysis will include separate regressors for scene, face and scramble conditions. For second-level analysis researchers will use a contrast estimating the difference in average response to scene and face, versus the scrambled condition. Researchers will perform whole-brain analysis, and ROI analysis for the hippocampus, for levetiracetam vs placebo conditions using paired t-tests (p<0.05 family-wise error corrected). Performance on the 1-back task will be measured using mean hit rate, correct rejection rate, and reaction time for each condition. To examine differences in performance researchers will conduct within-subject ANOVAs on hit rate, correct rejection rate, and reaction time, with group as a within-subject factors. For the pattern separation task the performance will be assessed using response bias- corrected recognition score and response bias-corrected pattern separation score. The response bias-corrected pattern separation score will be calculated as P(similar|lure) minus P(similar|foil), and the response bias-corrected recognition score will be calculated as P(old|target) minus P(old|foil). The difference for levetiracetam vs placebo will be compared using paired t-tests (p<0.05 family-wise error corrected). Hypothesis 4. Levetiracetam (vs placebo) will decrease levels of cortical glutamatergic metabolites and increase levels of GABA 1H-MRS data will be analysed according to current recommendations. Changes in Glx levels (glutamate + glutamine) and GABA between levetiracetam and placebo conditions will be assessed using a paired t-test (p<0.05, two-tailed). Hypothesis 5. The above neuroimaging measures are associated with baseline cognitive function, clinical symptoms and blood markers. Pearson's correlation (Bonferroni corrected p<0.05, two-tailed) will be used to test for associations between changes in the MRI measures for levetiracetam and placebo and baseline symptom severity (CAARMS symptom scores and CANTAB cognitive performance), to determine whether those CHR-P individuals with higher symptom severity / cognitive dysfunction show a greater change in MRI measures after levetiracetam. Pearson's correlation (Bonferroni corrected p<0.05, two-tailed) will be used to test for associations between peripheral blood markers (SV2A, neuroinflammation and mitochondrial function markers) and hippocampal rCBF, and cognitive performance.


36 estimated patients




18 to 40 years old


No Healthy Volunteers

Inclusion criteria

  1. Age range 18-40 years
  2. Capacity to consent to participation in the study
  3. Inclusion into attenuated psychosis group as assessed by the CAARMS
  4. Scores 3-5 on CAARMS unusual thought content or non-bizarre ideas subscales

Exclusion criteria

  1. Past episode of psychosis
  2. Current exposure to drugs with strong GABAergic or glutamatergic effects (benzodiazepines, anticonvulsants, mood stabilisers, zopiclone, zolpidem, ketamine, opiates, atomoxetine, memantine)
  3. Current/recent exposure to any antipsychotic medication
  4. Diagnosis of any neurological disorder, including epilepsy
  5. Current pregnancy/breastfeeding
  6. Severe renal impairment
  7. Known allergy to levetiracetam
  8. Contraindication to MRI scanning
  9. IQ<70 as determined with WAIS-III
  10. CHR-P individuals are not deemed to have a full-blown mental health disorder. However, in the event that a CHR-P individual is acutely ill and lacking capacity to consent, they will not be approached to take part in this study.

Trial design

Primary purpose




Interventional model

Crossover Assignment


Quadruple Blind

36 participants in 2 patient groups

Levetiracetam, then Placebo
Experimental group
Participants will receive two levetiracetam 250mg capsules on the first scanning visit. On the second scanning visit they will receive two 37.5mg capsules of ascorbic acid.
Drug: Levetiracetam
Drug: Placebo
Placebo, then Levetiracetam
Experimental group
Participants will receive two 37.5mg capsules of ascorbic acid on the first scanning visit. On the second scanning visit they will receive two levetiracetam 250mg capsules.
Drug: Levetiracetam
Drug: Placebo

Trial contacts and locations



Central trial contact

Abigail A Gee, MBChB MSc

Data sourced from

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