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

NCT06224530 | Recruiting

• 2 other identifiers: 331790223486/Z/21/Z
• Study Type: interventional
• Target: 69
• Locations: 1 country
• Sites: 1

Brief Summary

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. A case-control sample of 33 healthy individuals aged 18-40 will be recruited from Greater London. We will recruit a healthy control (HC) sample to establish the presence of hippocampal dysfunction in our CHR-P group by comparing the MRI data for CHR-P under the placebo condition with that of the HC sample. The HC individuals will attend the screening visit and one scanning visit. They will not receive any medication. 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.

Conditions

Psychosis

Keywords

Clinical high risk; Levetiracetam; Psychosis risk; Neuroimaging; Hippocampus; GABA; Glutamate; SV2A; Experimental medicine; Magnetic Resonance Spectroscopy; Magnetic Resonance Imaging

Outcome Measures

Primary Outcomes (1)

• Magnetic resonance Imaging (MRI) measure of rCBF using arterial spin labelling (ASL) in the hippocampus.

  3D pseudo-Continuous Arterial Spin Labelling (3D-pCASL) sequence will be used to measure rCBF.

  1 hour after single dose levetiracetam vs placebo

Secondary Outcomes (5)

• Brain functional resting-state fMRI measures (including Amplitude of Low-Frequency Fluctuation (ALFF))

  1 hour after single dose levetiracetam vs placebo

• Brain functional MRI activation during a scene processing task.

  1 hour after single dose levetiracetam vs placebo

• Levels of GABAergic and glutamatergic metabolites in the anterior cingulate cortex (ACC) as measured by proton magnetic resonance spectroscopy (1H-MRS).

  1 hour after single dose levetiracetam vs placebo

• Emotion recognition performance

  30 mins after single dose of levetiracetam vs placebo and at screening visit

• Spatial Span working memory performance

  30 mins after administration of levetiracetam/placebo and at screening visit for CHR participants

Study Arms (2)

Levetiracetam, then Placebo

EXPERIMENTAL

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

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

Interventions

Levetiracetam DRUG

Single dose of 500mg levetiracetam The capsules of levetiracetam and placebo will be visibly the same.

Also known as: Keppra

Levetiracetam, then Placebo; Placebo, then Levetiracetam

Placebo DRUG

Single dose of 75mg ascorbic acid. The capsules of levetiracetam and placebo will be visibly the same.

Levetiracetam, then Placebo; Placebo, then Levetiracetam

Eligibility Criteria

• Age: 18 Years - 40 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Age range 18-40 years
• Capacity to consent to participation in the study
• Scores 3-5 on CAARMS unusual thought content or non-bizarre ideas subscales

You may not qualify if:

• Past episode of psychosis
• Current exposure to drugs with strong GABAergic or glutamatergic effects (benzodiazepines, anticonvulsants, mood stabilisers, zopiclone, zolpidem, ketamine, opiates, atomoxetine, memantine)
• Current/recent exposure to any antipsychotic medication
• Diagnosis of any neurological disorder, including epilepsy
• Current pregnancy/breastfeeding
• Severe renal impairment
• Known allergy to levetiracetam
• Contraindication to MRI scanning
• IQ\<70 as determined with WAIS-III
• 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.
• Age range 18-40 years
• Capacity to consent to participation in the study
• Personal history of mental health conditions
• Any first-degree relative with a psychotic disorder
• Diagnosis of any neurological disorder, including epilepsy

Sponsors & Collaborators

• King's College London: lead

Study Sites (1)

Institute of Psychiatry, Psychology and Neuroscience, King's College London

London, London, SE5 8AF, United Kingdom

RECRUITING

MeSH Terms

Conditions

Psychotic Disorders

Interventions

Levetiracetam

Condition Hierarchy (Ancestors)

Schizophrenia Spectrum and Other Psychotic Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Acetamides; Amides; Organic Chemicals; Acetates; Acids, Acyclic; Carboxylic Acids; Pyrrolidinones; Pyrrolidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Gemma Modinos, BSc MSc PhD

  King's College London

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Abigail A Gee, MBChB MSc

CONTACT

abigail.gee@kcl.ac.uk

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Participants and investigators will be blinded to the randomised order of administration of levetiracetam and placebo. Once screening procedures have confirmed the subject's eligibility to enter the study, a random list (i.e., of A B B A A A B B) will be created using an automated online random generator. A researcher that is not involved in the study will be responsible for randomisation and documentation. This information will then be given to the South London and Maudsley NHS Foundation Trust Pharmacy where the levetiracetam / placebo capsules will be dispensed from in visually identical capsules for blinding to the A's or B's. Only the SLaM Pharmacy contact will know what capsules were allocated to A's or B's and will keep the enrolment log blinded from the enrolment log kept by the study researcher.
• Purpose: OTHER
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Basic science study involving procedures with human participants. Randomised, double-blind, placebo-paired, levetiracetam versus placebo challenge before scanning. Comparison of CHR individuals (n=36) under placebo condition to baseline HC (n=33) without administration of medication.

Study Record Dates

• First Submitted: January 4, 2024
• First Posted: January 25, 2024
• Study Start: July 19, 2024
• Primary Completion: February 1, 2026
• Study Completion: February 1, 2026
• Last Updated: February 4, 2025

Record last verified: 2025-01

Data Sharing

• IPD Sharing: Will not share

Locations

GB (1)