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

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 33 healthy controls recruited from the Greater London area.

Sample:

36 individuals at CHR of psychosis 33 healthy control participants

Methodology:

CHR-P participants will undergo:

* Screening visit * Scanning Visit 1 (under placebo/levetiracetam) * Scanning Visit 2 (under levetiracetam/placebo)

HC participants will undergo:

* Screening visit (without blood test) * Scanning Visit 1 (without administration of any medication)

SCREENING VISIT:

The screening visit will last approximately 2 hours (CHR-P) or 1.5 hours (HCs) and will be conducted at the IoPPN by a qualified study researcher. Procedures during this visit, except blood sampling for CHR-P and cognitive assessments, may also be conducted remotely over the telephone or video call (e.g. Microsoft Teams) in the case that a face-to-face meeting is not possible or feasible without putting participant and researcher at risk. All participants 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 (Dr Modinos and trained research workers).

\- Procedures involved in the screening visit:

* Consent / capacity assessment * Sociodemographic information, including medical, family, substance use history (including current pregnancy and breast feeding) * Brief assessment of inclusion/exclusion criteria - including MRI safety questionnaire * Blood sampling (CHR-P only)\_ * 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 (CHR only):

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 CHR-P

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. Basic physical examination (weight, height, blood pressure, and standard systems exam). Urine drug screen (UDS) and urine pregnancy test (for female participants). * 60min Dose of levetiracetam or placebo administered. * 25 min Administration of emotion recognition and spatial span tasks. T = 0 MRI scan

* 60min End scan. Subject escorted to recovery room. Subject provided with snack and refreshment. * 70 min Post-scan monitoring.

Scanning Visits HCs MRI scans will take place at the Centre for Neuroimaging Sciences, IoPPN..

* 45 mins Arrive at the centre

\-- 40 mins ID, neuroimaging consent and recap of pre-scan checklist. Measurement of weight and height. UDS. * 30 mins Administration of emotion recognition and spatial span tasks. T = 0 MRI scan

* 60min End scan. Subject provided with optional snack and refreshment.

Emotion Recognition Task The CANTAB Emotion Recognition Task66 will be administered after the levetiracetam/placebo dose (CHR-P only) and before MRI imaging. This computer-generated paradigm measures the six basic facial emotional expressions: anger, disgust, fear, happiness, sadness and surprise. Participants are presented with computer-morphed faces expressing one emotion, with each face shown for 200 ms. Participants are then required to select the displayed emotion from the six basic emotions or choose a neutral option. The task lasts approximately 12 minutes. Outcome measures include percentage and number of correct or incorrect responses and overall response latencies, which can be analysed either across individual emotions or across all emotions.

Spatial Span Task The CANTAB Spatial Span66 assesses visuospatial working memory capacity and will be administered after the levetiracetam/placebo dose (CHR-P) and before MRI imaging. In this computerised task, participants are shown white squares on a screen, some of which briefly change colour in a variable sequence. Participants are required to select the boxes that changed colour in the same order displayed by the computer, either as shown or in reverse. The sequence ranges from two to nine boxes changing colour, with varied colour throughout. Outcome measures include span length errors, number of attempts, and latency.

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 (CHR only):

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.

• Brain functional resting-state fMRI measures (including Amplitude of Low-Frequency Fluctuation (ALFF)) [Срок оценки: 1 hour after single dose levetiracetam vs placebo]
• Brain functional MRI activation during a scene processing task. [Срок оценки: 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). [Срок оценки: 1 hour after single dose levetiracetam vs placebo]
• Emotion recognition performance [Срок оценки: 30 mins after single dose of levetiracetam vs placebo and at screening visit]
• Spatial Span working memory performance [Срок оценки: 30 mins after administration of levetiracetam/placebo and at screening visit for CHR participants]