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.
Capacity to consent to participation in the study
Inclusion into attenuated psychosis group as assessed by the CAARMS
Scores 3-5 on CAARMS unusual thought content or non-bizarre ideas subscales
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
Crossover
Levetiracetam
DrugSingle dose of 500mg levetiracetam The capsules of levetiracetam and placebo will be visibly the same.
Placebo
DrugSingle dose of 75mg ascorbic acid. The capsules of levetiracetam and placebo will be visibly the same.
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.
Brain functional resting-state fMRI measures (including Amplitude of Low-Frequency Fluctuation (ALFF))
A state-of-the-art resting-state fMRI sequence will be used to measure intrinsic activity and connectivity of the hippocampus.
Brain functional MRI activation during a scene processing task.
Scene processing tasks have been used before in fMRI studies with the general population and patients with early psychosis. Research has demonstrated that perceptual scene processing involves the hippocampus, and this is not just dependent on memory encoding. This task demonstrated reduced fMRI activation and increase cerebral blood volume in the anterior hippocampus of patients with early psychosis compared to controls. This task will last approximately 5 minutes.
Levels of GABAergic and glutamatergic metabolites in the anterior cingulate cortex (ACC) as measured by proton magnetic resonance spectroscopy (1H-MRS).
1H-MRS spectra will be acquired in the ACC using a well-established local protocol for glutamate and GABA quantification (MEGA-PRESS)
Emotion recognition performance
The CANTAB Emotion Recognition Task will be administered after the levetiracetam/placebo dose (CHR-P only) and before MRI imaging.
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