The goal of this study is to investigate the effects of selective histamine 3 antagonist pitolisant on brain function and cognition in healthy individuals. The main questions it aims to answer are: 1. Does pitolisant alter functional activity in brain regions linked to reward and cognitive processing during rest or cognitive task performance? 2. Does pitolisant alter cognitive ability across a range of psychological domains, including working memory, executive functioning and emotional processing? Participants will undertake fMRI scanning in addition to a battery of tasks designed to measure cognitive and emotional processing after taking a single dose of pitolisant or placebo. Researchers will compare differences in functional activity, cognition and emotional processing across the pitolisant and placebo groups.
Cognitive and affective processing are underpinned by monoaminergic neurotransmission and neurosteroid systems, yet there are many aspects of these systems that remain unknown in humans. In particular, monoaminergic histamine 3 (H3) receptors are abundant in CNS regions underpinning cognitive processing (prefrontal cortex, hippocampus, and striatum), yet the role of these receptors in humans remains unclear. Evidence from animal models suggests H3R antagonism improves cognitive functioning, however these specific effects are yet to be examined in humans. Similarly, the function of sigma-1 (σ-1) receptors in the brain is not well understood in humans despite strong evidence of pro-cognitive effects in animal models. The study will investigate the effect of pitolisant, a dual H3R antagonist and σ-1R agonist, on cognitive and affective processing, in addition to changes in functional connectivity. These effects will be measured with a battery of neuropsychological tasks (e.g., Affective Go/No-Go Task; Adaptive dual n-back task), self-rated measures of cognitive function (PDQ), and resting state fMRI and fMRI data acquisition during the verbal n-back and memory encoding tasks.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
OTHER
Masking
TRIPLE
Enrollment
58
Single dose pitoliosant (36mg)
Single dose placebo
Department of Psychiatry, University of Oxford
Oxford, United Kingdom
BOLD signal levels during resting state fMRI sequence
Blood Oxygenation Level Dependent (BOLD) signal level in prior regions of interest (striatum, hippocampus and anterior cingulate cortex) in pilosant group compared with the placebo group
Time frame: 3-6 hours after single dose of drug or placebo.
BOLD signal levels during fMRI memory encoding task
BOLD signal level in prior regions of interest during the task (hippocampus; perirhinal cortex) in pilosant group compared with the placebo group
Time frame: 3-6 hours after single dose of drug or placebo.
BOLD signal levels during fMRI n-back task
BOLD signal level in prior regions of interest during the task (dorsolateral prefrontal cortex; hippocampus; anterior cingulate cortex) in pilosant group compared with the placebo group
Time frame: 3-6 hours after single dose of drug or placebo.
Optimal choice selection during loss and reward conditions in Probabilistic Instrumental Learning Task (PILT)
Optimal choice selection during loss and reward conditions in Probabilistic Instrumental Learning Task (PILT) in pilosant group compared with the placebo group
Time frame: 3-6 hours after single dose of drug or placebo.
Number of inhibited 'no-go' responses during the affective Interference Go/No-Go Task performance
Number of inhibited 'no-go' responses during the affective Interference Go/No-Go Task in pilosant group compared with the placebo group
Time frame: 3-6 hours after single dose of drug or placebo.
Accuracy of target selection on the Colour Change Detection Task
Accuracy of target selection on the Colour Change Detection Task in pilosant group compared with the placebo group
Time frame: 3-6 hours after single dose of drug or placebo.
Accuracy of emotional labeling of facial expressions during the facial emotion recognition task
Accuracy of emotion labels (e.g. disgusted face) assigned by participants to expressive faces during the facial emotion recognition task in pilosant group compared with the placebo group
Time frame: 3-6 hours after single dose of drug or placebo.
Accuracy of target selection during n-back fMRI task
Accuracy of target selection during n-back fMRI task in pilosant group compared with the placebo group
Time frame: 3-6 hours after single dose of drug or placebo.
Accuracy of stimuli labeling (novel or familiar) during fMRI memory encoding task
Accuracy of stimuli labeling (novel or familiar) during fMRI memory encoding task in pilosant group compared with the placebo group
Time frame: 3-6 hours after single dose of drug or placebo.
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