Administration of low-dose selective noradrenaline reuptake inhibitor (sNRI) (e.g. atomoxetine) to healthy subjects is a validated model of increasing cortical noradrenaline levels which, combined with computational modelling of behaviour, allows fine-grained analysis of the impact on learning processes of noradrenaline's fluctuations in the human cortex.
The study goal is to characterize the modifications of certain cognitive processes and associated brain circuits under low-dose sNRI using validated computational learning models. The study will be interested in how subjects will modify their learning under the effect of the drug across two separate investigations; one utilizing in a stable evidence accumulation task and one utilising a changing evidence accumulation task. This approach will help to better understand the link between noradrenaline and accumulation of evidence in healthy subjects, and indirectly in some neuropsychiatric pathologies.
The study is a single centre, double-blinded, randomized, placebo-controlled, cross-over study involving evaluable healthy adults separated in 2 cohorts: A for participants having the stable task and B for those having the changing one. Participants will then be randomized in a 1:1 ratio to one of the following treatment sequences:
* Atomoxetine 40 mg - Placebo (Subgroups A1 or B1); * Placebo - Atomoxetine 40 mg (Subgroups A2 or B2).
Right-handed, assessed by the Edinburgh scale;
Written signed informed consent;
Subject covered by a social security regimen.
Pregnant, parturient or breastfeeding woman;
First-degree family history of axis I disorder (DSM-IV-TR), excepted unipolar mood and anxiety disorders with OCD;
Personal history of axis I disorder (DSM-IV-TR) in the 6 months preceding the study entry;
Dependence on a psychoactive substance in the 12 months preceding the study entry, excluding nicotine, any behavioural disorder incompatible with a 2-hour electroencephalographic recording;
Crossover
Atomoxetine
DrugOne single capsule of atomoxetine 40 mg given at one visit according to the sequence randomly allocated. Placebo of atomoxetine will be administered at the other visit for the participant (according to the sequence randomly allocated)
Placebo
DrugOne single capsule of placebo given at one visit according to the sequence randomly allocated.
Apparent Learning rate
Paired difference in the apparent learning rates (in both environmental contexts: stable task and changing task), between the sNRI (atomoxetine) and control (placebo) conditions. Apparent learning rate will be calculate with the following formula: αt=(vt- vt-(1) )/(xt- vt-1) according to Foucault and Meyniel (Foucault C, Meyniel F (2024) Two Determinants of Dynamic Adaptive Learning for Magnitudes and Probabilities. Open Mind : Discov Cogn Sci 8:615-638) The learning rate measures the amount of update of the learned value (from vt-(1 to vt) induced by the observation xt in proportion to its deviation from the previously learned value.
Number of adverse events
Side effects (treatment related adverse events) in all groups between study drug administration at Visit 1 (Day 0) and Visit 2 (Day 7) including vital signs worsening and ECG findings
Change from Visit 1 (Day 0) in the computational modelling of behaviour at Visit 2 (Day 7)
Computational modelling of behaviour at Visit 1 and 2: paired difference in latent behavioral parameters of the computational models that characterize the learning process (in a stable accumulation task and in a dynamic accumulation task), between the sNRI (atomoxetine) and control (placebo) conditions.
Change from Visit 1 (Day 0) in the score of the State Trait Anxiety Inventory (STAI) questionnaire at Visit 2
The scores of the State Trait Anxiety Inventory (STAI) questionnaire (Spielberger et al., 1983) will be compared between Hour 0 and Hour 3 at Visit 1 and 2 to control for the effect of the substance on the subjects' levels of depression and anxiety. The STAI comprises 2 questionnaires of 20 items with the following ranges: * STAI-YA (state anxiety): 0-80 with 0 equivalent to no anxiety and 80 the worst possible anxiety * STAI-YB (Trait anxiety): 0-80 with 0 equivalent to no anxiety and 80 the worst possible anxiety
Change from Visit 1 (Day 0) in the score of the Beck Depression Inventory (BDI) questionnaire at Visit 2
The scores of the Beck Depression Inventory (BDI) questionnaire (Beck et al., 1961) will be compared between Hour 0 and Hour 3 at Visit 1 and Visit 2 to control for the effect of the substance on the subjects' levels of depression. The BDI comprises 21 items with the following ranges: 0-63 with 0 equivalent to no depression and 63 the worst possible depression.
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