Clinical trial NCT04239339: Serotonergic Modulation of Cognition, Emotion and Brain Activation in Healthy Volunteers
Official title: Serotonergic Modulation of Cognition, Emotion and Brain Activation in Healthy Volunteers
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Healthy
Keywords: Serotonin
Cognition
Emotion
Neural Activation
Lead sponsor: Rigshospitalet, Denmark
Sponsor class: OTHER
Collaborators: name: University of Cambridge
name: Lundbeck Foundation
First posted: 2020-01-27
Enrollment: 66
Sex: ALL
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

Brief summary: The aim of this project is:

* To apply a pharmacological tool of selective serotonin (5-hydroxytryptamine, 5-HT system) reuptake inhibition in healthy humans. Specifically:
* To investigate how sub-chronic administration of 20 mg of escitalopram affects cognitive performance ('cold' cognition) and social-emotional functioning ('hot' cognition) compared with placebo; and
* To investigate how sub-chronic administration of 20 mg of escitalopram affects functional brain activation during a paradigm of reinforcement learning following drug administration compared with placebo, and how activation relates to cognitive performance and social-emotional functioning.

Detailed description: The aim of this project is:

* To apply a pharmacological tool of selective serotonin (5-hydroxytryptamine, 5-HT system) reuptake inhibition in healthy humans. Specifically:
* To investigate how sub-chronic administration of 20 mg of escitalopram affects cognitive performance ('cold' cognition) and social-emotional functioning ('hot' cognition) compared with placebo; and
* To investigate how sub-chronic administration of 20 mg of escitalopram affects functional brain activation during a paradigm of reinforcement learning following drug administration compared with placebo, and how activation relates to cognitive performance and social-emotional functioning.

Serotonin is a monoamine neurotransmitter implicated in diverse cognitive and affective brain functions. Serotonin has a significant role in the regulation of cognition and mood, including emotional appraisal, perception and flexible behaviour, with 5-HT receptors found in the cortex, amygdala and hippocampus. The investigators have previously shown that in healthy human experimental studies, acute dietary tryptophan depletion induces 'waiting' impulsivity and impulsive behaviours, impairs goal-directed behaviour and shifts behavioural control toward habitual responding when appetitive, but goal-directed when aversive. Reduced availability of forebrain serotonin has also shown to impair a range of cognitive processes, such as psychomotor processing, episodic memory, attention and executive function. Recently, the research team have shown that using an acute and clinically relevant dose (20 mg) of escitalopram impaired learning and cognitive flexibility, but improved response inhibition in healthy humans, suggesting a dissociation of effects possibly mediated by differential modulation of brain serotonin levels in distinct functional neural circuits.

The investigators now aim to investigate the effects of sub-chronic administration of 20 mg of escitalopram (i.e. three weeks) in healthy volunteers using sophisticated neuropsychological testing (Cambridge Neuropsychological Test Automated Battery and EMOTICOM) and functional magnetic resonance imaging (fMRI). Whereas 'cold' cognition refers to the use of non-emotional processing (e.g. episodic memory; spatial working memory), 'hot' cognition is emotion-laden and used in response to stimuli with affective salience (e.g. decision-making under high levels of risk of uncertainty). It has been suggested that cognitive-emotional effects, such as the re-appraisal and re-evaluation of emotions underlying learning mechanisms, may mediate improvements in mood associated with SSRI treatment. This project will help further the understanding of the role of serotonin in the regulation of cognitive and emotional processes, as well the neural correlates underlying reinforcement learning, in healthy humans.

Eligibility criteria: Inclusion Criteria:

* Healthy volunteer (male or female) between 18 and 45 years.

Exclusion Criteria:

* Current or former primary psychiatric disorder (DSM IV Axis I or WHO ICD-10 diagnostic classification).
* Current or previous neurological disease, severe somatic disease, or the consumption of drugs likely to influence the test results.
* Non- fluent in Danish or pronounced visual or auditory impairments.
* Current or past learning disability.
* Pregnancy (females).
* Lactation (females).
* Contraindications for MRI (pacemaker, metal implants, etc.).
* Allergy to the ingredients in the administered drug.
* Abnormal ECG (e.g. prolonged QT syndrome).
* Dizzy when changing from supine to upright position (e.g. postural orthostatic tachycardia syndrome).
* Mild hypotension (blood pressure below 100/70 mmHg) or hypertension (blood pressure above 140/90 mmHg).
* Head injury or concussion resulting in loss of consciousness for more than 2 min.
* Alcohol or drug abuse.
* Drug use other than tobacco and alcohol within the last 30 days.
* Hash \> 50 x lifetime.
* Drugs \> 10 x lifetime (for each substance).
* Nicotine addiction.
* Current psychoactive medication.
* Severe physical impairments affecting eyesight or motor performance.
* Hamilton-6 depression scale score \> 5.

Primary outcomes:
measure: Learning Primary Outcome 1: Mean errors Stage 1 (Learning) - Probability Reversal Learning.
timeFrame: 3 years
measure: Learning Primary Outcome 2: Mean errors Stage 2 (Reversal) - Probability Reversal Learning.
timeFrame: 3 Years
measure: Learning Primary Outcome 3: Learning Rate in Reward Trial - Reinforcement Learning.
timeFrame: 3 Years
measure: Learning Primary Outcome 4: Learning Rate in Punishment Trials - Reinforcement Learning.
timeFrame: 3 Years
measure: Inhibition Primary Outcome 1: Stop Signal Reaction Time - Interleaved Stop Signal Task/Go-NoGo.
timeFrame: 3 Years
measure: Executive Function Primary Outcome 1: Extra Dimensional Set Errors -3Dimensional Intra/Extra Dimensional Shift.
timeFrame: 3 Years
measure: Reinforcement Behaviour Model
timeFrame: 3 Years
measure: Social Cognition Primary Outcome 1: Proportion of offers accepted - Ultimatum Game
timeFrame: 3 Years
measure: Social Cognition Primary Outcome 2: Agent Guilt Score - Moral Emotions Task.
timeFrame: 3 Years
measure: Social Cognition Primary Outcome 3: Agent Shame Score - Moral Emotions Task.
timeFrame: 3 Years
measure: Emotion Recognition Primary Outcome 1: Affective bias in decreasing condition - EMOTICOM Intensity Morphing.
timeFrame: 3 Years
measure: Emotion Recognition Primary Outcome 2: Affective bias for D' - EMOTICOM Emotion Recognition Task.
timeFrame: 3 Years
measure: Emotion Recognition Primary Outcome 3: Detection threshold decreasing - EMOTICOM Intensity Morphing.
timeFrame: 3 Years
measure: Emotion Recognition Primary Outcome 4: D'Prime for Emotion Recognition - EMOTICOM Emotion Recognition Task.
timeFrame: 3 Years
measure: Biofluids: Serum Escitalopram levels
timeFrame: 3 Years
measure: PET Imaging: Cerebral (particularly hippocampal) presynaptic density, as measured with 11 C-UCB-J-PET.
timeFrame: 3 Years
Secondary outcomes:
measure: Learning Secondary Outcome 1: Stage 1 Reward-Stay/Lose-Shift behaviour - Probability Reversal Learning.
timeFrame: 3 Years
measure: Learning Secondary Outcome 2: Stage 2 Reward-Stay/ Lose-Shift behaviour - Probability Reversal Learning.
timeFrame: 3 Years
measure: Learning Secondary Outcome 3: Pre Extra Dimension Set Errors - 3Dimensional Intra/Extra Dimensional Shift.
timeFrame: 3 Years
measure: Learning Secondary Outcome 4: Proportion of Stays - Sequential Model-Based/Model-Free.
timeFrame: 3 Years
measure: Inhibition Secondary Outcome 1: Go reaction time - Interleaved Stop Signal Task/Go-NoGo.
timeFrame: 3 Years
measure: Inhibition Secondary Outcome 2: Go omission error rate - Interleaved Stop Signal Task/Go-NoGo.
timeFrame: 3 Years
measure: Inhibition Secondary Outcome 3: Go commission error rate - Interleaved Stop Signal Task/Go-NoGo.
timeFrame: 3 Years
measure: Inhibition Secondary Outcome 4: No-Go error rate - Interleaved Stop Signal Task/Go-NoGo.
timeFrame: 3 Years
measure: Executive Function Secondary Outcome 1: Total Errors Adjusted - 3Dimensional Intra/Extra Dimensional Shift.
timeFrame: 3 Years
measure: Executive Function Secondary Outcome 2: Strategy Score - CANTAB Spatial Working Memory.
timeFrame: 3 Years
measure: Social Cognition Secondary Outcome 1: Fairness Sensitivity---------- Ultimatum Game
timeFrame: 3 Years
measure: Emotion Recognition Secondary Outcome 1: Detection threshold increasing - EMOTICOM Intensity Morphing.
timeFrame: 3 Years
measure: Emotion Recognition Secondary Outcome 2: Affective bias in increasing condition - EMOTICOM Intensity Morphing.
timeFrame: 3 Years
measure: Emotion Recognition Secondary Outcome 3: Affective bias for Hit Rate - EMOTICOM Emotion Recognition Task.
timeFrame: 3 Years
measure: Emotion Recognition Secondary Outcome 4: Hit Rate for Emotion Recognition - EMOTICOM Emotion Recognition Task.
timeFrame: 3 Years
measure: Faces and geometric figure discrimination Outcome 1: Accuracy - Faces fMRI paradigm
timeFrame: 3 Years
measure: Faces and geometric figure discrimination Outcome 2: Response Speed - Faces fMRI paradigm.
timeFrame: 3 Years
measure: Memory Outcome 1: Total Errors Adj - CANTAB Paired Associates Learning
timeFrame: 3 Years
measure: Memory Outcome 2: First Trial Memory Score - CANTAB Paired Associates Learning.
timeFrame: 3 Years
measure: Memory Outcome 3: Between Search Errors - CANTAB Spatial Working Memory.
timeFrame: 3 Years
measure: Attention Outcome 1: Target Sensitivity (A') - CANTAB Rapid Visual Processing.
timeFrame: 3 Years
measure: Attention Outcome 2: Latency - CANTAB Rapid Visual Processing
timeFrame: 3 Years
measure: Attention Outcome 3: Probability of False Alarms - CANTAB Rapid Visual Processing
timeFrame: 3 Years
measure: Risky Decision Making Outcome Outcome 1. Quality of Decision Making - EMOTICOM Cambridge Gamble Task.
timeFrame: 3 Years
measure: Risky Decision Making Outcome 2: Risk Adjustment - EMOTICOM Cambridge Gamble Task
timeFrame: 3 Years
measure: Risky Decision Making Outcome 3: Overall Proportion Bet - EMOTICOM Cambridge Gamble Task
timeFrame: 3 Years
measure: Risky Decision Making Outcome 4: Deliberation Time - EMOTICOM Cambridge Gamble Task.
timeFrame: 3 Years
measure: Psychomotor Speed Outcome 1: Simple reaction time - CANTAB Reaction Time Task
timeFrame: 3 Years
measure: Psychomotor Speed Outcome 2: Five Choice reaction time - CANTAB Reaction Time Task
timeFrame: 3 Years
measure: Neural Activations and Correlations - Reinforcement Learning fMRI paradigm
timeFrame: 3 Years
measure: Neural Activations and Correlations - Faces fMRI paradigm
timeFrame: 3 Years
measure: Resting State fMRI
timeFrame: 3 Years
measure: Structural VBM
timeFrame: 3 Years
measure: Diffusion Tensor Imaging
timeFrame: 3 Years
measure: Profile of Mood State Score
timeFrame: 3 Years
measure: Beck Depression Inventory-II Score
timeFrame: 3 Years
measure: State-Trait Anxiety Inventory Scale -State Score
timeFrame: 3 Years
measure: State and Trait Aggression Questionnaire-State Score
timeFrame: 3 Years
measure: Baret Impulsivity Scale-State Score
timeFrame: 3 Years
measure: Visual Analogue Scale Score
timeFrame: 3 Years
measure: Interpersonal Reactivity Index Score
timeFrame: 3 Years
measure: Obsessive- Compulsive Inventory Score
timeFrame: 3 Years
measure: Brief Symptom Checklist Score
timeFrame: 3 Years
measure: Pittsburgh Sleep Quality Index Score
timeFrame: 3 Years
Other outcomes:
measure: Emotion Recognition Other Outcome 1: Detection threshold decreasing Happy - Intensity Morphing
timeFrame: 3 Years
measure: Emotion Recognition Other Outcome 2: Detection threshold decreasing Sad - Intensity Morphing
timeFrame: 3 Years
measure: Emotion Recognition Other Outcome 3: Detection threshold decreasing Anger - Intensity Morphing
timeFrame: 3 Years
measure: Emotion Recognition Other Outcome 4: Detection threshold decreasing Fear - Intensity Morphing
timeFrame: 3 Years
measure: Emotion Recognition Other Outcome 5: Detection threshold decreasing Disgust - Intensity Morphing
timeFrame: 3 Years
measure: Emotion Recognition Other Outcome 6: D' Happy - Emotion Recognition Task
timeFrame: 3 Years
measure: Emotion Recognition Other Outcome 7: D' Sad - Emotion Recognition Task
timeFrame: 3 Years
measure: Emotion Recognition Other Outcome 8: D' Fear - Emotion Recognition Task
timeFrame: 3 Years
measure: Emotion Recognition Other Outcome 9: D' Anger - Emotion Recognition Task
timeFrame: 3 Years
measure: Activity Level Score
timeFrame: 3 Years
measure: Behavioural Inhibition/ Behavioural Avoidance Scale Score
timeFrame: 3 Years
measure: The Compulsive Personality Assessment Scale Score
timeFrame: 3 Years
measure: Sexuality Questionnaire Score
timeFrame: 3 Years
measure: Edinburgh Handedness Inventory Score
timeFrame: 3 Years
measure: Revised NEO Personality Questionnaire Score
timeFrame: 3 Years
measure: Family History Assessment Module Score
timeFrame: 3 Years
measure: Positive Life Events Score
timeFrame: 3 Years
measure: Stressful Life Events Score
timeFrame: 3 Years
measure: State and Trait Aggression Questionnaire -Trait Score
timeFrame: 3 Years
measure: Barret Impulsivity Scale-Trait Score
timeFrame: 3 Years
measure: The Penn State Worry Questionnaire- Trait Score
timeFrame: 3 Years
measure: The Penn State Worry Questionnaire- State Score
timeFrame: 3 Years
measure: The Self-Control Scale- Trait Score
timeFrame: 3 Years
measure: The Self-Control Scale- State Score
timeFrame: 3 Years
measure: State- Trait Anxiety Inventory- Trait Score
timeFrame: 3 Years
measure: The Warwick-Edinburgh Mental Well-being Scale -Trait Score
timeFrame: 3 Years
measure: The Warwick-Edinburgh Mental Well-being Scale -State Score
timeFrame: 3 Years
measure: Mindful Attention and Awareness Scale -Trait Score
timeFrame: 3 Years
measure: Mindful Attention and Awareness Scale -State Score
timeFrame: 3 Years
measure: The Intolerance of Uncertainty Scale - Trait Score
timeFrame: 3 Years
measure: The Intolerance of Uncertainty Scale - State Score
timeFrame: 3 Years
measure: Verran Snyder-Halpern (VSH) Sleep Scale Score
timeFrame: 3 Years
Locations:
city: Copenhagen
country: Denmark
facility: Neurobiology Research Unit
Study officials:
References:
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citation: Bland AR, Roiser JP, Mehta MA, Schei T, Boland H, Campbell-Meiklejohn DK, Emsley RA, Munafo MR, Penton-Voak IS, Seara-Cardoso A, Viding E, Voon V, Sahakian BJ, Robbins TW, Elliott R. EMOTICOM: A Neuropsychological Test Battery to Evaluate Emotion, Motivation, Impulsivity, and Social Cognition. Front Behav Neurosci. 2016 Feb 24;10:25. doi: 10.3389/fnbeh.2016.00025. eCollection 2016.