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.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
BASIC_SCIENCE
Masking
TRIPLE
Enrollment
66
20mg daily for approximately 3 weeks.
Placebo daily for approximately 3 weeks.
Neurobiology Research Unit
Copenhagen, Denmark
Learning Primary Outcome 1: Mean errors Stage 1 (Learning) - Probability Reversal Learning.
Outcome variables have been grouped a priori into carefully defined cognitive domains. FDR correction, for multiple comparisons, using the Benjamin Hochberg procedure will be applied to the outcomes within each cognitive domain.
Time frame: 3 years
Learning Primary Outcome 2: Mean errors Stage 2 (Reversal) - Probability Reversal Learning.
Outcome variables have been grouped a priori into carefully defined cognitive domains. FDR correction, for multiple comparisons, using the Benjamin Hochberg procedure will be applied to the outcomes within each cognitive domain.
Time frame: 3 Years
Learning Primary Outcome 3: Learning Rate in Reward Trial - Reinforcement Learning.
Outcome variables have been grouped a priori into carefully defined cognitive domains. FDR correction, for multiple comparisons, using the Benjamin Hochberg procedure will be applied to the outcomes within each cognitive domain.
Time frame: 3 Years
Learning Primary Outcome 4: Learning Rate in Punishment Trials - Reinforcement Learning.
Outcome variables have been grouped a priori into carefully defined cognitive domains. FDR correction, for multiple comparisons, using the Benjamin Hochberg procedure will be applied to the outcomes within each cognitive domain.
Time frame: 3 Years
Inhibition Primary Outcome 1: Stop Signal Reaction Time - Interleaved Stop Signal Task/Go-NoGo.
Outcome variables have been grouped a priori into carefully defined cognitive domains.
Time frame: 3 Years
Executive Function Primary Outcome 1: Extra Dimensional Set Errors -3Dimensional Intra/Extra Dimensional Shift.
Outcome variables have been grouped a priori into carefully defined cognitive domains.
Time frame: 3 Years
Reinforcement Behaviour Model
A model comparison will be conducted to determine the winning model of reinforcement behaviour using one, a combination of, or all these parameters. The winning model will be a single outcome model. 1. Reward Learning Rate 2. Punishment Learning Rate 3. Reinforcement Sensitivity 4. Stimulus Stickiness
Time frame: 3 Years
Social Cognition Primary Outcome 1: Proportion of offers accepted - Ultimatum Game
Outcome variables have been grouped a priori into carefully defined cognitive domains. FDR correction, for multiple comparisons, using the Benjamin Hochberg procedure will be applied to the outcomes within each cognitive domain.
Time frame: 3 Years
Social Cognition Primary Outcome 2: Agent Guilt Score - Moral Emotions Task.
3\. Agent Shame Score ---------- Moral Emotions Task Outcome variables have been grouped a priori into carefully defined cognitive domains. FDR correction, for multiple comparisons, using the Benjamin Hochberg procedure will be applied to the outcomes within each cognitive domain.
Time frame: 3 Years
Social Cognition Primary Outcome 3: Agent Shame Score - Moral Emotions Task.
Outcome variables have been grouped a priori into carefully defined cognitive domains. FDR correction, for multiple comparisons, using the Benjamin Hochberg procedure will be applied to the outcomes within each cognitive domain.
Time frame: 3 Years
Emotion Recognition Primary Outcome 1: Affective bias in decreasing condition - EMOTICOM Intensity Morphing.
Outcome variables have been grouped a priori into carefully defined cognitive domains. FDR correction, for multiple comparisons, using the Benjamin Hochberg procedure will be applied to the outcomes within each cognitive domain.
Time frame: 3 Years
Emotion Recognition Primary Outcome 2: Affective bias for D' - EMOTICOM Emotion Recognition Task.
Outcome variables have been grouped a priori into carefully defined cognitive domains. FDR correction, for multiple comparisons, using the Benjamin Hochberg procedure will be applied to the outcomes within each cognitive domain.
Time frame: 3 Years
Emotion Recognition Primary Outcome 3: Detection threshold decreasing - EMOTICOM Intensity Morphing.
Outcome variables have been grouped a priori into carefully defined cognitive domains. FDR correction, for multiple comparisons, using the Benjamin Hochberg procedure will be applied to the outcomes within each cognitive domain.
Time frame: 3 Years
Emotion Recognition Primary Outcome 4: D'Prime for Emotion Recognition - EMOTICOM Emotion Recognition Task.
Outcome variables have been grouped a priori into carefully defined cognitive domains. FDR correction, for multiple comparisons, using the Benjamin Hochberg procedure will be applied to the outcomes within each cognitive domain.
Time frame: 3 Years
Biofluids: Serum Escitalopram levels
Time frame: 3 Years
PET Imaging: Cerebral (particularly hippocampal) presynaptic density, as measured with 11 C-UCB-J-PET.
Collected in a sub-sample of participants.
Time frame: 3 Years
Learning Secondary Outcome 1: Stage 1 Reward-Stay/Lose-Shift behaviour - Probability Reversal Learning.
Outcome variables have been grouped a priori into carefully defined cognitive domains. FDR correction, for multiple comparisons, using the Benjamin Hochberg procedure will be applied to the outcomes within each cognitive domain.
Time frame: 3 Years
Learning Secondary Outcome 2: Stage 2 Reward-Stay/ Lose-Shift behaviour - Probability Reversal Learning.
Outcome variables have been grouped a priori into carefully defined cognitive domains. FDR correction, for multiple comparisons, using the Benjamin Hochberg procedure will be applied to the outcomes within each cognitive domain.
Time frame: 3 Years
Learning Secondary Outcome 3: Pre Extra Dimension Set Errors - 3Dimensional Intra/Extra Dimensional Shift.
Outcome variables have been grouped a priori into carefully defined cognitive domains. FDR correction, for multiple comparisons, using the Benjamin Hochberg procedure will be applied to the outcomes within each cognitive domain.
Time frame: 3 Years
Learning Secondary Outcome 4: Proportion of Stays - Sequential Model-Based/Model-Free.
Outcome variables have been grouped a priori into carefully defined cognitive domains. FDR correction, for multiple comparisons, using the Benjamin Hochberg procedure will be applied to the outcomes within each cognitive domain.
Time frame: 3 Years
Inhibition Secondary Outcome 1: Go reaction time - Interleaved Stop Signal Task/Go-NoGo.
Outcome variables have been grouped a priori into carefully defined cognitive domains. FDR correction, for multiple comparisons, using the Benjamin Hochberg procedure will be applied to the outcomes within each cognitive domain.
Time frame: 3 Years
Inhibition Secondary Outcome 2: Go omission error rate - Interleaved Stop Signal Task/Go-NoGo.
Outcome variables have been grouped a priori into carefully defined cognitive domains. FDR correction, for multiple comparisons, using the Benjamin Hochberg procedure will be applied to the outcomes within each cognitive domain.
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Time frame: 3 Years
Inhibition Secondary Outcome 3: Go commission error rate - Interleaved Stop Signal Task/Go-NoGo.
Outcome variables have been grouped a priori into carefully defined cognitive domains. FDR correction, for multiple comparisons, using the Benjamin Hochberg procedure will be applied to the outcomes within each cognitive domain.
Time frame: 3 Years
Inhibition Secondary Outcome 4: No-Go error rate - Interleaved Stop Signal Task/Go-NoGo.
Outcome variables have been grouped a priori into carefully defined cognitive domains. FDR correction, for multiple comparisons, using the Benjamin Hochberg procedure will be applied to the outcomes within each cognitive domain.
Time frame: 3 Years
Executive Function Secondary Outcome 1: Total Errors Adjusted - 3Dimensional Intra/Extra Dimensional Shift.
Outcome variables have been grouped a priori into carefully defined cognitive domains. FDR correction, for multiple comparisons, using the Benjamin Hochberg procedure will be applied to the outcomes within each cognitive domain.
Time frame: 3 Years
Executive Function Secondary Outcome 2: Strategy Score - CANTAB Spatial Working Memory.
Outcome variables have been grouped a priori into carefully defined cognitive domains. FDR correction, for multiple comparisons, using the Benjamin Hochberg procedure will be applied to the outcomes within each cognitive domain.
Time frame: 3 Years
Social Cognition Secondary Outcome 1: Fairness Sensitivity---------- Ultimatum Game
Outcome variables have been grouped a priori into carefully defined cognitive domains.
Time frame: 3 Years
Emotion Recognition Secondary Outcome 1: Detection threshold increasing - EMOTICOM Intensity Morphing.
Outcome variables have been grouped a priori into carefully defined cognitive domains. FDR correction, for multiple comparisons, using the Benjamin Hochberg procedure will be applied to the outcomes within each cognitive domain.
Time frame: 3 Years
Emotion Recognition Secondary Outcome 2: Affective bias in increasing condition - EMOTICOM Intensity Morphing.
Outcome variables have been grouped a priori into carefully defined cognitive domains. FDR correction, for multiple comparisons, using the Benjamin Hochberg procedure will be applied to the outcomes within each cognitive domain.
Time frame: 3 Years
Emotion Recognition Secondary Outcome 3: Affective bias for Hit Rate - EMOTICOM Emotion Recognition Task.
Outcome variables have been grouped a priori into carefully defined cognitive domains. FDR correction, for multiple comparisons, using the Benjamin Hochberg procedure will be applied to the outcomes within each cognitive domain.
Time frame: 3 Years
Emotion Recognition Secondary Outcome 4: Hit Rate for Emotion Recognition - EMOTICOM Emotion Recognition Task.
Outcome variables have been grouped a priori into carefully defined cognitive domains. FDR correction, for multiple comparisons, using the Benjamin Hochberg procedure will be applied to the outcomes within each cognitive domain.
Time frame: 3 Years
Faces and geometric figure discrimination Outcome 1: Accuracy - Faces fMRI paradigm
Outcome variables have been grouped a priori into carefully defined cognitive domains. FDR correction, for multiple comparisons, using the Benjamin Hochberg procedure will be applied to the outcomes within each cognitive domain.
Time frame: 3 Years
Faces and geometric figure discrimination Outcome 2: Response Speed - Faces fMRI paradigm.
Outcome variables have been grouped a priori into carefully defined cognitive domains. FDR correction, for multiple comparisons, using the Benjamin Hochberg procedure will be applied to the outcomes within each cognitive domain.
Time frame: 3 Years
Memory Outcome 1: Total Errors Adj - CANTAB Paired Associates Learning
Outcome variables have been grouped a priori into carefully defined cognitive domains. FDR correction, for multiple comparisons, using the Benjamin Hochberg procedure will be applied to the outcomes within each cognitive domain.
Time frame: 3 Years
Memory Outcome 2: First Trial Memory Score - CANTAB Paired Associates Learning.
Outcome variables have been grouped a priori into carefully defined cognitive domains. FDR correction, for multiple comparisons, using the Benjamin Hochberg procedure will be applied to the outcomes within each cognitive domain.
Time frame: 3 Years
Memory Outcome 3: Between Search Errors - CANTAB Spatial Working Memory.
Outcome variables have been grouped a priori into carefully defined cognitive domains. FDR correction, for multiple comparisons, using the Benjamin Hochberg procedure will be applied to the outcomes within each cognitive domain.
Time frame: 3 Years
Attention Outcome 1: Target Sensitivity (A') - CANTAB Rapid Visual Processing.
Outcome variables have been grouped a priori into carefully defined cognitive domains. FDR correction, for multiple comparisons, using the Benjamin Hochberg procedure will be applied to the outcomes within each cognitive domain.
Time frame: 3 Years
Attention Outcome 2: Latency - CANTAB Rapid Visual Processing
Outcome variables have been grouped a priori into carefully defined cognitive domains. FDR correction, for multiple comparisons, using the Benjamin Hochberg procedure will be applied to the outcomes within each cognitive domain.
Time frame: 3 Years
Attention Outcome 3: Probability of False Alarms - CANTAB Rapid Visual Processing
Outcome variables have been grouped a priori into carefully defined cognitive domains. FDR correction, for multiple comparisons, using the Benjamin Hochberg procedure will be applied to the outcomes within each cognitive domain.
Time frame: 3 Years
Risky Decision Making Outcome Outcome 1. Quality of Decision Making - EMOTICOM Cambridge Gamble Task.
Outcome variables have been grouped a priori into carefully defined cognitive domains. FDR correction, for multiple comparisons, using the Benjamin Hochberg procedure will be applied to the outcomes within each cognitive domain.
Time frame: 3 Years
Risky Decision Making Outcome 2: Risk Adjustment - EMOTICOM Cambridge Gamble Task
Outcome variables have been grouped a priori into carefully defined cognitive domains. FDR correction, for multiple comparisons, using the Benjamin Hochberg procedure will be applied to the outcomes within each cognitive domain.
Time frame: 3 Years
Risky Decision Making Outcome 3: Overall Proportion Bet - EMOTICOM Cambridge Gamble Task
Outcome variables have been grouped a priori into carefully defined cognitive domains. FDR correction, for multiple comparisons, using the Benjamin Hochberg procedure will be applied to the outcomes within each cognitive domain.
Time frame: 3 Years
Risky Decision Making Outcome 4: Deliberation Time - EMOTICOM Cambridge Gamble Task.
Outcome variables have been grouped a priori into carefully defined cognitive domains. FDR correction, for multiple comparisons, using the Benjamin Hochberg procedure will be applied to the outcomes within each cognitive domain.
Time frame: 3 Years
Psychomotor Speed Outcome 1: Simple reaction time - CANTAB Reaction Time Task
Outcome variables have been grouped a priori into carefully defined cognitive domains. FDR correction, for multiple comparisons, using the Benjamin Hochberg procedure will be applied to the outcomes within each cognitive domain.
Time frame: 3 Years
Psychomotor Speed Outcome 2: Five Choice reaction time - CANTAB Reaction Time Task
Outcome variables have been grouped a priori into carefully defined cognitive domains. FDR correction, for multiple comparisons, using the Benjamin Hochberg procedure will be applied to the outcomes within each cognitive domain.
Time frame: 3 Years
Neural Activations and Correlations - Reinforcement Learning fMRI paradigm
Imaging outcomes will be FWE corrected using Random Field Theory as implemented in SPM12.
Time frame: 3 Years
Neural Activations and Correlations - Faces fMRI paradigm
Imaging outcomes will be FWE corrected using Random Field Theory as implemented in SPM12.
Time frame: 3 Years
Resting State fMRI
Imaging outcomes will be FWE corrected using Random Field Theory as implemented in SPM12.
Time frame: 3 Years
Structural VBM
Imaging outcomes will be FWE corrected using Random Field Theory as implemented in SPM12.
Time frame: 3 Years
Diffusion Tensor Imaging
Time frame: 3 Years
Profile of Mood State Score
Time frame: 3 Years
Beck Depression Inventory-II Score
Time frame: 3 Years
State-Trait Anxiety Inventory Scale -State Score
Time frame: 3 Years
State and Trait Aggression Questionnaire-State Score
Time frame: 3 Years
Baret Impulsivity Scale-State Score
Time frame: 3 Years
Visual Analogue Scale Score
Time frame: 3 Years
Interpersonal Reactivity Index Score
Time frame: 3 Years
Obsessive- Compulsive Inventory Score
Time frame: 3 Years
Brief Symptom Checklist Score
Time frame: 3 Years
Pittsburgh Sleep Quality Index Score
Time frame: 3 Years