The Role of Serotonin in Compulsive Behavior in Humans: Underlying Brain Mechanisms

The aim of this project is to investigate: The status of the central serotonin (5-hydroxytryptamine, 5-HT) system in compulsive behaviour and how it is affected by sub-chronic escitalopram administration The mechanisms underlying how sub-chronic administration of escitalopram affects the central 5-HT system How changes in cognitive performance, including the balance between habitual and goal-directed mechanisms, are affected in compulsive behaviour by boosting 5-HT function How functional brain changes in cognitive function measured with magnetic resonance imaging relate to altered 5-HT function following escitalopram administration.

Previous studies have shown that 5-HT is strongly implicated in compulsive behaviours in experimental animals. Manipulation of 5-HT influences neuronal interactions underlying action selection. Reduced forebrain 5-HT causes perseveration and impairs goal-directed behaviour under reward but not punishment. Dysfunctional 5-HT neurotransmission has also been implicated in Obsessive-Compulsive Disorder (OCD) based on the selective efficacy of relatively high doses of selective serotonin reuptake inhibitors (SSRIs) in treating this disorder. Hitherto, it is unknown whether there is a primary defect in the serotonergic system or whether SSRIs ameliorate symptoms by modulating other brain neurotransmitter pathways. So far, only one study of central 5-HT release in OCD patients has been conducted and its methodology may be questioned. A number of behavioural and cognitive features of OCD, including endophenotype markers that appear to characterise the disorder have been determined. These include a shift in cognitive control from a goal-directed strategy to a habitual (stimulus-response, S-R) strategy, cognitive rigidity in terms of both reversal learning and attentional set-shifting, impaired response inhibition and planning, and a tendency to over-respond to spurious negative feedback in a probabilistic learning paradigm. Neural substrates of these deficits are being investigated using brain imaging methodologies based on magnetic resonance and preliminary evidence suggests an over-active medial prefrontal cortex-caudate nucleus circuits and underactive lateral prefrontal cortex-putamen circuits. However, little evidence exists that relates to the hypothesis of an over-active habit system in this disorder or to the role of serotonin in all these cognitive and behavioural deficits observed in OCD and compulsivity in general.

The healthy placebo control group will be administered the exact same procedure as the intervention group, the only difference being that this group will be administered a placebo tablet.

The OCD/high compulsivity placebo control group will be administered the exact same procedure as the intervention group, the only difference being that this group will be administered a placebo tablet.

The OCD/high compulsivity intervention group will be administered 20mg of Escitalopram daily for 3-4 weeks.

Learning Primary Outcome 1 measured with Probability Reversal Learning test: Mean errors Stage 1 (Learning)

Outcome variables have been grouped a priori into carefully defined cognitive domains. False discovery rate (FDR) correction, for multiple comparisons, using the Benjamini-Hochberg procedure will be applied to the outcomes within each cognitive domain.

Learning Primary Outcome 2 measured with Probability Reversal Learning test: Mean errors Stage 2 (Reversal)

Outcome variables have been grouped a priori into carefully defined cognitive domains. False discovery rate (FDR) correction, for multiple comparisons, using the Benjamini-Hochberg procedure will be applied to the outcomes within each cognitive domain.

Learning Primary Outcome 3 measured with Deterministic Reversal Learning test: Percent correct per stage

Outcome variables have been grouped a priori into carefully defined cognitive domains. False discovery rate (FDR) correction, for multiple comparisons, using the Benjamini-Hochberg procedure will be applied to the outcomes within each cognitive domain.

Inhibition Primary Outcome 1 measured with Interleaved Stop Signal Task/Go-NoGo: Stop Signal Reaction Time

Flexibility Primary Outcome 1 measured with 3Dimensional Intra/Extra Dimensional Shift test: Extra Dimensional Set Errors

Flexibility Primary Outcome 2 measured with Sequential model-based model-free test: Model-based Model-free Weight

Outcome variables have been grouped a priori into carefully defined cognitive domains. False discovery rate (FDR) correction, for multiple comparisons, using the Benjamini-Hochberg procedure will be applied to the outcomes within each cognitive domain.

Outcome variables have been grouped a priori into carefully defined cognitive domains. The false discovery rate (FDR) correction, for multiple comparisons, using the Benjamini-Hochberg procedure will be applied to the outcomes within each cognitive domain.

Emotion Recognition Primary Outcome 1 measures with EMOTICOM Intensity Morphing: Affective bias in decreasing condition

Outcome variables have been grouped a priori into carefully defined cognitive domains. False discovery rate (FDR) correction, for multiple comparisons, using the Benjamini-Hochberg procedure will be applied to the outcomes within each cognitive domain.

Emotion Recognition Primary Outcome 2 measured with EMOTICOM Emotion Recognition Task: Affective bias for D'

Outcome variables have been grouped a priori into carefully defined cognitive domains. False discovery rate (FDR) correction, for multiple comparisons, using the Benjamini-Hochberg procedure will be applied to the outcomes within each cognitive domain.

Emotion Recognition Primary Outcome 3 measured with EMOTICOM Intensity Morphing task: Detection threshold decreasing

Outcome variables have been grouped a priori into carefully defined cognitive domains. False discovery rate (FDR) correction, for multiple comparisons, using the Benjamini-Hochberg procedure will be applied to the outcomes within each cognitive domain.

Emotion Recognition Primary Outcome 4 measured with EMOTICOM Emotion Recognition task: D'Prime for emotion recognition

Emotion Recognition Task. Outcome variables have been grouped a priori into carefully defined cognitive domains. False discovery rate (FDR) correction, for multiple comparisons, using the Benjamini-Hochberg procedure will be applied to the outcomes within each cognitive domain.

Outcome variables have been grouped a priori into carefully defined cognitive domains. False discovery rate (FDR) correction, for multiple comparisons, using the Benjamini-Hochberg procedure will be applied to the outcomes within each cognitive domain.

Neural Activations and Correlations measured with functional magnetic resonance imaging (fMRI) paradigm named Slip of Actions

Imaging outcomes will be Family-Wise Error (FWE) corrected using Random Field Theory as implemented in SPM12.

Neural Activations and Correlations measured with functional magnetic resonance imaging (fMRI) paradigm named Cohabit

Imaging outcomes will be Family-Wise Error (FWE) corrected using Random Field Theory as implemented in SPM12Co-habit fMRI paradigm Imaging outcomes will be FWE corrected using Random Field Theory as implemented in SPM12.

Neural Activations and Correlations measured with functional magnetic resonance imaging (fMRI) paradigm named Faces

Imaging outcomes will be Family-Wise Error (FWE) corrected using Random Field Theory as implemented in SPM12.

Imaging outcomes will be Family-Wise Error (FWE) corrected using Random Field Theory as implemented in SPM12.

Imaging outcomes will be Family-Wise Error (FWE) corrected using Random Field Theory as implemented in SPM12.

Learning Secondary Outcome 1 measured with Probability Reversal Learning test: Stage 1 Reward-Stay/Lose-Shift behaviour

Outcome variables have been grouped a priori into carefully defined cognitive domains. False discovery rate (FDR) correction, for multiple comparisons, using the Benjamini-Hochberg procedure will be applied to the outcomes within each cognitive domain.

Learning Secondary Outcome 2 measured with Probability Reversal Learning test: Stage 1 Reward/Punishment learning

Outcome variables have been grouped a priori into carefully defined cognitive domains. False discovery rate (FDR) correction, for multiple comparisons, using the Benjamini-Hochberg procedure will be applied to the outcomes within each cognitive domain.

Learning Secondary Outcome 3 measured with Probability Reversal Learning test: Stage 1. Stimulus Stickiness

Outcome variables have been grouped a priori into carefully defined cognitive domains. False discovery rate (FDR) correction, for multiple comparisons, using the Benjamini-Hochberg procedure will be applied to the outcomes within each cognitive domain.

Learning Secondary Outcome 4 measured with Probability Reversal Learning test: Stage 2 Reward-Stay/ Lose-Shift behaviour

Outcome variables have been grouped a priori into carefully defined cognitive domains. False discovery rate (FDR) correction, for multiple comparisons, using the Benjamini-Hochberg procedure will be applied to the outcomes within each cognitive domain.

Learning Secondary Outcome 5 measured with Probability Reversal Learning test: Stage 2 Reward/Punishment learning

Outcome variables have been grouped a priori into carefully defined cognitive domains. False discovery rate (FDR) correction, for multiple comparisons, using the Benjamini-Hochberg procedure will be applied to the outcomes within each cognitive domain.

Learning Secondary Outcome 6 measured with Probability Reversal Learning test: Stage 2. Stimulus Stickiness

Outcome variables have been grouped a priori into carefully defined cognitive domains. False discovery rate (FDR) correction, for multiple comparisons, using the Benjamini-Hochberg procedure will be applied to the outcomes within each cognitive domain.

Learning Secondary Outcome 7 measured with Deterministic Reversal Learning test: Reward-Stay/ Lose-Shift behaviour

Outcome variables have been grouped a priori into carefully defined cognitive domains. False discovery rate (FDR) correction, for multiple comparisons, using the Benjamini-Hochberg procedure will be applied to the outcomes within each cognitive domain.

Flexibility Secondary Outcome 1 measured with Sequential Model-Based/Model-Free test: Proportion of Stays

Outcome variables have been grouped a priori into carefully defined cognitive domains. False discovery rate (FDR) correction, for multiple comparisons, using the Benjamini-Hochberg procedure will be applied to the outcomes within each cognitive domain.

Outcome variables have been grouped a priori into carefully defined cognitive domains. False discovery rate (FDR) correction, for multiple comparisons, using the Benjamini-Hochberg procedure will be applied to the outcomes within each cognitive domain.

Flexibility Secondary Outcome 3 measured with Sequential Model-Based/Model-Free test: Stimulus Stickiness

Outcome variables have been grouped a priori into carefully defined cognitive domains. False discovery rate (FDR) correction, for multiple comparisons, using the Benjamini-Hochberg procedure will be applied to the outcomes within each cognitive domain.

Outcome variables have been grouped a priori into carefully defined cognitive domains. False discovery rate (FDR) correction, for multiple comparisons, using the Benjamini-Hochberg procedure will be applied to the outcomes within each cognitive domain.

Flexibility Secondary Outcome 5 measured with 3Dimensional Intra/Extra Dimensional Shift test: Pre Extra Dimension Set Errors

Outcome variables have been grouped a priori into carefully defined cognitive domains. False discovery rate (FDR) correction, for multiple comparisons, using the Benjamini-Hochberg procedure will be applied to the outcomes within each cognitive domain.

Flexibility Secondary Outcome 6 measured with 3Dimensional Intra/Extra Dimensional Shift test: Latency

Outcome variables have been grouped a priori into carefully defined cognitive domains. False discovery rate (FDR) correction, for multiple comparisons, using the Benjamini-Hochberg procedure will be applied to the outcomes within each cognitive domain.

Outcome variables have been grouped a priori into carefully defined cognitive domains. False discovery rate (FDR) correction, for multiple comparisons, using the Benjamini-Hochberg procedure will be applied to the outcomes within each cognitive domain.

Inhibition Secondary Outcome 2 measured with Interleaved Stop Signal Task/Go-NoGo: Go omission error rate

Outcome variables have been grouped a priori into carefully defined cognitive domains. False discovery rate (FDR) correction, for multiple comparisons, using the Benjamini-Hochberg procedure will be applied to the outcomes within each cognitive domain.

Inhibition Secondary Outcome 3 measured with Interleaved Stop Signal Task/Go-NoGo: Go commission error rate

Outcome variables have been grouped a priori into carefully defined cognitive domains. False discovery rate (FDR) correction, for multiple comparisons, using the Benjamini-Hochberg procedure will be applied to the outcomes within each cognitive domain.

Outcome variables have been grouped a priori into carefully defined cognitive domains. False discovery rate (FDR) correction, for multiple comparisons, using the Benjamini-Hochberg procedure will be applied to the outcomes within each cognitive domain.

Executive Function Secondary Outcome 1 measured with 3Dimensional Intra/Extra Dimensional Shift test: Total Errors Adjusted

Outcome variables have been grouped a priori into carefully defined cognitive domains. False discovery rate (FDR) correction, for multiple comparisons, using the Benjamini-Hochberg procedure will be applied to the outcomes within each cognitive domain.

Emotion Recognition Secondary Outcome 1 measured with EMOTICOM Intensity Morphing Task: Detection threshold increasing

Outcome variables have been grouped a priori into carefully defined cognitive domains. False discovery rate (FDR) correction, for multiple comparisons, using the Benjamini-Hochberg procedure will be applied to the outcomes within each cognitive domain.

Emotion Recognition Secondary Outcome 2 measured with EMOTICOM Intensity Morphing Task: Affective bias in increasing condition

Outcome variables have been grouped a priori into carefully defined cognitive domains. False discovery rate (FDR) correction, for multiple comparisons, using the Benjamini-Hochberg procedure will be applied to the outcomes within each cognitive domain.

Emotion Recognition Secondary Outcome 3 measured with EMOTICOM Emotion Recognition Task: Affective bias for Hit Rate

Outcome variables have been grouped a priori into carefully defined cognitive domains. False discovery rate (FDR) correction, for multiple comparisons, using the Benjamini-Hochberg procedure will be applied to the outcomes within each cognitive domain.

Emotion Recognition Secondary Outcome 4 measured with EMOTICOM Emotion Recognition Task.: Hit Rate for Emotion Recognition

Outcome variables have been grouped a priori into carefully defined cognitive domains. False discovery rate (FDR) correction, for multiple comparisons, using the Benjamini-Hochberg procedure will be applied to the outcomes within each cognitive domain.

Outcome variables have been grouped a priori into carefully defined cognitive domains. False discovery rate (FDR) correction, for multiple comparisons, using the Benjamini-Hochberg procedure will be applied to the outcomes within each cognitive domain.

Behavioural outcomes with Faces and geometric figure discrimination Outcome 2 measured with fMRI faces paradigm: Response Speed

Outcome variables have been grouped a priori into carefully defined cognitive domains. False discovery rate (FDR) correction, for multiple comparisons, using the Benjamini-Hochberg procedure will be applied to the outcomes within each cognitive domain.

Outcome variables have been grouped a priori into carefully defined cognitive domains. False discovery rate (FDR) correction, for multiple comparisons, using the Benjamini-Hochberg procedure will be applied to the outcomes within each cognitive domain.

Outcome variables have been grouped a priori into carefully defined cognitive domains. False discovery rate (FDR) correction, for multiple comparisons, using the Benjamini-Hochberg procedure will be applied to the outcomes within each cognitive domain.

Outcome variables have been grouped a priori into carefully defined cognitive domains. False discovery rate (FDR) correction, for multiple comparisons, using the Benjamini-Hochberg procedure will be applied to the outcomes within each cognitive domain.

Outcome variables have been grouped a priori into carefully defined cognitive domains. False discovery rate (FDR) correction, for multiple comparisons, using the Benjamini-Hochberg procedure will be applied to the outcomes within each cognitive domain.

Memory Primary outcome 3 measured with Verbal Affective Memory Test-26: Latent variable model of the association between positive, negative and neutral word recall and 5-HT4R binding

Outcome variables have been grouped a priori into carefully defined cognitive domains. False discovery rate (FDR) correction, for multiple comparisons, using the Benjamini-Hochberg procedure will be applied to the outcomes within each cognitive domain.

Risky Decision Making Outcome Outcome 1 measured with EMOTICOM Cambridge Gamble Task: Quality of Decision Making

Outcome variables have been grouped a priori into carefully defined cognitive domains. False discovery rate (FDR) correction, for multiple comparisons, using the Benjamini-Hochberg procedure will be applied to the outcomes within each cognitive domain.

Outcome variables have been grouped a priori into carefully defined cognitive domains. False discovery rate (FDR) correction, for multiple comparisons, using the Benjamini-Hochberg procedure will be applied to the outcomes within each cognitive domain.

Outcome variables have been grouped a priori into carefully defined cognitive domains. False discovery rate (FDR) correction, for multiple comparisons, using the Benjamini-Hochberg procedure will be applied to the outcomes within each cognitive domain.

Outcome variables have been grouped a priori into carefully defined cognitive domains. False discovery rate (FDR) correction, for multiple comparisons, using the Benjamini-Hochberg procedure will be applied to the outcomes within each cognitive domain.

Outcome variables have been grouped a priori into carefully defined cognitive domains. False discovery rate (FDR) correction, for multiple comparisons, using the Benjamini-Hochberg procedure will be applied to the outcomes within each cognitive domain.

Intelligence Quotient (IQ) outcome 1 measured with Reynolds Intellectual assessment Scales subtest "guess what" and "what does not fit": Total age adjusted score

Outcome variables have been grouped a priori into carefully defined cognitive domains. False discovery rate (FDR) correction, for multiple comparisons, using the Benjamini-Hochberg procedure will be applied to the outcomes within each cognitive domain

Inclusion Criteria: OCD patients, compulsive individuals without an OCD diagnosis, and healthy volunteers (male or female) between 18 and 70 years. Compulsive individuals without an OCD diagnosis are individuals without a history of psychiatric or other major medical conditions but scoring abnormally high on the Obsessive-Compulsive Inventory (OCI) questionnaire. Exclusion Criteria: Current or previous neurological disease, severe somatic disease, or consumption of medical 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). Participation in experiments with radioactivity (> 10 mSv) within the last year or significant occupational exposure to radioactivity. 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). Current medication with serotonergic acting compounds. Use of other psychoactive substances must be stable at least one month prior to inclusion and maintained throughout the study. Severe physical impairments affecting eyesight or motor performance. For the OCD group: other Axis I mental disorder as primary diagnosis according to ICD-10 criteria. For healthy volunteers: any current or former primary psychiatric disorder (Axis I WHO ICD-10 diagnostic classification).

Upon completion of the study all data will be uploaded to the existing Center for Integrated Molecular Brain Imaging (CIMBI) Database. Researchers may apply for access to the data.

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