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

Healthy Individuals Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04336228
• Other study ID #: H-18038325
• Status: Recruiting
• Phase: Phase 4
• Start date: April 1, 2020
• Est. completion date: August 2024

Study information

• Verified date: November 2022
• Source: Rigshospitalet, Denmark
• Contact: Gitte M. Knudsen, Professor
• Phone: +45 35456720
• Email: gitte[@]nru.dk
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 48
• Est. completion date: August 2024
• Est. primary completion date: August 2024
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

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).

Related Conditions & MeSH terms

• Compulsive Behavior
• Healthy Individuals
• Obsessive-Compulsive Disorder

Intervention

Drug:
• Escitalopram
20mg daily for 3-4 weeks.
• Placebo oral tablet
20mg placebo tablet daily for 3-4 weeks.

Locations

Country	Name	City	State
Denmark	Neurobiology Research Unit, Rigshospitalet	Copenhagen

Sponsors (3)

Lead Sponsor	Collaborator
Rigshospitalet, Denmark	Lundbeck Foundation, University of Cambridge

Country where clinical trial is conducted

Denmark, 

References & Publications (17)

Apergis-Schoute AM, Gillan CM, Fineberg NA, Fernandez-Egea E, Sahakian BJ, Robbins TW. Neural basis of impaired safety signaling in Obsessive Compulsive Disorder. Proc Natl Acad Sci U S A. 2017 Mar 21;114(12):3216-3221. doi: 10.1073/pnas.1609194114. Epub 2017 Mar 6. — View Citation

Banca P, Voon V, Vestergaard MD, Philipiak G, Almeida I, Pocinho F, Relvas J, Castelo-Branco M. Imbalance in habitual versus goal directed neural systems during symptom provocation in obsessive-compulsive disorder. Brain. 2015 Mar;138(Pt 3):798-811. doi: 10.1093/brain/awu379. Epub 2015 Jan 6. — View Citation

Chamberlain SR, Fineberg NA, Blackwell AD, Robbins TW, Sahakian BJ. Motor inhibition and cognitive flexibility in obsessive-compulsive disorder and trichotillomania. Am J Psychiatry. 2006 Jul;163(7):1282-4. — View Citation

Chamberlain SR, Fineberg NA, Menzies LA, Blackwell AD, Bullmore ET, Robbins TW, Sahakian BJ. Impaired cognitive flexibility and motor inhibition in unaffected first-degree relatives of patients with obsessive-compulsive disorder. Am J Psychiatry. 2007 Feb;164(2):335-8. — View Citation

Clarke HF, Dalley JW, Crofts HS, Robbins TW, Roberts AC. Cognitive inflexibility after prefrontal serotonin depletion. Science. 2004 May 7;304(5672):878-80. — View Citation

Dayan P, Huys QJ. Serotonin in affective control. Annu Rev Neurosci. 2009;32:95-126. doi: 10.1146/annurev.neuro.051508.135607. Review. — View Citation

el Mansari M, Bouchard C, Blier P. Alteration of serotonin release in the guinea pig orbito-frontal cortex by selective serotonin reuptake inhibitors. Relevance to treatment of obsessive-compulsive disorder. Neuropsychopharmacology. 1995 Oct;13(2):117-27. — View Citation

Foa, E. B. et al. The validation of a new obsessive-compulsive disorder scale: The obsessive-compulsive inventory. Psychological Assessment 10(3), 206-214, 1998.

Gillan CM, Papmeyer M, Morein-Zamir S, Sahakian BJ, Fineberg NA, Robbins TW, de Wit S. Disruption in the balance between goal-directed behavior and habit learning in obsessive-compulsive disorder. Am J Psychiatry. 2011 Jul;168(7):718-26. doi: 10.1176/appi.ajp.2011.10071062. Epub 2011 May 15. — View Citation

Goodman WK, Price LH, Rasmussen SA, Mazure C, Delgado P, Heninger GR, Charney DS. The Yale-Brown Obsessive Compulsive Scale. II. Validity. Arch Gen Psychiatry. 1989 Nov;46(11):1012-6. — View Citation

Groman SM, James AS, Seu E, Crawford MA, Harpster SN, Jentsch JD. Monoamine levels within the orbitofrontal cortex and putamen interact to predict reversal learning performance. Biol Psychiatry. 2013 Apr 15;73(8):756-62. doi: 10.1016/j.biopsych.2012.12.002. Epub 2013 Jan 16. — View Citation

Haahr ME, Fisher PM, Jensen CG, Frokjaer VG, Mahon BM, Madsen K, Baaré WF, Lehel S, Norremolle A, Rabiner EA, Knudsen GM. Central 5-HT4 receptor binding as biomarker of serotonergic tonus in humans: a [11C]SB207145 PET study. Mol Psychiatry. 2014 Apr;19(4):427-32. doi: 10.1038/mp.2013.147. Epub 2013 Nov 5. — View Citation

Lissemore JI, Sookman D, Gravel P, Berney A, Barsoum A, Diksic M, Nordahl TE, Pinard G, Sibon I, Cottraux J, Leyton M, Benkelfat C. Brain serotonin synthesis capacity in obsessive-compulsive disorder: effects of cognitive behavioral therapy and sertraline. Transl Psychiatry. 2018 Apr 18;8(1):82. doi: 10.1038/s41398-018-0128-4. — View Citation

Palminteri S, Clair AH, Mallet L, Pessiglione M. Similar improvement of reward and punishment learning by serotonin reuptake inhibitors in obsessive-compulsive disorder. Biol Psychiatry. 2012 Aug 1;72(3):244-50. doi: 10.1016/j.biopsych.2011.12.028. Epub 2012 Feb 10. — View Citation

Pelloux Y, Dilleen R, Economidou D, Theobald D, Everitt BJ. Reduced forebrain serotonin transmission is causally involved in the development of compulsive cocaine seeking in rats. Neuropsychopharmacology. 2012 Oct;37(11):2505-14. doi: 10.1038/npp.2012.111. Epub 2012 Jul 4. — View Citation

Vaghi MM, Vértes PE, Kitzbichler MG, Apergis-Schoute AM, van der Flier FE, Fineberg NA, Sule A, Zaman R, Voon V, Kundu P, Bullmore ET, Robbins TW. Specific Frontostriatal Circuits for Impaired Cognitive Flexibility and Goal-Directed Planning in Obsessive-Compulsive Disorder: Evidence From Resting-State Functional Connectivity. Biol Psychiatry. 2017 Apr 15;81(8):708-717. doi: 10.1016/j.biopsych.2016.08.009. Epub 2016 Aug 11. — View Citation

Worbe Y, Palminteri S, Savulich G, Daw ND, Fernandez-Egea E, Robbins TW, Voon V. Valence-dependent influence of serotonin depletion on model-based choice strategy. Mol Psychiatry. 2016 May;21(5):624-9. doi: 10.1038/mp.2015.46. Epub 2015 Apr 14. — View Citation

* Note: There are 17 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Emotion Recognition Other Outcome 1: Detection threshold decreasing Happy - Intensity Morphing	Outcome variables have been grouped a priori into carefully defined cognitive domains.	3 Years
Other	Emotion Recognition Other Outcome 2: Detection threshold decreasing Sad - Intensity Morphing	Outcome variables have been grouped a priori into carefully defined cognitive domains.	3 Years
Other	Emotion Recognition Other Outcome 3: Detection threshold decreasing Anger - Intensity Morphing	Outcome variables have been grouped a priori into carefully defined cognitive domains.	3 Years
Other	Emotion Recognition Other Outcome 4: Detection threshold decreasing Fear - Intensity Morphing	Outcome variables have been grouped a priori into carefully defined cognitive domains.	3 Years
Other	Emotion Recognition Other Outcome 5: Detection threshold decreasing Disgust - Intensity Morphing	Outcome variables have been grouped a priori into carefully defined cognitive domains.	3 Years
Other	Emotion Recognition Other Outcome 6: D' Happy - Emotion Recognition Task	Outcome variables have been grouped a priori into carefully defined cognitive domains.	3 Years
Other	Emotion Recognition Other Outcome 7: D' Sad - Emotion Recognition Task	Outcome variables have been grouped a priori into carefully defined cognitive domains.	3 Years
Other	Emotion Recognition Other Outcome 8: D' Fear - Emotion Recognition Task	Outcome variables have been grouped a priori into carefully defined cognitive domains.	3 Years
Other	Emotion Recognition Other Outcome 9: D' Anger - Emotion Recognition Task	Outcome variables have been grouped a priori into carefully defined cognitive domains.	3 Years
Other	Activity Level Score		3 Years
Other	Behavioural Inhibition/ Behavioural Avoidance Scale Score		3 Years
Other	The Compulsive Personality Assessment Scale Score		3 Years
Other	Sexuality Questionnaire Score		3 Years
Other	Edinburgh Handedness Inventory Score		3 Years
Other	Revised NEO Personality Questionnaire Score		3 Years
Other	Family History Assessment Module Score		3 Years
Other	Positive Life Events Score		3 Years
Other	Stressful Life Events Score		3 Years
Other	Perceived stress scale		3 Years
Other	Barratt Impulsiveness Scale-Trait Score		3 Years
Other	The Penn State Worry Questionnaire- Trait Score		3 Years
Other	The Penn State Worry Questionnaire- State Score		3 Years
Other	The Self-Control Scale- Trait Score		3 Years
Other	The Self-Control Scale- State Score		3 Years
Other	State- Trait Anxiety Inventory- Trait Score		3 Years
Other	The Warwick-Edinburgh Mental Well-being Scale -State Score		3 Years
Other	The Warwick-Edinburgh Mental Well-being Scale -Trait Score		3 Years
Other	Mindful Attention and Awareness Scale -State Score		3 Years
Other	Mindful Attention and Awareness Scale -Trait Score		3 Years
Other	The Intolerance of Uncertainty Scale - Trait Score		3 Years
Other	The Intolerance of Uncertainty Scale - State Score		3 Years
Other	Verran and Snyder-Halpern (VSH) Sleep Scale Score		3 Years
Primary	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.	3 years
Primary	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.	3 Years
Primary	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.	3 Years
Primary	Inhibition Primary Outcome 1 measured with Interleaved Stop Signal Task/Go-NoGo: Stop Signal Reaction Time	Outcome variables have been grouped a priori into carefully defined cognitive domains.	3 Years
Primary	Flexibility Primary Outcome 1 measured with 3Dimensional Intra/Extra Dimensional Shift test: Extra Dimensional Set Errors	Outcome variables have been grouped a priori into carefully defined cognitive domains.	3 Years
Primary	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.	3 Years
Primary	Social Cognition Primary Outcome 1 measured with EMOTICOM Moral Emotions Task: Agent Guilt 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.	3 Years
Primary	Social Cognition Primary Outcome 2 measured with EMOTICOM Moral Emotions Task: Agent Shame Score	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.	3 Years
Primary	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.	3 Years
Primary	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.	3 Years
Primary	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.	3 Years
Primary	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.	3 Years
Primary	Memory Primary Outcome 1 measured with CANTAB Paired Associates Learning: Total Errors Adj	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.	3 Years
Primary	Biofluids	Serum Escitalopram levels	3 Years
Primary	Positron emission tomography (PET) Imaging: Cerebral [11C]SB207145 PET binding.	Collected before and after participant's intervention.	3 Years
Primary	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.	3 Years
Primary	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.	3 Years
Primary	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.	3 Years
Primary	Resting State fMRI	Imaging outcomes will be Family-Wise Error (FWE) corrected using Random Field Theory as implemented in SPM12.	3 Years
Primary	Structural Voxel-based morphometry (VBM) MRI	Imaging outcomes will be Family-Wise Error (FWE) corrected using Random Field Theory as implemented in SPM12.	3 Years
Primary	Diffusion Tensor Imaging MRI		3 Years
Primary	Habit formation outcome 1: response times for each day of training	Daily app training paradigm	3 Years
Primary	Habit formation outcome 2: mean errors per sequence and moves	Daily app training paradigm	3 Years
Primary	Habit formation outcome 3: confidence and enjoyable rates.	Daily app training paradigm	3 Years
Secondary	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.	3 Years
Secondary	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.	3 Years
Secondary	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.	3 Years
Secondary	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.	3 Years
Secondary	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.	3 Years
Secondary	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.	3 Years
Secondary	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.	3 Years
Secondary	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.	3 Years
Secondary	Flexibility Secondary Outcome 2 measured with Sequential Model-Based/Model-Free test: Exploration	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.	3 Years
Secondary	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.	3 Years
Secondary	Flexibility Secondary Outcome 4 measured with Sequential Model-Based/Model-Free test: Learning 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.	3 Years
Secondary	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.	3 Years
Secondary	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.	3 Years
Secondary	Inhibition Secondary Outcome 1 measured with Interleaved Stop Signal Task/Go-NoGo: Go reaction time	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.	3 Years
Secondary	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.	3 Years
Secondary	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.	3 Years
Secondary	Inhibition Secondary Outcome 4 measured with Interleaved Stop Signal Task/Go-NoGo: No-Go 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.	3 Years
Secondary	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.	3 Years
Secondary	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.	3 Years
Secondary	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.	3 Years
Secondary	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.	3 Years
Secondary	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.	3 Years
Secondary	Faces and geometric figure discrimination Outcome 1 measured with fMRI faces paradigm: Accuracy	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.	3 Years
Secondary	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.	3 Years
Secondary	Behavioural outcomes with fMRI paradigm slip of Actions : accuracy and 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.	3 Years
Secondary	Behavioural outcomes with fMRI paradigm Co-habit: accuracy and 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.	3 Years
Secondary	Memory Outcome 1 measured with CANTAB Paired Associates Learning test: First Trial Memory 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.	3 Years
Secondary	Memory Outcome 2 measured with Letter-number sequencing test: Total 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.	3 Years
Secondary	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.	3 Years
Secondary	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.	3 Years
Secondary	Risky Decision Making Outcome 2 measured with EMOTICOM Cambridge Gamble Task: Risk Adjustment	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.	3 Years
Secondary	Risky Decision Making Outcome 3 measured with EMOTICOM Cambridge Gamble Task: Overall Proportion Bet	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.	3 Years
Secondary	Risky Decision Making Outcome 4 measured with EMOTICOM Cambridge Gamble Task: Deliberation Time	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.	3 Years
Secondary	Psychomotor Speed Outcome 1 measured with CANTAB Reaction Time Task: Simple reaction time	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.	3 Years
Secondary	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	3 Years
Secondary	Interpersonal Reactivity Index (IRI) Score		3 Years
Secondary	Obsessive- Compulsive Inventory (OCI)- state Score		3 Years
Secondary	Obsessive- Compulsive Inventory- trait Score		3 Years
Secondary	Brief Symptom Inventory (BSI) Score		3 Years
Secondary	Pittsburgh Sleep Quality Index Score		3 Years
Secondary	Profile of Mood State Score		3 Years
Secondary	Beck Depression Inventory-II Score	Contain 21-items, scored on a scale value of 0 to 3	3 Years
Secondary	State-Trait Anxiety Inventory Scale Score	Contain 40-items	3 Years
Secondary	State and Trait Aggression Questionnaire Score		3 Years
Secondary	Barratt Impulsiveness Scale-State Score		3 Years
Secondary	Visual Analogue Scale Score		3 Years