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

NCT04336228 | Active Not Recruiting Phase 4

• 1 other identifier: H-18038325
• Study Type: interventional
• Target: 46
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Obsessive-Compulsive Disorder/High Compulsive Individuals; Healthy Individuals

Keywords

Serotonin; Cognition; Emotion; Neural Activation

Outcome Measures

Primary Outcomes (24)

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• Biofluids

  Serum Escitalopram levels

  3 Years

• Positron emission tomography (PET) Imaging: Cerebral [11C]SB207145 PET binding.

  Collected before and after participant's intervention.

  3 Years

• 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

• 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

• 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

• Resting State fMRI

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

  3 Years

• 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

• Diffusion Tensor Imaging MRI

  3 Years

• Habit formation outcome 1: response times for each day of training

  Daily app training paradigm

  3 Years

• Habit formation outcome 2: mean errors per sequence and moves

  Daily app training paradigm

  3 Years

• Habit formation outcome 3: confidence and enjoyable rates.

  Daily app training paradigm

  3 Years

Secondary Outcomes (46)

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

  3 Years

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

  3 Years

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

  3 Years

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

  3 Years

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

  3 Years

Other Outcomes (32)

• Emotion Recognition Other Outcome 1: Detection threshold decreasing Happy - Intensity Morphing

  3 Years

• Emotion Recognition Other Outcome 2: Detection threshold decreasing Sad - Intensity Morphing

  3 Years

• Emotion Recognition Other Outcome 3: Detection threshold decreasing Anger - Intensity Morphing

  3 Years

Study Arms (4)

Healthy Control Group

PLACEBO COMPARATOR

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.

Drug: Placebo oral tablet

Obsessive-Compulsive Disorder / High Compulsivity Control Group

PLACEBO COMPARATOR

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.

Drug: Placebo oral tablet

Healthy Intervention Group

EXPERIMENTAL

The healthy intervention group will be administered 20mg of Escitalopram daily for 3-4 weeks.

Drug: Escitalopram

Obsessive-Compulsive Disorder / High Compulsivity Intervention Group

EXPERIMENTAL

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

Drug: Escitalopram

Interventions

Escitalopram DRUG

20mg daily for 3-4 weeks.

Also known as: Escitalopram STADA

Healthy Intervention Group; Obsessive-Compulsive Disorder / High Compulsivity Intervention Group

Placebo oral tablet DRUG

20mg placebo tablet daily for 3-4 weeks.

Also known as: calcium tables

Healthy Control Group; Obsessive-Compulsive Disorder / High Compulsivity Control Group

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Individuals with high scores on obsessive-compulsive traits (with or without a diagnosis of OCD established by a psychiatrist) 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.

You may not qualify if:

• 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
• Lactation
• 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.

Sponsors & Collaborators

• Rigshospitalet, Denmark: lead
• University of Cambridge: collaborator
• Lundbeck Foundation: collaborator

Study Sites (1)

Neurobiology Research Unit, Rigshospitalet

Copenhagen, 2100, Denmark

Location

Related Publications (17)

• Clarke HF, Dalley JW, Crofts HS, Robbins TW, Roberts AC. Cognitive inflexibility after prefrontal serotonin depletion. Science. 2004 May 7;304(5672):878-80. doi: 10.1126/science.1094987.

  PMID: 15131308 BACKGROUND

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

  PMID: 19400722 BACKGROUND

• 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.

  PMID: 22325972 BACKGROUND

• 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.

  PMID: 22763621 BACKGROUND

• 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.

  PMID: 23332512 BACKGROUND

• 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.

  PMID: 25869808 BACKGROUND

• 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. doi: 10.1016/0893-133X(95)00045-F.

  PMID: 8597523 BACKGROUND

• 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.

  PMID: 29666372 BACKGROUND

• 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.

  PMID: 25567322 BACKGROUND

• 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.

  PMID: 21572165 BACKGROUND

• 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.

  PMID: 28265059 BACKGROUND

• 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. doi: 10.1176/ajp.2006.163.7.1282.

  PMID: 16816237 BACKGROUND

• 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. doi: 10.1176/ajp.2007.164.2.335.

  PMID: 17267798 BACKGROUND

• Vaghi MM, Vertes 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.

  PMID: 27769568 BACKGROUND

• 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. doi: 10.1001/archpsyc.1989.01810110054008.

  PMID: 2510699 BACKGROUND

• Haahr ME, Fisher PM, Jensen CG, Frokjaer VG, Mahon BM, Madsen K, Baare 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.

  PMID: 24189342 BACKGROUND

• 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.

  BACKGROUND

MeSH Terms

Interventions

Escitalopram

Intervention Hierarchy (Ancestors)

Propylamines; Amines; Organic Chemicals; Nitriles; Benzofurans; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Gitte M. Knudsen, Professor

  Neurobiology Research Unit, Rigshospitalet

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor, MD, DMSc

Study Record Dates

• First Submitted: March 25, 2020
• First Posted: April 7, 2020
• Study Start: April 1, 2020
• Primary Completion (Estimated): December 31, 2027
• Study Completion (Estimated): December 31, 2027
• Last Updated: December 18, 2024

Record last verified: 2024-12

Data Sharing

• IPD Sharing: Will share
• Time Frame: Upon completion of the study.
• Access Criteria: Researchers may apply for access to the data.

Locations

DK (1)