Clinical trial NCT04336228: The Role of Serotonin in Compulsive Behavior in Humans: Underlying Brain Mechanisms
Official title: The Role of Serotonin in Compulsive Behavior in Humans: Underlying Brain Mechanisms
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE4
Conditions: Obsessive-Compulsive Disorder/High Compulsive Individuals
Healthy Individuals
Keywords: Serotonin
Cognition
Emotion
Neural Activation
Lead sponsor: Rigshospitalet, Denmark
Sponsor class: OTHER
Collaborators: name: University of Cambridge
name: Lundbeck Foundation
First posted: 2020-04-07
Enrollment: 46
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

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.

Detailed 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.

Eligibility criteria: Inclusion Criteria:

* 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.

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
* 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.
* 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).

Primary outcomes:
measure: Learning Primary Outcome 1 measured with Probability Reversal Learning test: Mean errors Stage 1 (Learning)
timeFrame: 3 years
measure: Learning Primary Outcome 2 measured with Probability Reversal Learning test: Mean errors Stage 2 (Reversal)
timeFrame: 3 Years
measure: Learning Primary Outcome 3 measured with Deterministic Reversal Learning test: Percent correct per stage
timeFrame: 3 Years
measure: Inhibition Primary Outcome 1 measured with Interleaved Stop Signal Task/Go-NoGo: Stop Signal Reaction Time
timeFrame: 3 Years
measure: Flexibility Primary Outcome 1 measured with 3Dimensional Intra/Extra Dimensional Shift test: Extra Dimensional Set Errors
timeFrame: 3 Years
measure: Flexibility Primary Outcome 2 measured with Sequential model-based model-free test: Model-based Model-free Weight
timeFrame: 3 Years
measure: Social Cognition Primary Outcome 1 measured with EMOTICOM Moral Emotions Task: Agent Guilt Score
timeFrame: 3 Years
measure: Social Cognition Primary Outcome 2 measured with EMOTICOM Moral Emotions Task: Agent Shame Score
timeFrame: 3 Years
measure: Emotion Recognition Primary Outcome 1 measures with EMOTICOM Intensity Morphing: Affective bias in decreasing condition
timeFrame: 3 Years
measure: Emotion Recognition Primary Outcome 2 measured with EMOTICOM Emotion Recognition Task: Affective bias for D'
timeFrame: 3 Years
measure: Emotion Recognition Primary Outcome 3 measured with EMOTICOM Intensity Morphing task: Detection threshold decreasing
timeFrame: 3 Years
measure: Emotion Recognition Primary Outcome 4 measured with EMOTICOM Emotion Recognition task: D'Prime for emotion recognition
timeFrame: 3 Years
measure: Memory Primary Outcome 1 measured with CANTAB Paired Associates Learning: Total Errors Adj
timeFrame: 3 Years
measure: Biofluids
timeFrame: 3 Years
measure: Positron emission tomography (PET) Imaging: Cerebral [11C]SB207145 PET binding.
timeFrame: 3 Years
measure: Neural Activations and Correlations measured with functional magnetic resonance imaging (fMRI) paradigm named Slip of Actions
timeFrame: 3 Years
measure: Neural Activations and Correlations measured with functional magnetic resonance imaging (fMRI) paradigm named Cohabit
timeFrame: 3 Years
measure: Neural Activations and Correlations measured with functional magnetic resonance imaging (fMRI) paradigm named Faces
timeFrame: 3 Years
measure: Resting State fMRI
timeFrame: 3 Years
measure: Structural Voxel-based morphometry (VBM) MRI
timeFrame: 3 Years
measure: Diffusion Tensor Imaging MRI
timeFrame: 3 Years
measure: Habit formation outcome 1: response times for each day of training
timeFrame: 3 Years
measure: Habit formation outcome 2: mean errors per sequence and moves
timeFrame: 3 Years
measure: Habit formation outcome 3: confidence and enjoyable rates.
timeFrame: 3 Years
Secondary outcomes:
measure: Learning Secondary Outcome 1 measured with Probability Reversal Learning test: Stage 1 Reward-Stay/Lose-Shift behaviour
timeFrame: 3 Years
measure: Learning Secondary Outcome 2 measured with Probability Reversal Learning test: Stage 1 Reward/Punishment learning
timeFrame: 3 Years
measure: Learning Secondary Outcome 3 measured with Probability Reversal Learning test: Stage 1. Stimulus Stickiness
timeFrame: 3 Years
measure: Learning Secondary Outcome 4 measured with Probability Reversal Learning test: Stage 2 Reward-Stay/ Lose-Shift behaviour
timeFrame: 3 Years
measure: Learning Secondary Outcome 5 measured with Probability Reversal Learning test: Stage 2 Reward/Punishment learning
timeFrame: 3 Years
measure: Learning Secondary Outcome 6 measured with Probability Reversal Learning test: Stage 2. Stimulus Stickiness
timeFrame: 3 Years
measure: Learning Secondary Outcome 7 measured with Deterministic Reversal Learning test: Reward-Stay/ Lose-Shift behaviour
timeFrame: 3 Years
measure: Flexibility Secondary Outcome 1 measured with Sequential Model-Based/Model-Free test: Proportion of Stays
timeFrame: 3 Years
measure: Flexibility Secondary Outcome 2 measured with Sequential Model-Based/Model-Free test: Exploration
timeFrame: 3 Years
measure: Flexibility Secondary Outcome 3 measured with Sequential Model-Based/Model-Free test: Stimulus Stickiness
timeFrame: 3 Years
measure: Flexibility Secondary Outcome 4 measured with Sequential Model-Based/Model-Free test: Learning rate
timeFrame: 3 Years
measure: Flexibility Secondary Outcome 5 measured with 3Dimensional Intra/Extra Dimensional Shift test: Pre Extra Dimension Set Errors
timeFrame: 3 Years
measure: Flexibility Secondary Outcome 6 measured with 3Dimensional Intra/Extra Dimensional Shift test: Latency
timeFrame: 3 Years
measure: Inhibition Secondary Outcome 1 measured with Interleaved Stop Signal Task/Go-NoGo: Go reaction time
timeFrame: 3 Years
measure: Inhibition Secondary Outcome 2 measured with Interleaved Stop Signal Task/Go-NoGo: Go omission error rate
timeFrame: 3 Years
measure: Inhibition Secondary Outcome 3 measured with Interleaved Stop Signal Task/Go-NoGo: Go commission error rate
timeFrame: 3 Years
measure: Inhibition Secondary Outcome 4 measured with Interleaved Stop Signal Task/Go-NoGo: No-Go error rate
timeFrame: 3 Years
measure: Executive Function Secondary Outcome 1 measured with 3Dimensional Intra/Extra Dimensional Shift test: Total Errors Adjusted
timeFrame: 3 Years
measure: Emotion Recognition Secondary Outcome 1 measured with EMOTICOM Intensity Morphing Task: Detection threshold increasing
timeFrame: 3 Years
measure: Emotion Recognition Secondary Outcome 2 measured with EMOTICOM Intensity Morphing Task: Affective bias in increasing condition
timeFrame: 3 Years
measure: Emotion Recognition Secondary Outcome 3 measured with EMOTICOM Emotion Recognition Task: Affective bias for Hit Rate
timeFrame: 3 Years
measure: Emotion Recognition Secondary Outcome 4 measured with EMOTICOM Emotion Recognition Task.: Hit Rate for Emotion Recognition
timeFrame: 3 Years
measure: Faces and geometric figure discrimination Outcome 1 measured with fMRI faces paradigm: Accuracy
timeFrame: 3 Years
measure: Behavioural outcomes with Faces and geometric figure discrimination Outcome 2 measured with fMRI faces paradigm: Response Speed
timeFrame: 3 Years
measure: Behavioural outcomes with fMRI paradigm slip of Actions : accuracy and latency
timeFrame: 3 Years
measure: Behavioural outcomes with fMRI paradigm Co-habit: accuracy and latency.
timeFrame: 3 Years
measure: Memory Outcome 1 measured with CANTAB Paired Associates Learning test: First Trial Memory Score
timeFrame: 3 Years
measure: Memory Outcome 2 measured with Letter-number sequencing test: Total score
timeFrame: 3 Years
measure: 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
timeFrame: 3 Years
measure: Risky Decision Making Outcome Outcome 1 measured with EMOTICOM Cambridge Gamble Task: Quality of Decision Making
timeFrame: 3 Years
measure: Risky Decision Making Outcome 2 measured with EMOTICOM Cambridge Gamble Task: Risk Adjustment
timeFrame: 3 Years
measure: Risky Decision Making Outcome 3 measured with EMOTICOM Cambridge Gamble Task: Overall Proportion Bet
timeFrame: 3 Years
measure: Risky Decision Making Outcome 4 measured with EMOTICOM Cambridge Gamble Task: Deliberation Time
timeFrame: 3 Years
measure: Psychomotor Speed Outcome 1 measured with CANTAB Reaction Time Task: Simple reaction time
timeFrame: 3 Years
measure: Intelligence Quotient (IQ) outcome 1 measured with Reynolds Intellectual assessment Scales subtest "guess what" and "what does not fit": Total age adjusted score
timeFrame: 3 Years
measure: Interpersonal Reactivity Index (IRI) Score
timeFrame: 3 Years
measure: Obsessive- Compulsive Inventory (OCI)- state Score
timeFrame: 3 Years
measure: Obsessive- Compulsive Inventory- trait Score
timeFrame: 3 Years
measure: Brief Symptom Inventory (BSI) Score
timeFrame: 3 Years
measure: Pittsburgh Sleep Quality Index Score
timeFrame: 3 Years
measure: Profile of Mood State Score
timeFrame: 3 Years
measure: Beck Depression Inventory-II Score
timeFrame: 3 Years
measure: State-Trait Anxiety Inventory Scale Score
timeFrame: 3 Years
measure: State and Trait Aggression Questionnaire Score
timeFrame: 3 Years
measure: Barratt Impulsiveness Scale-State Score
timeFrame: 3 Years
measure: Visual Analogue Scale Score
timeFrame: 3 Years
Other outcomes:
measure: Emotion Recognition Other Outcome 1: Detection threshold decreasing Happy - Intensity Morphing
timeFrame: 3 Years
measure: Emotion Recognition Other Outcome 2: Detection threshold decreasing Sad - Intensity Morphing
timeFrame: 3 Years
measure: Emotion Recognition Other Outcome 3: Detection threshold decreasing Anger - Intensity Morphing
timeFrame: 3 Years
measure: Emotion Recognition Other Outcome 4: Detection threshold decreasing Fear - Intensity Morphing
timeFrame: 3 Years
measure: Emotion Recognition Other Outcome 5: Detection threshold decreasing Disgust - Intensity Morphing
timeFrame: 3 Years
measure: Emotion Recognition Other Outcome 6: D' Happy - Emotion Recognition Task
timeFrame: 3 Years
measure: Emotion Recognition Other Outcome 7: D' Sad - Emotion Recognition Task
timeFrame: 3 Years
measure: Emotion Recognition Other Outcome 8: D' Fear - Emotion Recognition Task
timeFrame: 3 Years
measure: Emotion Recognition Other Outcome 9: D' Anger - Emotion Recognition Task
timeFrame: 3 Years
measure: Activity Level Score
timeFrame: 3 Years
measure: Behavioural Inhibition/ Behavioural Avoidance Scale Score
timeFrame: 3 Years
measure: The Compulsive Personality Assessment Scale Score
timeFrame: 3 Years
measure: Sexuality Questionnaire Score
timeFrame: 3 Years
measure: Edinburgh Handedness Inventory Score
timeFrame: 3 Years
measure: Revised NEO Personality Questionnaire Score
timeFrame: 3 Years
measure: Family History Assessment Module Score
timeFrame: 3 Years
measure: Positive Life Events Score
timeFrame: 3 Years
measure: Stressful Life Events Score
timeFrame: 3 Years
measure: Perceived stress scale
timeFrame: 3 Years
measure: Barratt Impulsiveness Scale-Trait Score
timeFrame: 3 Years
measure: The Penn State Worry Questionnaire- Trait Score
timeFrame: 3 Years
measure: The Penn State Worry Questionnaire- State Score
timeFrame: 3 Years
measure: The Self-Control Scale- Trait Score
timeFrame: 3 Years
measure: The Self-Control Scale- State Score
timeFrame: 3 Years
measure: State- Trait Anxiety Inventory- Trait Score
timeFrame: 3 Years
measure: The Warwick-Edinburgh Mental Well-being Scale -State Score
timeFrame: 3 Years
measure: The Warwick-Edinburgh Mental Well-being Scale -Trait Score
timeFrame: 3 Years
measure: Mindful Attention and Awareness Scale -State Score
timeFrame: 3 Years
measure: Mindful Attention and Awareness Scale -Trait Score
timeFrame: 3 Years
measure: The Intolerance of Uncertainty Scale - Trait Score
timeFrame: 3 Years
measure: The Intolerance of Uncertainty Scale - State Score
timeFrame: 3 Years
measure: Verran and Snyder-Halpern (VSH) Sleep Scale Score
timeFrame: 3 Years
Locations:
city: Copenhagen
country: Denmark
facility: Neurobiology Research Unit, Rigshospitalet
Study officials:
affiliation: Neurobiology Research Unit, Rigshospitalet
name: Gitte M. Knudsen, Professor
role: STUDY_CHAIR
References:
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. doi: 10.1126/science.1094987.
citation: Dayan P, Huys QJ. Serotonin in affective control. Annu Rev Neurosci. 2009;32:95-126. doi: 10.1146/annurev.neuro.051508.135607.
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.
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.
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.
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.
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. doi: 10.1016/0893-133X(95)00045-F.
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.
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.
citation: 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.
citation: 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.
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. doi: 10.1176/ajp.2006.163.7.1282.
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. doi: 10.1176/ajp.2007.164.2.335.
citation: 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.
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. doi: 10.1001/archpsyc.1989.01810110054008.
citation: 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.
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.