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

Phase 4Active Not RecruitingNCT04336228

Rigshospitalet, Denmark46 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

Purpose

BASIC_SCIENCE

Interventions

EscitalopramDRUG

20mg daily for 3-4 weeks.

Placebo oral tabletDRUG

20mg placebo tablet daily for 3-4 weeks.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 70 YearsHealthy volunteers:

Medical Language ↔ Plain English

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).

Locations (1)

Neurobiology Research Unit, Rigshospitalet

Copenhagen, Denmark

Outcomes

Primary Outcomes

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.

Time frame: 3 years

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

Time frame: 3 Years

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

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 3 Years

Social Cognition Primary Outcome 1 measured with EMOTICOM Moral Emotions Task: Agent Guilt Score

Time frame: 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.

Time frame: 3 Years

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

Time frame: 3 Years

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

Time frame: 3 Years

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

Time frame: 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.

Time frame: 3 Years

Memory Primary Outcome 1 measured with CANTAB Paired Associates Learning: Total Errors Adj

Time frame: 3 Years

Biofluids

Serum Escitalopram levels

Time frame: 3 Years

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

Collected before and after participant's intervention.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 3 Years

Resting State fMRI

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

Time frame: 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.

Time frame: 3 Years

Diffusion Tensor Imaging MRI

Time frame: 3 Years

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

Daily app training paradigm

Time frame: 3 Years

Habit formation outcome 2: mean errors per sequence and moves

Daily app training paradigm

Time frame: 3 Years

Habit formation outcome 3: confidence and enjoyable rates.

Daily app training paradigm

Time frame: 3 Years

Secondary Outcomes

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

Time frame: 3 Years

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

Time frame: 3 Years

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

Time frame: 3 Years

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

Time frame: 3 Years

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

Time frame: 3 Years

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

Data from ClinicalTrials.gov

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

Time frame: 3 Years

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

Time frame: 3 Years

Flexibility Secondary Outcome 2 measured with Sequential Model-Based/Model-Free test: Exploration

Time frame: 3 Years

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

Time frame: 3 Years

Flexibility Secondary Outcome 4 measured with Sequential Model-Based/Model-Free test: Learning rate

Time frame: 3 Years

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

Time frame: 3 Years

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

Time frame: 3 Years

Inhibition Secondary Outcome 1 measured with Interleaved Stop Signal Task/Go-NoGo: Go reaction time

Time frame: 3 Years

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

Time frame: 3 Years

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

Time frame: 3 Years

Inhibition Secondary Outcome 4 measured with Interleaved Stop Signal Task/Go-NoGo: No-Go error rate

Time frame: 3 Years

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

Time frame: 3 Years

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

Time frame: 3 Years

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

Time frame: 3 Years

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

Time frame: 3 Years

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

Time frame: 3 Years

Faces and geometric figure discrimination Outcome 1 measured with fMRI faces paradigm: Accuracy

Time frame: 3 Years

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

Time frame: 3 Years

Behavioural outcomes with fMRI paradigm slip of Actions : accuracy and latency

Time frame: 3 Years

Behavioural outcomes with fMRI paradigm Co-habit: accuracy and latency.

Time frame: 3 Years

Memory Outcome 1 measured with CANTAB Paired Associates Learning test: First Trial Memory Score

Time frame: 3 Years

Memory Outcome 2 measured with Letter-number sequencing test: Total score

Time frame: 3 Years

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

Time frame: 3 Years

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

Time frame: 3 Years

Risky Decision Making Outcome 2 measured with EMOTICOM Cambridge Gamble Task: Risk Adjustment

Time frame: 3 Years

Risky Decision Making Outcome 3 measured with EMOTICOM Cambridge Gamble Task: Overall Proportion Bet

Time frame: 3 Years

Risky Decision Making Outcome 4 measured with EMOTICOM Cambridge Gamble Task: Deliberation Time

Time frame: 3 Years

Psychomotor Speed Outcome 1 measured with CANTAB Reaction Time Task: Simple reaction time

Time frame: 3 Years

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

Time frame: 3 Years

Interpersonal Reactivity Index (IRI) Score

Time frame: 3 Years

Obsessive- Compulsive Inventory (OCI)- state Score

Time frame: 3 Years

Obsessive- Compulsive Inventory- trait Score

Time frame: 3 Years

Brief Symptom Inventory (BSI) Score

Time frame: 3 Years

Pittsburgh Sleep Quality Index Score

Time frame: 3 Years

Profile of Mood State Score

Time frame: 3 Years

Beck Depression Inventory-II Score

Contain 21-items, scored on a scale value of 0 to 3

Time frame: 3 Years

State-Trait Anxiety Inventory Scale Score

Contain 40-items

Time frame: 3 Years

State and Trait Aggression Questionnaire Score

Time frame: 3 Years

Barratt Impulsiveness Scale-State Score

Time frame: 3 Years

Visual Analogue Scale Score

Time frame: 3 Years

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

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes