The Role of Serotonin in Compulsive Behavior in Humans: Underlying Brain Mechanisms
试验速览
- 阶段
- 4 期
- 状态
- 进行中（未招募）
- 入组人数
- 46
- 试验地点
- 1
- 主要终点
- Habit formation outcome 1: response times for each day of training
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Basic Science
- 盲法
- Triple (Participant, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •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.
排除标准
- •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).
研究组 & 干预措施
Healthy Control Group
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.
干预措施: Placebo oral tablet (Drug)
Obsessive-Compulsive Disorder / High Compulsivity Control Group
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.
干预措施: Placebo oral tablet (Drug)
Healthy Intervention Group
The healthy intervention group will be administered 20mg of Escitalopram daily for 3-4 weeks.
干预措施: Escitalopram (Drug)
Obsessive-Compulsive Disorder / High Compulsivity Intervention Group
The OCD/high compulsivity intervention group will be administered 20mg of Escitalopram daily for 3-4 weeks.
干预措施: Escitalopram (Drug)
结局指标
主要结局
Habit formation outcome 1: response times for each day of training
时间窗: 3 Years
Daily app training paradigm
Learning Primary Outcome 2 measured with Probability Reversal Learning test: Mean errors Stage 2 (Reversal)
时间窗: 3 Years
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.
Habit formation outcome 3: confidence and enjoyable rates.
时间窗: 3 Years
Daily app training paradigm
Learning Primary Outcome 1 measured with Probability Reversal Learning test: Mean errors Stage 1 (Learning)
时间窗: 3 years
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
时间窗: 3 Years
Outcome variables have been grouped a priori into carefully defined cognitive domains.
Flexibility Primary Outcome 1 measured with 3Dimensional Intra/Extra Dimensional Shift test: Extra Dimensional Set Errors
时间窗: 3 Years
Outcome variables have been grouped a priori into carefully defined cognitive domains.
Flexibility Primary Outcome 2 measured with Sequential model-based model-free test: Model-based Model-free Weight
时间窗: 3 Years
Outcome variables have been grouped a priori into carefully defined cognitive domains.
Emotion Recognition Primary Outcome 1 measures with EMOTICOM Intensity Morphing: Affective bias in decreasing condition
时间窗: 3 Years
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
时间窗: 3 Years
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
时间窗: 3 Years
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'
时间窗: 3 Years
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.
Positron emission tomography (PET) Imaging: Cerebral [11C]SB207145 PET binding.
时间窗: 3 Years
Collected before and after participant's intervention.
Neural Activations and Correlations measured with functional magnetic resonance imaging (fMRI) paradigm named Cohabit
时间窗: 3 Years
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.
Social Cognition Primary Outcome 1 measured with EMOTICOM Moral Emotions Task: Agent Guilt Score
时间窗: 3 Years
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.
Social Cognition Primary Outcome 2 measured with EMOTICOM Moral Emotions Task: Agent Shame Score
时间窗: 3 Years
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 4 measured with EMOTICOM Emotion Recognition task: D'Prime for emotion recognition
时间窗: 3 Years
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.
Memory Primary Outcome 1 measured with CANTAB Paired Associates Learning: Total Errors Adj
时间窗: 3 Years
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.
Biofluids
时间窗: 3 Years
Serum Escitalopram levels
Diffusion Tensor Imaging MRI
时间窗: 3 Years
Neural Activations and Correlations measured with functional magnetic resonance imaging (fMRI) paradigm named Slip of Actions
时间窗: 3 Years
Imaging outcomes will be Family-Wise Error (FWE) corrected using Random Field Theory as implemented in SPM12.
Habit formation outcome 2: mean errors per sequence and moves
时间窗: 3 Years
Daily app training paradigm
Neural Activations and Correlations measured with functional magnetic resonance imaging (fMRI) paradigm named Faces
时间窗: 3 Years
Imaging outcomes will be Family-Wise Error (FWE) corrected using Random Field Theory as implemented in SPM12.
Resting State fMRI
时间窗: 3 Years
Imaging outcomes will be Family-Wise Error (FWE) corrected using Random Field Theory as implemented in SPM12.
Structural Voxel-based morphometry (VBM) MRI
时间窗: 3 Years
Imaging outcomes will be Family-Wise Error (FWE) corrected using Random Field Theory as implemented in SPM12.
次要结局
- Learning Secondary Outcome 2 measured with Probability Reversal Learning test: Stage 1 Reward/Punishment learning(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)
- Learning Secondary Outcome 7 measured with Deterministic Reversal Learning test: Reward-Stay/ Lose-Shift behaviour(3 Years)
- Behavioural outcomes with Faces and geometric figure discrimination Outcome 2 measured with fMRI faces paradigm: Response Speed(3 Years)
- Learning Secondary Outcome 6 measured with Probability Reversal Learning test: Stage 2. Stimulus Stickiness(3 Years)
- Learning Secondary Outcome 1 measured with Probability Reversal Learning test: Stage 1 Reward-Stay/Lose-Shift behaviour(3 Years)
- Learning Secondary Outcome 3 measured with Probability Reversal Learning test: Stage 1. Stimulus Stickiness(3 Years)
- Inhibition Secondary Outcome 2 measured with Interleaved Stop Signal Task/Go-NoGo: Go omission error rate(3 Years)
- Emotion Recognition Secondary Outcome 3 measured with EMOTICOM Emotion Recognition Task: Affective bias for Hit Rate(3 Years)
- Flexibility Secondary Outcome 2 measured with Sequential Model-Based/Model-Free test: Exploration(3 Years)
- Flexibility Secondary Outcome 3 measured with Sequential Model-Based/Model-Free test: Stimulus Stickiness(3 Years)
- Flexibility Secondary Outcome 5 measured with 3Dimensional Intra/Extra Dimensional Shift test: Pre Extra Dimension Set Errors(3 Years)
- Flexibility Secondary Outcome 6 measured with 3Dimensional Intra/Extra Dimensional Shift test: Latency(3 Years)
- Inhibition Secondary Outcome 4 measured with Interleaved Stop Signal Task/Go-NoGo: No-Go error rate(3 Years)
- Emotion Recognition Secondary Outcome 4 measured with EMOTICOM Emotion Recognition Task.: Hit Rate for Emotion Recognition(3 Years)
- Behavioural outcomes with fMRI paradigm Co-habit: accuracy and latency.(3 Years)
- Executive Function Secondary Outcome 1 measured with 3Dimensional Intra/Extra Dimensional Shift test: Total Errors Adjusted(3 Years)
- Memory Outcome 2 measured with Letter-number sequencing test: Total score(3 Years)
- Risky Decision Making Outcome 3 measured with EMOTICOM Cambridge Gamble Task: Overall Proportion Bet(3 Years)
- Risky Decision Making Outcome 4 measured with EMOTICOM Cambridge Gamble Task: Deliberation Time(3 Years)
- Interpersonal Reactivity Index (IRI) Score(3 Years)
- State and Trait Aggression Questionnaire Score(3 Years)
- Visual Analogue Scale Score(3 Years)
- Flexibility Secondary Outcome 1 measured with Sequential Model-Based/Model-Free test: Proportion of Stays(3 Years)
- Inhibition Secondary Outcome 1 measured with Interleaved Stop Signal Task/Go-NoGo: Go reaction time(3 Years)
- Inhibition Secondary Outcome 3 measured with Interleaved Stop Signal Task/Go-NoGo: Go commission error rate(3 Years)
- Emotion Recognition Secondary Outcome 1 measured with EMOTICOM Intensity Morphing Task: Detection threshold increasing(3 Years)
- Emotion Recognition Secondary Outcome 2 measured with EMOTICOM Intensity Morphing Task: Affective bias in increasing condition(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(3 Years)
- Flexibility Secondary Outcome 4 measured with Sequential Model-Based/Model-Free test: Learning rate(3 Years)
- Faces and geometric figure discrimination Outcome 1 measured with fMRI faces paradigm: Accuracy(3 Years)
- Behavioural outcomes with fMRI paradigm slip of Actions : accuracy and latency(3 Years)
- Psychomotor Speed Outcome 1 measured with CANTAB Reaction Time Task: Simple reaction time(3 Years)
- Obsessive- Compulsive Inventory (OCI)- state Score(3 Years)
- Risky Decision Making Outcome Outcome 1 measured with EMOTICOM Cambridge Gamble Task: Quality of Decision Making(3 Years)
- Risky Decision Making Outcome 2 measured with EMOTICOM Cambridge Gamble Task: Risk Adjustment(3 Years)
- Barratt Impulsiveness Scale-State Score(3 Years)
- Memory Outcome 1 measured with CANTAB Paired Associates Learning test: First Trial Memory Score(3 Years)
- Obsessive- Compulsive Inventory- trait Score(3 Years)
- State-Trait Anxiety Inventory Scale Score(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(3 Years)
- Brief Symptom Inventory (BSI) Score(3 Years)
- Pittsburgh Sleep Quality Index Score(3 Years)
- Profile of Mood State Score(3 Years)
- Beck Depression Inventory-II Score(3 Years)
研究者
Gitte Moos Knudsen
Professor, MD, DMSc
Rigshospitalet, Denmark