Influence of Dopaminergic Blockade on Stress Responses, Motivation and Emotional Reactivity in Humans.

Study Overview
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Brief Summary
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The study aims to identify whether partial blockade of human dopamine signaling with antipsychotic drugs affects human stress responses, motivation and emotion. 84 healthy adult participants are planned to complete the study protocol. Therefore three experiments are planned: Experiment 1: Influence of amisulpride on human stress responses. Experiment 2: Influence of amisulpride on motivated effort. Experiment 3: Influence of amisulpride on emotion.

Detailed Description
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The study is a double blind, placebo controlled, randomized trial with two groups. One group will be receiving placebo (PG) and the other group will receive 300 mg amisulpride (VG). All participants are planned to complete all three experiments sequentially after drug/placebo intake. In experiment 1 we want to test whether a medium single dosage of amisulpride (VG) changes human stress responses compared to the PG. Therefore test subjects take the medication / placebo and wait for peak plasma levels. Afterwards they undergo a standardized stress test (MAST procedure,e.g. Shilton et al., 2017) where they submerge their non-dominant hand in cold water and have to do mental arithmetic tasks. We collect ECG, cortisol and skin conductance data as well as subjective measures of the stress response. In experiment 2 that is done after completion of experiment 1 the aim is testing whether the VG compared to the PG has an altered motivated effort. Therefore so called effort based paradigms (Reddy et al., 2015) are used. In these paradigms participants are given the option between an easy and effortless way of solving a trial that is reinforced with a small monetary reward or a harder and effortful way of trial solving that is rewarded higher. We measure how often the VG versus the PG will take the easy, low reward option over the hard, high reward option. In experiment 3 and after the completion of experiment to the aim is it to test whether the mean intensity of visually evoked emotions in the VG is changed compared to the PG. Therefore we use a stimulus set (15 positive images, 15 negative images, 15 neutral images) out of the International Affective Picture System images to evoke emotions and plan to analyze data like in positivity offset research (detailed description in: Strauss et al, 2017).

Official Title
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Influence of Partial Blockade of Dopaminergic Neurotransmission Using Amisulpride on Stress Responsivity, Motivated Behavior and Emotional Reactivity in Humans.

Conditions
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Healthy Participants

Intervention / Treatment
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* Drug: Amisulpride 300 MG
* Drug: Placebo oral capsule


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Common European Framework of Reference for Languages level B2 in German language. Consent ability for all relevant aspects of the experiment. Exclusion Criteria: Amisulpride allergy. Allergy to other components of amisulpride / placebo capsules like lactose. Daily intake of other medication including contraceptives. Tendency to seizures. Diagnosis of cancer especially pheochromocytoma, prolactinoma, or breast cancer. Kidney dysfunction: creatinine clearance below 10 ml per minute. High risk for stroke or thrombosis. Known prolongation of the QT interval, Any substantial medical condition that is capable of reducing the volunteers ability to participate at the study. Suicidal thoughts or suicide attempts in the past or at present. Substantial mental disorders especially schizophrenia, bipolar disorder, drug abuse, or personality disorders. Pregnancy or breastfeeding.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: amisulpride group<br>300 mg of the atypical antipsychotic drug amisulpride | Drug: Amisulpride 300 MG<br>* A single dose of 300 mg amisulpride that looks identical to placebo control capsules.<br>|
| Placebo Comparator: placebo group<br>Similar looking capsules for placebo control | Drug: Placebo oral capsule<br>* A placebo capsule with no inert pharmacological effect. Looks identical to the amisulpride capsules.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Perceived stress level from baseline to post stress period. | Before and after the stress test of experiment 1 we ask every participant for their perceived stress level. These data serve as an indicator of subjective stress responses. We analyze changes in subjective stress level compared to baseline measurements (76 min and 22 min before). Five minutes before the stress test starts we measure subjective anticipatory stress response and directly after the completion we measure post stressor responses and possible residual feelings of stress (16 minutes post completion). All measurements reflect a single time series. Stress levels are obtained with visual analogue scales ranging from 0 (no stress) to 100 points (extremely stressed). | After preparation period. Before (76 min before, 22 min before, 5min before) and after the stress test (directly after, 16 min as well as 30 min after completion). | 
| Percentage of difficult trials in the balloon effort task. | In experiment 2 which is a computer task, participants can choose between an easy task with low monetary reinforcement or a hard task with higher monetary reinforcement. Easy means that there is a low amount of physical or cognitive effort per trial and hard means that there is a higher amount of physical or cognitive effort per trial. From the tasks that are described in Reddy et al (2015) the balloon effort task (physical effort) and the deck choice task (mental effort) will be used. For both tasks our software automatically obtains the percentage of difficult trials with respect to the total number of trials. Note that only a single composite score is obtained after finishing the balloon effort task. | After the cortisol response of experiment 1 is subsided and directly when experiment is 2 is completely finished. This will be approximately 121 minutes after medication / placebo intake. | 
| Percentage of difficult trials in the deck choice task. | In experiment 2 which is a computer task, participants can choose between an easy task with low monetary reinforcement or a hard task with higher monetary reinforcement. Easy means that there is a low amount of physical or cognitive effort per trial and hard means that there is a higher amount of physical or cognitive effort per trial. From the tasks that are described in Reddy et al (2015) the balloon effort task (physical effort) and the deck choice task (mental effort) will be used. For both tasks our software automatically obtains the percentage of difficult trials with respect to the total number of trials. Note that only a single composite score is obtained after finishing the deck choice effort task. | After finishing the balloon effort task. This will be approximately 145 minutes after medication / placebo intake. | 
| Mean positive affect ratings in response to International Affective Picture System (IAPS) images. | Valence and arousal measures are collected as in Strauss et al. (2017) after presentation of IAPS pictures during experiment 3. Ratings for positive affect, negative affect and arousal ratings are obtained with a 10 point self-assessment manikin scale after the presentation of each individual picture. Note that only a single composite score for positive affect is calculated as the mean value of all evaluations following the individual pictures. | After experiment 3 is finished. This will be approximately 216 minutes after medication / placebo intake. | 
| Mean negative affect ratings in response to International Affective Picture System (IAPS) images. | Valence and arousal measures are collected as in Strauss et al. (2017) after presentation of IAPS pictures during experiment 3. Ratings for positive affect, negative affect and arousal ratings are obtained with a 10 point self-assessment manikin scale. Note that only a single composite score for negative affect is calculated as the mean value of all evaluations following the individual pictures. | After experiment 3 is finished. This will be approximately 216 minutes after medication / placebo intake. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Saliva cortisol levels. | Before and at three time points after the stress test is completed of experiment 1 we take saliva cortisol samples of each participant. These samples are analysed for cortisol levels and serve as an indicator of Hypothalamic-pituitary-adrenal axis reactivity. Cortisol levels are measured in nmol/liter. | After preparation period. Before (62 min before, 2 min before) and after the stress test (5, 15 and 25 min after completion). | 
| Heart rate changes and changes in heart rate variability. | Before, during and after the stress test of experiment 1 we use blood volume pulse measures for obtaining heart rate data and calculate heart rate change scores and heart rate variability scores (HRV). These data serve as an indicator of cardiovascular stress responses. Heart rate changes are measured in Δ1/s. Changes in heart rate variability is normalized for heart rate change because higher HR during stress exposure could induce a mathematical bias. Data that will be obtained include the low frequency band and the high frequency / low frequency ratio. A short introduction into the topic can be found in Billmann et al (2015). | After preparation period. Before (68 min before, 49 min before), during (the whole procedure) and after (directly after completion) the stress test. | 
| Mean arousal ratings in response to International Affective Picture System (IAPS) images. | Valence and arousal measures are collected as in Strauss et al. (2017) after presentation of IAPS pictures during experiment 3. Ratings for positive affect, negative affect and arousal ratings are obtained with a 10 point self-assessment manikin scale. Note that only a single composite score for negative affect is calculated as the mean value of all evaluations following the individual pictures. | After experiment 3 is finished. This will be approximately 216 minutes after medication / placebo intake. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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dopamine antagonists, dopamine blockade, psychophysiological stress response, Maastricht acute stress test (MAST), effort based paradigms, positivity offset theory, international affective picture system (IAPS)