The Role of Dopamine, Reward Learning and Prefrontal Activity in Expectation-induced Mood Enhancement

Study Overview
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Brief Summary
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Although placebo effects on depressive symptoms are well documented, the underlying mechanisms and moderating factors of expectation effects on mood and depression are poorly understood. Various studies show reduced reward processing in clinical and subclinical depression, presumably due to abnormalities in the dopamine (DA) system. Here, the investigators will test whether expectation-induced mood enhancement is mediated by endogenous DA activity and reward learning, and moderated by individual differences in depression-related personality traits. Healthy participants (N=296) will be tested for potentially relevant personality traits and given an inactive substance (placebo) or a DA D2-receptor antagonist sulpiride (400 mg) in combination with a low vs. high expectation manipulation (fully crossed 2x2 placebo design) before performing a probabilistic reinforcement learning task, an effort expenditure task, and undergo a depressed mood induction procedure. Further, EEG indices will be assessed throughout the tasks. The investigators expect that positive expectation improves participants' reinforcement learning, increases participants' willingness to make effort in order to obtain reward, and leads to less depressive symptoms as indicated by mood ratings upon depressive mood induction. If the overall effect of positive expectations is mediated by DA, high-dose sulpiride should block expectation-induced effects, i.e., the anticipated enhanced reinforcement learning and effort expenditure as well as mood improvement in the high vs. low expectation group.

Detailed Description
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The placebo effect, i.e., raising expectations towards a successful treatment by applying an inactive substance, reportedly improves therapeutic outcomes in clinical trials. Although there is supporting evidence for the neurotransmitter dopamine (DA) and reinforcement learning, i.e. learning from reward and punishment, to mediate this effect, to the knowledge of the authors, no study has tested these underpinnings yet. The objective of the present project is to investigate whether expectation-induced mood enhancement is mediated by DA activity and reward learning, and moderated by individual differences in depression-related personality traits. To this end, participants will be told to either receive a placebo (low expectation) or a medicine which is labeled as antidepressant (high expectation) that improves mood. Orthogonal to this expectation manipulation, participants actually receive either 400 mg of sulpiride (sulpiride group) or a placebo (inactive substance group). Sulpiride is a selective D2-recptor antagonist which presumably elevates DA levels in low doses and has been used as an antidepressant. However, as a part of the high expectation group's expectation manipulation, while participants are told to receive an antidepressant, the sulpiride group actually receives a dose that is presumably too high to increase DA levels and produce antidepressant effects. Rather, 400mg of sulpirid presumably leads to a blockade of dopamine receptors and may thereby block expectation placebo effects. Participants then undergo three tasks, in which behavioral and computational markers of reinforcement learning and willingness to make effort in order to obtain reward are investigated. Further, mood ratings upon depressive mood induction will be assessed. In addition to participants behavioral responses, EEG indices will be recorded throughout the tasks. Prior to testing, participants will be asked to fill out questionnaires with regard to personality traits as well as reward response. In order to assess dopamine-related plasma prolactin, the study physician will draw one blood sample (ca. 8 ml) at the beginning of the testing session (at approximately 9 a.m.) and one hour after substance intake (at approximately 10 a.m.), which presumably corresponds with the latency of the peak of the prolactin response to sulpiride. Saliva and gene samples will be collected for hypotheses that are tested in the context of the overarching collaborative research center 289 and preregistered elsewhere. It is expected that positive expectation improves participants' reinforcement learning, increases participants' willingness to make effort in order to obtain reward, and leads to less depressive symptoms as indicated by mood ratings upon depressive mood induction. If the overall effect of positive expectations is mediated by DA, high-dose sulpiride should block expectation-induced effects, i.e., the anticipated enhanced reinforcement learning and effort expenditure as well as mood improvement in the high vs. low expectation group. Hypotheses: Expectation enhancement (high vs. low) within the placebo group is associated with lower negative mood ratings after the mood induction procedure. Expectation enhancement (high vs. low) within the placebo group enhances computationally modeled reward learning parameters and EEG markers of reward processing during the reinforcement learning task. Within the placebo group, the expectation effect on negative mood ratings mentioned in (1) is correlated with the expectation effect on reward learning parameters in the probabilistic reinforcement learning task mentioned in (2). Across the two expectation groups and within the placebo group, reward learning parameters and electrophysiological markers of reward processing are positively correlated with questionnaire measures of agentic extraversion (and negatively with self-reported depressive symptoms). In the sulpiride group, the effects described in (1), (2), and (3) are lower than in the placebo group. The prolactin response to sulpiride is correlated with the magnitude of expectation effects on reinforcement learning, negative mood, and self-reported agentic extraversion as well as depressive symptoms. High levels of the personality trait agentic extraversion (and low levels of depressive symptoms) are associated with higher expectancy effects on negative mood.

Official Title
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The Role of Dopamine, Reward Learning and Prefrontal Activity in Expectation-induced Mood Enhancement

Conditions
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Placebo Effect on Mood Improvement

Intervention / Treatment
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* Drug: Sulpiride 400 MG
* Drug: Placebo
* Behavioral: High expectation manipulation
* Behavioral: Low expectation manipulation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Right-handed Aged 18-60 years German native speaker Informed consent Normal or corrected sight Exclusion Criteria: Current pregnancy Current or history of general medical, neurological or psychological disorders, which preclude sulpiride intake Self-reported presence of mental disorders Liver, kidney, and bowel disorders Regular smoking Reported alcohol abuse Illegal drug intake Regular drug intake by prescription in the past three months Dreadlocks BMI < 19 or > 30 Unremovable metal objects around the head Previous knowledge of Japanese characters Excessive caffeine intake (> 8 cups per day)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 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
Interventional Model Description: A fully crossed 2x2 placebo design will be employed by giving participants either a placebo or a sulpiride capsule in combination with a low vs. high expectation manipulation.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: High expectation with sulpiride group<br>Prior to the experimental procedure, participants are told by the study clinicians that an antidepressant sulpiride capsule is administrated, while participants actually receive a sulpiride 400mg-capsule (note that the dose is presumably too high to produce antidepressant effects). | Drug: Sulpiride 400 MG<br>* The substituted benzamide sulpiride is a selective D2-receptor antagonist that is generally well tolerated and has a low affinity to histaminergic, cholinergic, serotonergic, adrenergic, or GABA receptors. Sulpiride is slowly absorbed from the gastrointestinal tract and peak serum levels occur at 3 hours . In low doses (50-200 mg), sulpiride presumably blocks presynaptic autoreceptors, thereby elevating DA levels and reducing depressive symptoms, whereas higher doses lead to a predominant blockade of postsynaptic receptors. The dose in the present study (400 mg) is sufficient for behaviorally relevant modulations of dopaminergic processing with minimal risk of side effects. Note that participants in the sulpiride group actually receive a dose that is presumably too high to produce antidepressant effects.<br>Behavioral: High expectation manipulation<br>* Participants will be told by the study clinicians that an antidepressive sulpiride capsule is administrated.<br>|
| Experimental: High expectation with placebo group<br>Prior to the experimental procedure, participants are told by the study clinicians that an antidepressant sulpiride capsule is administrated, while participants actually receive a placebo capsule. | Drug: Placebo<br>* Participants receive an inactive placebo capsule.<br>Behavioral: High expectation manipulation<br>* Participants will be told by the study clinicians that an antidepressive sulpiride capsule is administrated.<br>|
| Experimental: Low expectation with sulpiride group<br>Prior to the experimental procedure, participants are told by the study clinicians that an inactive placebo capsule is administrated, while participants actually receive a sulpiride capsule (400 mg). | Drug: Sulpiride 400 MG<br>* The substituted benzamide sulpiride is a selective D2-receptor antagonist that is generally well tolerated and has a low affinity to histaminergic, cholinergic, serotonergic, adrenergic, or GABA receptors. Sulpiride is slowly absorbed from the gastrointestinal tract and peak serum levels occur at 3 hours . In low doses (50-200 mg), sulpiride presumably blocks presynaptic autoreceptors, thereby elevating DA levels and reducing depressive symptoms, whereas higher doses lead to a predominant blockade of postsynaptic receptors. The dose in the present study (400 mg) is sufficient for behaviorally relevant modulations of dopaminergic processing with minimal risk of side effects. Note that participants in the sulpiride group actually receive a dose that is presumably too high to produce antidepressant effects.<br>Behavioral: Low expectation manipulation<br>* Participants will be told by the study clinicians that an inactive placebo capsule is administrated.<br>|
| Experimental: Low expectation with placebo group<br>Prior to the experimental procedure, participants are told by the study clinicians that an inactive placebo capsule is administrated, and participants actually receive a placebo capsule. | Drug: Placebo<br>* Participants receive an inactive placebo capsule.<br>Behavioral: Low expectation manipulation<br>* Participants will be told by the study clinicians that an inactive placebo capsule is administrated.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Positive and Negative Affect Schedule (PANAS) | With regard to depressive mood induction: the mean of participants' five mood ratings during and immediately after the mood induction procedure. Participants' current mood will be rated on a 5-point Likert scale ranging from 1 = very slightly or not at all to 5 = extremely. | Five time points: approximately 3 hours after treatment (i.e., substance intake), approximately 4 hours after treatment, approximately 4.5 hours after treatment, approximately 4.75 hours after treatment, and approximately 5 hours after treatment. | 
| The probabilistic reinforcement learning task | With regard to probabilistic reinforcement learning: participants' reward learning rate parameter αG as estimated in computational modeling. | This will be the first task participants undergo approximately 3 hours after treatment (i.e., substance intake) followed by the two other tasks. | 
| The Effort Expenditure for Rewards Task (EEfRT) | With regard to effort expenditure: The number of participants' choices for the hard task which required more effort. | This will be the second task participants undergo which follows the probabilistic reinforcement learning task (approximately 4 hours after treatment) followed by the mood induction procedure. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mood ratings | Several further mood items will be rated on an 8-point scale ranging from 0 = not at all to 8 = very. | Simultaneously as PANAS (see primary outcome 1). | 
| EEG responses to mood induction | With regard to depressive mood: the late positive potential (LPP) in response to depressive vs. neutral statements, and frontal alpha asymmetry during the 5-minute resting phase immediately after the mood induction procedure. | Approximately 4. 5 hours after treatment (i.e., during the mood induction procedure which follows the probabilistic reinforcement learning task and the EEfRT tasks). | 
| EEG responses to reward feedback | With regard to probabilistic reinforcement learning: the reward positivity and frontomedial theta power in response to positive vs. negative feedback in the task. | Approximately 3 hours after treatment (i.e., simultaneously during the probabilistic reinforcement learning task). | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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placebo effect, treatment expectations, depression, reinforcement learning, mesolimbic dopamine, EEG