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.

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:

1. Expectation enhancement (high vs. low) within the placebo group is associated with lower negative mood ratings after the mood induction procedure.
2. 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.
3. 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).
4. 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).
5. In the sulpiride group, the effects described in (1), (2), and (3) are lower than in the placebo group.
6. 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.
7. High levels of the personality trait agentic extraversion (and low levels of depressive symptoms) are associated with higher expectancy effects on negative mood.

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)

With publication

Participants will be blinded to the actual substance groups. In order to carry out the expectation manipulation, the clinician scientists will provide participants with substance information that is unrelated to the actual substance that is received by the participants. Hence the clinician scientists are blind to the actual substance (double blind design). Other than providing (invalid) substance information (i.e. the expectation manipulation) and drawing blood samples, the study clinicians do not take part in the remaining experimental procedure. The investigators who accompany participants throughout the experimental procedure are not aware of participants' true substance and expectation allocation.