The Role of Dopamine, Reward Learning and Prefrontal Activity in Expectation-induced Mood Enhancement
Condition: Placebo Effect on Mood Improvement
Study type: Interventional

Summary: 
      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: 
      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.
    

Intervention name(s): Sulpiride 400 MG; Placebo; High expectation manipulation; Low expectation manipulation
Intervention type(s): Drug; Drug; Behavioral; Behavioral
Intervention description(s): 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.; Participants receive an inactive placebo capsule.; Participants will be told by the study clinicians that an antidepressive sulpiride capsule is administrated.; Participants will be told by the study clinicians that an inactive placebo capsule is administrated.
Intervention MeSH terms: Sulpiride
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention 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 (Participant, Investigator, Outcomes Assessor)
Primary purpose: Basic Science
Keywords: placebo effect; treatment expectations; depression; reinforcement learning; mesolimbic dopamine; EEG