The Role of Dopamine, Reward Learning and Prefrontal Activity in Expectation-induced Mood Enhancement (CRC289A07)

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.

Study Overview

• Status: Completed
• Conditions: Placebo Effect on Mood Improvement
• Intervention / Treatment: Drug: Sulpiride 400 MG; Behavioral: High expectation manipulation; Drug: Placebo; Behavioral: Low expectation manipulation

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.

• Study Type: Interventional
• Enrollment (Actual): 297
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Erik M Mueller, Prof. Dr.; Phone Number: +49 6421 28-23659; Email: erik.mueller@staff.uni-marburg.de

Study Locations

• Germany
  • Hessen
    • Marburg, Hessen, Germany, 35032
      • Department of Psychology, Differential Psychology and Personality Research, Philipps-University of Marburg

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: High expectation with sulpiride group; 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; 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.; Behavioral: High expectation manipulation; Participants will be told by the study clinicians that an antidepressive sulpiride capsule is administrated.
Experimental: High expectation with placebo group; 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.	Behavioral: High expectation manipulation; Participants will be told by the study clinicians that an antidepressive sulpiride capsule is administrated.; Drug: Placebo; Participants receive an inactive placebo capsule.
Experimental: Low expectation with sulpiride group; 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; 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.; Behavioral: Low expectation manipulation; Participants will be told by the study clinicians that an inactive placebo capsule is administrated.
Experimental: Low expectation with placebo group; 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; Participants receive an inactive placebo capsule.; Behavioral: Low expectation manipulation; Participants will be told by the study clinicians that an inactive placebo capsule is administrated.

What is the study measuring?

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).

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
State-Trait-Anxiety-Depression Inventory (STADI)	STADI offers separate scales for anxiety and depression and while enabling differentiation of state and trait aspects, which are rated on a 4-point scale ranging from 1 = not at all to 4 = very.	For trait aspects: one week to two days prior to the experiment; for state aspects: approximately 30 minutes before treatment.
Behaviroal Approach System Sensitivity (BIS BAS)	Personality traits with regard to individual differences in reward processing are assessed ranging from 1 = totally disagree to 4 = totally agree.	One week to two days prior to the experiment session.
Perceived Stress Scale (PSS-10)	Participants' acute stress level are assessed on a 5-point scale ranging from 0 = never to 4 = very often, with a focus on psychophysiological stress aspects.	One week to two days prior to the experiment session.
Somatosensory Amplification Scale (SSAS)	Participants' somatosensory amplification in the development of side effects/nocebo effects are assessed on a 5-point scale ranging from 1 to 5. A higher total score indicates greater symptom amplification.	One week to two days prior to the experiment session.
Big Five Short Screener (BFI-10)	A short scale for assessing the Big Five dimensions of personality. Statements with regard to personality are rated on a 5-point scale ranging from 1 = disagree strongly to 5 = agree strongly.	One week to two days prior to the experiment session.
Beck Depression Inventory (BDI-II)	Self-rating scale with regard to depressiveness which is scored on a scale of 0-3 in a list of four statements arranged in increasing severity about depressive symptoms. Higher scores indicate higher degree of the presence and intensity of mood symptoms.	One week to two days prior to the experiment session.
Generic Assessment of Side Effects (GASE)	Assessment of side effects of clinical and experimental therapeutic interventions which is based on the statistics of the Food and Drug Administration, USA.	Approximately 30 minutes prior to treatment.
Generic Rating for Treatment Pre-Experiences, Treatment Expectations, and Treatment Effects (G-EEE)	Self-report questionnaire about participants' experience, expectation and current state with regard to the treatment (i.e., sulpiride intake) are assessed on a 11-point scale ranging from 0 to 10, while higher scores indicate stronger degree of expectancy.	Approximately 30 minutes prior to treatment.
The Positive Valence System Scale (PVSS)	Measure of response to a wide range of rewards with regard to reward-related abnormalities in depression and other disorders. Higher scores indicate stronger responding to rewards.	Approximately 30 minutes prior to treatment.
The Snaith-Hamilton Pleasure Scale (SHPS)	Assessment of hedonic tone and its absence, i.e., anhedonia.	Approximately 30 minutes prior to treatment.
PANAS trait and state	Assessment of positive and negative affect on the trait and state level, respectively.	For trait level, one week to two days prior to the experiment session; for state level, approximately 30 minutes prior to treatment.
The Temporal Experience of Pleasure Scale (TEPS)	Assessment of individual trait dispositions in both anticipatory and consummatory experiences of pleasure.	One week to two days prior to the experiment session.
Mood and Anxiety Symptom Questionnaire (MASQ-30)	Assessment of anhedonia as well as negative affectivity.	One week to two days prior to the experiment session.
Revised Life-Orientation-Tests (LOT-R)	Assessment of dispositional agentic extraversion and negative affectivity.	One week to two days prior to the experiment session.
Reinforcement Sensitivity Theory Personality Questionnaire (RST-PQ)	Assessment of dispositional agentic extraversion and negative affectivity.	One week to two days prior to the experiment session.

Collaborators and Investigators

• Sponsor: Philipps University Marburg Medical Center
• Investigators: Principal Investigator: Erik M Mueller, Prof. Dr., Philipps University Marburg Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): December 9, 2021
• Primary Completion (Actual): September 22, 2023
• Study Completion (Actual): September 22, 2023

Study Registration Dates

• First Submitted: December 21, 2021
• First Submitted That Met QC Criteria: January 13, 2022
• First Posted (Actual): January 26, 2022

Study Record Updates

• Last Update Posted (Actual): January 16, 2024
• Last Update Submitted That Met QC Criteria: January 12, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: depression; placebo effect; EEG; reinforcement learning; treatment expectations; mesolimbic dopamine
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Antipsychotic Agents; Tranquilizing Agents; Psychotropic Drugs; Antidepressive Agents; Dopamine Agents; Dopamine Antagonists; Antidepressive Agents, Second-Generation; Sulpiride
• Other Study ID Numbers: CRC 289 Projekt A07

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Sharing Time Frame: With publication
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ANALYTIC_CODE

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No