Dopamine Receptor Contributions to Prediction Error and Reversal Learning in Anorexia Nervosa

March 25, 2025 updated by: Guido Frank, University of California, San Diego

Toward Understanding Dopamine Receptor Contributions to Prediction Error and Reversal Learning in Anorexia Nervosa

Anorexia nervosa (AN) is an eating disorder associated with intense fear of weight gain, food refusal, and severe weight loss. AN has the highest mortality rate among the psychiatric disorders; however, little is known about biomarkers, and no medication has been approved for AN. Many individuals only partially recover, and treatment options, especially for the psychological components of the illness, are not very effective, highlighting the need for more effective treatments.

Brain reward pathways have a direct impact on the drive to eat, and a variety of neuroimaging studies have suggested altered reward processing in AN. The neurotransmitter dopamine has a central role in the reward circuitry to drive food approach, and the dynamic interplay between dopamine receptor response and food restriction could have implications for the pathophysiology of AN. Dopamine-related brain function has been studied indirectly using functional magnetic resonance brain imaging (fMRI) and tasks that deliver reward stimuli unexpectedly, that elicit the so-called prediction error (PE) response.

Research in AN showed repeatedly altered PE processing suggesting altered dopamine circuit function in the disorder.

Dopamine and PE response have also been associated with altered reversal learning, which has important treatment implication for AN as reversal learning is impaired in the disorder and modulation of the dopamine system could improve treatment.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Actual)

31

Phase

  • Early Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • California
      • San Diego, California, United States, 92121
        • University of California San Diego

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

14 years to 25 years (Adult)

Accepts Healthy Volunteers

Yes

Description

Inclusion Criteria:

Healthy Controls

  • Females ages 18-29 years
  • Healthy body weight between 90 and 110 % average body weight since puberty.
  • Regular monthly menstrual cycle
  • Edinburgh Handedness Inventory Revised (EHI-R) LQ* score > +200
  • English is primary language spoken

Restricting Type Anorexia Nervosa

  • Females ages 18-29 years
  • Diagnostic criteria. Current diagnosis of AN, including being underweight below 17.5 body mass index (BMI, kg/m2), will have a severe fear of weight gain, body image distortion and absence of the menstrual cycle over three consecutive months.
  • First 1-2 weeks in treatment at The University of California San Diego Eating Disorders Center for Treatment and Research or Rady Children's Hospital San Diego Medical Behavioral Unit.
  • Restricting subtype, that is without binge/purge behaviors
  • Edinburgh Handedness Inventory Revised (EHI-R) LQ* score > +200
  • English is primary language spoken

Exclusion Criteria:

Healthy Controls

  • Current pregnancy or breast feeding within last 3 months
  • Illiterate/Blind individuals
  • First degree relative with current or past eating disorder
  • Current Medications other than BCP or IUD
  • Contraindications to amisulpride or bromocriptine (as determined through medical history in bioscreen and PI interview) including: Syncopal migraine; Uncontrolled hypertension; Pheochromocytoma; Prolactinoma; Breast cancer; hypersensitivity/allergy to amisulpride or bromocriptine; History of long QT syndrome; Family history of sudden death or long QT syndrome; History of seizures or seizure disorder
  • Past or present Axis I psychiatric disorder including substance or alcohol use disorder as determined through SCID-5 clinical interview

  • Major Medical illness (as determined through medical history in bioscreen and PI interview) such as:

    o Conditions that are life threatening: cancer heart disease stroke HIV/AIDS

    o Conditions that are life threatening Conditions that cause serious disability without necessarily being life threatening: stroke closed head or spinal cord injuries mental retardation congenital malformations.

    o Conditions that cause significant pain or discomfort that can cause serious interruptions to life activities: severe allergies migraine arthritis sickle cell disease

    o Conditions that require major commitments of time and effort from care-givers for a substantial period of time: mobility disorders blindness Alzheimer's disease and other dementias chronic obstructive pulmonary disease paraplegia or quadriplegia Down's syndrome depression

    o Conditions that may require frequent monitoring: diabetes conditions requiring anticoagulation treatment severe asthma severe allergies schizophrenia and other psychotic illnesses.

    o Conditions that predict or are associated with severe consequences: hypertension (associated with heart disease) depression (associated with suicide) diabetes (associated with blindness, kidney failure) alcohol and other substance abuse (associated with intentional and unintentional injuries).

  • Recent history of suspected substance abuse or a lifetime history of psychostimulant abuse and/or dependence
  • Metal implants or braces (as determined through fMRI screening form)

Anorexia Nervosa

  • Pregnancy or breast feeding within last 3 months
  • Lifetime history of bipolar disorder or psychosis
  • Illiterate/Blind individuals
  • Contraindications to amisulpride or bromocriptine (as determined through medical history in bioscreen and PI interview) including: Syncopal migraine; Uncontrolled hypertension; Pheochromocytoma; Prolactinoma; Breast cancer; hypersensitivity/allergy to amisulpride or bromocriptine; History of long QT syndrome; Family history of sudden death or long QT syndrome; History of seizures or seizure disorder
  • Use of an anti-psychotic or other dopamine acting medication including stimulants within the past week at time of MRI
  • Recent history of substance abuse or dependence (within the last month)

  • Major Medical illness (as determined through medical history in bioscreen and PI interview) such as:

    o Conditions that are life threatening: cancer heart disease stroke HIV/AIDS

    o Conditions that are life threatening Conditions that cause serious disability without necessarily being life threatening: stroke closed head or spinal cord injuries mental retardation congenital malformations.

    o Conditions that cause significant pain or discomfort that can cause serious interruptions to life activities: severe allergies migraine arthritis sickle cell disease

    o Conditions that require major commitments of time and effort from care-givers for a substantial period of time: mobility disorders blindness Alzheimer's disease and other dementias chronic obstructive pulmonary disease paraplegia or quadriplegia Down's syndrome

    o Conditions that may require frequent monitoring: diabetes conditions requiring anticoagulation treatment severe asthma severe allergies schizophrenia and other psychotic illnesses.

    o Conditions that predict or are associated with severe consequences: hypertension (associated with heart disease) diabetes (associated with blindness, kidney failure) alcohol and other substance abuse (associated with intentional and unintentional injuries) within the last month

  • Metal implants or braces (as determined through fMRI screening form)

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Other
  • Allocation: Randomized
  • Interventional Model: Crossover Assignment
  • Masking: Single

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Healthy Controls, Scan1: Placebo; Scan2: Amisulpride; Scan3: Bromocriptine

Individuals in the healthy control group were randomized to the following scan order. Participants were administered a study medication or placebo 3 hours prior to the start of the scan. The participant did not know what study medication they received for each scan:

Scan 1: Placebo(single dose, 3 hours pre-scan) Scan 2: Amisulpride (single dose, 400 mg, 3 hours pre-scan) Scan 3: Bromocriptine (single dose, 1.25 mg, 3 hours pre-scan)
Drug: amisulpride
Dopamine D2 antagonist to test how it affects brain response and behavior to prediction error and reversal tasks during functional magnetic resonance imaging (fMRI).
Other Names:
  • Solian
Drug: bromocriptine
Dopamine D2 receptor agonist test how it affects brain response and behavior to prediction error and reversal tasks during functional magnetic resonance imaging (fMRI).
Other Names:
  • Parlodel
Drug: Placebo
Placebo pill with no active drug ingredients
Experimental: Healthy Controls, Scan1: Placebo; Scan2: Bromocriptine; Scan3: Amisulpride;

Individuals in the healthy control group were randomized to the following scan order. Participants were administered a study medication or placebo 3 hours prior to the start of the scan. The participant did not know what study medication they received for each scan:

Scan 1: Placebo(single dose, 3 hours pre-scan) Scan 2: Bromocriptine (single dose, 1.25 mg, 3 hours pre-scan) Scan 3: Amisulpride (single dose, 400 mg, 3 hours pre-scan)
Drug: amisulpride
Dopamine D2 antagonist to test how it affects brain response and behavior to prediction error and reversal tasks during functional magnetic resonance imaging (fMRI).
Other Names:
  • Solian
Drug: bromocriptine
Dopamine D2 receptor agonist test how it affects brain response and behavior to prediction error and reversal tasks during functional magnetic resonance imaging (fMRI).
Other Names:
  • Parlodel
Drug: Placebo
Placebo pill with no active drug ingredients
Experimental: Healthy Controls, Scan1: Amisulpride; Scan2: Placebo; Scan3: Bromocriptine

Individuals in the healthy control group were randomized to the following scan order. Participants were administered a study medication or placebo 3 hours prior to the start of the scan. The participant did not know what study medication they received for each scan:

Scan 1: Amisulpride (single dose, 400 mg, 3 hours pre-scan) Scan 2: Placebo(single dose, 3 hours pre-scan) Scan 3: Bromocriptine (single dose, 1.25 mg, 3 hours pre-scan)
Drug: amisulpride
Dopamine D2 antagonist to test how it affects brain response and behavior to prediction error and reversal tasks during functional magnetic resonance imaging (fMRI).
Other Names:
  • Solian
Drug: bromocriptine
Dopamine D2 receptor agonist test how it affects brain response and behavior to prediction error and reversal tasks during functional magnetic resonance imaging (fMRI).
Other Names:
  • Parlodel
Drug: Placebo
Placebo pill with no active drug ingredients
Experimental: Healthy Controls, Scan1: Amisulpride; Scan2: Bromocriptine; Scan1: Placebo

Individuals in the healthy control group were randomized to the following scan order. Participants were administered a study medication or placebo 3 hours prior to the start of the scan. The participant did not know what study medication they received for each scan:

Scan 1: Amisulpride (single dose, 400 mg, 3 hours pre-scan) Scan 2: Bromocriptine (single dose, 1.25 mg, 3 hours pre-scan) Scan 3: Placebo(single dose, 3 hours pre-scan)
Drug: amisulpride
Dopamine D2 antagonist to test how it affects brain response and behavior to prediction error and reversal tasks during functional magnetic resonance imaging (fMRI).
Other Names:
  • Solian
Drug: bromocriptine
Dopamine D2 receptor agonist test how it affects brain response and behavior to prediction error and reversal tasks during functional magnetic resonance imaging (fMRI).
Other Names:
  • Parlodel
Drug: Placebo
Placebo pill with no active drug ingredients
Experimental: Healthy Controls, Scan1: Bromocriptine; Scan2: Placebo; Scan 3: Amisulpride

Individuals in the healthy control group were randomized to the following scan order. Participants were administered a study medication or placebo 3 hours prior to the start of the scan. The participant did not know what study medication they received for each scan:

Scan 1: Bromocriptine (single dose, 1.25 mg, 3 hours pre-scan) Scan 2: Placebo(single dose, 3 hours pre-scan) Scan 3: Amisulpride (single dose, 400 mg, 3 hours pre-scan)
Drug: amisulpride
Dopamine D2 antagonist to test how it affects brain response and behavior to prediction error and reversal tasks during functional magnetic resonance imaging (fMRI).
Other Names:
  • Solian
Drug: bromocriptine
Dopamine D2 receptor agonist test how it affects brain response and behavior to prediction error and reversal tasks during functional magnetic resonance imaging (fMRI).
Other Names:
  • Parlodel
Drug: Placebo
Placebo pill with no active drug ingredients
Experimental: Healthy Controls, Scan1: Bromocriptine; Scan2: Amisulpride; Scan3: Placebo

Individuals in the healthy control group were randomized to the following scan order. Participants were administered a study medication or placebo 3 hours prior to the start of the scan. The participant did not know what study medication they received for each scan:

Scan 1: Bromocriptine (single dose, 1.25 mg, 3 hours pre-scan) Scan 2: Amisulpride (single dose, 400 mg, 3 hours pre-scan) Scan 3: Placebo(single dose, 3 hours pre-scan)
Drug: amisulpride
Dopamine D2 antagonist to test how it affects brain response and behavior to prediction error and reversal tasks during functional magnetic resonance imaging (fMRI).
Other Names:
  • Solian
Drug: bromocriptine
Dopamine D2 receptor agonist test how it affects brain response and behavior to prediction error and reversal tasks during functional magnetic resonance imaging (fMRI).
Other Names:
  • Parlodel
Drug: Placebo
Placebo pill with no active drug ingredients
Experimental: Anorexia Nervosa, Scan1: Placebo; Scan2: Amisulpride; Scan3: Bromocriptine

Individuals in the anorexia nervosa group were randomized to the following scan order. Participants were administered a study medication or placebo 3 hours prior to the start of the scan. The participant did not know what study medication they received for each scan:

Scan 1: Placebo(single dose, 3 hours pre-scan) Scan 2: Amisulpride (single dose, 400 mg, 3 hours pre-scan) Scan 3: Bromocriptine (single dose, 1.25 mg, 3 hours pre-scan)
Drug: amisulpride
Dopamine D2 antagonist to test how it affects brain response and behavior to prediction error and reversal tasks during functional magnetic resonance imaging (fMRI).
Other Names:
  • Solian
Drug: bromocriptine
Dopamine D2 receptor agonist test how it affects brain response and behavior to prediction error and reversal tasks during functional magnetic resonance imaging (fMRI).
Other Names:
  • Parlodel
Drug: Placebo
Placebo pill with no active drug ingredients
Experimental: Anorexia Nervosa, Scan1: Placebo; Scan2: Bromocriptine; Scan3: Amisulpride;

Individuals in the anorexia nervosa group were randomized to the following scan order. Participants were administered a study medication or placebo 3 hours prior to the start of the scan. The participant did not know what study medication they received for each scan:

Scan 1: Placebo(single dose, 3 hours pre-scan) Scan 2: Bromocriptine (single dose, 1.25 mg, 3 hours pre-scan) Scan 3: Amisulpride (single dose, 400 mg, 3 hours pre-scan)
Drug: amisulpride
Dopamine D2 antagonist to test how it affects brain response and behavior to prediction error and reversal tasks during functional magnetic resonance imaging (fMRI).
Other Names:
  • Solian
Drug: bromocriptine
Dopamine D2 receptor agonist test how it affects brain response and behavior to prediction error and reversal tasks during functional magnetic resonance imaging (fMRI).
Other Names:
  • Parlodel
Drug: Placebo
Placebo pill with no active drug ingredients
Experimental: Anorexia Nervosa, Scan1: Amisulpride; Scan2: Placebo; Scan3: Bromocriptine

Individuals in the anorexia nervosa group were randomized to the following scan order. Participants were administered a study medication or placebo 3 hours prior to the start of the scan. The participant did not know what study medication they received for each scan:

Scan 1: Amisulpride (single dose, 400 mg, 3 hours pre-scan) Scan 2: Placebo(single dose, 3 hours pre-scan) Scan 3: Bromocriptine (single dose, 1.25 mg, 3 hours pre-scan)
Drug: amisulpride
Dopamine D2 antagonist to test how it affects brain response and behavior to prediction error and reversal tasks during functional magnetic resonance imaging (fMRI).
Other Names:
  • Solian
Drug: bromocriptine
Dopamine D2 receptor agonist test how it affects brain response and behavior to prediction error and reversal tasks during functional magnetic resonance imaging (fMRI).
Other Names:
  • Parlodel
Drug: Placebo
Placebo pill with no active drug ingredients
Experimental: Anorexia Nervosa, Scan1: Amisulpride; Scan2: Bromocriptine; Scan1: Placebo

Individuals in the anorexia nervosa group were randomized to the following scan order. Participants were administered a study medication or placebo 3 hours prior to the start of the scan. The participant did not know what study medication they received for each scan:

Scan 1: Amisulpride (single dose, 400 mg, 3 hours pre-scan) Scan 2: Bromocriptine (single dose, 1.25 mg, 3 hours pre-scan) Scan 3: Placebo(single dose, 3 hours pre-scan)
Drug: amisulpride
Dopamine D2 antagonist to test how it affects brain response and behavior to prediction error and reversal tasks during functional magnetic resonance imaging (fMRI).
Other Names:
  • Solian
Drug: bromocriptine
Dopamine D2 receptor agonist test how it affects brain response and behavior to prediction error and reversal tasks during functional magnetic resonance imaging (fMRI).
Other Names:
  • Parlodel
Drug: Placebo
Placebo pill with no active drug ingredients
Experimental: Anorexia Nervosa, Scan1: Bromocriptine; Scan2: Placebo; Scan 3: Amisulpride

Individuals in the anorexia nervosa group were randomized to the following scan order. Participants were administered a study medication or placebo 3 hours prior to the start of the scan. The participant did not know what study medication they received for each scan:

Scan 1: Bromocriptine (single dose, 1.25 mg, 3 hours pre-scan) Scan 2: Placebo(single dose, 3 hours pre-scan) Scan 3: Amisulpride (single dose, 400 mg, 3 hours pre-scan)
Drug: amisulpride
Dopamine D2 antagonist to test how it affects brain response and behavior to prediction error and reversal tasks during functional magnetic resonance imaging (fMRI).
Other Names:
  • Solian
Drug: bromocriptine
Dopamine D2 receptor agonist test how it affects brain response and behavior to prediction error and reversal tasks during functional magnetic resonance imaging (fMRI).
Other Names:
  • Parlodel
Drug: Placebo
Placebo pill with no active drug ingredients
Experimental: Anorexia Nervosa, Scan1: Bromocriptine; Scan2: Amisulpride; Scan3: Placebo

Individuals in the anorexia nervosa group were randomized to the following scan order. Participants were administered a study medication or placebo 3 hours prior to the start of the scan. The participant did not know what study medication they received for each scan:

Scan 1: Bromocriptine (single dose, 1.25 mg, 3 hours pre-scan) Scan 2: Amisulpride (single dose, 400 mg, 3 hours pre-scan) Scan 3: Placebo(single dose, 3 hours pre-scan)
Drug: amisulpride
Dopamine D2 antagonist to test how it affects brain response and behavior to prediction error and reversal tasks during functional magnetic resonance imaging (fMRI).
Other Names:
  • Solian
Drug: bromocriptine
Dopamine D2 receptor agonist test how it affects brain response and behavior to prediction error and reversal tasks during functional magnetic resonance imaging (fMRI).
Other Names:
  • Parlodel
Drug: Placebo
Placebo pill with no active drug ingredients

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Measurement of Brain Activation (Measured in Percent Signal Change) During a Prediction Error Taste Reward Task Using Functional Magnetic Resonance Imaging (fMRI).
Time Frame: The outcome measure was assessed during the taste MRI task on each of the 3 intervention scan days over the course of 9 to 12 days
This task measures responsiveness to unexpected stimulus in the dopamine related brain circuitry. Study participants in both the healthy control group and anorexia nervosa group completed 3 fMRI scans. Prior to each scan subjects were administered one of three study medications (amisulpride, bromocriptine, or placebo). During the fMRI scan, subjects completed a taste reward prediction error task where they viewed visual stimuli and then received one of three conditions: sweet taste, neutral taste, or no solution. 20 percent of stimulus receipt was unexpected, that is there is a mismatch between expectation and outcome. Using a region of interest (ROI)-based approach, brain activation percent signal change values were extracted from the brain images for each subject and compared across groups and medication scans. A repeated measures ANOVA was used to calculate the mean brain activation for each group and each medication scan.
The outcome measure was assessed during the taste MRI task on each of the 3 intervention scan days over the course of 9 to 12 days
Measurement of Brain Activation (Measured in Percent Signal Change) During Taste Stimulus Expectation Using Functional Magnetic Resonance Imaging (fMRI).
Time Frame: The outcome measure was assessed during the taste MRI task on each of the 3 intervention scan days over the course of 9 to 12 days
Study participants in both the healthy control group and anorexia nervosa group completed 3 fMRI scans. Prior to each scan subjects were administered one of three study medications (amisulpride, bromocriptine, or placebo). During the fMRI scan, subjects completed a taste reward prediction error task where they viewed visual stimuli and then received one of three conditions: sweet taste, neutral taste, or no solution. Using a region of interest (ROI)-based approach, brain activation percent signal change values were extracted from the brain images for each subject and compared across groups and medication scans. Here only stimulus expectation data were analyzed. A repeated measures ANOVA was used to calculate the mean brain activation for each group and each medication scan.
The outcome measure was assessed during the taste MRI task on each of the 3 intervention scan days over the course of 9 to 12 days

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Difference in brain response between groups
Time Frame: Immediate during brain scanning
Study participants will have three study days with either a medication or placebo condition and will undergo fMRI during which they perform prediction error or reversal learning tasks and the effect on brain response and behavior are measured immediately during scanning.
Immediate during brain scanning

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of California, San Diego

Collaborators

National Institute of Mental Health (NIMH)

Investigators

  • Principal Investigator: Guido Frank, MD, University of California, San Diego

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

October 20, 2020

Primary Completion (Actual)

September 6, 2023

Study Completion (Actual)

January 1, 2025

Study Registration Dates

First Submitted

October 14, 2019

First Submitted That Met QC Criteria

October 14, 2019

First Posted (Actual)

October 16, 2019

Study Record Updates

Last Update Posted (Actual)

April 11, 2025

Last Update Submitted That Met QC Criteria

March 25, 2025

Last Verified

March 1, 2025

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 191348
  • 5R21MH120475 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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