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

NCT ID: NCT04128683

Last Updated: 2025-04-11

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: EARLY_PHASE1
• Total Enrollment: 31 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-10-20
• Study Completion Date: 2025-01-01

Brief Summary

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.

Conditions

Anorexia Nervosa

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: OTHER
• Blinding Strategy: SINGLE

Study Groups

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)

Group Type: EXPERIMENTAL

amisulpride

Intervention Type: DRUG

Dopamine D2 antagonist to test how it affects brain response and behavior to prediction error and reversal tasks during functional magnetic resonance imaging (fMRI).

bromocriptine

Intervention Type: DRUG

Dopamine D2 receptor agonist test how it affects brain response and behavior to prediction error and reversal tasks during functional magnetic resonance imaging (fMRI).

Placebo

Intervention Type: DRUG

Placebo pill with no active drug ingredients

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)

Group Type: EXPERIMENTAL

amisulpride

Intervention Type: DRUG

Dopamine D2 antagonist to test how it affects brain response and behavior to prediction error and reversal tasks during functional magnetic resonance imaging (fMRI).

bromocriptine

Intervention Type: DRUG

Dopamine D2 receptor agonist test how it affects brain response and behavior to prediction error and reversal tasks during functional magnetic resonance imaging (fMRI).

Placebo

Intervention Type: DRUG

Placebo pill with no active drug ingredients

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)

Group Type: EXPERIMENTAL

amisulpride

Intervention Type: DRUG

Dopamine D2 antagonist to test how it affects brain response and behavior to prediction error and reversal tasks during functional magnetic resonance imaging (fMRI).

bromocriptine

Intervention Type: DRUG

Dopamine D2 receptor agonist test how it affects brain response and behavior to prediction error and reversal tasks during functional magnetic resonance imaging (fMRI).

Placebo

Intervention Type: DRUG

Placebo pill with no active drug ingredients

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)

Group Type: EXPERIMENTAL

amisulpride

Intervention Type: DRUG

Dopamine D2 antagonist to test how it affects brain response and behavior to prediction error and reversal tasks during functional magnetic resonance imaging (fMRI).

bromocriptine

Intervention Type: DRUG

Dopamine D2 receptor agonist test how it affects brain response and behavior to prediction error and reversal tasks during functional magnetic resonance imaging (fMRI).

Placebo

Intervention Type: DRUG

Placebo pill with no active drug ingredients

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)

Group Type: EXPERIMENTAL

amisulpride

Intervention Type: DRUG

Dopamine D2 antagonist to test how it affects brain response and behavior to prediction error and reversal tasks during functional magnetic resonance imaging (fMRI).

bromocriptine

Intervention Type: DRUG

Dopamine D2 receptor agonist test how it affects brain response and behavior to prediction error and reversal tasks during functional magnetic resonance imaging (fMRI).

Placebo

Intervention Type: DRUG

Placebo pill with no active drug ingredients

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)

Group Type: EXPERIMENTAL

amisulpride

Intervention Type: DRUG

Dopamine D2 antagonist to test how it affects brain response and behavior to prediction error and reversal tasks during functional magnetic resonance imaging (fMRI).

bromocriptine

Intervention Type: DRUG

Dopamine D2 receptor agonist test how it affects brain response and behavior to prediction error and reversal tasks during functional magnetic resonance imaging (fMRI).

Placebo

Intervention Type: DRUG

Placebo pill with no active drug ingredients

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)

Group Type: EXPERIMENTAL

amisulpride

Intervention Type: DRUG

Dopamine D2 antagonist to test how it affects brain response and behavior to prediction error and reversal tasks during functional magnetic resonance imaging (fMRI).

bromocriptine

Intervention Type: DRUG

Dopamine D2 receptor agonist test how it affects brain response and behavior to prediction error and reversal tasks during functional magnetic resonance imaging (fMRI).

Placebo

Intervention Type: DRUG

Placebo pill with no active drug ingredients

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)

Group Type: EXPERIMENTAL

amisulpride

Intervention Type: DRUG

Dopamine D2 antagonist to test how it affects brain response and behavior to prediction error and reversal tasks during functional magnetic resonance imaging (fMRI).

bromocriptine

Intervention Type: DRUG

Dopamine D2 receptor agonist test how it affects brain response and behavior to prediction error and reversal tasks during functional magnetic resonance imaging (fMRI).

Placebo

Intervention Type: DRUG

Placebo pill with no active drug ingredients

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)

Group Type: EXPERIMENTAL

amisulpride

Intervention Type: DRUG

Dopamine D2 antagonist to test how it affects brain response and behavior to prediction error and reversal tasks during functional magnetic resonance imaging (fMRI).

bromocriptine

Intervention Type: DRUG

Dopamine D2 receptor agonist test how it affects brain response and behavior to prediction error and reversal tasks during functional magnetic resonance imaging (fMRI).

Placebo

Intervention Type: DRUG

Placebo pill with no active drug ingredients

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)

Group Type: EXPERIMENTAL

amisulpride

Intervention Type: DRUG

Dopamine D2 antagonist to test how it affects brain response and behavior to prediction error and reversal tasks during functional magnetic resonance imaging (fMRI).

bromocriptine

Intervention Type: DRUG

Dopamine D2 receptor agonist test how it affects brain response and behavior to prediction error and reversal tasks during functional magnetic resonance imaging (fMRI).

Placebo

Intervention Type: DRUG

Placebo pill with no active drug ingredients

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)

Group Type: EXPERIMENTAL

amisulpride

Intervention Type: DRUG

Dopamine D2 antagonist to test how it affects brain response and behavior to prediction error and reversal tasks during functional magnetic resonance imaging (fMRI).

bromocriptine

Intervention Type: DRUG

Dopamine D2 receptor agonist test how it affects brain response and behavior to prediction error and reversal tasks during functional magnetic resonance imaging (fMRI).

Placebo

Intervention Type: DRUG

Placebo pill with no active drug ingredients

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)

Group Type: EXPERIMENTAL

amisulpride

Intervention Type: DRUG

Dopamine D2 antagonist to test how it affects brain response and behavior to prediction error and reversal tasks during functional magnetic resonance imaging (fMRI).

bromocriptine

Intervention Type: DRUG

Dopamine D2 receptor agonist test how it affects brain response and behavior to prediction error and reversal tasks during functional magnetic resonance imaging (fMRI).

Placebo

Intervention Type: DRUG

Placebo pill with no active drug ingredients

Interventions

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).

Intervention Type: 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).

Intervention Type: DRUG

Placebo

Placebo pill with no active drug ingredients

Intervention Type: DRUG

Other Intervention Names

Solian; Parlodel

Eligibility Criteria

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)

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 29 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: Yes

Sponsors

National Institute of Mental Health (NIMH)

NIH

Sponsor Role: collaborator

University of California, San Diego

OTHER

Sponsor Role: lead

Responsible Party

Guido Frank

Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Guido Frank, MD

Role: PRINCIPAL_INVESTIGATOR

University of California, San Diego

Locations

University of California San Diego

San Diego, California, United States

Countries

United States

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

5R21MH120475

Identifier Type: NIH

Identifier Source: secondary_id

View Link

191348

Identifier Type: -

Identifier Source: org_study_id