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

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: Active, not recruiting
• Conditions: Anorexia Nervosa
• Intervention / Treatment: Drug: amisulpride; Drug: bromocriptine

• Study Type: Interventional
• Enrollment (Actual): 31
• Phase: Early Phase 1

Contacts and Locations

• Study Contact: Name: Megan E Shott, BS; Phone Number: 858-246-5272; Email: mshott@ucsd.edu

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 27 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

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Healthy Controls; Healthy Control Subjects	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
Experimental: Anorexia Nervosa; Anorexia Nervosa Subjects	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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
fMRI brain response within group across the three conditions and distinction between conditions within groups	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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Difference in brain response between groups	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

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

Study record dates

Study Major Dates

• Study Start (Actual): October 20, 2020
• Primary Completion (Actual): September 6, 2023
• Study Completion (Estimated): December 1, 2024

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): March 5, 2024
• Last Update Submitted That Met QC Criteria: March 2, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Signs and Symptoms, Digestive; Feeding and Eating Disorders; Anorexia; Anorexia Nervosa; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Hormones, Hormone Substitutes, and Hormone Antagonists; Antipsychotic Agents; Tranquilizing Agents; Psychotropic Drugs; Antidepressive Agents; Dopamine Agonists; Dopamine Agents; Dopamine Antagonists; Antidepressive Agents, Second-Generation; Hormone Antagonists; Antiparkinson Agents; Anti-Dyskinesia Agents; Amisulpride; Bromocriptine
• Other Study ID Numbers: 191348

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