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

Study Overview
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Brief Summary
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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.

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

Conditions
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Anorexia Nervosa

Intervention / Treatment
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* Drug: amisulpride
* Drug: bromocriptine


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 29 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Healthy Controls<br>Healthy Control Subjects | Drug: amisulpride<br>* Dopamine D2 antagonist to test how it affects brain response and behavior to prediction error and reversal tasks during functional magnetic resonance imaging (fMRI).<br>* Other names: Solian;Drug: bromocriptine<br>* Dopamine D2 receptor agonist test how it affects brain response and behavior to prediction error and reversal tasks during functional magnetic resonance imaging (fMRI).<br>* Other names: Parlodel;|
| Experimental: Anorexia Nervosa<br>Anorexia Nervosa Subjects | Drug: amisulpride<br>* Dopamine D2 antagonist to test how it affects brain response and behavior to prediction error and reversal tasks during functional magnetic resonance imaging (fMRI).<br>* Other names: Solian;Drug: bromocriptine<br>* Dopamine D2 receptor agonist test how it affects brain response and behavior to prediction error and reversal tasks during functional magnetic resonance imaging (fMRI).<br>* Other names: Parlodel;|

What is the study measuring?
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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 |