Pharmaco-Neuroimaging Studies of Approach/Avoidance Behaviors and Post-Mortem Studies: Pharmacological Manipulation

Study Overview
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Brief Summary
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The study will investigate whether a nociceptin receptor antagonist will normalize neural and behavioral processes of approach/avoidance decision-making in unmedicated individuals with major depressive disorder (MDD) and anxiety disorders. More specifically, the study aims to investigate dysregulation within (1) corticostriatal-midbrain circuitry and (2) nociceptin/orphanin FQ peptide and the nociceptin receptor (NOPR).

Official Title
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Pharmaco-Neuroimaging Studies of Approach/Avoidance Behaviors and Post-Mortem Studies: Study 1.1. (Pharmacological Manipulation)

Conditions
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Depressive Disorder, Major, Anxiety Disorder

Intervention / Treatment
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* Drug: Nociceptin Receptor Antagonist
* Device: Aversive stimuli


Participation Criteria
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Eligibility Criteria
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Inclusion criteria for MDD/anxiety disorder group: DSM-5 diagnostic criteria for MDD, Generalized Anxiety Disorder, Social Phobia, Panic Disorder, Post Traumatic Stress (diagnosed using the SCID-5) Written informed consent For MDD subjects, a baseline Hamilton Depression Rating Scale score > 16 (17-item version) Right-handed Has a smartphone (iPhone or Android) (needed for Ecological Momentary Assessment) Absence of any psychotropic medications for at least 2 weeks (6 weeks for fluoxetine, 6 months for neuroleptics, 2 weeks for benzodiazepines, 2 weeks for any other antidepressants) Inclusion criteria for healthy controls: Absence of medical, neurological, and psychiatric illness (including alcohol and substance abuse), as assessed by subject history and a structured clinical interview (diagnosed using the SCID-5) Written informed consent Right-handed Absence of any medications for at least 3 weeks Has a smartphone (iPhone or Android) (needed for Ecological Momentary Assessment) Exclusion criteria for all participants: Subjects with suicidal ideation where outpatient treatment is determined unsafe by the study clinician Pregnant women or women of childbearing potential who are not using a medically accepted means of contraception Serious or unstable medical illness, including cardiovascular, hepatic, renal, respiratory, endocrine, neurologic or hematologic disease History of seizure disorder History or current diagnosis of any of the following DSM-IV psychiatric illnesses: organic mental disorder, schizophrenia, schizoaffective disorder, delusional disorder, psychotic disorders not otherwise specified, bipolar disorder, obsessive-compulsive disorder, patients with mood congruent or mood incongruent psychotic features, substance dependence, substance abuse within the last 12 months (with the exception of cocaine or stimulant abuse; which will lead to exclusion) History of cocaine or stimulant use (e.g., amphetamine, cocaine, methamphetamine) History of use of dopaminergic drugs (including methylphenidate) History or current diagnosis of dementia Patients with mood congruent or mood incongruent psychotic features Current use of other psychotropic drugs Clinical or laboratory evidence of hypothyroidism Patients with a lifetime history of electroconvulsive therapy Failure to meet standard magnetic resonance imaging safety requirements Abnormal ECG and lab results History of seizure disorder or currently on anticonvulsants

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

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: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Participants with MDD or an anxiety disorder receiving the nociceptin receptor antagonist<br>After a diagnostic interview (determining the presence of MDD or an anxiety disorder) and collection of blood for Orphanin FQ/Nociceptin assays, participants will receive the nociceptin receptor antagonist. Participants will then complete an approach/avoidance task. Functional magnetic resonance imagining (fMRI) will begin 2 hours after the nociceptin receptor antagonist is administered. | Drug: Nociceptin Receptor Antagonist<br>* Participants in the experimental arms will receive 40 mg of the nociceptin receptor antagonist. Peak concentrations are achieved 2-4 hours post-administration.<br>* Other names: BTRX-246040;Device: Aversive stimuli<br>* As part of the approach/avoidance task, electrotactile stimulation will be used. The aversive stimulus is delivered in the form of a mild half-second stimulation to the ankle, calibrated to a subjective threshold that is uncomfortable but not painful. This stimulation is delivered by Digitimer DS8R Constant Current Stimulator (Digitimer North America, LLC. Ft. Lauderdale, FL). Its previous model, DS71, has been safely implemented in studies within Massachusetts General Hospital (Milad et al., 2013).<br>|
| Placebo Comparator: Participants with MDD or an anxiety disorder receiving the placebo<br>After a diagnostic interview (determining the presence of MDD or an anxiety disorder) and collection of blood for Orphanin FQ/Nociceptin assays, participants will receive the placebo. Participants will then complete an approach/avoidance task. fMRI will begin 2 hours after the placebo is administered. | Device: Aversive stimuli<br>* As part of the approach/avoidance task, electrotactile stimulation will be used. The aversive stimulus is delivered in the form of a mild half-second stimulation to the ankle, calibrated to a subjective threshold that is uncomfortable but not painful. This stimulation is delivered by Digitimer DS8R Constant Current Stimulator (Digitimer North America, LLC. Ft. Lauderdale, FL). Its previous model, DS71, has been safely implemented in studies within Massachusetts General Hospital (Milad et al., 2013).<br>|
| Experimental: Healthy controls receiving the nociceptin receptor antagonist<br>After a diagnostic interview (determining healthy control status) and collection of blood for Orphanin FQ/Nociceptin assays, participants will receive a nociceptin receptor antagonist. Participants will then complete an approach/avoidance task. fMRI will begin 2 hours after the nociceptin receptor antagonist is administered. | Drug: Nociceptin Receptor Antagonist<br>* Participants in the experimental arms will receive 40 mg of the nociceptin receptor antagonist. Peak concentrations are achieved 2-4 hours post-administration.<br>* Other names: BTRX-246040;Device: Aversive stimuli<br>* As part of the approach/avoidance task, electrotactile stimulation will be used. The aversive stimulus is delivered in the form of a mild half-second stimulation to the ankle, calibrated to a subjective threshold that is uncomfortable but not painful. This stimulation is delivered by Digitimer DS8R Constant Current Stimulator (Digitimer North America, LLC. Ft. Lauderdale, FL). Its previous model, DS71, has been safely implemented in studies within Massachusetts General Hospital (Milad et al., 2013).<br>|
| Placebo Comparator: Healthy controls receiving the placebo<br>After a diagnostic interview (determining healthy control status) and collection of blood for Orphanin FQ/Nociceptin assays, participants will receive the placebo. Participants will then complete an approach/avoidance task. fMRI will begin 2 hours after the placebo is administered. | Device: Aversive stimuli<br>* As part of the approach/avoidance task, electrotactile stimulation will be used. The aversive stimulus is delivered in the form of a mild half-second stimulation to the ankle, calibrated to a subjective threshold that is uncomfortable but not painful. This stimulation is delivered by Digitimer DS8R Constant Current Stimulator (Digitimer North America, LLC. Ft. Lauderdale, FL). Its previous model, DS71, has been safely implemented in studies within Massachusetts General Hospital (Milad et al., 2013).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) (SCID-5) | Diagnostic assessment | Baseline | 
| Magnetic Resonance Imagining | Both structural and functional brain images | Within 30 days of the clinical interview | 
| Approach/Avoidance Task | A novel behavioral task assessing approach/avoidance decision-making | During the MRI scan | 
| Orphanin FQ/Nociceptin assays (using blood samples) | Measure of Orphanin FQ/Nociceptin | On the day of the MRI scan | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Beck Depression Inventory-II | 21-item measure of depression severity; scores range from 0 to 63; higher scores indicate higher depression severity | Baseline, 6-month follow-up, 12-month follow-up | 
| Hamilton Rating Scale for Depression | 17-item measure of depression severity; scores range from 0 to 34; higher scores indicate higher depression severity | Baseline, 6-month follow-up, 12-month follow-up | 
| Perceived Stress Scale | 14-item measure of stress appraisal; scores range from 0 to 56; higher scores indicate higher perceived stress | Baseline, 6-month follow-up, 12-month follow-up | 
| Snaith Hamilton Pleasure Scale | 14-item measure of anhedonia; scores range from 14 to 56; higher scores indicate higher anhedonia | Baseline, 6-month follow-up, 12-month follow-up | 
| Medical Outcome Survey- Short Form | 36-item measure of physical and social functioning; score range from 36 to 149; higher scores indicate higher physical and social functioning | Baseline, 6-month follow-up, 12-month follow-up | 
| Quality of Life Enjoyment and Satisfaction Questionnaire | 16-item measure of satisfaction and enjoyment across domains (e.g., work, interpersonal); scores range from 16 to 80; higher scores indicate higher life enjoyment and satisfaction | Baseline, 6-month follow-up, 12-month follow-up | 
| Temporal Experience of Pleasure Scale | 24-item measure of anticipatory and consummatory pleasure; scores range from 24 to 144; higher scores indicate higher anticipatory/consummatory pleasure | Baseline, 6-month follow-up, 12-month follow-up | 
| Life Events and Difficulties Schedule | Measure of acute events, difficulties, stressors | Baseline, 6-month follow-up, 12-month follow-up | 
| Longitudinal Interval Follow-Up Evaluation (LIFE) (Keller et al., 1987) | Retrospectively assesses different DSM-5 disorders, social and occupational functioning, and life satisfaction over the past 6 months | 6-month follow-up, 12-month follow-up | 
| Columbia-Suicide Severity Rating Scale | Suicide assessment | Baseline, 6-month follow-up, 12-month follow-up |