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

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

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).

Study Overview

• Status: Not yet recruiting
• Conditions: Depressive Disorder, Major; Anxiety Disorder
• Intervention / Treatment: Drug: Nociceptin Receptor Antagonist; Device: Aversive stimuli

• Study Type: Interventional
• Enrollment (Estimated): 112
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: David Crowley, ALM; Phone Number: 617-855-4432; Email: djcrowley@mclean.harvard.edu
• Study Contact Backup: Name: Emma Palermo, BA; Phone Number: 617-855-4412; Email: ehpalermo@mclean.harvard.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Participants with MDD or an anxiety disorder receiving the nociceptin receptor antagonist; 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; Participants in the experimental arms will receive 40 mg of the nociceptin receptor antagonist. Peak concentrations are achieved 2-4 hours post-administration.; Other Names: BTRX-246040; Device: Aversive stimuli; 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).
Placebo Comparator: Participants with MDD or an anxiety disorder receiving the placebo; 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; 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).
Experimental: Healthy controls receiving the nociceptin receptor antagonist; 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; Participants in the experimental arms will receive 40 mg of the nociceptin receptor antagonist. Peak concentrations are achieved 2-4 hours post-administration.; Other Names: BTRX-246040; Device: Aversive stimuli; 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).
Placebo Comparator: Healthy controls receiving the placebo; 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; 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).

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Mclean Hospital
• Collaborators: National Institute of Mental Health (NIMH); Massachusetts General Hospital; Brown University; Massachusetts Institute of Technology; University of Washington
• Investigators: Principal Investigator: Diego Pizzagalli, Ph.D., McLean Hospital

Study record dates

Study Major Dates

• Study Start (Estimated): April 1, 2024
• Primary Completion (Estimated): March 31, 2025
• Study Completion (Estimated): March 31, 2025

Study Registration Dates

• First Submitted: February 1, 2022
• First Submitted That Met QC Criteria: February 1, 2022
• First Posted (Actual): February 9, 2022

Study Record Updates

• Last Update Posted (Actual): March 13, 2024
• Last Update Submitted That Met QC Criteria: March 11, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Mood Disorders; Depressive Disorder; Anxiety Disorders; Depressive Disorder, Major; Physiological Effects of Drugs; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Opioid; Narcotics; Nocistatin
• Other Study ID Numbers: 5P50MH119467-02 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Through the Conte Center website, we will share de-identified data and tools with the scientific community (e.g., code developed by the Computational Modeling Core). In close collaboration with NIMH, we will develop a certification similar to the "NIMH Data Archive Data Use Certification" currently used by NIMH.

Through the National Database for Clinical Trials Related to Mental Illness, we will share five principal human datasets generated within the Conte Center: (1) Clinical rating scales and self-report scales of affect, mood, symptoms and functioning; (2) Behavioral performance during approach-avoidance tasks; (3) Electrophysiological data; (4) Functional magnetic resonance imaging data; and (5) Hormonal (cortisol) responses.

Through ClinicalTrials.gov, we will share the primary and secondary outcomes.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No