Beyond Monoamines: The Role of the Nociceptin/Orphanin FQ Receptor in Major Depression

This study looks at the role of the Nociceptin/Orphanin FQ receptor system in the brain of individuals with current or past major depressive disorder (MDD). It also examines how individuals with a history of depression make certain decisions and which brain regions are involved in such decisions. Information collected through MRI, PET, biospecimens (i.e., blood, saliva) and behavioral tasks will be used to predict depressive symptoms in the future.

Study Overview

• Status: Recruiting
• Conditions: Major Depressive Disorder
• Intervention / Treatment: Device: Aversive stimuli; Drug: PET radiotracer

Detailed Description

The overarching goals of this research are to investigate: (1) the activity of the Nociceptin/Orphanin FQ receptor system among individuals with current or remitted MDD; (2) neural foundations of approach/avoidance behaviors in current or remitted MDDs; (3) stress-induced inflammation in individuals with remitted MDD; (4) neural markers that predict future disease course.

This will be achieved through an innovative method of using functional magnetic resonance imaging (fMRI) during an approach/avoidance decision-making task, in addition to a resting positron emission tomography (PET) scan.

• Study Type: Observational
• Enrollment (Estimated): 228

Contacts and Locations

• Study Contact: Name: David Crowley, ALM; Phone Number: 617-855-4432; Email: djcrowley@mclean.harvard.edu
• Study Contact Backup: Name: Claire Anderson, BA; Phone Number: 617-855-4290; Email: canderson1@mclean.harvard.edu

Study Locations

• United States
  • Massachusetts
    • Belmont, Massachusetts, United States, 02478
      • Recruiting
      • McLean Hospital
      • Contact: Claire Anderson, BA; Phone Number: 617-855-4290; Email: canderson1@mclean.harvard.edu

Participation Criteria

Eligibility Criteria

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

• Sampling Method: Non-Probability Sample

Study Population

The subjects for this research will be 228 participants recruited from the community by the Center for Depression, Anxiety and Stress Research (Director: Dr. Diego Pizzagalli, Ph.D.). Demographically-matched participants will include: (1) 38 participants with current MDD; (2) 38 participants with past MDD; and (3) 38 healthy controls.

Description

Inclusion Criteria for all participants:

• All genders, races, and ethnic origins, aged between 18 and 45
• Capable of providing written informed consent, and fluent in English
• Right-handed
• Absence of any psychotropic medications for at least 2 weeks
• Has a smartphone (iPhone or Android) (needed for Ecological Momentary Assessment)

Inclusion Criteria for "Remitted MDD" group:

• Meets inclusion criteria for all subjects, plus:
• History of MDD as defined by DSM-5
• Absence of anxiety disorder for the past two months

Inclusion Criteria for "Current MDD" group:

• Meets inclusion criteria for all subjects, plus:
• Presence of MDD as defined by DSM-5
• Absence of anxiety disorder for the past two months

Exclusion Criteria for all participants:

• Subjects with suicidal ideation where outpatient treatment is determined unsafe by the study clinician. These patients will be immediately referred to appropriate clinical treatment
• Pregnant women or women of childbearing potential who are not using a medically accepted means of contraception (defined as oral contraceptive pill or implant, condom, diaphragm, spermicide, IUD, s/p tubal ligation, or partner with vasectomy)
• Serious or unstable medical illness, including cardiovascular, hepatic, renal, respiratory, endocrine, neurologic or hematologic disease
• History of seizure disorder
• History of psychiatric illnesses, other than depression or anxiety disorders among the Current MDD and Remitted MDD groups
• History of substance use disorder or alcohol use disorder (as these terms are defined by DSM-5); except depressed subjects may have a history of 'Mild' substance/alcohol use disorder only if it ended as least 12 months ago
• History of cocaine or stimulant use or dopaminergic drugs
• History or current diagnosis of dementia, or a score of < 26 on the Mini Mental State Examination at the screening visit;
• 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 (ECT)
• Failure to meet standard MRI safety requirements
• Abnormal ECG and lab results
• History of seizure disorder
• Contraindications for arterial line (e.g., abnormal result on Allen test, Raynaud's syndrome, history of anemia or bleeding disorder, history of fainting from blood draws).

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Prospective

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
MDD subjects; Subjects diagnosed with Major Depression Disorder	Device: Aversive stimuli; Electrotactile stimulation will be used as the aversive stimulus. 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 with previously MGH-approved IRB's (Milad et al., 2013).; Drug: PET radiotracer; A Nociceptin/Orphanin FQ ("N/OFQ") peptide tracer ([11C] NOP-1A) will be used as the PET radiotracer. Approximately 10 mCi of this tracer will be delivered intravenously as a slow bolus over 60 seconds with beginning of the PET imaging acquisition. Approximately 60 ml of blood will be drawn from an artery throughout the dynamic PET acquisition in order to measure the blood N/OFQ levels.
Remitted MDD subjects; Subjects with a history of major depressive disorder episode in the past	Device: Aversive stimuli; Electrotactile stimulation will be used as the aversive stimulus. 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 with previously MGH-approved IRB's (Milad et al., 2013).; Drug: PET radiotracer; A Nociceptin/Orphanin FQ ("N/OFQ") peptide tracer ([11C] NOP-1A) will be used as the PET radiotracer. Approximately 10 mCi of this tracer will be delivered intravenously as a slow bolus over 60 seconds with beginning of the PET imaging acquisition. Approximately 60 ml of blood will be drawn from an artery throughout the dynamic PET acquisition in order to measure the blood N/OFQ levels.
Control subjects; Subjects with no history of known neurological and psychiatric illness.	Device: Aversive stimuli; Electrotactile stimulation will be used as the aversive stimulus. 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 with previously MGH-approved IRB's (Milad et al., 2013).; Drug: PET radiotracer; A Nociceptin/Orphanin FQ ("N/OFQ") peptide tracer ([11C] NOP-1A) will be used as the PET radiotracer. Approximately 10 mCi of this tracer will be delivered intravenously as a slow bolus over 60 seconds with beginning of the PET imaging acquisition. Approximately 60 ml of blood will be drawn from an artery throughout the dynamic PET acquisition in order to measure the blood N/OFQ levels.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical Interview	For assessing psychological state	Baseline
Behavioral Performance on the Probabilistic Reward Task (PRT)	the PRT assesses individuals' ability to learn from rewards	Baseline
MRI Data	For testing the neural correlates of approach-avoidance decision making behaviors	within 30 days of Screening Visit
Salivary Cortisol	For assessing stress level	Baseline
PET Data	For assessing the Nociceptin/Oprhanin FQ receptor system activity	within 30 days of Screening Visit
Arterial blood data	for PET modeling and assessing Nociceptin/Orphanin FQ levels in bloodstream	Baseline
Follow-up Clinical Interviews	To assess psychological state changes	Change from Baseline at 6 months and 12 months after the PET visit

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Beck Depression Inventory-II (BDI)	self-report measure of depressive symptoms	Change from Baseline at 6 months and 12 months after the PET visit
Childhood Trauma Questionnaire (CTQ)	self-report measure of childhood trauma	Baseline
Medical Outcome Survey-Short form (SF-36)	self-report with subscales measuring physical functioning, physical role functioning, social functioning, etc.	Change from Baseline at 6 months and 12 months after the PET visit
Perceived Stress Scale (PSS)	self-report measure of stress levels	Change from Baseline at 6 months and 12 months after the PET visit
Positive and Negative Affect Schedule (PANAS)	self-report measure of positive and negative affect	Baseline
Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q)	self-report measure of satisfaction and enjoyment across domains (e.g., work, leisure, social relations)	Change from Baseline at 6 months and 12 months after the PET visit
Snaith Hamilton Pleasure Scale (SHAPS)	self-report measure of pleasure	Change from Baseline at 6 months and 12 months after the PET visit
Thought and Feeling Questionnaire (TFQ)	self-report measure of perception of being stuck in difficult situations	Baseline
Defeat Scale (DS)	self-report measure of perception of defeat	Baseline
Questionnaire of Unpredictability in Childhood (QUIC)	self-report measure of unpredictability of parental environment growing up	Change from Baseline at 6 months and 12 months after the PET visit
Mood and Anxiety Symptom Questionnaire (MASQ)	self-report measure of mood symptom severity including 4 subscales related to depression and anxiety	Baseline
State-Trait Anxiety Inventory (STAI)	Measures and differentiates between anxiety	Baseline
PRT Post-task Questionnaire	self-report measure of participants' thoughts regarding the PRT task stimuli	Baseline
Temporal Experience of Pleasure Scale (TEPS)	self-report measure of ability to want and enjoy rewards	Change from Baseline at 6 months and 12 months after the PET visit
Columbia-Suicide Severity Rating Scale (C-SSRS)	clinical measure of suicidality	Baseline
Hamilton-Depression Rating Scale (HAMD-17)	clinical measure of depression severity	Change from Baseline at 6 months and 12 months after the PET visit
Quick Inventory of Depressive Symptomatology (QIDS)	clinical measure of depression severity	Change from Baseline at 6 months and 12 months after the PET visit
Cognitive-Behavioral Avoidance Scale (CBAS)	self-report measure of trait avoidance	Baseline
Stress and Adversity Inventory (STRAIN)	self-report measure of lifetime exposure to acute and chronic stress that may affect mental and physical health	Change from Baseline at 12 months after the PET visit

Collaborators and Investigators

• Sponsor: Mclean Hospital
• Collaborators: National Institute of Mental Health (NIMH)
• Investigators: Principal Investigator: Diego Pizzagalli, PhD, McLean Hospital

Study record dates

Study Major Dates

• Study Start (Actual): December 29, 2021
• Primary Completion (Estimated): October 28, 2026
• Study Completion (Estimated): February 28, 2027

Study Registration Dates

• First Submitted: November 16, 2022
• First Submitted That Met QC Criteria: November 18, 2022
• First Posted (Actual): November 30, 2022

Study Record Updates

• Last Update Posted (Estimated): January 11, 2024
• Last Update Submitted That Met QC Criteria: January 9, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Mood Disorders; Depressive Disorder; Depressive Disorder, Major
• Other Study ID Numbers: 2018P000318; 4R37MH068376-17 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

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

Drug and device information, study documents

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