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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Major Depressive Disorder

Intervention / Treatment
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* Device: Aversive stimuli
* Drug: PET radiotracer


Participation Criteria
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Eligibility Criteria
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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).

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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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| MDD subjects<br>Subjects diagnosed with Major Depression Disorder | Device: Aversive stimuli<br>* 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).<br>Drug: PET radiotracer<br>* 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.<br>|
| Remitted MDD subjects<br>Subjects with a history of major depressive disorder episode in the past | Device: Aversive stimuli<br>* 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).<br>Drug: PET radiotracer<br>* 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.<br>|
| Control subjects<br>Subjects with no history of known neurological and psychiatric illness. | Device: Aversive stimuli<br>* 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).<br>Drug: PET radiotracer<br>* 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.<br>|

What is the study measuring?
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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 |