Recruiting
Phase 2

Nociceptin Receptor Antagonist

Sponsor:

Mclean Hospital

Code:

NCT05232032

Conditions

Depressive Disorder, Major

Anxiety Disorder

Eligibility Criteria

Sex: All

Age: 18 - 45

Healthy Volunteers: Accepted

Interventions

Nociceptin Receptor Antagonist

Aversive stimuli

Study Details

Brief summary:

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).

Conditions

Depressive Disorder, Major

Anxiety Disorder

Study ID

NCT05232032

Start date

Feb 1, 2025

Status verified date

May, 2026

Completion date

Mar 31, 2027

Anticipated

Primary completion date

Mar 31, 2027

Anticipated

Eligibility Criteria

Eligibility Criteria

Sex: All

Age: 18 - 45

Healthy Volunteers: Accepted

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 Design

Enrollment

112 participants

Anticipated

Allocation

Randomized

Intervention Model

Parallel Assignment

Primary purpose

Basic Science

Interventions and Outcome Measures

Arms

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.

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.

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.

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.

Interventions

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.

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).

Primary outcome measure

  • Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) (SCID-5) [ Time Frame: Baseline ]
  • Magnetic Resonance Imagining [ Time Frame: Within 30 days of the clinical interview ]
  • Approach/Avoidance Task [ Time Frame: During the MRI scan ]
  • Orphanin FQ/Nociceptin assays (using blood samples) [ Time Frame: On the day of the MRI scan ]

Central Contacts and Locations

Central contacts

Ethan M Zhang, BA

617-855-4434ezhang24@mclean.harvard.edu

David Crowley, ALM

617-855-4432djcrowley@mclean.harvard.edu

Locations

Mclean Hospital

Recruiting

Belmont, Massachusetts, United States, 02478

Contacts

Ethan Zhang, BA

617-855-4434ezhang24@mclean.harvard.edu

David Crowley, ALM

djcrowley@mclean.harvard.edu

More Information

Sponsor

Mclean Hospital

Last update posted

May 18, 2026

Last verified

May, 2026

Trial information was received from ClinicalTrials.gov and was last updated on 2026-09-10. This information was provided to ClinicalTrials.gov by Mclean Hospital on 2026-05-18.