Investigating the Protective Impact of LY-2940094 on Stress-induced Depression- and Anxiety-related Phenotypes in Humans

NCT ID: NCT06786637

Last Updated: 2025-09-25

Basic Information

• Recruitment Status: WITHDRAWN
• Clinical Phase: PHASE2
• Study Classification: INTERVENTIONAL
• Study Start Date: 2025-06-30
• Study Completion Date: 2026-08-31

Brief Summary

This project will integrate pharmacological and psychophysiological methodology to mechanistically investigate, in humans, the role of N/OFQ in laboratory phenotypes of both disorders. Specifically, a N/OFQ receptor (NOPR) antagonist will be used to test the hypothesis that NOPR blockage will have antidepressant-like effects (potentiate reward processing); in addition, this study will also evaluate a key anxiety phenotype (fear learning). Finally, the impact of recent life stress on these processes will be assessed. Results will demonstrate the specificity of NOPR blockage on depressive phenotypes or suggest a common pathway for emotional disorders and will confirm a modulatory role of life stress.

Conditions

Depression - Major Depressive Disorder; Anxiety; Stress

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: TRIPLE

Study Groups

Participants receiving the nociceptin receptor antagonist

After a diagnostic interview during the first visit, participants will receive the nociceptin receptor antagonist (LY-2940094) at the beginning of the second visit. Participants will then complete two computerized tasks (the Probabilistic Rewards Task (PRT) and a context fear conditioning paradigm). Tasks will begin 2 hours after the nociceptin receptor antagonist is administered.

Group Type: EXPERIMENTAL

Nociceptin Receptor Antagonist (LY-2940094)

Intervention Type: DRUG

Participants in the experimental arms will receive 40 mg of the nociceptin receptor antagonist LY-2940094. Peak concentrations are achieved 2-4 hours post-administration.

DS8R Biphasic Constant Current Stimulator

Intervention Type: DEVICE

As part of the fear conditioning 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). This model has been safely implemented in studies within McLean Hospital and Massachusetts General Hospital.

Participants receiving the placebo

After a diagnostic interview during the first visit, participants will receive the placebo at the beginning of the second visit. Participants will then complete two computerized tasks (the Probabilistic Rewards Task (PRT) and a context fear conditioning paradigm). Tasks will begin 2 hours after the placebo is administered.

Group Type: PLACEBO_COMPARATOR

DS8R Biphasic Constant Current Stimulator

Intervention Type: DEVICE

As part of the fear conditioning 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). This model has been safely implemented in studies within McLean Hospital and Massachusetts General Hospital.

Interventions

Nociceptin Receptor Antagonist (LY-2940094)

Participants in the experimental arms will receive 40 mg of the nociceptin receptor antagonist LY-2940094. Peak concentrations are achieved 2-4 hours post-administration.

Intervention Type: DRUG

DS8R Biphasic Constant Current Stimulator

As part of the fear conditioning 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). This model has been safely implemented in studies within McLean Hospital and Massachusetts General Hospital.

Intervention Type: DEVICE

Other Intervention Names

Nociceptin Receptor Antagonist (BTRX-246040); Nociceptin Receptor Antagonist (C220614004-FP)

Eligibility Criteria

Inclusion Criteria

• 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
• Absence of any medications for at least 3 weeks

Exclusion Criteria

• 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
• Abnormal ECG and lab results
• History of seizure disorder or currently on anticonvulsants

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

National Institute of Mental Health (NIMH)

NIH

Sponsor Role: collaborator

Mclean Hospital

OTHER

Sponsor Role: lead

Responsible Party

Manuel Kuhn

Instructor, Department of Psychiatry, Harvard Medical School, McLean Hospital, McLean Hospital

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Manuel Kuhn, Ph.D.

Role: PRINCIPAL_INVESTIGATOR

Mclean Hospital

Other Identifiers

5P50MH119467-05

Identifier Type: NIH

Identifier Source: secondary_id

View Link

2023A062574

Identifier Type: -

Identifier Source: org_study_id