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

Mclean Hospital

Overview

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

BASIC_SCIENCE

Masking

TRIPLE

Conditions

Depression - Major Depressive Disorder Anxiety Stress

Interventions

Nociceptin Receptor Antagonist (LY-2940094)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 StimulatorDEVICE

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.

Eligibility

Sex: ALLMin age: 18 YearsHealthy volunteers:

Medical Language ↔ Plain English

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

Outcomes

Primary Outcomes

Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) (SCID-5)

The Structured Clinical Interview for DSM-5 (SCID-5) is a clinician-administered diagnostic tool used to assess and diagnose mental disorders based on DSM-5 criteria. The SCID-5 categorically identifies the presence or absence of specific diagnoses and does not provide numerical minimum/maximum values.

Time frame: Baseline

Childhood Trauma Questionnaire (CTQ)

The Childhood Trauma Questionnaire (CTQ) is a self-report tool assessing childhood emotional abuse, physical abuse, sexual abuse, emotional neglect, and physical neglect. Scores on each subscale range from 5 to 25, with a total score ranging from 25 to 125; higher scores indicate greater severity of childhood trauma.

Time frame: Baseline

List of Threatening Experiences Questionnaire (LTE)

The List of Threatening Experiences Questionnaire (LTE) is a self-report measure assessing the occurrence of stressful life events, such as bereavement, illness, or job loss, over a specified period. Scores range from 0 to 12, representing the number of endorsed events, with higher scores indicating a greater number of stressful experiences.

Time frame: Baseline

Combined Cue-Context Fear Conditioning Task: Subjective Fear Ratings

The combined cue-context fear conditioning task is a paradigm to assess fear learning and extinction in response to discrete cues as well as different contexts. Subjective ratings of fear are collected via visual analog scales throughout the task. Higher ratings mean higher expression of fear towards cues and contexts (min-max: 0-100).

Time frame: Baseline

Probabilistic Reward Task (PRT)

The Probabilistic Reward Task (PRT) is a behavioral measure assessing reward sensitivity and reinforcement learning. It evaluates participants' ability to modulate behavior based on probabilistic feedback associated with correct responses. The primary outcome is the response bias score, which ranges from negative values to positive values. Higher scores indicate a stronger bias toward the more frequently rewarded response, reflecting greater reward sensitivity and reinforcement learning. Lower or negative scores suggest impaired reward responsiveness, which is often associated with anhedonia or mood disorders.

Data from ClinicalTrials.gov

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