Dextromethorphan-Bupropion on Striatal Activity in Adults With Major Depressive Disorder

NCT07523048 | Recruiting Phase 2 FDA Drug

• 1 other identifier: BCDF004
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

This study will look at how a new medication (dextromethorphan and bupropion taken together in one pill) affects the brain in people with depression. All participants will take the medication for two weeks and have brain scans done. Since people with depression often feel reduced enjoyment in day-to-day activities, our goal is to learn if this treatment can change brain activities in ways that could help improve mood and enjoyment in life.

Conditions

Major Depressive Disorder (MDD)

Keywords

Major Depressive Disorder; Neuroimaging; Striatal Reactivity; Reward; Cognition; Dextromethorphan HBr/Bupropion HCl

Outcome Measures

Primary Outcomes (1)

• Change in Striatal BOLD Signal During Reward Processing

  Change from baseline (Day 1) to endpoint (Day 14) in task-evoked blood oxygen level-dependent (BOLD) signal within striatal regions of interest during the Effort Expenditure for Rewards Task (EEfRT), as measured by functional magnetic resonance imaging (fMRI).

  Baseline (Day 1) to endpoint (Day 14)

Secondary Outcomes (23)

• Change in Effort-Based Decision-Making During Reward Task

  Baseline (Day 1) to endpoint (Day 14)

• Change in Anhedonia as Measured by the Snaith-Hamilton Pleasure Scale (SHAPS)

  Baseline (Day 1) to endpoint (Day 14).

• Change in Anhedonia as Measured by the Dimensional Anhedonia Rating Scale (DARS)

  Baseline (Day 1) to endpoint (Day 14)

• Change in Anhedonia as Measured by the Montgomery-Åsberg Depression Rating Scale - Anhedonia Factor (MADRS-AF)

  Baseline (Day 1) to endpoint (Day 14)

• Change in Processing Speed as Measured by Trail Making Test Part A (TMT-A)

  Baseline (Day 1) to endpoint (Day 14)

Other Outcomes (1)

• Change in Insulin Resistance as Measured by Homeostasis Model Assessment of Insulin Resistance (HOMA-IR)

  Baseline (Day 1) to endpoint (Day 14)

Study Arms (1)

Single group, open-label treatment arm

EXPERIMENTAL

All participants who meet eligibility criteria and provide informed consent will be assigned to receive daily oral dextromethorphan-bupropion (DXM/BUP) extended release tablets in an open-label manner for a 14-day treatment period. No randomization or masking will be applied, and all participants and researchers will be aware of the study treatment allocation.

Drug: Dextromethorphan-Bupropion

Interventions

Dextromethorphan-Bupropion DRUG

The generic name of the study drug is dextromethorphan-bupropion (150 mg), which is an oral, extended-release tablet comprised of 45 mg dextromethorphan HBr and 105 mg bupropion HCl. The brand name of this study drug is Auvelity. Eligible participants that provide written informed consent will be assigned to a single-arm, open-label treatment group, for a treatment period of 14 days. Participants in this treatment group will be asked to take one oral dextromethorphan-bupropion extended-release tablet once daily for Days 1-3 of the treatment period. Participants will then be asked to increase their dose to one oral dextromethorphan-bupropion extended-release tablet twice daily, for Days 4-14 of the treatment period.

Also known as: Auvelity, DXM-BUP, AXS-05

Single group, open-label treatment arm

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Capable of providing voluntary, written, informed consent prior to study enrollment.
• Male or female between the age of 18 to 65 years, inclusive.
• Meets DSM-5-TR criteria for a Major Depressive Disorder and currently experiencing a Major Depressive Episode (MDE) without psychotic features. Diagnosis will be confirmed using the Mini-International Neuropsychiatric Interview (MINI) conducted by a delegated physician or trained research study staff.
• Must present with a current MDE with moderate to severe intensity, as determined by the Montgomery-Åsberg Depression Rating Scale (MADRS) total score equal to or greater than 21 and Clinical Global Impression Scale-Severity (CGI-S) total score equal to or greater than 4.
• Lifetime history of less than five prior adequate trials of a pharmacologic treatment for depression.
• Deemed safe and eligible by the study doctor, study investigator, trained research staff and/or fMRI technicians/trained staff to participate in fMRI scans according to intake screening form and (if applicable) related medical documentation (e.g., doctor notes, medical charts documenting medical/dental implants, pacemakers).
• Access to reliable internet for the entire study period and an internet-based device (i.e., a smartphone, laptop, desktop or tablet).
• Must have the ability to speak and read English. This is due to the diagnostic and study assessments being administered in English.

You may not qualify if:

• Currently has symptoms of mania or hypomania or mixed state bipolar disorder, as determined by the Young Mania Rating Scale (YMRS) score greater than 12.
• Current symptoms of psychosis or a substance use disorder within the past 12 months. Other select secondary psychiatric comorbidities (e.g. anxiety disorders, trauma-related disorders) will not be excluded according to the clinical judgment of an investigator.
• Lifetime history of a primary psychotic disorder (including, but not limited to, schizophrenia or schizoaffective disorder).
• Failure of five or more prior trials of pharmacological treatment for depression.
• Lifetime history of failure of electroconvulsive therapy (ECT) or repetitive transcranial magnetic stimulation (rTMS).
• Lifetime history of treatment with intravenous racemic ketamine and/or intranasal esketamine for depression.
• History of non-response to a prior trial of dextromethorphan-bupropion
• Hypersensitive to bupropion in any formulation
• Duration of current MDE greater than 2 years
• Recreational cannabis use daily, weekly or cannabis use disorder.
• History of neurological disorders (including, but not limited to, uncontrolled seizure disorder, history of stroke within past 12 months, major head injuries, aneurysmal vascular disease \[including thoracic and abdominal aorta, intracranial, and peripheral arterial vessels\], arteriovenous malformation, or intracerebral hemorrhage).
• Are actively suicidal (e.g., any suicide attempts within the past 12 months) or are at serious suicidal risk as indicated by any current suicidal intent, including a plan, as assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS) (score of "YES" on suicidal ideation Item 4 or 5 within 3 months prior to Visit 1 \[Screening\]) and/or based on clinical evaluation by the Investigator; or are homicidal, in the opinion of the Investigator. Participants who are currently hospitalized for MDD symptoms or suicidality are not allowed into the study.
• Pregnant or breastfeeding women or women who intend to become pregnant in the next 6 months. Patients who are sexually active must agree to use a highly effective contraceptive method (as outlined in section 9.7).
• Current or history of severe hepatic or renal impairment.
• Use of prohibited concomitant medications \[e.g., antidepressants, monoamine oxidase inhibitors (MAOIs), CYP2B6 or CYP2D6 inhibitors\]. See section 9 for details on contraindications, side effects, prohibited concomitant medication, warnings and precautions with the investigational agent.

Sponsors & Collaborators

• Roger McIntyre: lead
• Axsome Therapeutics, Inc.: collaborator

Study Sites (1)

Brain and Cognition Discovery Foundation

Toronto, Ontario, M5S1M2, Canada

RECRUITING

MeSH Terms

Conditions

Depressive Disorder, Major

Condition Hierarchy (Ancestors)

Depressive Disorder; Mood Disorders; Mental Disorders

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: OTHER
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Principal Investigator

Model Details: This is a pilot, open-label, mechanistic, neuroimaging study evaluating the effects of a rapid-acting antidepressant, dextromethorphan-bupropion, on brain activity in adults with major depressive disorder (MDD). Dextromethorphan-bupropion is a rapid-acting antidepressant for persons with MDD, with modulatory effects on glutamatergic-signalling. The primary objective of the study is to investigate changes in brain activity in the striatum, an area involved in reward processing, while participants complete a validated reward task. Changes in striatal activity will be measured using functional magnetic resonance imaging (fMRI) at baseline (pre-treatment) and at Day 14 (post-treatment). Findings will provide new data on the neurobiological mechanisms underlying treatment response and aims to inform the design of future studies.

Study Record Dates

• First Submitted: December 8, 2025
• First Posted: April 13, 2026
• Study Start: November 21, 2025
• Primary Completion (Estimated): July 1, 2026
• Study Completion (Estimated): January 1, 2027
• Last Updated: April 13, 2026

Record last verified: 2025-12

Data Sharing

• IPD Sharing: Will not share

Locations

CA (1)