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NCT Number: NCT07523048

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

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.

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Key information

Conditions

Major Depressive Disorder (MDD) Depressive Disorder Depressive Disorder, Major Mental Disorders Mood Disorders

Age range

18 year–65 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2

Primary location

Brain and Cognition Discovery Foundation

Toronto, Ontario, M5S1M2, Canada

Location status: Recruiting

Location contact

Roger S. McIntyre, MD, FRCPC

CONTACT

[email protected]

416-669-5279

Roger S. McIntyre, MD, FRCPC

PRINCIPAL_INVESTIGATOR

About this study

Dextromethorphan-bupropion (DXM/BUP) is a novel, rapid-acting, glutamatergic antidepressant approved by the US FDA in the treatment of adults with MDD, with clinical evidence of antidepressant effect within two weeks of administration. This pilot, two-week, open-label neuroimaging study will examine the effect of DXM/BUP on striatal activity in adults with major depressive disorder (MDD). The region of interest is the striatum, a core structure in the human reward circuit. Adults with a primary diagnosis of MDD currently experiencing a moderate-severe major depressive episode will receive open-label DXM/BUP (150 mg orally, twice daily) for 14 days. Task-based functional MRI scans will be conducted at baseline (Day 1, prior to treatment) and at primary endpoint (Day 14, following treatment) to evaluate changes in striatal activation. During each scan, participants will perform the Effort Expenditure for Rewards Task (EEfRT), a validated measure of reward motivation and effort-based decision-making that is particularly sensitive to anhedonia. Changes in striatal activation associated with open-label DXM/BUP treatment in adults with MDD will be evaluated by comparing pre-treatment and post-treatment fMRI blood-oxygenation level-dependent (BOLD) measures.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • 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.
  • Note: there is no inclusion/exclusion based on prior history of manual-based psychotherapy (e.g., cognitive behavioural therapy).

Exclusion criteria

  • 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.
  • Any medical or psychiatric history that may exclusionary for fMRI scanning, including but not limited to:
  • Cardiac pacemaker
  • Surgical aneurysm clips
  • Neurostimulator
  • Implanted pumps
  • Metal fragments in body/eyes
  • Pregnancy
  • Nitroglycerin patch
  • Certain cochlear implants
  • Weight> 440 lbs
  • Presence of any contraindications for dextromethorphan-bupropion (DXM/BUP):
  • Seizure: Do not use DXM/BUP in patients with a seizure disorder.
  • Current or prior diagnosis of bulimia or anorexia nervosa: A higher incidence of seizure was observed in such patients treated with bupropion.
  • Undergoing abrupt discontinuation of alcohol, benzodiazepines, barbiturates, and antiepileptic drugs: Due to risk of seizure.
  • Monoamine Oxidase Inhibitors (MAOIs): Do not use DXM/BUP concomitantly with, or within 14 days of stopping, an MAOI due to the risk of serious and possibly fatal drug interactions, including hypertensive crisis and serotonin syndrome. Conversely, at least 14 days must be allowed after stopping DXM/BUP before starting an MAOI antidepressant. Do not use DXM/BUP with reversible MAOIs such as linezolid or intravenous methylene blue.
  • Hypersensitivity: Do not use in patients with known hypersensitivity to dextromethorphan, bupropion, or any component of DXM/BUP.

Anaphylactoid/anaphylactic reactions and Stevens-Johnson syndrome have been reported with bupropion. Arthralgia, myalgia, fever with rash, and other serum sickness-like symptoms suggestive of delayed hypersensitivity have also been reported with bupropion.

Treatment and study plan

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.

Other names: Auvelity, DXM-BUP, AXS-05

Primary outcomes

  1. Change in Striatal BOLD Signal During Reward Processing

    Time frame: Baseline (Day 1) to endpoint (Day 14)

    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).

Secondary outcomes

  1. Change in Effort-Based Decision-Making During Reward Task

    Time frame: Baseline (Day 1) to endpoint (Day 14)

    Change from baseline (Day 1) to endpoint (Day 14) in effort-based decision-making as measured by the proportion of hard-task choices selected during the Effort Expenditure for Rewards Task (EEfRT), with higher values indicating greater willingness to exert effort for reward.

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

    Time frame: Baseline (Day 1) to endpoint (Day 14).

    Change from baseline (Day 1) to endpoint (Day 14) in anhedonia severity as measured by the Snaith-Hamilton Pleasure Scale (SHAPS), a 14-item self-report scale in which each item is rated on a 4-point Likert scale (1 = strongly agree to 4 = strongly disagree). Total scores range from 14 to 56, with higher scores indicating greater anhedonia.

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

    Time frame: Baseline (Day 1) to endpoint (Day 14)

    Change from baseline (Day 1) to endpoint (Day 14) in anhedonia severity as measured by the Dimensional Anhedonia Rating Scale (DARS), a self-report scale assessing interest and pleasure across multiple domains, with scores ranging from 0 to 68, where higher scores indicate greater hedonic capacity (i.e., lower anhedonia).

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

    Time frame: Baseline (Day 1) to endpoint (Day 14)

    Change from baseline (Day 1) to endpoint (Day 14) in anhedonia severity as measured by the Montgomery-Åsberg Depression Rating Scale - Anhedonia Factor (MADRS-AF), a clinician-rated subscale derived from the MADRS consisting of 5 items, each scored from 0 to 6, with total scores on this subscale ranging from 0 to 30, where higher scores indicate greater anhedonia.

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

    Time frame: Baseline (Day 1) to endpoint (Day 14)

    Change from baseline (Day 1) to endpoint (Day 14) in processing speed as measured by completion time on the Trail Making Test Part A (TMT-A), where shorter completion times (in seconds) indicate better performance.

  6. Change in Executive Function as Measured by Trail Making Test Part B (TMT-B)

    Time frame: Baseline (Day 1) to endpoint (Day 14)

    Change from baseline (Day 1) to endpoint (Day 14) in executive function as measured by completion time on the Trail Making Test Part B (TMT-B), where shorter completion times (in seconds) indicate better performance.

  7. Change in Processing Speed as Measured by the Wechsler Adult Intelligence Scale (WAIS) Symbol Search Subtest

    Time frame: Baseline (Day 1) to endpoint (Day 14)

    Change from baseline (Day 1) to endpoint (Day 14) in processing speed as measured by the Symbol Search subtest of the Wechsler Adult Intelligence Scale (WAIS), a timed task in which participants identify target symbols within a fixed time period. Scores reflect the number of correct responses achieved within 2 minutes, with total scores ranging from 0 to 60, and higher scores indicating better performance.

  8. Change in Cognitive Performance as Measured by the Digit Symbol Substitution Test (DSST)

    Time frame: Baseline (Day 1) to endpoint (Day 14)

    Change from baseline (Day 1) to endpoint (Day 14) in cognitive performance as measured by the Digit Symbol Substitution Test (DSST), a timed test of processing speed in which participants match symbols to numbers according to a key. Raw scores reflect the number of correct symbol-digit pairings completed within a fixed time period (120 seconds), with higher scores indicating better performance.

  9. Change in Depressive Symptom Severity as Measured by the Montgomery-Åsberg Depression Rating Scale (MADRS)

    Time frame: Baseline (Day 1) to endpoint (Day 14)

    Change from baseline (Day 1) to endpoint (Day 14) in depressive symptom severity as measured by the Montgomery-Åsberg Depression Rating Scale (MADRS), a clinician-rated scale with total scores ranging from 0 to 60, where higher scores indicate greater depression severity.

  10. Change in Depressive Symptom Severity as Measured by the Quick Inventory of Depressive Symptomatology - Self Report (QIDS-SR-16)

    Time frame: Baseline (Day 1) to endpoint (Day 14)

    Change from baseline (Day 1) to endpoint (Day 14) in depressive symptom severity as measured by the Quick Inventory of Depressive Symptomatology - Self Report (QIDS-SR-16), a 16-item self-report scale with total scores ranging from 0 to 27, where higher scores indicate greater depression severity.

  11. Change in Depressive Symptom Severity as Measured by the Patient Health Questionnaire-9 (PHQ-9)

    Time frame: Baseline (Day 1) to endpoint (Day 14)

    Change from baseline (Day 1) to endpoint (Day 14) in depressive symptom severity as measured by the Patient Health Questionnaire-9 (PHQ-9), a 9-item self-report scale with total scores ranging from 0 to 27, where higher scores indicate greater depression severity.

  12. Change in Depressive Symptom Severity as Measured by the Patient Global Impression of Severity (PGI-S)

    Time frame: Baseline (Day 1) to endpoint (Day 14)

    Change from baseline (Day 1) to endpoint (Day 14) in depressive symptom severity as measured by the Patient Global Impression of Severity (PGI-S), a single-item self-report scale ranging from 1 (normal, not at all ill) to 7 (among the most extremely ill patients), where higher scores indicate greater illness severity.

  13. Change in Anxiety Symptom Severity as Measured by the Generalized Anxiety Disorder-7 (GAD-7)

    Time frame: Baseline (Day 1) to endpoint (Day 14)

    Change from baseline (Day 1) to endpoint (Day 14) in anxiety symptom severity as measured by the Generalized Anxiety Disorder-7 (GAD-7), a 7-item self-report scale with total scores ranging from 0 to 21, where higher scores indicate greater anxiety severity.

  14. Change in Functional Impairment as Measured by the Sheehan Disability Scale (SDS)

    Time frame: Baseline (Day 1) to endpoint (Day 14)

    Change from baseline (Day 1) to endpoint (Day 14) in functional impairment as measured by the Sheehan Disability Scale (SDS), a 3-item self-report scale assessing impairment in work/school, social life, and family life, with each item scored from 0 to 10 and total scores ranging from 0 to 30, where higher scores indicate greater functional impairment.

  15. Change in Well-Being as Measured by the World Health Organization Well-Being Index (WHO-5)

    Time frame: Baseline (Day 1) to endpoint (Day 14)

    Change from baseline (Day 1) to endpoint (Day 14) in subjective well-being as measured by the World Health Organization Well-Being Index (WHO-5), a 5-item self-report scale with raw scores ranging from 0 to 25, where higher scores indicate greater well-being.

  16. Change in Emotional Blunting as Measured by the Oxford Depression Questionnaire (ODQ)

    Time frame: Baseline (Day 1) to endpoint (Day 14)

    Change from baseline (Day 1) to endpoint (Day 14) in emotional blunting as measured by the Oxford Depression Questionnaire (ODQ-26), a 26-item self-report scale with each item rated on a 5-point Likert scale (1 = disagree to 5 = agree). Total scores range from 26 to 130, with higher scores indicating greater emotional blunting.

  17. Change in Implicit Associations Related to Depression as Measured by the Implicit Association Test, Depression Version (IAT-D)

    Time frame: Baseline (Day 1) to endpoint (Day 14)

    Change from baseline (Day 1) to endpoint (Day 14) in implicit associations related to depression as measured by the Implicit Association Test (IAT; depression version). Scores are reported as a D-score, a continuous standardized measure of the difference in reaction times between congruent and incongruent conditions, with positive values indicating stronger implicit associations of the self with sad relative to happy, and negative values indicating stronger associations of the self with happy relative to sad.

  18. Change in Physical Activity Level as Measured by the International Physical Activity Questionnaire (IPAQ)

    Time frame: Baseline (Day 1) to endpoint (Day 14)

    Change from baseline (Day 1) to endpoint (Day 14) in physical activity level as measured by the International Physical Activity Questionnaire (IPAQ), which assesses self-reported physical activity across multiple domains. Scores are expressed in metabolic equivalent (MET)-minutes per week, with higher scores indicating greater levels of physical activity.

  19. Change in Rumination as Measured by the Ruminative Responses Scale (RRS-10)

    Time frame: Baseline (Day 1) to endpoint (Day 14)

    Change from baseline (Day 1) to endpoint (Day 14) in rumination as measured by the Ruminative Responses Scale (RRS-10), a 10-item self-report scale with total scores ranging from 10 to 40, where higher scores indicate greater rumination.

  20. Change in Sleep Quality as Measured by the Pittsburgh Sleep Quality Index (PSQI)

    Time frame: Baseline (Day 1) to endpoint (Day 14)

    Change from baseline (Day 1) to endpoint (Day 14) in sleep quality as measured by the Pittsburgh Sleep Quality Index (PSQI), a self-report questionnaire with total scores ranging from 0 to 21, where higher scores indicate poorer sleep quality.

  21. Change in Motivation as Measured by the Motivation and Energy Inventory (MEI)

    Time frame: Baseline (Day 1) to endpoint (Day 14)

    Change from baseline (Day 1) to endpoint (Day 14) in motivation and energy as measured by the Motivation and Energy Inventory (MEI), a 27-item self-report scale with each item rated on a 6-point Likert scale (1 = never to 6 = every day or nearly every day). Total scores range from 27 to 162, with higher scores indicating greater impairment in motivation and energy.

  22. Change in Whole-Brain Task-Evoked BOLD Signal During Reward Processing

    Time frame: Baseline (Day 1) to endpoint (Day 14)

    Change from baseline (Day 1) to endpoint (Day 14) in task-evoked blood oxygen level-dependent (BOLD) signal across the whole brain during the Effort Expenditure for Rewards Task (EEfRT), as measured by functional magnetic resonance imaging (fMRI). Exploratory whole-brain analyses will be conducted to assess changes in neural activation associated with reward processing.

  23. Change in Depression Severity as Measured by the Clinical Global Impression - Severity (CGI-S)

    Time frame: Baseline (Day 1) to endpoint (Day 14)

    Change from baseline (Day 1) to endpoint (Day 14) in depression severity as measured by the Clinical Global Impression - Severity (CGI-S), a clinician-rated scale ranging from 1 (not at all ill) to 7 (among the most extremely ill), where higher scores indicate greater illness severity.

Other outcomes

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

    Time frame: Baseline (Day 1) to endpoint (Day 14)

    Change from baseline (Day 1) to endpoint (Day 14) in insulin resistance as measured by the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR), calculated from fasting glucose and insulin levels, with higher values indicating greater insulin resistance.

Sponsors and collaborators

Lead sponsor

Roger McIntyre

Other

Collaborators

  • Axsome Therapeutics, Inc.

Registry information

Official study title

Two-Week, Open-Label, Exploratory Neuroimaging Study Evaluating the Effect of Dextromethorphan-HBr Bupropion-HCl on Striatal Reactivity During Reward Processing in Adults With Major Depressive Disorder

Important dates

Study start
2025
Primary completion
2026
Study completion
2027
First posted
Apr 13, 2026
Registry last updated
Apr 13, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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