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

Official 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

Overview

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.

Detailed description

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.

Interventions

• Drug Dextromethorphan-Bupropion
  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 t

Primary outcome measures

• Change in Striatal BOLD Signal During Reward Processing [Time frame: Baseline (Day 1) to endpoint (Day 14)]

Secondary outcome measures (12)

• Change in Effort-Based Decision-Making During Reward Task [Time frame: Baseline (Day 1) to endpoint (Day 14)]
• Change in Anhedonia as Measured by the Snaith-Hamilton Pleasure Scale (SHAPS) [Time frame: Baseline (Day 1) to endpoint (Day 14).]
• Change in Anhedonia as Measured by the Dimensional Anhedonia Rating Scale (DARS) [Time frame: Baseline (Day 1) to endpoint (Day 14)]
• 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 in Processing Speed as Measured by Trail Making Test Part A (TMT-A) [Time frame: Baseline (Day 1) to endpoint (Day 14)]
• Change in Executive Function as Measured by Trail Making Test Part B (TMT-B) [Time frame: Baseline (Day 1) to endpoint (Day 14)]
• 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 in Cognitive Performance as Measured by the Digit Symbol Substitution Test (DSST) [Time frame: Baseline (Day 1) to endpoint (Day 14)]
• 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 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 in Depressive Symptom Severity as Measured by the Patient Health Questionnaire-9 (PHQ-9) [Time frame: Baseline (Day 1) to endpoint (Day 14)]
• 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)]

Eligibility criteria

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Other

Study locations

Canada · 1 center

• Brain and Cognition Discovery Foundation — Toronto

Identifiers

NCT: NCT07523048 · BCDF004

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗