Inclusion Criteria:
1. Capable of providing voluntary, written, informed consent prior to study enrollment.
2. Male or female between the age of 18 to 65 years, inclusive.
3. 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.
4. 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.
5. Lifetime history of less than five prior adequate trials of a pharmacologic treatment for depression.
6. 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).
7. Access to reliable internet for the entire study period and an internet-based device (i.e., a smartphone, laptop, desktop or tablet).
8. Must have the ability to speak and read English. This is due to the diagnostic and study assessments being administered in English.
9. Note: there is no inclusion/exclusion based on prior history of manual-based psychotherapy (e.g., cognitive behavioural therapy).
Exclusion Criteria:
1. 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.
2. 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.
3. Lifetime history of a primary psychotic disorder (including, but not limited to, schizophrenia or schizoaffective disorder).
4. Failure of five or more prior trials of pharmacological treatment for depression.
5. Lifetime history of failure of electroconvulsive therapy (ECT) or repetitive transcranial magnetic stimulation (rTMS).
6. Lifetime history of treatment with intravenous racemic ketamine and/or intranasal esketamine for depression.
7. History of non-response to a prior trial of dextromethorphan-bupropion
8. Hypersensitive to bupropion in any formulation
9. Duration of current MDE greater than 2 years
10. Recreational cannabis use daily, weekly or cannabis use disorder.
11. 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).
12. 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.
13. 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).
14. Current or history of severe hepatic or renal impairment.
15. 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.
16. Any medical or psychiatric history that may exclusionary for fMRI scanning, including but not limited to:
1. Cardiac pacemaker
2. Surgical aneurysm clips
3. Neurostimulator
4. Implanted pumps
5. Metal fragments in body/eyes
6. Pregnancy
7. Nitroglycerin patch
8. Certain cochlear implants
9. Weight\> 440 lbs
17. Presence of any contraindications for dextromethorphan-bupropion (DXM/BUP):
1. Seizure: Do not use DXM/BUP in patients with a seizure disorder.
2. Current or prior diagnosis of bulimia or anorexia nervosa: A higher incidence of seizure was observed in such patients treated with bupropion.
3. Undergoing abrupt discontinuation of alcohol, benzodiazepines, barbiturates, and antiepileptic drugs: Due to risk of seizure.
4. 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.
5. 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.
