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| Name | Class |
|---|---|
| Axsome Therapeutics, Inc. | INDUSTRY |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 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. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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) |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Effort-Based Decision-Making During Reward Task | 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. | Baseline (Day 1) to endpoint (Day 14) |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Insulin Resistance as Measured by Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) | 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. | Baseline (Day 1) to endpoint (Day 14) |
Inclusion Criteria:
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:
Presence of any contraindications for dextromethorphan-bupropion (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.
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Brain and Cognition Discovery Foundation | Recruiting | Toronto | Ontario | M5S1M2 | Canada |
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| ID | Term |
|---|---|
| D003865 | Depressive Disorder, Major |
| ID | Term |
|---|---|
| D003866 | Depressive Disorder |
| D019964 | Mood Disorders |
| D001523 | Mental Disorders |
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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.
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| Change in Anhedonia as Measured by the Snaith-Hamilton Pleasure Scale (SHAPS) | 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. | Baseline (Day 1) to endpoint (Day 14). |
| Change in Anhedonia as Measured by the Dimensional Anhedonia Rating Scale (DARS) | 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). | Baseline (Day 1) to endpoint (Day 14) |
| Change in Anhedonia as Measured by the Montgomery-Åsberg Depression Rating Scale - Anhedonia Factor (MADRS-AF) | 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. | Baseline (Day 1) to endpoint (Day 14) |
| Change in Processing Speed as Measured by Trail Making Test Part A (TMT-A) | 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. | Baseline (Day 1) to endpoint (Day 14) |
| Change in Executive Function as Measured by Trail Making Test Part B (TMT-B) | 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. | Baseline (Day 1) to endpoint (Day 14) |
| Change in Processing Speed as Measured by the Wechsler Adult Intelligence Scale (WAIS) Symbol Search Subtest | 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. | Baseline (Day 1) to endpoint (Day 14) |
| Change in Cognitive Performance as Measured by the Digit Symbol Substitution Test (DSST) | 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. | Baseline (Day 1) to endpoint (Day 14) |
| Change in Depressive Symptom Severity as Measured by the Montgomery-Åsberg Depression Rating Scale (MADRS) | 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. | 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) | 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. | Baseline (Day 1) to endpoint (Day 14) |
| Change in Depressive Symptom Severity as Measured by the Patient Health Questionnaire-9 (PHQ-9) | 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. | Baseline (Day 1) to endpoint (Day 14) |
| Change in Depressive Symptom Severity as Measured by the Patient Global Impression of Severity (PGI-S) | 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. | Baseline (Day 1) to endpoint (Day 14) |
| Change in Anxiety Symptom Severity as Measured by the Generalized Anxiety Disorder-7 (GAD-7) | 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. | Baseline (Day 1) to endpoint (Day 14) |
| Change in Functional Impairment as Measured by the Sheehan Disability Scale (SDS) | 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. | Baseline (Day 1) to endpoint (Day 14) |
| Change in Well-Being as Measured by the World Health Organization Well-Being Index (WHO-5) | 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. | Baseline (Day 1) to endpoint (Day 14) |
| Change in Emotional Blunting as Measured by the Oxford Depression Questionnaire (ODQ) | 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. | Baseline (Day 1) to endpoint (Day 14) |
| Change in Implicit Associations Related to Depression as Measured by the Implicit Association Test, Depression Version (IAT-D) | 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. | Baseline (Day 1) to endpoint (Day 14) |
| Change in Physical Activity Level as Measured by the International Physical Activity Questionnaire (IPAQ) | 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. | Baseline (Day 1) to endpoint (Day 14) |
| Change in Rumination as Measured by the Ruminative Responses Scale (RRS-10) | 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. | Baseline (Day 1) to endpoint (Day 14) |
| Change in Sleep Quality as Measured by the Pittsburgh Sleep Quality Index (PSQI) | 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. | Baseline (Day 1) to endpoint (Day 14) |
| Change in Motivation as Measured by the Motivation and Energy Inventory (MEI) | 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. | Baseline (Day 1) to endpoint (Day 14) |
| Change in Whole-Brain Task-Evoked BOLD Signal During Reward Processing | 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. | Baseline (Day 1) to endpoint (Day 14) |
| Change in Depression Severity as Measured by the Clinical Global Impression - Severity (CGI-S) | 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. | Baseline (Day 1) to endpoint (Day 14) |