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

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.

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.

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).

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.