Patients randomized to this treatment arm will be instructed to continue all permitted psychotropics at their current dose throughout the 8-week trial and initiate adjunctive aripiprazole. The starting dose will be 5mg daily. The dose may be reduced to as low as 2mg for tolerability issues (this will be the lowest dose permitted for continuation in the trial). The dose may be adjusted in 2 or 5mg increments. The minimum time per increment will be 7 days. The maximum dose will be set at 15mg daily. For patients who are not on potent cytochrome 2D6 inhibitors (such as paroxetine, fluoxetine, duloxetine) or on potent cytochrome 3A4 inhibitors (such as fluvoxamine and nefazodone) and who are able to tolerate 15mg daily, the maximum dose can be raised to 20mg daily for efficacy.

Patients randomized to this treatment arm will be instructed to continue all permitted psychotropics at their current dose throughout the 8-week trial. We will use clinical TMS stimulators with focal figure-of-eight coils. We will start by measuring the patient´s motor threshold (MT), which is a measure of cortical excitability used to standardize the intensity of stimulation across subjects.

Patients randomized to this treatment arm will be instructed to continue all permitted psychotropics throughout the 8-week trial, except for their antidepressant(s). They will be instructed to discontinue all antidepressants and initiate venlafaxine that day, as direct switch to serotonergic antidepressants is well tolerated and avoids loss of precious therapeutic time (Montgomery et al., 2014), including to switching to venlafaxine in STAR*D (Rush et al., 2006b). For patients who do not prefer a direct switch, or when clinically indicated otherwise in the opinion of the site investigator, a gradual tapering during the screening period will be permitted as long as a direct switch to venlafaxine is made on the baseline visit from the final antidepressant dose. The starting dose of venlafaxine will be 75mg daily. The dose may be reduced to as low as 37.5mg for tolerability issues (this will be the lowest dose permitted for continuation in the trial).

Oral adjunctive therapy with aripiprazole, dose adjusted for effectiveness and tolerability.

The Montgomery-Åsberg Depression Rating Scale (MADRS) is a clinician-rated scale that assesses the severity of depressive symptoms. The scale consists of 10 items evaluating apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, and suicidal thoughts. Each item is scored from 0 to 6. Item scores are summed to calculate a total MADRS score ranging from 0 to 60, with higher scores indicating more severe depressive symptoms and a worse outcome.

The Quality of Life Enjoyment and Satisfaction Questionnaire - Short Form (Q-LES-Q-SF) is a self-reported assessment tool used to evaluate an individual's degree of enjoyment and satisfaction across various areas of daily functioning. The questionnaire assesses domains such as physical health, mood, work, household activities, social relationships, leisure activities, and overall well-being. The short form consists of 16 items, with respondents rating their level of satisfaction and functioning over the past week. The first 14 items are summed to generate a total raw score ranging from 14 to 70, with higher scores indicating greater life satisfaction and better quality of life. Raw scores may also be converted to a percentage of the maximum possible score, ranging from 0% to 100%, to facilitate interpretation and comparison across studies. The final two items assess overall medication satisfaction and overall life satisfaction and are typically analyzed separately rather than included

The Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (MGH CPFQ) is a self-reported assessment tool designed to evaluate cognitive and physical symptoms commonly associated with depression and its treatment. The questionnaire assesses areas such as motivation, wakefulness, energy, focus, memory, mental sharpness, and physical well-being. The instrument consists of 7 items, each rated on a 6-point scale from 1 (greater than normal functioning) to 6 (totally absent or severe impairment). Item scores are summed to generate a total score ranging from 7 to 42, with higher scores indicating greater impairment in cognitive and physical functioning. The MGH CPFQ is widely used in clinical research to assess functional deficits associated with depression and to monitor changes in cognitive and physical symptoms during treatment.