*Full Title of the Submission: Psychostimulant Augmentation of Repetitive TMS (rTMS) for the Treatment of Major Depressive Disorder: A Randomized, Placebo-controlled Clinical Trial

This study aims to recruit 30 subjects between the ages of 18-65 who meet the Diagnostic and Statistical Manual of Mental Disorders (DSM-V) criteria for a current episode of major depressive disorder. Participants will be recruited from the population of patients seeking rTMS from the University of California Los Angeles(UCLA) Transcranial Magnetic Stimulation Clinic. All patients considered for participation in the study will carry a diagnosis of major depression as established by the referring psychiatrist and this will be confirmed based on an interview using the Mini International Neuropsychiatric Interview (MINI). Moreover, they will meet criteria for treatment resistance as defined by lack of response to two prior antidepressant trials at adequate dosage and duration. After providing voluntary, capable, informed consent, participants will be enrolled in the study. Participants will then complete baseline assessments including the Antidepressant Treatment History Form (ATHF) and the 30-item Inventory of Depressive Symptomatology Self Report (IDS-SR30) as well as the clinician-rated 17-item Hamilton Depression Rating Scale (HAM-D17).

Once a diagnosis of treatment resistant major depression has been established, the primary outcome measure will be the IDS-SR30 score, which is our standard procedure for monitoring treatment outcome in the TMS clinic. Participants will be randomly assigned to one of two treatment conditions: Adderall XR (n=15) versus placebo (n=15). Participants and all research team members will be blinded to the assigned treatment condition. Timing of all steps in the study protocol will use 'study time', meaning that although patients remain on the drug during weekends, only weekdays (Mon-Fri) count when assessing progress through the protocol. For example, a patient that started day 1 of the study on a Thursday, would reach day 5 on Wednesday the following week. Adderall XR or placebo will be initiated at least 10 days prior to the start of rTMS treatment in order to assess side effects and establish stable mood on the study drug. In order to study how Adderall XR affects response to rTMS, independent of any direct antidepressant effects, patients must exhibit stable mood prior to initiating rTMS. IDS-SR30 and HAM-D17 will be repeated on study days 5 and 10 on drug to determine if patients have a stable baseline mood (see study schedule chart, below). Patients will be considered to exhibit stable mood and qualify for initiating treatment if the IDS-SR30 score changes by less than 10% between assessments at study day 5 and 10.

The investigators predict that some patients may exhibit improvement in IDS score at day 5, however, if they exhibit significant additional improvement between day 5 and 10, starting rTMS will be delayed until depression scores are stabilized. Specifically, if the mood score changes by more than 10%, the Subject will wait an additional 5 days or multiples of 5 days up to 15 days as needed, until the weekly change in mood score meets this criterion. The investigators predict that few of these treatment-resistant, depressed patients will exhibit more than a couple weeks of continuous improvement, but if they do they may be better suited by continuing stimulant treatment with their primary provider rather than undergoing TMS. Study subjects who no longer complain of depression and no longer meet criteria for Major Depressive Disorder (MDD) after initiating treatment (Adderall XR vs. placebo) will be removed from the study because rTMS is no longer indicated. For such patients, the blind will be broken and they would have the option to continue the study medication at the discretion of their primary prescribing physician.

Participants will be assessed for medication side effects alongside IDS-SR30 assessments and rTMS will begin once they exhibit stably depressed mood. Participants in both treatment groups will begin a standard, FDA approved rTMS treatment protocol, delivered with a Magstim or Magventure device. Participants will be assessed for side effects at each rTMS treatment session. Participants will complete the IDS-SR30, HAM-D17 and a Visual Analog Scale (VAS) for overall tolerability after 5 and 10 rTMS treatment sessions. After completion of the 10th treatment session and the final set of assessments, all study related activities will be complete and the blind will be broken.

Based on our recent observational study, the investigators predict that the effect Adderall XR on rTMS outcome will be most apparent early in the treatment course. Moreover, in our standard treatment algorithm, rTMS treatment parameters are generally kept uniform during the first 10 treatments and begin to diverge thereafter depending on treatment response. Thus, examining outcomes after treatment 10 will yield the best controlled dataset for detecting a significant effect of the study drug. Patients may complete additional rTMS treatments at the discretion of the treating physician, and may elect to continue taking the study drug at the discretion of their prescribing psychiatrist. Therefore, patients that exhibit significant improvement in depression while taking Adderall XR would have the option to continue beyond the initial 10 treatments. Otherwise, patients will discontinue the study medication at this point and given the low dose and short duration of treatment, it is not anticipated that patients will require any need to wean off the study medication.