This program of research constitutes a three-arm, randomized, placebo-controlled trial testing noninvasive brain stimulation for the treatment of anhedonic depression. This trial is part of a larger, three-site study that will be conducted at UCSD, Stanford University, and Cornell University, with the overarching goals to compare competing interventions tested at each site and to combine data that will allow for the creation of an end-to-end model of anhedonic depression. By doing this, the investigators hope to gain insight and lead to the development of brain-behavior biomarkers to identify who is best suited for the different treatment options tested at each site. An additional exploratory objective is phenotyping anhedonic depression from the acquired measures.

Anhedonic patients recruited at UCSD will be randomized to one of three treatment arms to receive different forms of accelerated intermittent theta burst stimulation (aiTBS),a novel form of repetitive transcranial magnetic stimulation (rTMS) that is an FDA approved treatment for depression. These arms include: individualized accelerated iTBS (Ind-aiTBS),based on both the frequency of brain responses and electric-field (e-field) modeling of brain bioconductivity; standard accelerated iTBS (Std-aiTBS); and accelerated sham iTBS(sham). Treatment will be delivered on an accelerated schedule, over one week. Additional study sessions will occur both before and after treatment to assess for clinical, neurophysiological, and cognitive measures that will allow for both individualization of treatment and detailed assessment of the effects of the different treatment arms.

Inclusion Criteria:

• Male or Female, between the ages of 18 and 80 at the time of screening.
• Able to read, understand, and provide written, dated informed consent prior to screening. Proficiency in English sufficient to complete questionnaires / follow instructions during fMRI assessments and aiTBS interventions. Stated willingness to comply with all study procedures, including availability for the duration of the study, and to communicate with study personnel about adverse events and other clinically important information.
• Currently diagnosed with Major Depressive Disorder (MDD) or Bipolar Disorder type II and meets criteria for a Major Depressive Episode, according to the criteria defined in the Diagnosis and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision (DSM-5).
• Medical records confirming a history of moderate to severe treatment-resistance as defined an Antidepressant Treatment History Form (ATHF) score for that antidepressant trial of > 3 in the current episode OR have been unable to tolerate at least 2 separate trials of antidepressants of inadequate dose and duration (ATHF score of 1 or 2 on those 2 separate antidepressants) OR have a combination of one failed trial and one not tolerated trial, per the definitions above.
• MADRS score of ≥20 at screening (Visit 1).
• Access to ongoing psychiatric care before and after completion of the study.
• Access to open label neuromodulation treatment after study completion.
• Must be on a stable antidepressant therapeutic regimen for 6 weeks prior to study enrollment and agree to continue this regimen throughout the study period.
• In good general health, as evidenced by medical history.
• For females of reproductive potential: use of highly effective contraception for at least 1 month prior to screening and agreement to use such a method during study participation.
• Agreement to adhere to Lifestyle Considerations throughout study duration.

Exclusion Criteria:

• Pregnancy
• History of or current psychotic disorder or depression with psychotic features
• Severe borderline personality disorder.
• Diagnosis of Intellectual Disability or Autism Spectrum Disorder
• Current moderate or severe substance use disorder or demonstrating signs of acute substance withdrawal
• Urine screening test positive for illicit substances
• Clinically significant suicidal ideation with plan
• Any history of ECT (greater than 8 sessions) without a clinical meaningful response.
• Recent (during the current depressive episode) or concurrent use of rapid acting antidepressant agent (i.e., ketamine or a course of ECT) in the last 30 days
• History of significant neurologic disease, including dementia, Parkinson's or Huntington's disease, brain tumor, seizure disorder, subdural hematoma, multiple sclerosis, or history of significant head trauma
• Untreated or insufficiently treated endocrine disorder.
• Contraindication to receiving rTMS (e.g., metal in head, history of seizure, known brain lesion)
• Contraindication to MRI (ferromagnetic metal in their body)
• Treatment with an investigational drug or other intervention within the study period
• Unstable symptoms between screening and baseline as defined by a ≥ 30% change in MADRS score.
• Require a benzodiazepine with a dose > lorazepam 2 mg/day or equivalent or any anticonvulsant.

Blinding will be achieved via a sham rTMS coil (Cool-B65 A/P) used with the device. This coil can deliver either active or sham stimulation in a manner that is randomized by the system itself and therefore blinded to the treater. The sham setting on this coil looks and sounds identical to the active setting but has a hidden aluminum plate blocking actual stimulation. The MagVenture TMS device holds a blinded key code that is kept by the individual that holds the blind. During the rTMS setup, the operator is instructed to flip the coil to correspond with the key code, but the operator is not able to discern the active versus sham stimulation. Additional measures will be taken to ensure that the treater remains blinded during treatment administration.