This study aims to evaluate the feasibility, safety, and tolerability of an innovative approach to treating Major Depressive Disorder (MDD), particularly in cases where patients have not responded well to traditional therapies. Specifically, the objective is to evaluate the antidepressant effects of a Dose-Optimized and Spaced Transcranial Direct Current Stimulation (DOS-tDCS) protocol in participants with treatment-resistant depression (TRD) compared to spaced tDCS only and sham tDCS in a 3-arm randomized controlled trial (RCT). The proposed method involves applying low-intensity electrical currents through the scalp in a manner that is both more intense and more frequently spaced than standard treatments. This approach is hypothesized to lead to a significant reduction in depressive symptoms. Participants in the study will be randomly assigned to one of three groups: the experimental group receiving the DOS-tDCS treatment, a group receiving spaced tDCS only, or a control group receiving a sham (placebo) treatment. Outcomes will be measured over a period of six weeks. The study's goal is to offer a potentially more accessible and effective treatment option for individuals who have not benefited from existing MDD therapies.

Inclusion Criteria:

In order to be eligible to participate in this study, an individual must meet all of the following criteria:

1. People between the ages of 18 and 85 at the time of screening.
2. Able to read, understand, and provide written, dated informed consent prior to screening. Proficiency in English sufficient to complete questionnaires / follow instructions during 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.
3. Currently diagnosed with Major Depressive Disorder (MDD) 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).
4. Medical records confirming a history of at least moderate treatment-resistance as defined an Antidepressant Treatment History Form (ATHF) score for that antidepressant trial of > 2 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.
5. MADRS score of ≥20 at screening (Visit 1).
6. Existing relationship with mental health provider and access to ongoing psychiatric care before and after completion of the study.
7. Must be on a stable antidepressant therapeutic regimen, or not receiving treatment for 4 weeks prior to study enrollment and agree to continue this regimen throughout the study period.
8. In good general health, as evidenced by medical history.
9. For persons of child-bearing potential: use of highly effective contraception for at least 1 month prior to screening and agreement to use such a method during study participation.
10. Agreement to adhere to Lifestyle Considerations (i.e. must continue with any existing treatments) throughout study duration.
11. For persons of child-bearing potential: must take a pregnancy test at the screening visit, with results confirmed as negative by study staff.

Exclusion Criteria:

An individual will be excluded from participation in this study if they meet any of the following criteria, as determined from a review of medical records prior to screening or at the screening visit:

1. Pregnancy;
2. History of psychotic or bipolar disorder or depression with psychotic features;
3. Significant borderline personality disorder;
4. Significant comorbid obsessive-compulsive or post-traumatic stress disorder;
5. Previously diagnosed Intellectual Disability or Autism Spectrum Disorder;
6. Current moderate or severe substance use disorder or demonstrating signs of acute substance withdrawal;
7. Clinically significant suicidality;
8. Any history of tDCS;
9. Any history of ECT;
10. History of TMS (greater than 15 sessions) without a clinically meaningful response.
11. History of ketamine (greater than 4 sessions) without a clinically meaningful response;
12. Chronic depression (defined as of over 5 years duration);
13. 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 with persistent symptoms;
14. Untreated or insufficiently treated endocrine disorder;
15. Contraindication to receiving tDCS (e.g., ferromagnetic implant, history of seizure, known brain lesion);
16. Treatment with an investigational drug or other intervention within the study period;
17. Unstable symptoms between screening and baseline as defined by a ≥ 30% change in MADRS score;
18. Require a benzodiazepine with a dose > lorazepam 2 mg/day
19. Has started a new psychotherapeutic process in the past 3 months from screening;
20. Use of potentially irritant topical treatments (ex: retinoids, alpha hydroxy acids)
21. Aesthetic procedure the area of the forehead directly below the stimulation area within the last 6 months (laser, fillers, surgery, etc.)
22. Any active dermatological condition on face or scalp that would in the opinion of the PI represent a contraindication to the treatment.