Is Transcranial Magnetic Stimulation (TMS) augmentation therapy effective for a patient with treatment-resistant depression who has not responded to multiple antidepressant medications and psychotherapies?

TMS as Augmentation Therapy for Treatment-Resistant Depression

Yes, Transcranial Magnetic Stimulation (TMS) is an effective augmentation therapy for treatment-resistant depression and should be considered for patients who have failed medication trials. 1, 2

Evidence-Based Positioning of TMS

TMS is specifically recommended as a treatment option for patients with treatment-resistant depression who have not responded to adequate antidepressant trials. 1, 2 The most recent guidelines from 2025 explicitly position TMS alongside other augmentation strategies in the treatment algorithm for TRD. 1, 2

Key Clinical Context

• TMS is classified as a non-continuous, non-invasive brain stimulation intervention, which distinguishes it from more invasive options like deep brain stimulation (DBS) or vagus nerve stimulation (VNS). 3
• Patients who have failed TMS treatment should not be excluded from other TRD treatment trials, indicating that TMS failure does not represent an insurmountable level of treatment resistance. 3
• This contrasts with DBS and VNS failures, where patients are recommended for exclusion from TRD studies due to their unusually high treatment resistance. 3

Treatment Algorithm Placement

TMS should be considered after patients have failed at least two adequate antidepressant trials (minimum effective dosage for ≥4 weeks each, with different mechanisms of action). 1, 2

The treatment hierarchy typically follows:

• First-line augmentation: Atypical antipsychotics (particularly aripiprazole) remain the primary first-line augmentation strategy. 1, 2, 4
• TMS positioning: TMS is recommended for patients who have failed medication trials, positioning it as an alternative or subsequent option to pharmacological augmentation. 1, 2
• Highly refractory cases: Esketamine/ketamine is reserved for highly refractory cases. 1

Clinical Efficacy Evidence

TMS demonstrates moderate effect sizes in treatment-resistant depression, comparable to antidepressant treatment in TRD, though less robust than ECT. 5

Response and Remission Rates

• The Clinical TMS Society consensus review confirms substantial evidence of efficacy and safety for daily left prefrontal TMS in treating acute depression in treatment-resistant or intolerant patients. 6
• Standard TMS protocols (20-30 sessions over 4-6 weeks) show response rates of approximately 36-43% and remission rates of 29-36%. 7
• Early improvement during high-frequency left-sided stimulation is an important predictor of longer-term outcome, but most patients benefit later in their treatment course. 8

Predictors of Response

Lower age, lower degrees of treatment resistance, and absence of comorbid anxiety or psychotic symptoms predict better TMS response. 5

Practical Implementation Considerations

Standard Protocol

• Daily left prefrontal TMS is FDA-approved for adults with major depressive disorder who have not responded to prior antidepressant medications. 6
• Treatment requires 20-30 sessions delivered over 4-6 weeks. 6
• The standard approach uses high-frequency left-sided stimulation of the dorsolateral prefrontal cortex. 8, 6

Augmentation Strategies for TMS Non-Responders

For patients showing <20% improvement by treatment 10, augmentation strategies can improve outcomes rather than continuing standard TMS. 8

Two augmentation approaches show promise:

• Bilateral stimulation (high-frequency left followed by low-frequency right DLPFC stimulation) trends toward improved outcomes. 8
• Intermittent theta-burst priming (iTBS-P) shows significantly greater improvement than continued standard TMS. 8
• At least 10 sessions of augmentation appear necessary to determine likelihood of benefit. 8

Accelerated Protocols

Accelerated TMS (15 sessions over 2 days) demonstrates comparable efficacy to daily TMS with an excellent safety profile, though this requires further validation in larger studies. 7 Response rates of 36-43% and remission rates of 29-36% were observed at 3 and 6 weeks post-treatment. 7

Integration with Other Therapies

Cognitive behavioral therapy should be used in conjunction with TMS throughout treatment, as psychotherapy augments outcomes across all TRD interventions. 1, 2, 4

Safety Profile

TMS demonstrates an excellent safety profile with no seizure activity in most studies. 7 The most common reason for discontinuation is lack of response rather than adverse effects. 7 Serious adverse events are rare, with increased suicidal ideation being the most concerning potential complication requiring monitoring. 7

Cost-Effectiveness

TMS is cost-effective when compared to existing treatments for TRD including psychopharmacological interventions and ECT. 5