What is the appropriate clinical application and protocol for Theta Burst Stimulation (TBS), including intermittent TBS (iTBS) and continuous TBS (cTBS), in patients with treatment-resistant depression or other conditions where Transcranial Magnetic Stimulation (TMS) is indicated?

Theta Burst Stimulation Protocol for Treatment-Resistant Depression

Direct Recommendation

For treatment-resistant depression, use intermittent theta burst stimulation (iTBS) targeting the left dorsolateral prefrontal cortex (L-DLPFC) or bilateral sequential TBS (combining continuous TBS to right DLPFC with iTBS to left DLPFC), as these protocols demonstrate non-inferiority to standard 10 Hz rTMS while reducing treatment time from 37.5 minutes to 3 minutes per session. 1

However, the 2022 VA/DoD guidelines state there is insufficient evidence to make a recommendation for or against theta-burst stimulation, despite its demonstrated non-inferiority to standard rTMS. 2 This conservative guideline position conflicts with the robust clinical trial data showing TBS effectiveness.

Clinical Protocol Selection Algorithm

First-Line TBS Protocol

• Use iTBS to L-DLPFC as the primary protocol, delivering 600 pulses per session at 120% resting motor threshold 1, 3
• Treatment schedule: 5 sessions per week for 4-6 weeks 1
• This protocol achieved response rates of 36-47% and remission rates of 26-34% in naturalistic studies 4

Enhanced Protocol for Severe Cases

• Use bilateral sequential TBS: continuous TBS (cTBS) to right DLPFC (600 pulses) followed by iTBS to left DLPFC (600 pulses) 5, 4
• Bilateral TBS demonstrated superior anxiolytic effects compared to unilateral stimulation 4
• Bilateral protocols required fewer total treatments (27 vs 29 sessions on average) to achieve response 4
• Meta-analysis confirms bilateral TBS (cTBS R-DLPFC + iTBS L-DLPFC) provides favorable risk-benefit balance 5

Accelerated Protocol Considerations

• Accelerated protocols deliver multiple sessions per day (up to 5 sequential bilateral treatments daily for 5 days) 3
• Response rates of 38% achieved within 2 weeks post-treatment with accelerated iTBS, with 30% achieving remission 6
• Critical caveat: 60% of patients could not tolerate high-intensity accelerated stimulation in one study 3
• Delayed clinical effects are common—response rates increase from 20% at day 5 to 32% at 2 weeks post-treatment 3

Patient Eligibility Criteria

Minimum Requirements

• Failed at least 2 adequate antidepressant trials (minimum 4 weeks each at therapeutic dose, different mechanisms of action) 7
• Trials must have occurred within current depressive episode 7
• Baseline HDRS-17 score ≥18 1

Patients Who Should NOT Be Excluded

• Multiple prior medication failures (even numerous augmentation strategies) 7
• Previous ECT or TMS failure 7
• Comorbid personality disorders or other mental health conditions (unless these clearly preceded and are independent of MDD) 7
• High rates of comorbid PTSD or substance use disorders 2

Critical Eligibility Pitfall

• Do not count medication trials discontinued before 4 weeks due to side effects as failed trials for establishing treatment-resistant depression 7

Treatment Parameters

Standard iTBS Protocol

• Target: Left DLPFC
• Intensity: 120% resting motor threshold 3
• Pulses per session: 600 1, 3
• Session duration: 3 minutes 1
• Frequency: 5 days per week 1
• Total duration: 4-6 weeks (20-30 sessions) 1, 4

Bilateral Sequential TBS Protocol

• First: cTBS to right DLPFC (600 pulses)
• Second: iTBS to left DLPFC (600 pulses)
• Same intensity and frequency parameters as unilateral 4, 3

Expected Outcomes and Timeline

Response Rates

• Unilateral iTBS: 36% response, 26% remission 4
• Bilateral TBS: 47% response, 34% remission 4
• Meta-analysis confirms iTBS (L-DLPFC) demonstrates higher response and remission rates compared to sham 5

Temporal Pattern of Response

• Delayed clinical effects are common—assess response at 2 weeks post-treatment, not immediately after final session 3, 6
• Response rates increase from 28% at end of treatment to 38% two weeks later 6
• 69% of responders maintained response at 6 months without additional treatment or medication changes 4

Safety and Tolerability Profile

Common Adverse Events

• Headache is most common (64-65% of patients) 1
• Self-rated pain intensity slightly higher with iTBS compared to standard rTMS (3.8 vs 3.4 out of 10) 1
• No significant differences in switch to mania or treatment site discomfort between TBS protocols and sham 5

Dropout Rates

• Low discontinuation rates: 6-8% across protocols 1
• No significant differences in all-cause discontinuation between TBS and sham 5

Cognitive Effects During Treatment

• High-frequency stimulation (≥10 Hz) can temporarily disrupt memory precision during treatment 8
• Effects are temporary and occur during the treatment period 8
• Inform patients about possible transient memory difficulties during active treatment 8

Access and Practical Considerations

Treatment Burden

• Standard TBS requires frequent onsite visits (5 sessions per week for 4-6 weeks) 9
• Accelerated protocols reduce total treatment duration but require multiple daily sessions 3, 6
• Only highly motivated patients should be recruited for intensive accelerated protocols 9

Advantages Over Standard rTMS

• Treatment time reduced from 37.5 minutes to 3 minutes per session 1
• Allows treatment of multiple patients per day with current rTMS devices 1
• Non-inferior clinical effectiveness to standard 10 Hz rTMS 1

Maintenance Strategies

• Some protocols incorporate maintenance interventions twice weekly for 3 months following acute treatment phase 9
• Response duration: 3-6 months following standard acute treatment course 9
• At least 4-6 weeks of daily treatment required to induce significant clinical improvement 9
• Protocols with fewer than 4 weeks (3 weeks or less) showed no difference from sham treatment 9

Guideline-Evidence Discordance

Important clinical context: The 2022 VA/DoD guidelines state insufficient evidence for TBS 2, yet the THREE-D trial (2018) definitively established non-inferiority 1, and subsequent meta-analyses confirm favorable risk-benefit balance 5. This discordance reflects guideline lag rather than lack of evidence. The aggregate literature supports TBS as an effective, faster alternative to standard rTMS for treatment-resistant depression.