Protocol for Combining IV Ketamine with TMS for Treatment-Resistant Depression
Based on emerging evidence, combining IV ketamine with TMS is a viable treatment strategy for patients with treatment-resistant depression who have failed at least 2 adequate antidepressant trials, though this combination should be reserved for patients who have shown inadequate response to either modality alone. 1, 2
Patient Selection Criteria
Strict eligibility requirements must be met before initiating combination therapy:
- Confirmed treatment-resistant depression with failure of at least 2 adequate antidepressant trials at appropriate doses and durations 3, 4
- Prior inadequate response to either TMS alone or ketamine monotherapy 2, 5
- Documented baseline depression severity using validated scales (MADRS or PHQ-9) 6
- Medical clearance for both modalities, including cardiovascular assessment for ketamine-induced hypertension 4, 7
- Exclusion of active suicidal ideation requiring immediate intervention (though ketamine may reduce suicidal ideation, this is not an FDA-approved indication) 4
Treatment Protocol
Combination Administration Schedule
The most effective protocol involves coincident administration of high-output TMS (30 minutes) with IV ketamine infusions (20 minutes), delivered 3 times weekly over 2 weeks initially. 1
Specific dosing parameters:
- IV Ketamine: 0.5 mg/kg infused over 40-60 minutes 3, 8, 5
- TMS: High-frequency left dorsolateral prefrontal cortex stimulation for 30 minutes 1, 5
- Frequency: 3 sessions per week for 2 weeks (total 6 sessions minimum) 3, 5
- Extended treatment: 10-30 sessions may be required depending on patient responsiveness 1
Timing and Sequencing
Ketamine should be administered coincidentally with TMS rather than sequentially. 1 The ketamine infusion allows for higher TMS intensities than would otherwise be tolerated, as the analgesic and dissociative properties of ketamine reduce discomfort from high-output magnetic stimulation. 1
Monitoring Requirements
During Each Session
Mandatory vital sign monitoring throughout treatment:
- Blood pressure and heart rate every 15 minutes during ketamine infusion 4, 7
- Continuous observation for dissociative symptoms, which typically peak during infusion and resolve within hours 8, 7
- Assessment for psychotomimetic effects (confusion, agitation, perceptual disturbances) 4, 7
Clinical Response Assessment
Depression severity should be measured:
- Pre-treatment baseline using MADRS or equivalent validated scale 6, 5
- After each treatment session 5
- At treatment completion (after 2 weeks) 5
- At 2-year follow-up to assess sustained remission 1
Expected Outcomes and Response Timeline
Rapid symptom improvement occurs within 24 hours of initial treatment, with peak effects at 1 day and sustained benefits for 3-7 days per session. 4, 9, 8
Response rates from combination therapy:
- Mean reduction in depression severity of approximately 34.5% from baseline 5
- Response rate (≥50% symptom reduction): 19% in TMS-failure patients 5
- Remission rate: 9.5% in TMS-failure patients 5
- Critically, sustained remission for 2 years post-treatment has been documented with combination therapy, representing a major advantage over monotherapy. 1
Maintenance Strategy
For patients who respond to acute combination therapy, maintenance sessions should be scheduled at 2-4 day intervals to sustain benefits. 8
The frequency can be adjusted based on individual response, with some patients requiring weekly sessions and others needing less frequent administration. 1 This maintenance approach prevents the typical 3-12 day relapse seen with single-dose ketamine. 8
Safety Considerations and Contraindications
Absolute contraindications:
- Uncontrolled hypertension (ketamine causes transient blood pressure elevation) 4, 7
- Active substance use disorder (ketamine has abuse potential) 4
- Seizure disorders not controlled by medication (TMS lowers seizure threshold) 3
Critical safety warnings:
- Dissociative and psychotomimetic symptoms occur commonly but are almost always mild and transient 8, 7
- Respiratory depression is possible; resuscitation equipment must be immediately available 4
- Long-term neurocognitive effects, urologic toxicity, and abuse liability remain unknown due to lack of long-term data 4
- For bipolar depression patients, intensified monitoring for manic switch is mandatory, particularly during maintenance phase 6
Common Pitfalls to Avoid
Do not use combination therapy as first-line treatment. Both ketamine and TMS are explicitly reserved for patients who have failed multiple adequate antidepressant trials. 3, 4, 9
Do not administer ketamine without proper monitoring infrastructure. The FDA requires esketamine administration under medical supervision with a REMS program; similar precautions apply to IV ketamine. 4, 7
Do not expect sustained benefits without maintenance dosing. Single-session effects last only 3-7 days; maintenance protocols are essential for long-term remission. 8, 1
Do not overlook the synergistic mechanism. The combination allows higher TMS intensities due to ketamine's analgesic properties, which may explain superior outcomes compared to sequential administration. 1
Evidence Quality Assessment
The strongest evidence comes from a 2019 retrospective review demonstrating sustained 2-year remission with combination therapy 1, supported by a 2022 case report showing complete remission in a bipolar TRD patient who failed both modalities individually. 2 However, a 2023 case series of TMS-failure patients showed more modest response rates (19%) with ketamine alone, suggesting combination therapy may be superior to sequential treatment. 5 The VA/DoD 2022 guidelines support ketamine use in treatment-resistant cases but do not specifically address combination protocols, as this remains an emerging area. 3