Timing of IV Ketamine Administration with TMS Treatment
Based on the available evidence, IV ketamine should be administered during (coincident with) TMS treatment rather than after, as this approach allows for higher TMS intensities and has demonstrated superior long-term remission rates.
Evidence for Concurrent Administration
The most compelling evidence comes from a retrospective clinical review examining combination TMS with ketamine (CTK), where ketamine infusions (20 minutes) were administered coincidentally with high-output TMS sessions (30 minutes) 1. This concurrent approach demonstrated:
- Mean CGI severity reduction of 4.46 ± 0.54 (p < 0.0001) following treatment 1
- Sustained remission for two years after treatment completion (p < 0.0001) 1
- The ability to use higher TMS intensities than would otherwise be tolerated by patients when ketamine was not administered 1
A more recent pilot study (2024) also examined synergistic use, administering 6 IV ketamine infusions over 9 weeks alongside 36 Deep TMS treatments, though the timing relationship (during vs. after each session) was not explicitly specified 2. This study showed an 80.30% response rate and 43.42% remission rate, though these rates were not significantly different from TMS-only treatment 2.
Practical Implementation
When implementing concurrent administration:
- Ketamine infusion duration: 20 minutes during the TMS session 1
- TMS session duration: 30 minutes of high-output stimulation 1
- Treatment frequency: 10-30 sessions depending on patient responsiveness 1
- Standard ketamine dosing: 0.5 mg/kg over 60 minutes when used in TRD patients who failed TMS 3, though the concurrent protocol used 20-minute infusions 1
Sequential Administration Evidence
For patients who have already failed TMS treatment, subsequent IV ketamine can still provide benefit 3. In TRD patients who failed to respond to standard high-frequency left-dorsolateral prefrontal cortex TMS:
- Mean MADRS score decreased from 27.6 ± 6.4 to 18.6 ± 8.9 (p < 0.001) 3
- 19% response rate and 9.5% remission rate with ketamine administered after TMS failure 3
- Protocol used 0.5 mg/kg infusions over 60 minutes, 3 times weekly for 2 weeks 3
Clinical Advantages of Concurrent Administration
The key mechanistic advantage of concurrent administration is that ketamine allows patients to tolerate higher TMS intensities 1. This is clinically significant because:
- Higher TMS output may enhance neuroplastic effects
- Ketamine's NMDA antagonism may synergize with TMS-induced cortical excitability changes
- The analgesic properties of ketamine reduce discomfort from high-intensity TMS pulses
Important Caveats
The evidence base is limited to retrospective reviews and pilot studies 2, 1. The 2024 pilot study found no significant added benefit of combining ketamine with TMS compared to TMS alone, though both groups showed high response rates (80.30% vs. 76.92%) 2. However, this study did not use the concurrent administration protocol that allowed for higher TMS intensities 2, 1.
Standard ketamine safety monitoring applies: continuous vital signs monitoring, oxygen saturation >93%, and screening for contraindications including uncontrolled cardiovascular disease, active psychosis, and pregnancy 4, 5.
The 2022 VA/DoD guidelines support ketamine for treatment-resistant depression but do not specifically address timing with TMS 6. The evidence for concurrent administration comes from clinical practice reports rather than randomized controlled trials 1.