Major depressive disorder (MDD) affects millions of people worldwide, yet nearly one-third of patients fail to achieve remission despite trying multiple antidepressant medications. This condition, known as treatment-resistant depression (TRD), remains one of the greatest challenges in modern psychiatry. Fortunately, advances in interventional psychiatry are providing new hope.
Two of the most transformative treatments introduced over the past decade are Transcranial Magnetic Stimulation (TMS) and ketamine-based therapies, including intravenous (IV) ketamine and intranasal esketamine (Spravato). Individually, these therapies have demonstrated significant benefits for patients who have not responded adequately to traditional medications. More recently, researchers have begun exploring whether combining these treatments may produce even greater clinical improvement.
How TMS and Ketamine Work Differently
Although both therapies ultimately improve depressive symptoms, they target different aspects of brain function.
TMS is a non-invasive neuromodulation treatment that uses focused magnetic pulses to stimulate the dorsolateral prefrontal cortex, an area involved in mood regulation, motivation, and executive functioning. Repeated stimulation helps normalize dysfunctional brain networks over several weeks while promoting long-term neuroplasticity.
Ketamine and Spravato, on the other hand, work through glutamate modulation by antagonizing NMDA receptors. This rapidly increases synaptic plasticity and promotes new neural connections, often resulting in symptom improvement within hours to days. These rapid effects make ketamine particularly valuable for patients experiencing severe depression or suicidal ideation.
So, one treatment is a chemistry intervention into the brain’s fast glutamate signaling system. The other is physics intervention into the brains underactive cortical control of mood. They are not competing for the same receptor. They are not completing for the same network node. Rather than competing therapies, these treatments may complement one another by targeting different neurobiological pathways involved in depression.
Why Researchers Are Interested in Combination Therapy
One of the most exciting concepts in neuroscience is neuroplasticity, the brain’s remarkable ability to form new connections and reorganize itself.
Ketamine appears to create a temporary “window of enhanced plasticity,” during which the brain may be more receptive to change. Delivering TMS during this period could reinforce healthier neural circuits, potentially leading to faster symptom improvement and more durable remission.
While this hypothesis is biologically compelling, robust randomized clinical trials evaluating concurrent treatment remain limited. Most evidence currently comes from observational studies, case reports, and early clinical experiences.
Why combining is even a question
For decades, the standard “what next” after two failed antidepressants was: add a second-generation antipsychotic, switch classes, augment with lithium, or refer for ECT. Those algorithms still hold. But two things have shifted in the last five years.
First, both SPRAVATO and TMS moved from “novel” to “established.” Major treatment guidelines now name both as evidence-supported interventions for TRD. They are no longer experimental. They are no longer rare. They are mainstream, and most academic centers and a growing number of community psychiatric specialty practices offer one or both.
Second, mechanistic research started pointing at a shared downstream story. Both rTMS and ketamine/esketamine, despite working through entirely different upstream mechanisms, appear to converge on common final pathways involving cortical excitability, BDNF-mediated synaptic plasticity, and the endocannabinoid system. In animal models and human studies, both treatments raise endocannabinoid levels (anandamide and 2-arachidonoylglycerol) in ways that correlate with clinical improvement. The implication: you may be hitting the same final circuit twice, once chemically, once electrically, and the brain may not mind.
Third, the clinical evidence on the actual combination started to accumulate. A 2024 systematic review by Arubuolawe and colleagues pulled together six published studies, three case reports, one retrospective study, one pilot study, and one prior review examining TMS combined with ketamine in TRD. Across studies, the combination produced “substantial and sustained improvement” in depressive symptoms, with efficacy higher than either treatment alone and adverse effects that were “generally mild and transient, with no severe adverse events reported in most studies” . A separate 2024 analysis of clinical trial activity over the past decade noted that combinatorial treatment with rTMS, ECT, psychotherapy, and other non-pharmacologic interventions has become explicitly common in ketamine and esketamine research.
This is still small. Six studies is not a phase III randomized trial. The Arubuolawe review explicitly notes the heterogeneity of designs and the small sample sizes, what we have is signal, not certainty. But it is a consistent signal, in the same direction, with no offsetting safety alarm. That is more than we had in 2019.
Potential Advantages of Combining Treatments
If ongoing research confirms current observations, combined therapy could offer several advantages:
These potential benefits are particularly attractive for patients who have failed multiple medication trials or experienced incomplete responses to either therapy alone.
Safety Considerations
Both TMS and Spravato have well-established safety profiles when administered according to clinical guidelines.
TMS is generally associated with mild scalp discomfort or headache, while seizures remain exceedingly rare.
Spravato requires Risk Evaluation and Mitigation Strategy (REMS) monitoring because transient dissociation, sedation, dizziness, and blood pressure elevations can occur following treatment.
Although early reports suggest that combining these therapies appears feasible in carefully selected patients, there are currently no universally accepted protocols regarding the optimal timing or sequencing of concurrent treatment. Individualized assessment remains essential.
How we Sequence at Advanced Psychiatry of Elgin
Every treatment-resistant depression patient is different, and there is no single right protocol. But here is the sequencing logic we use in practice when both treatments are on the table.
If you are already responding partially to antidepressants and the question is augmentation, we will often combine. SPRAVATO twice weekly (the standard induction phase) running alongside a course of TMS, either standard 6-week rTMS or accelerated theta-burst is the most common combined protocol we see in the published literature and in our own practice. The two treatments are scheduled on different days, or sequenced on the same day.
Maintenance is the longest stretch. Once a patient has reached remission, the question becomes how to keep it. The 2025 review of innovative TRD approaches notes that long-term maintenance increasingly involves periodic TMS booster sessions paired with weekly or biweekly SPRAVATO, neither alone, both together, to hold the response. This is the part of the algorithm where the combination strategy is doing the most work, because relapse is the central problem of TRD, and we now have two complementary tools to fight it instead of one.
Looking Ahead
Interventional psychiatry is rapidly transforming depression treatment. Instead of relying solely on medications that alter neurotransmitters, clinicians now have therapies capable of directly modifying dysfunctional brain circuits and enhancing neuroplasticity.
As evidence grows, combination approaches may become an important component of precision psychiatry.
A New Era of Hope
Treatment-resistant depression no longer means treatment-resistant forever.
The combination of TMS with ketamine or Spravato represents one of the most promising frontiers in interventional psychiatry. While additional high-quality research is needed before combination therapy becomes standard practice, early evidence suggests that leveraging two complementary mechanisms of action may offer new hope for patients who have exhausted conventional options.
