Intranasal Esketamine and iTBS for Severe Depression: A Case Study

Novel Combination for Severe Depression

A recent case report published on July 1, 2026, in a Tier 1 venue, discusses the innovative use of intranasal esketamine combined with accelerated intermittent theta-burst stimulation (iTBS) to treat severe treatment-resistant depression with suicidal ideation. This approach was applied to a 29-year-old female patient who had not responded adequately to multiple antidepressant therapies, augmentation strategies, psychotherapy, and standard repetitive transcranial magnetic stimulation (rTMS).

The treatment involved intranasal esketamine at a dose of 84 mg and an accelerated iTBS protocol targeting the left dorsolateral prefrontal cortex. The iTBS was delivered over four treatment days, totaling 6,000 pulses. The patient showed significant improvement in depressive symptoms and suicidal ideation, with scores on the Patient Health Questionnaire-9 (PHQ-9), Hamilton Depression Rating Scale (HAMD), and Beck Depression Inventory (BDI) decreasing notably during the treatment and at a two-week follow-up.

Mechanism and Clinical Context

Intranasal esketamine, a derivative of ketamine, is known for its rapid antidepressant effects, particularly in cases of treatment-resistant depression. It acts primarily as an NMDA receptor antagonist, which is thought to enhance synaptic plasticity and neurogenesis. Intermittent theta-burst stimulation (iTBS), a form of repetitive transcranial magnetic stimulation, is designed to modulate brain activity by targeting specific cortical areas, in this case, the left dorsolateral prefrontal cortex, which is often implicated in mood regulation.

The combination of these therapies aims to leverage the rapid onset of esketamine with the sustained modulation of neural circuits provided by iTBS. This approach could potentially offer a more comprehensive treatment strategy for patients with severe depression and high-risk suicidal ideation, who require immediate and effective intervention.

Research and Policy Implications

While the case report demonstrates potential feasibility and effectiveness, it underscores the necessity for further controlled studies to evaluate the efficacy, safety, and long-term outcomes of this combined approach. The findings suggest that this combination could be particularly beneficial in acute inpatient settings, where rapid stabilization of symptoms is critical.

Policy implications include the need for updated clinical guidelines that incorporate emerging evidence from novel treatment combinations. Regulatory bodies may need to consider fast-tracking research and approval processes for innovative therapies that address urgent psychiatric needs, such as treatment-resistant depression with suicidal ideation.

Risks and Unknowns

Despite promising results, the combination of intranasal esketamine and iTBS presents several risks and unknowns. The long-term safety and durability of the treatment effects are yet to be established. Additionally, the optimal sequencing and dosing of the therapies require further investigation to minimize potential side effects and maximize therapeutic benefits.

There is also a need for rigorous safety monitoring protocols, especially given the potent nature of esketamine and the intensity of iTBS. The potential for adverse effects, such as dissociative symptoms or increased anxiety, must be carefully managed in clinical settings.

Looking Forward

The case report provides a promising glimpse into the future of psychiatric treatment for severe depression, highlighting the potential of combining pharmacological and neuromodulatory approaches. As research progresses, it will be crucial to establish comprehensive clinical trials that can provide robust evidence on the efficacy and safety of this treatment combination.

Future studies should aim to refine treatment protocols, explore patient-specific factors that may influence outcomes, and develop guidelines for integrating such therapies into standard psychiatric care. The ultimate goal is to expand the therapeutic arsenal available to clinicians, offering hope to patients with the most challenging forms of depression.