Combination therapy with transcranial magnetic stimulation and ketamine for treatment-resistant depression: A long-term retrospective review of clinical use

Introduction

Treatment-resistant depression (TRD) denotes major depressive disorder that fails to remit after adequate trials of at least two antidepressants from different pharmacological classes. Best and colleagues describe the high prevalence of non-response in MDD and outline neurobiological models that implicate dysregulated thalamocortical and fronto-limbic circuitry, with particular emphasis on abnormalities in the dorsolateral prefrontal cortex and the anterior cingulate cortex (ACC). The introduction summarises established neuromodulation and pharmacological options: repetitive transcranial magnetic stimulation (rTMS) is an FDA‑approved, generally well-tolerated non‑invasive neuromodulatory treatment for TRD, while intravenous ketamine, an NMDA receptor antagonist, produces rapid but often short-lived antidepressant effects. Previous studies and meta-analyses indicate modest response and remission rates for rTMS alone and transient benefit for single-dose ketamine infusions, motivating combination approaches. This paper introduces a novel concurrent therapy—combination TMS with ketamine (CTK)—and sets out to explore its clinical utility in routine psychiatric practice. The investigators hypothesise that simultaneous administration of TMS (targeting the medial prefrontal/ACC region) and titrated IV ketamine could produce synergistic effects: TMS might disrupt pathological ACC synchrony while ketamine modulates neurotransmission. The current retrospective review aims to describe safety and long-term clinical outcomes of CTK in a private clinic cohort of patients diagnosed with TRD, with symptom severity assessed before treatment, immediately after, and at two years follow-up.