(1) Background: Major depressive disorder (MDD) generates a large proportion of global disease burden. Stereotactic radiofrequency ablation (SRA) may be beneficial for selected patients with its most debilitating and refractory forms, but effect size is uncertain. (2) Methods: A systematic literature review and meta-analysis on SRA for MDD was carried out. Patient-level data were extracted from articles reporting validated depression measures (Beck Depression Inventory (BDI), Montgomery–Åsberg Depression Rating Scale (MADRS)), pre- and at least six months post surgery. To accommodate different outcome measures, the standardised mean difference (SMD) between both scores was used as the principal effect size. Data were synthesised using a random-effects model. (3) Results: Five distinct studies were identified, comprising 116 patients (64 included in meta-analysis). Effect size comparing post- vs. pre-operative scores was 1.66 (CI 1.25–2.07). Anterior cingulotomy (two studies, n = 22) and anterior capsulotomy (three studies, n = 42) showed similar effect sizes: 1.51 (CI 0.82–2.20) vs. 1.74 (CI 1.23–2.26). Multiple procedures were performed in 30 of 116 (25.9%) patients. Based on patient-level data, 53% (n = 47) were responders (≥50% improvement), of which 34% reached remission (MADRS ≤ 10 or BDI ≤ 11). BDI mean improvement was 16.7 (44.0%) after a second procedure (n = 19). (4) Conclusions: The results are supportive of the benefit of SRA in selected patients with refractory MDD.
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