Efficacy of intranasal esketamine versus rTMS for treatment-resistant depression: analysis of individual participant data from two clinical trials.

Background: Repetitive transcranial magnetic stimulation (rTMS) and intranasal esketamine are effective treatment options for treatment-resistant depression (TRD) that have not been directly compared. We aimed to compare the effectiveness of rTMS, intranasal esketamine, and pharmacotherapy for TRD using data from two randomised clinical trials (RCTs). Methods: This secondary analysis of individual patient data (IPD) included data from two large clinical trials for rTMS (THREE-D; non-inferiority RCT, four sites in Canada from Sept 2013 to Oct 2016, n = 388 eligible) and intranasal esketamine (TRANSFORM-2; superiority RCT, 39 sites across five countries from Aug 2015 to Nov 2017, n = 227 eligible) to compare efficacy for TRD (defined as non-response to at least one evidence-based treatment). A third group included participants who received standard of care (new antidepressant medications) plus placebo nasal spray (TRANSFORM-2). rTMS was delivered in a once daily format, while intranasal esketamine was delivered twice weekly. Restriction, propensity-score matching, and regression adjustments were used to minimise confounding factors between studies. The primary outcome for this analysis was the severity of depressive symptoms using the 17-item Hamilton Depression Rating scale (HDRS), assessed as a continuous measure, after 4 weeks of treatment. THREE-D and TRANSFORM-2 are registered with ClinicalTrials.gov as NCT01887782 and NCT02418585, respectively. Findings: After restriction and propensity-score matching, the analytic sample consisted of 282 participants in three arms: rTMS (n = 94), intranasal esketamine (n = 94), and new antidepressant medication (n = 94). Both rTMS (β: -5.35 [95% CI, -8.77, -1.93]) and intranasal esketamine (-2.89 [-5.38, -0.40]) were superior at reducing depression severity when compared with initiating a new antidepressant medication. rTMS resulted in a non-statistically significant greater symptom reduction compared with intranasal esketamine (-2.46 [-5.82, 0.89]). The upper confidence limit interval for the rTMS and intranasal esketamine comparison provide preliminary evidence that intranasal esketamine is not superior to rTMS by a minimal clinically important difference. Interpretation: This analysis showed rTMS and intranasal esketamine are superior to initiation of a new antidepressant medication, which is consistent with prior randomised clinical trials. Acknowledging its limitations and exploratory nature, our work indicates that rTMS may be superior, or at least similarly effective, to intranasal esketamine and highlights the need for large, prospective, comparative effectiveness trials directly comparing these interventions. Funding: Support for this work was provided by the Delaney Family Foundation. THREE-D was funded by the Canadian Institutes of Health Research and TRANSFORM-2 was funded by Johnson and Johnson Pharmaceuticals.