Comparing fast-acting interventions for treatment-resistant depression: An explorative study of accelerated HF-rTMS versus intranasal esketamine

Treatment-resistant depression (TRD), the non-response to two different antidepressant classes during a major depressive episode, is a severe clinical condition in almost 30% of depressed patients, carrying substantial direct and indirect financial burdens on the healthcare system [[1]Zhdanava M. et al.The prevalence and national burden of treatment-resistant depression and major depressive disorder in the United States.J Clin Psychiatry. Mar. 2021; 82https://doi.org/10.4088/JCP.20m13699Crossref PubMed Google Scholar]. Accelerated ArTMS (arTMS) protocols are novel approaches that exert a comparable antidepressant efficacy without significantly compromising the safety and tolerability associated with the standard rTMS regimen [[2]Sonmez A.I. et al.Accelerated TMS for Depression: a systematic review and meta-analysis.Psychiatr Res. Mar. 2019; 273: 770-781https://doi.org/10.1016/j.psychres.2018.12.041Crossref PubMed Scopus (90) Google Scholar,[3]Fitzgerald P.B. Hoy K.E. Elliot D. Susan McQueen R.N. Wambeek L.E. Daskalakis Z.J. Accelerated repetitive transcranial magnetic stimulation in the treatment of depression.Neuropsychopharmacology. Jun. 2018; 43: 1565-1572https://doi.org/10.1038/s41386-018-0009-9Crossref PubMed Scopus (73) Google Scholar]. arTMS also ensures the potential for rapid antidepressant action, observable within the initial post-treatment weeks [[4]Cole E.J. et al.Stanford accelerated intelligent neuromodulation therapy for treatment-resistant depression.Am J Psychiatr. Aug. 2020; 177: 716-726https://doi.org/10.1176/appi.ajp.2019.19070720Crossref PubMed Scopus (184) Google Scholar]. This qualifies arTMS as a rapid therapeutic intervention for TRD, comparable to glutamatergic modulators like intranasal esketamine (ESK-NS), an N-methyl-d-aspartate (NMDA) receptor antagonist [[5]d'Andrea G. Pettorruso M. Di Lorenzo G. Mancusi G. McIntyre R.S. Martinotti G. Rethinking ketamine and esketamine action: are they antidepressants with mood-stabilizing properties?.Eur Neuropsychopharmacol. 2023; 70: 49-55https://doi.org/10.1016/j.euroneuro.2023.02.010Crossref Scopus (1) Google Scholar], approved as the first therapeutic agent for TRD by FDA and EMA [[6]Martinotti G. et al.Real-world experience of esketamine use to manage treatment-resistant depression: a multicentric study on safety and effectiveness (REAL-ESK study).J Affect Disord. Sep. 2022; 319: 646-654https://doi.org/10.1016/j.jad.2022.09.043Crossref Scopus (7) Google Scholar]. A direct comparison between these two treatment protocols is currently missing. Hence, this study aimed to compare (a) the effectiveness and the speed of antidepressant action and (b) the safety and tolerability of arTMS and ESK-NS in treating TRD. In a multicentric, observational, retrospective study, we studied 59 patients with TRD (women/men, n = 32/n = 27; age, 54.61 ± 11.32) who consecutively underwent either a one-week, high-frequency rTMS protocol (ReModula: four daily sessions of HF-rTMS over the left DLPFC for five consecutive days) or a three-month ESK-NS therapy (biweekly administrations in the first month; weekly in the second month: bimonthly in the third month). Study design and administration procedures of arTMS and ESK-NS are fully detailed in supplementary materials. Treatment assignment (arTMS: n = 30; ESK-NS: n = 29) was determined based on the clinician's judgment. The depression severity was assessed with the total score of the Montgomery–Åsberg Depression Rating Scale (MADRS) at baseline (T0), one month (T1), and three months (T2) after the initiation of treatment. Sociodemographic and clinical characteristics did not differ between treatment groups at T0 (see supplementary materials), except for a longer duration of the current episode among those patients treated with arTMS (months, 19.57 ± 13.42 vs. 12.03 ± 9.47; t57 = 2.484, p = 0.016). rm-ANCOVA (within-factor: "time"; between-factors: "gender", "protocol"; covariate: age, duration of the current episode, number of failed antidepressant trials in the current episode) showed a significant "time" × "protocol" interaction effect (F2.104 = 3.814, p = 0.025, ηp2 = 0.068) on MADRS score, with Mauchly's test of sphericity not significant (W = 0.893, χ22 = 5.794, p = 0.055). As shown in Fig. 1A, the MADRS scores between the two groups:a)did not differ at baseline (p = 0.307);b)decreased significantly and separately at T1 (arTMS, T0 vs. T1: p < 0.001, d = 1.709; ESK-NS, T0 vs. T1: p < 0.001, d = 1.361) and T2 (arTMS, T0 vs. T2: p < 0.001, d = 1.822; arTMS, T1 vs. T2: p = 0.989, d = 0.218; ESK-NS, T0 vs. T2: p < 0.001, d = 2.338; ESK-NS, T1 vs. T2: p < 0.001, d = 1.042);c)significantly differed at T1 (p = 0.048), with a higher MADRS decrease (d = 0.864) in the arTMS group, but did not at T2 (p = 1.000). As shown in the upper panels of Fig. 1B, the response rates (RRs) (≥50% decrease of MADRS total score) were significantly higher in arTMS than ESK-NS at T1 (respectively, n = 15/50% vs. n = 5/17.24%: χ12 = 7.062, p = 0.008), but not at T2 (n = 18/60% vs. n = 20/68.97%: χ12 = 0.517, p = 0.472). The remission rates (MADRS total score <10) did not differ between groups at T1 and T2 (T1, n = 5/16.67% vs. n = 1/3.45%: χ12 = 2.820, p = 0.093; T2, n = 12/40% vs. n = 10/34.48%: χ12 = 0.192, p = 0.661), as depicted in lower panels of Fig. 1B. Regarding safety and tolerability, eight patients (26.66%) from the arTMS group and 24 (82.75%) from the ESK-NS group reported treatment-related side effects (trSEs). The most frequent arTMS trSEs were transient post-stimulation headache (13.33%) and scalp discomfort at the stimulation site (10%). Additionally, one participant encountered a mid-episode of agitation throughout the stimulation session, which was transient and didn't require any specific intervention. The most prevalent ESK-NS trSEs were: temporary sedation (55.17%), transient dissociative symptoms (34.5%), short-lived hypertension (10%), and brief agitation (6.89%). Our findings revealed that arTMS had a more rapid effect, yielding higher RRs at the one-month follow-up than ESK-NS. arTMS accelerated response aligns with previous research, suggesting that faster protocols can shorten treatment duration, maintaining comparable efficacy [[2]Sonmez A.I. et al.Accelerated TMS for Depression: a systematic review and meta-analysis.Psychiatr Res. Mar. 2019; 273: 770-781https://doi.org/10.1016/j.psychres.2018.12.041Crossref PubMed Scopus (90) Google Scholar]. Simultaneously, they potentially lead to a swifter response than standard protocols [[4]Cole E.J. et al.Stanford accelerated intelligent neuromodulation therapy for treatment-resistant depression.Am J Psychiatr. Aug. 2020; 177: 716-726https://doi.org/10.1176/appi.ajp.2019.19070720Crossref PubMed Scopus (184) Google Scholar]. Besides, the RRs for arTMS and ESK-NS were consistent with existing literature, which reports three-month RRs of 60% for arTMS and 62.06% for ESK-NS among patients with TRD [[6]Martinotti G. et al.Real-world experience of esketamine use to manage treatment-resistant depression: a multicentric study on safety and effectiveness (REAL-ESK study).J Affect Disord. Sep. 2022; 319: 646-654https://doi.org/10.1016/j.jad.2022.09.043Crossref Scopus (7) Google Scholar,[7]Miron J.-P. Jodoin V.D. Lespérance P. Blumberger D.M. Repetitive transcranial magnetic stimulation for major depressive disorder: basic principles and future directions.Ther. Adv. Psychopharmacol. 2021; 1120451253211042696https://doi.org/10.1177/20451253211042696Crossref Google Scholar]. In terms of safety and tolerability, both treatments were found to be safe, with minor and transient trSEs. Notably, arTMS demonstrate lower trSEs incidence, potentially offering a more tolerable treatment option. However, the incidence of ESK-NS trSEs is consistent with real-world settings [[6]Martinotti G. et al.Real-world experience of esketamine use to manage treatment-resistant depression: a multicentric study on safety and effectiveness (REAL-ESK study).J Affect Disord. Sep. 2022; 319: 646-654https://doi.org/10.1016/j.jad.2022.09.043Crossref Scopus (7) Google Scholar]. Interestingly, neither treatment induced manic switches, confirming their safety [[6]Martinotti G. et al.Real-world experience of esketamine use to manage treatment-resistant depression: a multicentric study on safety and effectiveness (REAL-ESK study).J Affect Disord. Sep. 2022; 319: 646-654https://doi.org/10.1016/j.jad.2022.09.043Crossref Scopus (7) Google Scholar,[8]Miuli A. et al.Hypomanic/manic switch after transcranial magnetic stimulation in mood disorders: a systematic review and meta-analysis.World J Psychiatr. Aug. 2021; 11: 477-490https://doi.org/10.5498/wjp.v11.i8.477Crossref Google Scholar,[9]Martinotti G. et al.Treating bipolar depression with esketamine: safety and effectiveness data from a naturalistic multicentric study on esketamine in bipolar versus unipolar treatment-resistant depression.Bipolar Disord. 2023; n/ahttps://doi.org/10.1111/bdi.13296Crossref Scopus (3) Google Scholar]. Several limitations should be considered. Firstly, the retrospective and naturalistic nature of the study did not allow for treatment randomization or the use of blinded assessors. However, the study's design is also a strength since it is more representative of real-world conditions, unlike RCTs which often involve only pre-screened subjects. Secondly, the limited sample size of both treatment groups highlights the need for more extensive cohort studies for validation. The findings from this explorative research should be replicated, especially through randomized prospective studies. This work was supported by the Italian Ministry of Health (Ricerca Finalizzata, Young Researchers grant, GR-2019-12370173). This work was also supported by the "Departments of Excellence 2018–2022" initiative of the Italian Ministry of Education, University and Research for the Department of Neuroscience, Imaging and Clinical Sciences (DNISC) of the University of Chieti-Pescara.