rTMS for Antidepressant Nonresponders

vxnaghiyev/AdobeStock

Case Vignette

“Mr Host” is a 22 year-old Caucasian man with a history of severe major depressive disorder (MDD), without psychosis. The duration of his current depressive episode is 9 months. During this episode, Mr Host has failed trials of a selective serotonin reuptake inhibitor, bupropion, and aripiprazole.He declined electroconvulsive therapy (ECT) due to concerns about adverse cognitive effects from the procedure. His current regimen includes fluoxetine 80 mg daily and adjunctive amphetamine-dextroamphetamine extended-release 20 mg daily for the past 4 weeks, with no clinical response. At his most recent outpatient clinic visit, he expresses interest in transcranial magnetic stimulation (TMS). As his psychiatrist, how would you respond?

One-third of patients with MDD experience inadequate response to pharmacotherapy and psychotherapy. Remission rates drop from approximately 35% for the first to antidepressant trials to 15% thereafter.¹ These findings suggest that after 2 failed antidepressant trials, a different therapeutic modality might be beneficial. One such approach is repetitive transcranial magnetic stimulation (rTMS), which is commonly used in treatment-resistant depression (TRD).² However, the positioning of rTMS in sequential depression treatment algorithms remains unresolved.

The Current Study

Dalhuisen et al examined the comparative effectiveness of rTMS as an alternative to the next pharmacological step (ie, antidepressant switch or augmentation) in a randomized control trial.³ The authors investigated the effectiveness of rTMS plus psychotherapy and continued antidepressant medication compared with a switch from the current antidepressant medication in combination with psychotherapy over 8 weeks of unblinded treatment. Adult patients were recruited from outpatient clinics across the Netherlands between August 2019 and December 2022.

MDD was diagnosed based on the Structured Clinical Interview for DSM-5. Inclusion criteria were a score greater than 16 on the 17-item Hamilton Depression Rating Scale (HAM-D); no psychotic symptoms; inadequate response to at least 2 treatment trials (of which at least 1 was an antidepressant); and current depressive episode duration of less than 2 years. Patients taking antidepressants were on stable medication for 6 weeks. Exclusion criteria were contraindications to rTMS.⁴ Patients were randomized to either rTMS or medication using a stratified block design with treatment center, number of depressive episodes, and baseline depression severity as strata.

The Beam-F3 method was used to localize the left dorsolateral prefrontal cortex.⁵ rTMS was conducted using a high-frequency protocol (10 Hz), with 60 trains of 50 pulses with a duration of 5 seconds and an intertrain interval of 25 seconds (3000 pulses per session), at an intensive of 120% of the resting motor threshold. Twenty-five sessions were scheduled over the course of 8 weeks.

All patients received individual or group psychotherapy, at least once a week. Sessions were not standardized but could consist of cognitive behavior therapy, behavioral activation therapy, or supportive therapy.

Medication treatment as usual was based on pharmacological treatment steps of the Dutch guidelines.⁶ This consisted of either a switch from the current antidepressant to a tricyclic antidepressant or augmentation with lithium or a second-generation antipsychotic. If, for medical reasons, these were not suitable options, a different antidepressant could be prescribed.

The HAM-D and Beck Depression Inventory (BDI-II) were used to assess depressive symptoms and baseline and during treatment, after every fifth rTMS treatment or on corresponding days for patients on medication. Changes in depressive symptoms (HAM-D) were analyzed with longitudinal linear mixed models, controlling for age and gender. The proportion of responders (50% reduction in HAM-D score) and remitters (less than 8 on HAM-D) were also calculated. Analyses were performed using the intention-to-treat sample.

The intention-to-treat sample consisted of 89 patients (48 allocated to rTMS and 41 to medication). Seventy-six patients completed 78 weeks of treatment. Mean patient age was 44 and 33% were male. Mean baseline HAM-D score was 21.4. Patients in the rTMS group showed a larger decrease in HAM-D score (mean [SD] = -10.0 [-7.8]) compared with medication (-4.2 [7.2]) with a large effect size (Cohen’s d = -0.77). Response and remission rates were 38% and 27% in the rTMS group, vs 15% and 5% in the medication group. In a longitudinal linear mixed model, the interaction between treatment group and time predicted changed in depression severity. Log-rank tests found significant differences in time to both response and remission in favor of rTMS. After 8 weeks of treatment, the odds ratios were 3.5 for response and 7.2 for remission (number needed to treat = 4.4 and 4.5, respectively).

Study Conclusions

The authors performed the first large multi-center clinical trial of the comparative efficacy of rTMS and next-step antidepressant treatment, combined with psychotherapy. They found evidence for superior efficacy of rTMS across symptom reduction, response, and remission. They also found that patients’ expectations of treatment were significantly associated with response to both rTMS and medication. Based on findings, the authors argue that an explicit recommendation can be made regarding the placement of rTMS in the depression treatment algorithm. Study limitations included the uneven distribution of patients between the 2 treatment arms; the trial duration may have been too short to capture the full effect of antidepressant medication; the unconventional rTMS treatment schedule; and that the trial was unblinded.

The Bottom Line

rTMS was more effective than pharmacological treatment in patients with moderate TRD. rTMS could be considered a viable treatment option at an early stage of the depression treatment algorithm and may be more effective than medication switch or augmentation.

Dr Miller is professor in the Department of Psychiatry and Health Behavior, Augusta University, Augusta, Georgia. He is on the Editorial Board and serves as the schizophrenia section chief for Psychiatric Times. The author reports that he receives research support from Augusta University, the National Institute of Mental Health, and the Stanley Medical Research Institute.

References

1. Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR* D report. Am J Psychiatry. 2006;163(11):1905-1917.

2. Dalhuisen I, van Bronswijk S, Bors J, et al. The association between sample and treatment characteristics and the efficacy of repetitive transcranial magnetic stimulation in depression: a meta-analysis and meta-regression of sham-controlled trials. Neurosci Biobehav Rev. 2022;141:104848.

3. Dalhuisen I, van Oostrom I, Spijker J, et al. rTMS as a next step in antidepressant nonresponders: a randomized comparison with current antidepressant treatment approaches. Am J Psychiatry. 2024;181(9):806-814.

4. Dalhuisen I, Smit F, Spijker J, et al. rTMS combined with CBT as a next step in antidepressant non-responders: a study protocol for a randomized comparison with current antidepressant treatment approaches. BMC Psychiatry. 2022;22(1):88.

5. Beam W, Borckardt JJ, Reeves ST, et al. An efficient and accurate new method for locating the F3 position for prefrontal TMS applications. Brain Stimul. 2009;2(1):50-54.

6. Spijker J, Bockting CL, Meeuwissen JA, et al. Multidisciplinaire richtlijn Depressie (Derde revisie). Richtlijn voor de diagnostiek, behandeling en begeleiding van volwassen patiënten met een depressieve stoornis. Utrecht, Trimbos Instituut. 2013.