Clinical Predictors of Response to Repetitive Transcranial Magnetic Stimulation for Depression

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Case Vignette

“Mrs Carlson” is a 62 year-old Caucasian female with a history of major depressive disorder (MDD) that is recurrent and severe. In her 20s, she had a brief course of electroconvulsive therapy for a presumed episode of catatonia. She is currently treated with a selective serotonin-norepinephrine reuptake inhibitor, and has failed previous trials of a selective serotonin reuptake inhibitor and bupropion. After a period of illness remission lasting 5 years, at her most recent outpatient clinic visit, she reports a moderate worsening of depressive symptoms for the past 3 months. She does not identify any specific psychosocial stressors. She denies suicidal ideation during the present depressive episode. Mrs Carlson inquires about whether she is a candidate for and the likelihood of responding to transcranial magnetic stimulation, as she believes purchasing and using such a device would be helpful for her mood. As her psychiatrist, how would you respond?

The pooled response rate for repetitive transcranial magnetic stimulation (rTMS) in MDD clinical trials is 40%,¹ and 31% in natural clinical settings.² However, there are considerable inter-individual differences in patterns of response to rTMS. There is also emerging evidence that specific depressive symptoms may have unique trajectories.³ A recent analysis of a large clinical trial identified a subgroup of rapid responders by the second week of rTMS.⁴ Another study found that two-thirds of patients with a reduction in general depressive symptoms after 10 sessions were responders by session 20.⁵ However, previous studies have note explored whether early improvements in specific depressive symptoms during rTMS predict response.

The Current Study

Winninge et al described symptom trajectories in patients with depression undergoing rTMS to identify predictors of treatment response among baseline clinical factors and early symptom improvement.⁶ A patient cohort was recruited from consecutive referrals to a brain stimulation unit at a single site.

Inclusion criteria were age 18 or older, having a unipolar or bipolar depressive episode, and receiving left-sided iTBS or right-sided 1 Hx short rTMS for the first time. The coil was placed over the F3, targeting the left dorsolateral prefrontal cortex (DLPFC). The iTBS protocol consisted of 3 pulses at 50 Hz, repeated at 5 Hz for 2 seconds, followed by an 8-second break, and these trains were repeated 20 times, adding up to 600 pulses. In the second line rTMS protocol, the coil was placed over F4, targeting the right DLPFC. This protocol comprised 1 minute trains of 1 Hz stimulation followed by a 30-second break, repeated 6 times, resulting in 360 pulses. For both protocols, the treatment intensity was set at 120% of the resting motor threshold. Daily treatment sessions were administered every weekday for 4 to 6 weeks, 20 to 30 sessions in total, or until achieving remission. Treatment was stopped if there was less than 20% improvement in depressive symptoms at 4 weeks. Clinical data and symptom ratings were obtained from the medical record.

The primary outcome was rTMS response, defined as a greater than or equal to 50% reduction in the MADRS-S total score. The other primary outcome was rTMS response defined as “very much improved” or “much improved” on the CGI-I. The secondary outcome was rTMS remission, defined at “normal, not at all ill” or “borderline mentally ill” on the CGI scale.

Baseline predictors included sex, age, unipolar vs bipolar depression, treatment failures, medical augmentation, and previous ECT. Early predictors of response were: greater than or equal to 1 point reduction in all 9 MADRS-S individual items, greater than or equal to 20% reduction in MADRS-S total score, and greater than or equal to 1 point reduction in the CPRS memory items after 2 weeks of rTMS.

Data were plotted in linear graphs to visualize symptom trajectories. Binary logistic regression was used to analyze clinical characteristics at baseline and early improvement as predictors of rTMS response. All of these predictors were entered into a multivariate logistic regression analysis. All patients with a MADRS-S rating were included in an intent-to-treat analysis, using the last available rating (regardless of treatment duration).

Mean subject age was 35, 59% were female, 81% had unipolar depression, and 85% received iTBS. The mean MADRS-S score was 34, corresponding to moderate depression. The majority of study participants completed rTMS treatment after 5 weeks. The response rate was 21% based n MADRS-S and 45% based on CGI-I. The remission rate was 20%. All 9 MADRS-S items decreased numerically during rTMS treatment.

In multivariate analysis, participants aged 40 or older had a significantly lower odds (vs younger age groups) for rTMS response (OR=0.25, 95% CI 0.06-0.96). Longer duration of the depressive episodes (24 months or more; OR=0.25, 95% CI 0.07-0.93) and history of previous ECT (OR=0.14, 95% CI 0.03-0.79) was also associated with lower odds of response. Early improvement in initiative (OR=3.1, 95% CI 1.1-9.0), emotional involvement (OR=3.0, 95% CI 1.0-9.1), and pessimism (OR=0.24, 95% CI 0.07-0.80) were significant early predictors of response in multivariate analyses. Early improvement in the AMADRS-S total score was a significant predictor of CGI-I response (OR=3.6, 95% CI 1.4-9.5). Early improvement in the CPRS memory item was not a significant predictor of response.

Study Conclusions

The authors found that a longer depressive episode predicted a poorer MADRS-S response. Early improvement in the MADRS-S total score and the individual item emotional involvement predicted a CGI-I response. Furthermore, the MADRS-S response was predicted by an early improvement in initiative. This is the first known study to identify early improvements in specific depressive symptoms as positive predictors of rTMS response. Study strengths included recruitment of consecutive referral for rTMS, although 24% declined to participate, which could also introduce selection bias. Other study limitations included lack of consideration for effects of concurrent medications.

The Bottom Line

Baseline clinical factors (age, duration of depressive episode) and early improvement in overall and specific depressive symptoms (initiative, emotional involvement), predict response to rTMS in patients with depression. Findings have direct clinical relevance to patient care.

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. Vida RG, Sághy E, Bella R, et al. Efficacy of repetitive transcranial magnetic stimulation (rTMS) adjunctive therapy for major depressive disorder (MDD) after two antidepressant treatment failures: meta-analysis of randomized sham-controlled trials. BMC Psychiatry. 2023;23(1):545.

2. Bouaziz N, Laidi C, Bulteau S, et al. Real world transcranial magnetic stimulation for major depression: a multisite, naturalistic, retrospective study. J Affect Disord. 2023;326:26-35.

3. Sakurai H, Uribe S, Cirillo P, et al. Residual symptoms after achieving remission with repetitive transcranial magnetic stimulation in depression. J Affect Disord. 2022;301:154-161.

4. Kaster TS, Downar J, Vila-Rodriguez F, et al. Differential symptom cluster responses to repetitive transcranial magnetic stimulation treatment in depression. EClinicalMedicine. 2023;55:101765.

5. Gill J, De Felice N, Gill Jaspreet et al. Repetitive transcranial magnetic stimulation: course and early prediction of response in depression. J Psychiatr Res. 2023;157:108-111.

6. Winninge M, Cernvall M, Persson, J, et al. Early symptom improvement and other clinical predictors of response to repetitive transcranial magnetic stimulation for depression. J Affect Disord. 2024;361:383-389.