Predicting Response to rTMS in MDD

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Case Vignette

“Ms June” is a Caucasian woman aged 62 years with a history of major depressive disorder (MDD) that is recurrent and severe. In her 20s, she had a brief course of electroconvulsive therapy (ECT) for a presumed episode of catatonia. She is currently treated with a selective serotonin-norepinephrine reuptake inhibitor. Previous trials of a selective serotonin reuptake inhibitor and bupropion were unsuccessful. She had 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. Ms June inquires about whether she is a candidate for and the likelihood of responding to repetitive transcranial magnetic stimulation (rTMS), as she believes purchasing and using such a device would be helpful for her mood. As her psychiatrist, how would you respond?

The pooled rTMS in MDD clinical trials is 40%,¹ and 31% in natural clinical settings.² However, there are considerable interindividual differences in patterns of response, and emerging evidence shows 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 responded by session 20.⁵ Yet, previous studies have not explored whether early improvements in specific depressive symptoms during rTMS predict response.

The Study

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

Inclusion criteria were age 18 years or older, having a unipolar or bipolar depressive episode, and receiving left-sided intermittent θ-burst stimulation (iTBS) or right-sided 1-Hz 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, all repeated 20 times for a total of 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 weekdays for 4 to 6 weeks, 20 to 30 sessions in total, or until achieving remission. Treatment was stopped if there was <20% improvement in depressive symptoms at 4 weeks. Clinical data and symptom ratings were obtained from medical records.

The primary outcome was rTMS response, defined as ≥50% reduction in the self-rating Montgomery-Åsberg Depression Rating Scale (MADRS-S) total score, and defined as very much or much improved on the Clinical Global Impression-Improvement Scale (CGI-I). The secondary outcome was rTMS remission, defined as 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 ≥1-point reduction in all MADRS-S individual items, ≥20% reduction in MADRS-S total score, and ≥1-point reduction in the Comprehensive Psychopathological Rating Scale (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 the data. Predictors were entered into a multivariate logistic regression analysis. Patients with a MADRS-S rating were included in an intent-to-treat analysis using the last available rating (regardless of treatment duration).

Mean participant age was 35 years, 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 participants completed rTMS treatment after 5 weeks. The response rate was 21% based on MADRS-S and 45% based on CGI-I. The remission rate was 20%. All MADRS-S items decreased numerically during rTMS treatment.

In multivariate analysis, participants 40 years or older had 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) were 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 MADRS-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. Further, 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 referrals for rTMS, although 24% declined to participate, which could introduce selection bias. Other 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 a professor in the Department of Psychiatry and Health Behavior, Augusta University, Georgia. He is on the Editorial Board and serves as the schizophrenia section chief for Psychiatric Times. The author reports receiving 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. 2022;55:101765.

5. Gill J, De Felice N, Gill J, 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, Bodén R. Early symptom improvement and other clinical predictors of response to repetitive transcranial magnetic stimulation for depression. J Affect Disord. 2024;361:383-389.