Symptom cluster response trajectories with dorsolateral prefrontal rTMS for depression: A THREE-D Study

Using the Hamilton Depression Rating Scale (HDRS) sum score to quantify the efficacy of repetitive transcranial magnetic stimulation (rTMS) in major depressive disorder (MDD) may overlook the heterogeneity of distinct longitudinal symptom cluster response trajectories. We used data from the THREE-D clinical trial (N = 388) comparing two forms of rTMS delivered over 4–6 weeks to the left dorsolateral prefrontal cortex (DLPFC) for treatment-resistant depression (TRD). We examined the four symptom domains measured with the HDRS (anxiety, mood, insomnia, and somatic) and applied group-based multi-trajectory modeling (GBMTM) to identify latent groups based on responses simultaneously occurring within each symptom cluster. We then used multinomial regression to identify patient characteristics associated with each group. We identified four distinct longitudinal symptom cluster response trajectory groups: Optimal response (N = 119; 30.7%); Partial response, high anxiety (N = 128; 33.0%); Partial response, low anxiety (N = 91; 23.5%); Minimal response (N = 50; 12.9%). The optimal response trajectory was characterized by a rapid decrease in all symptom clusters by week 2, while the Minimal response trajectory group showed no or even worsened symptom severity. Two moderate response trajectories showed linear response but differing baseline anxiety severity. The optimal response group was associated with lower symptom scores, and the Minimal response group was associated with younger age, benzodiazepine use, lower baseline anxiety, and higher baseline depression symptoms. This work demonstrates that distinct symptom cluster response trajectories exist amongst individuals with TRD receiving rTMS, with anxiety symptoms being particularly important for identifying those most likely to benefit from treatment. ClinicalTrials.Gov: NCT01887782