Distinct Symptom Trajectories May Help plan Personalized Treatment of Resistant Depression: JAMA
A cohort study of adults with treatment-resistant depression has identified four distinct longitudinal symptom-cluster response trajectories, with substantial differences in clinical outcomes. Baseline anxiety severity and benzodiazepine use were associated with trajectory membership, suggesting these factors may help guide individualized treatment planning. Prospective studies are needed to confirm these findings. The study was published in JAMA Network Open by Tyler S. and colleagues.
To detect symptom-level responses, researchers performed post-hoc cohort analysis using prospectively collected data from a randomized controlled THREE-D study conducted at three Canadian academic hospitals. The analytical cohort consisted of 388 adults aged between 18 and 65 years with major depressive disorder (average age 42.33 ± 11.48 years; 229 female patients [59.02%] from 414 randomly selected patients).
Patients were treated with either high-frequency or intermittent theta-burst stimulation on the left dorsolateral prefrontal cortex once per day for 4 to 6 weeks. Group-based multitrajectory modeling was used to identify baseline predictors of trajectory group allocation using weighted multinomial logistic regression in four validated HDRS-17 symptom domains (mood, anxiety, insomnia, and somatic symptoms) during 4 weeks.
Key findings:
- Multitrajectory models based on the grouping of 388 study participants revealed four different response groups.
- With 119 patients (30.67%) involved, this response group showed significant symptom relief in all clusters, achieving a total response of 83.48% and remission of 65.22%.
- Two groups with partial response were distinguished: partial response with high baseline anxiety (128 patients [32.99%]) and partial response with low baseline anxiety (91 patients [23.45%]).
- Involving 50 patients (12.88%), this group did not show any improvement in the clinical state in all domains, resulting in an overall response and remission rate of 0%.
- The minimal response group was compared to the partial response, high anxiety group, revealing the association of minimal response with the age younger than in the partial response, high anxiety group (OR, 0.95; 95% CI, 0.92–0.99; P = 0.01), benzodiazepines usage (OR, 2.73; 95% CI, 1.24–6.05; P = 0.01), lower baseline anxiety score (OR, 0.73; 95% CI, 0.60–0.89; P < 0.001), and higher baseline mood symptoms severity (OR, 1.35; 95% CI, 1.13–1.61; P < 0.001).
In summary, rTMS targeting the dorsolateral prefrontal region of patients with treatment-resistant depression results in four different longitudinal symptom cluster trajectories, varying from complete remission to minimal effect of therapy. The conclusions of this study stress the importance of anxiety at the beginning of the treatment and the use of benzodiazepines as important predictors.
Reference:
Kaster TS, Chen X, Downar J, et al. Dorsolateral Prefrontal rTMS Symptom Cluster Response Trajectories for Depression. JAMA Netw Open. 2026;9(9):e2636032. doi:10.1001/jamanetworkopen.2026.36032
