Identifying Clinical Predictors of Unfavorable Treatment Trajectories in Major Depressive Disorder: A National...

While antidepressant side effects are often expected to diminish with continued treatment, empirical evidence remains limited. This study investigates co-trajectories of depressive severity with side-effect burden (SEB) and associated factors in patients with major depressive disorder (MDD).

We analyzed longitudinal data from 1377 MDD outpatients across three Chinese multicenter studies (2015-2022), with assessments at baseline, weeks 2, 4, 8, 12, and 24. Depression severity was measured using the Quick Inventory of Depressive Symptomatology-Self Report (QIDS-SR16). At the same time, SEB was quantified using the frequency, intensity, and burden of side effects rating (FIBSER). Dual-trajectory modeling was used to identify distinct SEB and depression severity trajectories, with linear mixed-effects models comparing depression changes across SEB groups.

Four SEB trajectories were identified: no SEB (41.5%), early-onset SEB (29.1%), late-onset SEB (14.7%), and persistent SEB (13.9%). Depressive severity followed three trajectories: mild-responsive (66.6%), moderate-progressive (18.7%), and chronic-severe (14.7%). Persistent SEB was associated with higher baseline depression severity (OR = 1.13, 95% CI: 1.08-1.17), antidepressant combination (OR = 3.7, 95% CI: 1.52- 9.02), and poorer treatment outcomes. 7.3% exhibited concurrent chronic-severe depressive severity and persistent SEB. Female (OR = 1.95, 95% CI: 1.11-3.42), younger age (OR = 5.02, 95% CI: 2.63-9.55), higher education (high school: OR = 2.5, 95% CI: 1.12-5.36; bachelor and above: OR = 2.68, 95% CI: 1.24-5.82), and combination antidepressant (OR = 8.27, 95% CI: 2.69-25.45) were significant risk factors for concurrent severe symptoms and persistent SEB.

Persistent antidepressant side effects coevolve with unfavorable depression trajectories over 6 months. Clinicians should prioritize early monitoring and tailored interventions for high-risk subgroups, particularly those with severe baseline symptoms or on combination therapy. These findings underscore the importance of continuous monitoring and personalized interventions to manage antidepressant side effects effectively.