Association between the combination of GABAergic agents and SSRIs at the first clinical visit and depressive symptom...

Depression is a leading cause of disability, with limited efficacy of current treatments: 30% - 40% of major depressive disorder patients fail first-line therapy, and relapse rates remain high. Combination pharmacotherapy shows promise, but real-world evidence on initial treatment strategies and longitudinal symptom trajectories is lacking. We conducted a longitudinal analysis of electronic health records from 1,876 patients who visited the Shanghai Mental Health Center between November 2021 and April 2023. Group-based trajectory modeling (GBTM) classified patients into subgroups based on PHQ-9 score trajectories. The Apriori algorithm identified common medication mechanism combinations for the first visit. Multinomial logistic regression evaluated associations between medication groups and trajectory subgroups. General linear modeling examined SDS score improvement. Network pharmacology was conducted as an exploratory analysis to investigate potential biological context. Three PHQ-9 trajectory groups were identified: Rapid Decline (29.96%), Gradual Decline (30.76%), and Worsening (39.28%). The Worsening Group had lower initial PHQ-9 scores but showed progressive severity elevation. Four medication mechanism combination groups were identified including GABAergic agents alone (GABA), selective serotonin reuptake inhibitors alone (SSRIs), GABA+SSRIs combination, and Others. GABA+SSRIs was the most frequent combination (31.02%). Compared with GABA+SSRIs, patients in the SSRIs group (OR adj, 1.809; 95% CI, 1.196 - 2.736) had significantly higher odds of belonging to the Worsening Group (P = 0.005). In the supplementary SDS analysis, GABA monotherapy was associated with significantly less symptom improvement than GABA+SSRIs (β = -1.790, 95% CI: -3.320, -0.258). Network analysis identified 33 intersecting targets between GABA+SSRIs and depression, enriched in neurotransmission and synaptic plasticity pathways. Overall, the combination of GABAergic agents and SSRIs at the first clinical visit was associated with a more favorable PHQ-9 trajectory group than SSRIs monotherapy. These findings may inform future prospective and mechanistic studies on medication mechanism combinations in depression treatment.