New combinations or alternative therapies for major depressive disorder (MDD) are necessary. Intradermal acupuncture (IA) shows promise but requires further investigation regarding its efficacy, safety, and mechanisms. Conducted across 3 centers from November 2022 to January 2024, our randomized controlled trial included 120 participants with moderate to severe MDD, divided into the selective serotonin reuptake inhibitors (SSRIs), SSRIs plus sham IA (SSRIs + SIA), and SSRIs plus active IA (SSRIs + AIA) groups. Acupuncture groups received 10 sessions over 6 weeks at Shenmen (HT7), Neiguan (PC6), Sanyinjiao (SP6) and Taichong (LR3) bilaterally, followed by a 4-week follow-up. The primary outcome was changes in Hamilton Depression Rating Scale-17 (HAMD-17) scores at week 6. Furthermore, healthy controls (HCs) and MDD patients underwent magnetic resonance imaging (MRI) scans for functional connectivity (FC) analysis. After 6 weeks of treatment, the SSRIs + AIA group showed a greater reduction in HAMD-17 score than the SSRIs + SIA group (MD, -4.9 [CI, -7.6 to -2.2], P <
0.002) and SSRIs group (MD, -5.1 [CI, -7.8 to -2.3], P <
0.002). No serious adverse events occurred. SSRIs + AIA resulted in lower incidences of palpitations (vs.SSRIs + SIA: OR, 0.1% [CI, 0.0-1.0%]
vs. SSRIs: OR, 0.1% [CI, 0.0-0.7%]
P <
0.05), somnolence (vs.SSRIs + SIA: OR, 0.1% [CI, 0.0-0.9%]
vs.SSRIs: OR, 0.1% [CI, 0.0-0.7%]
P <
0.05), and nausea (vs.SSRIs + SIA: OR, 0.1% [CI, 0.0-1.0%]
vs. SSRIs: OR, 0.1% [CI, 0.0-0.9%]
P <
0.05). MDD patients showed abnormal FCs, and IA enhanced FCs between striatum and frontal_inf_tri, and striatum and cerebellum in the MRI study. Overall, IA as adjunctive therapy provides clinical efficacy and safety for MDD, and it may exert antidepressant effects by modulating striatal FCs.