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Introduction Major depressive disorder (MDD) is the most prevalent mental illness. Antidepressants with rapid efficacy and acceptable tolerance have been investigated for many years. A preclinical study performed by our group revealed that the dysregulation of extracellular ATP is related to the pathophysiology of depression and that the medial prefrontal cortex-lateral habenula pathway is a potential cellular and neural circuit target for ATP involvement in depression-like behaviour. Moreover, through small-sample clinical trials, the group has preliminarily discovered the antidepressant effect of ATP. However, the antidepressant effects of and neural circuit mechanisms underlying ATP in depressed patients remain largely unexplored. This study pioneers the intravenous use of escitalopram in combination with oral escitalopram for the treatment of MDD, thus representing a new direction in antidepressant research.Methods and analysis This clinical study is a single-centre, randomised, double-blind, placebo-controlled, superiority trial involving 120 MDD patients evenly divided into two groups. The experimental group will receive an intravenous injection of 10 mL ATP in 100 mL normal saline (NS) two times per day (BD) for 2 weeks, whereas the control group will receive 110 mL NS BD for 2 weeks. All of the participants will take 10 mg of oral escitalopram daily for 4 weeks, with flexible adjustment thereafter based on clinical response. Our primary outcome will be the change in the Hamilton Depression Rating Scale 24 (HAMD-24) score from baseline to 2 and 4 weeks. The secondary outcomes assessment (at 1, 2, 4, 12 and 24 weeks) will be done by the Montgomery-Asberg Depression Rating Scale, HAMD-24, Hamilton Anxiety Scale, Beck Depression Inventory, Snaith-Hamilton Pleasure Scale, Clinical Global Impression, Insomnia Severity Index, Columbia-Suicide Severity Rating Scale, Side Effect Rating Scale of Asberg, MRI, cognitive function and cytokine level analyses.Ethics and dissemination The study protocol and all of the related materials were approved by the Institutional Ethics Committee of Nanfang Hospital, Southern Medical University (No. NFEC-2024-070, NFEC-2020-153, Guangzhou, China). Results will be disseminated through peer-reviewed publications and conference presentations.Trial registration number NCT06266715.