BackgroundAntidepressants still have some side effects in treating major depressive disorder (MDD), and acupuncture therapy is a complementary therapy of research interest for MDD. Acupoints are sensitive sites for disease response and stimulation points for acupuncture treatment. Prior studies suggest that the biological specificity of acupoints is altered in physiological and pathological situations. Therefore, we hypothesize that the biological specificity of acupoints is associated with the diagnosis of MDD and that stimulating acupoints with significant biological specificity can achieve a better therapeutic effect than clinical common acupoints. This study aims to investigate the efficacy and safety of intradermal acupuncture (IA) treatment for MDD based on changes in the biological specificity of acupoints.MethodsThe first part of the study will enroll 30 MDD patients and 30 healthy control (HC) participants to assess pain sensitivity and thermal specificity of MDD-related acupoints using a pressure pain threshold gauge (PTG) and infrared thermography (IRT). The potentially superior acupoints for treating MDD will be selected based on the results of PTG and IRT tests and referred to as pressure pain threshold strong response acupoints (PSA) and temperature strong response acupoints (TSA).The second part of the study will enroll 120 eligible MDD patients randomly assigned to waiting list (WL) group, clinical common acupoint (CCA) group, TSA group, and PSA group in a 1:1:1:1 ratio. The change in the Patient Health Questionnaire-9 Items (PHQ-9), the MOS item short-form health survey (SF-36), pressure pain threshold, temperature of acupoints, and adverse effects will be observed. The outcomes of PHQ-9 and SF-36 measures will be assessed before intervention, at 3 and 6 weeks after intervention, and at a 4-week follow-up. The biological specificity of acupoint measures will be assessed before intervention and at 6 weeks after intervention. All adverse effects will be assessed.DiscussionThis study will evaluate the therapeutic effect and safety of IA for MDD based on changes in the biological specificity of acupoints. It will investigate whether there is a correlation between the biological specificity of MDD-related acupoints and the diagnosis of MDD and whether stimulating strong response acupoints is superior to clinical common acupoints in the treatment of MDD. The study’s results may provide insights into the biological mechanisms of acupuncture and its potential as a complementary therapy for MDD.Clinical Trial RegistrationClinicalTrials.gov, identifier: NCT05524519.