Objective To preliminarily explore the correlation between changes in traditional Chinese medicine (TCM) syndromes and peripheral neurotransmitter levels in patients with depression of heart-kidney non-interaction syndrome treated with Jiaotai Pill (交泰丸, JTW) alone or in combination with selective serotonin reuptake inhibitors (SSRIs), and to exploratorily develop efficacy prediction models. Methods This post-hoc analysis utilized data from a randomized controlled trial (n = 91). Patients were divided into the JTW group (n = 31), JTW combined with SSRIs group (n = 30), and SSRIs group (n = 30). Response after eight weeks of treatment was defined as a ≥ 50% reduction rate in the Hamilton depression scale (HAMD) score. Changes in neurotransmitter levels and TCM syndrome scores before and after treatment were compared among the three groups. Spearman correlation analysis was used to assess the associations between changes in individual TCM syndrome scores and changes in neurotransmitter levels of 5-hydroxytryptamine (5-HT), norepinephrine (NE), and dopamine (DA). Firth's penalized-likelihood logistic regression, adjusted for confounders such as age and sex, was employed to analyze the independent associations between baseline characteristics and treatment response within each group, identifying potential predictors. Predictive models were constructed based on statistically significant predictors. Bootstrap internal validation (1 000 repetitions) was performed to correct for overfitting, and the optimism-corrected area under the curve (AUC) was reported to evaluate the discriminatory performance of the models. Results No statistically significant difference in response rates was observed among the three groups (P > 0.05). Comparisons before and after treatment showed that 5-HT and NE levels, as well as most TCM syndrome scores, improved significantly from baseline in all three groups (P < 0.05). Correlation analysis revealed that in the JTW group, Δ5-HT was positively correlated with Δinsomnia/dreamfulness (r = 0.521, P = 0.003) and Δdry throat and mouth (r = 0.438, P = 0.014). Multivariate analysis indicated that in the JTW group, baseline “forgetfulness” was a negative predictor of efficacy (OR = 0.60, P = 0.022). In the combination group, baseline “palpitations” was a positive predictor (OR = 1.62, P = 0.029), while “spermatorrhea or irregular menstruation” was a negative predictor (OR = 0.22, P = 0.007). Notably, the symptom of “spermatorrhea or irregular menstruation” itself did not show significant improvement after treatment. Predictive model analysis showed that in the JTW group, the model based on “forgetfulness” had a corrected AUC of 0.669 (original AUC = 0.838). In the combination group, the composite model including both “palpitations” and “spermatorrhea or irregular menstruation” demonstrated the best predictive performance, with a corrected AUC of 0.809 (original AUC = 0.937), suggesting preliminary discriminatory ability but also indicating potential overfitting. Conclusion By exploring the associations between TCM syndromes and neurotransmitter changes in depressed patients with heart-kidney non-interaction syndrome treated with JTW and by developing efficacy prediction models, this study provides preliminary evidence to guide treatment selection for clinical subtypes predominantly characterized by “exuberance of heart fire” or “kidney essence deficiency”. These findings offer exploratory clues for the precise application of JTW, though its predictive performance requires further validation in prospective and large-scale studies.

depression  /  heart-kidney non-interaction syndrome  /  Jiaotai Pill  /  neurotransmitter  /  5-hydroxytryptamine  /  efficacy predictive model  /  traditional Chinese medicine syndrome