Depression, Nutritional Status, and Substance P/NK‐1R Biomarkers in Dysmenorrhea: A Randomized Crossover Trial

Abstract

Substance P (SP) and neurokinin‐1 receptor (NK‐1R) as biomarkers of pain and stress SP and NK‐1R are neuropeptide related biomarkers involved in nociceptive pathways. Dysmenorrhea is frequently associated with psychological distress and biochemical alterations; however, their interrelationship across treatment phases remains insufficiently understood. Objectives To explore changes in psychological status (depression, anxiety, and stress), nutritional status, and SP/NK‐1R‐related biomarker levels across NSAID and dexamethasone plus aprepitant combination therapy phases in females with dysmenorrhea. Methods This was a randomized, sequential, within‐subject repeated‐measures crossover exploratory controlled trial with a parallel healthy control group. A total of 40 females were enrolled, including 30 with primary dysmenorrhea and 10 healthy controls. Dysmenorrhea participants were assessed over three menstrual cycles across three phases: baseline (no treatment), NSAID phase (ibuprofen 400 mg three times daily for 3 days), and combination therapy phase (dexamethasone plus aprepitant for 2 days). Psychological status was assessed using DASS‐21, and nutritional status using the mini nutritional assessment (MNA). Serum SP and NK‐1R levels were measured using ELISA in a subset of participants due to sample limitations. Data were analyzed using IBM SPSS Statistics (version 22), with repeated‐measures ANOVA and independent t‐tests; p  < 0.05 was considered statistically significant. Results Participants with dysmenorrhea were enrolled and assessed for ELISA based SP levels in blood. SP levels showed significant variation across treatment phases (p = 0.021), with the lowest values observed during the dexamethasone plus aprepitant phase compared to baseline and NSAID phases. NK‐1R levels did not show significant phase‐wise changes. Psychological subgroup analyses indicated greater SP variability in participants with moderate depression, stress, and anxiety, although several subgroups were small. Nutritional status showed partial associations with SP changes, with significant differences in malnourished and normal groups. Overall, biomarker changes were more pronounced than NK‐1R alterations across phases. Conclusion This study demonstrates phase‐dependent changes in SP levels alongside psychological and nutritional variations in women with dysmenorrhea. However, absence of clinical pain outcomes and small subgroup sizes limit causal interpretation, and findings should be considered preliminary and biomarker‐focused.