Mast Cell Stabilization as a Primary Antidepressant Mechanism: Evidence from Five Non-Serotonergic Clinical Observations, Three Kinetic Formalizations, and a Phase 2 Trial Blueprint

This paper argues that mast cell stabilization — not serotonin reuptake inhibition — is the primary therapeutic mechanism in the inflammatory hyperarousal subtype of major depressive disorder. Five non-serotonergic clinical observations are presented: omalizumab (depression remission OR 5.55, independent of urticaria response), masitinib (HAMD −43%, Lancet phase 3 primary endpoint), disodium cromoglycate (attenuates depressive behavior in two mouse models via peripheral mast cell stabilization), diphenhydramine (equals trazodone in PPD prevention, RCT n=54), and low-dose doxepin (FDA-approved for neuropsychiatric arousal via H1 blockade alone). A structural observation — every effective antidepressant intervention engages the circadian-mast cell axis — is supported by three kinetic formalizations (mast cell population kinetics explaining the 2–6 week onset delay; FcεRI–ATP Ca²⁺ dynamics; HNMT substrate inhibition). An operational diagnostic framework (NHDI) and a three-arm Phase 2 RCT blueprint are provided.