Depression in mastocytosis: A neglected dimension of a clonal mast cell disease

Depression is a highly prevalent but underrecognized comorbidity in mastocytosis, a clonal mast cell disorder characterized by aberrant proliferation and activation of mast cells. Historically, depression in patients with mastocytosis was considered secondary to chronic illness or diagnostic delay. Recent studies suggest a possible biological relationship between mastocytosis and affective disturbances. Here we review clinical, biochemical, and mechanistic evidence for a putative causal link between mast cell dysregulation and depressive symptomatology. The pathophysiological pathways connecting mastocytosis to mood disorders include 1) chronic histamine overproduction, which affects monoaminergic signaling; 2) inflammatory cytokines that disrupt blood-brain barrier integrity and activate neurotoxic microglial cascades; and 3) the diversion of tryptophan metabolism through indoleamine 2,3-dioxygenase (IDO1), leading to serotonin depletion and the activation of the neurotoxic kynurenine pathway. Mastocytosis patients exhibit significantly altered serotonin and tryptophan levels, with depressive symptoms correlating closely to inflammatory and metabolic markers. Despite these findings, current clinical practice does not routinely address psychiatric symptoms in mastocytosis, and no treatment guidelines or trials have evaluated targeted psychiatric interventions. Case reports suggest that antihistamines, mast cell stabilizers, and tyrosine kinase inhibitors may improve mood, but systematic evidence is lacking. The frequent underdiagnosis and dismissal of depressive symptoms in patients with mastocytosis further obscure their clinical relevance. We suggest that depression is an important and underrecognized comorbidity in mastocytosis, with immune-mediated mechanisms likely contributing to its onset and persistence in at least a subset of patients. Revised clinical and research settings are urgently needed to integrate psychiatric evaluation, identify mechanistic biomarkers, and test biologically informed interventions.