Elevated Matrix Metalloproteinase 9 in Treatment Resistant Bipolar Depression

Abstract

Objective: Matrix metalloproteinase is a family of proteases with different pathophysiological roles. Matrix metalloproteinase 9 (MMP9) plays an enzymatic role in the restructuring of the extracellular matrix and adhesion molecules. MMP9 is upregulated in pro-inflammatory states and leads to breakdown of tight junctions thereby increasing blood-brain barrier (BBB) permeability. MMP9 may contribute to the pathophysiology of bipolar disorder (BD) via proteolysis of the BBB thus allowing entry of cytokines and neurotoxic agents into CNS. Polymorphisms of the MMP9 gene may pose increased risk for BD and schizophrenia. In this study we sought to determine MMP9 levels in treatment resistant bipolar depressed patients before and after treatment. Methods: Treatment resistant bipolar depressed patients were treated with escitalopram, in combination with the COX-2 inhibitor, celecoxib. It was hypothesized that combination treatment would reverse resistance and augmented treatment responses. This was a 10-week, randomized, double-blind, two-arm, placebo-controlled study. Results: MMP9 levels were higher in bipolar depressed patients compared to healthy controls at baseline, however, the difference did not reach significance. Levels decreased after treatment reaching significance in the escitalopram plus placebo group. Female patients had significantly lower MMP9 levels at end of treatment. MMP9 was higher in carriers the MMP9 SNP, rs3918242, than in noncarriers, but the difference did not reach statistical significance. Conclusion: MMP9 decreased in bipolar depressed patients with treatment. Age, sex and the rs3918242 polymorphism play a role in MMP9 levels. Future studies should confirm the role of MMP9 in the pathogenesis and pathophysiology of bipolar disorder, as a potential diagnostic biomarker.