Matrix Metalloproteinase 9 Blood Alterations in Patients With Schizophrenia Spectrum Disorders: A Systematic Review and Meta-Analysis

Background: Matrix metalloproteinase 9 (MMP-9), an extracellular network protease implicated in glutamatergic signaling, may be part of the pathophysiology of schizophrenia spectrum disorders (SSD).

Methods: We performed a systematic review in PubMed/Embase until July 15, 2020, conducting a random-effects meta-analysis of studies comparing MMP-9 blood levels in SSD vs healthy controls (HCs) and psychiatric controls (PCs), calculating between-group differences in standardized mean differences (SMDs) ± 95% confidence intervals (CIs). Meta-regression analyses included sex, age, illness duration, antipsychotic dose, and Positive and Negative Syndrome Scale (PANSS) total/subscales. Subgroup analyses included first-episode patients (FEP) vs non-FEP, each vs HCs and vs PCs, and blood sample type. Study quality was assessed using the Newcastle-Ottawa scale.

Results: Four, five, and two trials were rated as high, fair, and low quality. In 11 studies (n = 1443), 643 patients (age = 36.7 ± 14.1 years, females = 42.9%) were compared with HCs (n = 631), with 4 studies including also 169 PCs. MMP-9 levels were higher in SSD vs HCs (SMD = 0.52, 95%CI = 0.20-0.85, P = .002), but not in PCs vs HCs (n = 132, after removing one implausible outlier [SMD = 0.33, 95%CI = -0.16 to 0.85, P = .082]). MMP-9 differences between SSD and HCs were associated with higher PANSS total (coefficient = 0.02, 95%CI = 0.01-0.02, P < .001), PANSS positive (coefficient = 0.08, 95%CI = 0.02-0.13, P = .006), and PANSS general scores (coefficient = 0.02, 95%CI = 0.01-0.03, P < .001). MMP-9 level differences vs HCs did not vary significantly between FEP (n = 103, SMD = 0.44, 95%CI = 0.15-0.72, P = .71) and non-FEP patients (n = 466, SMD = 0.59, 95%CI = 0.38-0.80; P = .34) (FEP vs non-FEP: P = .39). In four high-quality studies, MMP-9 levels remained significantly higher in SSD vs HCs (SMD = 0.82, 95%CI = 0.03-1.61).

Conclusions: Findings suggest MMP-9 upregulation in SSD, requiring further validation and understanding of related pathways.