Georgios Schoretsanitis1, Renato de Filippis2, Maria Ntogka3, Stefan Leucht4,5, Christoph U Correll6,7,8, John M Kane1,6,7. 1. Department of Psychiatry, The Zucker Hillside Hospital, Northwell Health, Glen Oaks, NY, USA. 2. Psychiatric Unit, Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy. 3. Department of Biology, University of Crete, Heraklion, Crete, Greece. 4. Department of Psychiatry and Psychotherapy, School of Medicine, Technical University of Munich, Munich, Germany. 5. Department of Psychosis Studies, Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London, UK. 6. Department of Psychiatry and Molecular Medicine, The Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA. 7. Center for Psychiatric Neuroscience, The Feinstein Institute for Medical Research, Manhasset, NY, USA. 8. Department of Child and Adolescent Psychiatry, Charité Universitätsmedizin, Berlin, Germany.
Abstract
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.
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.
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