Accessibility / Report Error

Serum plasminogen activator inhibitor-1 levels in patients with major depressive disorder vs. healthy controls: a systematic review and meta-analysis

Abstract

Introduction

Major depressive disorder (MDD) is a severe mental health condition that affects millions of people worldwide. Etiologically, several factors may play a role in its development. Previous studies have reported elevated plasminogen activator inhibitor-1 (PAI-1) levels in patients with depression, suggesting that PAI-1 levels might be linked to the etiology of MDD.

Methods

We systematically searched the following online databases: MEDLINE, Scopus, and Web of Science up to September 10, 2020, to identify studies in which PAI-1 levels were reported in subjects with MDD. Subsequently we used RevMan 5.3 to perform a meta-analysis of data extracted from the included studies using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and PICO criteria for the search and analysis.

Results

Six studies that reported mean ± standard deviation (SD) were included in the analysis, with a total of 507 MDD patients and 3,453 controls. The overall standardized mean difference (SMD) was 0.27 (95% confidence interval [95% CI] 0.01-0.53). PAI-1 serum levels were 0.27 SDs higher in MDD patients than in controls. The test for overall effect was significant (z = 2.04, p = 0.04). Substantial heterogeneity was detected among the studies, demonstrated by the inconsistency test (I2 = 72%) and the chi-square test (χ2 = 18.32; p = 0.003).

Conclusion

This systematic review and meta-analysis showed that MDD might be related to elevated PAI-1 levels. We propose larger prospective clinical studies to further investigate this clinical correlation and validate the clinical significance of these observations.

Plasminogen activator inhibitor-1; SERPINE1; major depression; meta-analysis; tissue plasminogen activator; BDNF

Introduction

Major depressive disorder (MDD) is a primary cause of morbidity and significantly affects the productivity of society.11. Andrade L, Caraveo-Anduaga JJ, Berglund P, Bijl RV, De Graaf R, Vollebergh W, et al. The epidemiology of major depressive episodes: results from the International Consortium of Psychiatric Epidemiology (ICPE) Surveys. Int J Meth Psychiatr Res. 2003;12:3-21. The lifetime prevalence of MDD is approximately 10%,22. Olesen J, Gustavsson A, Svensson M, Wittchen HU, Jönsson B. The economic cost of brain disorders in Europe. Eur J Neurol. 2011;19:155-62. imposing an economic burden of almost 92 billion Euros annually in Europe.22. Olesen J, Gustavsson A, Svensson M, Wittchen HU, Jönsson B. The economic cost of brain disorders in Europe. Eur J Neurol. 2011;19:155-62. MDD impacts personal and family life negatively and is considered a risk factor for severe disorders, for example, Alzheimer’s dementia,33. Sobieraj M, Williams J, Marley J, Ryan P. The impact of depression on the physical health of family members. Br J Gen Pract. 1998;48:1653-5. cardiovascular illness,44. Ownby RL, Crocco E, Acevedo A, John V, Loewenstein D. Depression and risk for Alzheimer disease: systematic review, meta-analysis, and metaregression analysis. Arch Gen Psychiatry. 2006;63:530-8. and dependence on alcohol and other drugs. MDD affects emotional functioning and quality of life,55. Dhar AK, Barton DA. Depression and the link with cardiovascular disease. Front Psychiatry. 2016;7:33. and therapy-resistant MDD is associated with high suicide incidence.66. Moylan S, Maes M, Wray NR, Berk M. The neuroprogressive nature of major depressive disorder: pathways to disease evolution and resistance, and therapeutic implications. Mol Psychiatry. 2012;18:595-606. The etiology is heterogeneous and clinical presentation, course of illness, and treatment response can differ considerably. Its pathophysiology is linked to altered neurocircuit activity, deficient monoamines, neurotrophic alterations, glucocorticoid dysregulation, immuno-inflammation, disturbed energy metabolism, imbalance in the microbiome, and oxidative stress.77. Tolentino JC, Schmidt SL. DSM-5 criteria and depression severity: implications for clinical practice. Front Psychiatry. 2018;9:450.

8. Belmaker RH, Agam G. Major depressive disorder. New Engl J Med. 2008;358:55-68.

9. Krishnan V, Nestler EJ. The molecular neurobiology of depression. Nature. 2008;455:894-902.
- 1010. Harper DG, Jensen JE, Ravichandran C, Perlis RH, Fava M, Renshaw PF, et al. Tissue type-specific bioenergetic abnormalities in adults with major depression. Neuropsychopharmacology. 2017;42:876-85. The exact underlying etiological pathomechanisms remain unknown and treatments are not always effective. Previous studies have reported that serum plasminogen activator inhibitor-1(PAI-1) levels were increased in patients with MDD and anxiety, suggesting that pAI-1 could play a vital role in MDD pathophysiology and stress response.1111. Sherwin E, Sandhu KV, Dinan TG, Cryan JF. May the force be with you: the light and dark sides of the microbiota-gut-brain axis in neuropsychiatry. CNS Drugs. 2016;30:1019-41.

12. Segawa M, Morinobu S, Matsumoto T, Fuchikami M, Yamawaki S. Electroconvulsive seizure, but not imipramine, rapidly up-regulates pro-BDNF and t-PA, leading to mature BDNF production, in the rat hippocampus. Int J Neuropsychopharmacol. 2012;16:339-50.

13. Sartori CR, Vieira AS, Ferrari EM, Langone F, Tongiorgi E, Parada CA. The antidepressive effect of the physical exercise correlates with increased levels of mature BDNF, and proBDNF proteolytic cleavage-related genes, p11 and tPA. Neuroscience. 2011;180:9-18.
- 1414. Geiser F, Meier C, Wegener I, Imbierowicz K, Conrad R, Liedtke R, et al. Association between anxiety and factors of coagulation and fibrinolysis. Psychother Psychosom. 2008;77:377-83.

Tissue plasminogen activator (tPA) is a major plasminogen activator that converts inactive plasminogen into active plasmin. Active plasmin breaks down fibrin clots, helping to restore vascular patency.1515. Melchor JP, Strickland S. Tissue plasminogen activator in central nervous system physiology and pathology. Thromb Haemost. 2005;93:655-60. PAI-1 is a critical inhibitor of tPA,1414. Geiser F, Meier C, Wegener I, Imbierowicz K, Conrad R, Liedtke R, et al. Association between anxiety and factors of coagulation and fibrinolysis. Psychother Psychosom. 2008;77:377-83. and it was reported that low tPA levels are related to increased levels of its inhibitor PAI-1.1414. Geiser F, Meier C, Wegener I, Imbierowicz K, Conrad R, Liedtke R, et al. Association between anxiety and factors of coagulation and fibrinolysis. Psychother Psychosom. 2008;77:377-83. The mechanism by which low tPA levels are related to MDD1616. Bahi A, Dreyer J-L. Hippocampus-specific deletion of tissue plasminogen activator “tPA” in adult mice impairs depression- and anxiety-like behaviors. Eur Neuropsychopharmacol. 2012;22:672-82. might involve brain-derived neurotrophic factor (BDNF). The precurser of brain-derived neurotrophic factor (proBDNF) is proteolytically cleaved into mature BDNF (mBDNF) by tPA and by plasmin (the end product of tPA)1616. Bahi A, Dreyer J-L. Hippocampus-specific deletion of tissue plasminogen activator “tPA” in adult mice impairs depression- and anxiety-like behaviors. Eur Neuropsychopharmacol. 2012;22:672-82. and promotes neuronal apoptosis and long-term depression, while mBDNF has anti-apoptotic properties and favors long-term potentiation.1717. Pang PT, Teng HK, Zaitsev E, Woo NT, Sakata K, Zhen S, et al. Cleavage of proBDNF by tPA/plasmin is essential for long-term hippocampal plasticity. Science. 2004;306:487-91. Moreover, physical exercise has antidepressant effects and increases tPA and mBDNF levels.1212. Segawa M, Morinobu S, Matsumoto T, Fuchikami M, Yamawaki S. Electroconvulsive seizure, but not imipramine, rapidly up-regulates pro-BDNF and t-PA, leading to mature BDNF production, in the rat hippocampus. Int J Neuropsychopharmacol. 2012;16:339-50. The inability to convert proBDNF into mBDNF is associated with depression pathogenesis and, consequently, mBDNF is implicated in the mechanism of action of antidepressants.1818. Lu B, Pang PT, Woo NH. The yin and yang of neurotrophin action. Nature Rev Neurosci. 2005;6:603-14.

Figure 1 shows the association between PAI-1 and MDD as different factors affecting PAI-1, including pleiotropic compounds, sleep disturbances, cortisol dysregulation, tPA level, hypothalamus-pituitary-gonadal (HPG)-axis dysregulation, and inflammation. The PAI-1 inhibits activation of plasminogen into plasmin which in turn leads to inhibition of conversion proBDNF into its mature form, mBDNF. Therefore, PAI-1 enhances apoptosis, spine retraction, and depression.

Figure 1
Plasminogen activator inhibitor-1 (PAI-1) and its association with major depressive disorder (MDD). HPG = hypothalamus-pituitary-gonadal; mBDMF = mature brain-derived neurotrophic factor; proBDNF = pro-BDNF; tPA = tissue plasminogen activator.

Figure 2 shows the association between PAI-1 and mBDNF. HPG-axis dysregulation, increased systemic inflammation, cortisol level, sleep disurbance, and obesity all increase PAI-1 levels. Elevated PAI-1 levels can cause MDD by inhibiting conversion of pro-BDNF into mBDNF.

Figure 2
Plasminogen activator inhibitor-1 (PAI-1) and its association with mature brain-derived neurotrophic factor (mBDNF). HPG = hypothalamus-pituitary-gonadal; MDD = major depressive disorder; proBDNF = pro-BDNF.

Considering the reported data on the effects of tPAI on MDD pathophysiology and treatment resistance ( Figure 1 ) and the lack of strong evidence on this topic, the authors decided to conduct a systematic review of existing studies in this field to provide a holistic, comprehensive conclusion on the impact of PAI-1 levels on depression. This study aims to examine and systematically review and analyze the literature and the reported results related to the impacts of PAI-1 levels on the pathophysiology of MDD and treatment options.

Methods and materials

Data sources and searches

We systematically searched the MEDLINE (through PubMed), Scopus, and Web of Science online databases up to September 10, 2020, in order to identify studies that assess PAI-1 levels in MDD subjects using the following MeSH terms: (“SERPINE1” OR “Serpin E1” OR “PAI-1” OR “Type 1 Plasminogen Activator Inhibitor” OR “Plasminogen Activator Inhibitor-1”) AND (“depression” OR “depressive”). We included the studies in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). We applied no study design or year of publication search filters. We exported the search results to EndNote X9.1 (Clarivate Analytics, https://clarivate.com/) to remove duplicate studies. Next, the studies were exported to an Excel spreadsheet and screened by title and abstract by three independent reviewers (KA, RA, MS). Any disagreements about inclusion or exclusion of the screened studies were resolved by a senior study member.

Data extraction

Data extraction was conducted by two independent authors. We extracted the summary data and statistical data to a Microsoft Excel spreadsheet template. More than one author checked the data extracted. The details of the searches and selection and inclusion of the studies are summarized in the following PRISMA diagram ( Figure 3 ).

Figure 3
Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram illustrating selection of studies to be included in the systematic review and meta-analysis. PAI-1 = plasminogen activator inhibitor-1; SD = standard deviation.

Study selection

Studies reporting PAI-1 levels in depressed human subjects published in English or German in international peer-reviewed journals were included. Studies reporting mean ± standard deviation (SD) were included in the quantitative analysis. We excluded studies that reported other variables such as correlation or regression coefficients or that did not report a clear relationship between MDD and PAI-1, or that did not include a precise definition of depression. We also excluded studies of psychiatric disorders not related to MDD, studies assessing the relation between genetics and depressive disorders, or animal studies reporting PAI-1.

Quality assessment of the included studies

The methodological quality of the included studies was assessed independently and discussed by two authors (ME, KTD) using the Newcastle-Ottawa-Scale (NOS). The NOS contains three main categories: patient selection, group comparability, and outcome assessment. It has nine questions allowing a maximum score of 9. Studies were considered to be of high (scored 7-9), moderate (scored 4-6), or low quality (scored 0-3). In addition, a modified version of the National Institutes of Health-Study Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies (NIH-SQAT) was also used. This tool consists of 14 questions and allows three overall ratings according to the total score; “good”, “fair”, or “poor”.

Data analysis

RevMan 5.3 was used in the meta-analysis of data.1919. McGrath S, Zhao X, Steele R, Thombs BD, Benedetti A, Levis B, et al. Estimating the sample mean and standard deviation from commonly reported quantiles in meta-analysis. Stat Meth Med Res. 2020;29:2520-37. Five studies2020. Eskandari F, Mistry S, Martinez PE, Torvik S, Kotila C, Sebring N, et al. Younger, premenopausal women with major depressive disorder have more abdominal fat and increased serum levels of prothrombotic factors: implications for greater cardiovascular risk. Metabolism. 2005;54:918-24.

21. Malan L, Mashele N, Malan NT, Harvey BH, Potgieter JC, Van Rooyen JM. Depression symptoms facilitated fibrinolytic dysregulation and future coronary artery disease risk in a black male cohort. J Cardiovasc Nurs. 2017;32:401-8.

22. Green S, Higgins JPT. Preparing a Cochrane Review. Cochrane Handbook for Systematic Reviews of Interventions. Hoboken: John Wiley & Sons; 2008. p. 11-30.

23. Pan A, Ye X, Franco OH, Li H, Yu Z, Wang J, et al. The association of depressive symptoms with inflammatory factors and adipokines in middle-aged and older Chinese. PloS One. 2008;3:e1392-e.
- 2424. Jiang H, Li X, Chen S, Lu N, Yue Y, Liang J, et al. Plasminogen activator inhibitor-1 in depression: results from animal and clinical studies. Sci Rep. 2016;6:30464. reported mean ± SD, and one study2525. Schroeder V, Borner U, Gutknecht S, Schmid J-P, Saner H, Kohler HP. Relation of depression to various markers of coagulation and fibrinolysis in patients with and without coronary artery disease. Eur J Cardiovasc Prev Rehabil. 2007;14:782-7. reported mean and range, so these data were transformed to mean and SD values using the method described by McGrath et al.1919. McGrath S, Zhao X, Steele R, Thombs BD, Benedetti A, Levis B, et al. Estimating the sample mean and standard deviation from commonly reported quantiles in meta-analysis. Stat Meth Med Res. 2020;29:2520-37. Eskandari et al.2020. Eskandari F, Mistry S, Martinez PE, Torvik S, Kotila C, Sebring N, et al. Younger, premenopausal women with major depressive disorder have more abdominal fat and increased serum levels of prothrombotic factors: implications for greater cardiovascular risk. Metabolism. 2005;54:918-24. reported two measurements of PAI-1 performed at 8:00 am and 8:00 pm; the average of both was calculated. Malan et al.2121. Malan L, Mashele N, Malan NT, Harvey BH, Potgieter JC, Van Rooyen JM. Depression symptoms facilitated fibrinolytic dysregulation and future coronary artery disease risk in a black male cohort. J Cardiovasc Nurs. 2017;32:401-8. reported the measurements of men and women separately; so the average of both measurements was taken, to be consistent with the other studies. SD was obtained from a 95% confidence interval (95%CI) using the method described in the Cochrane Handbook for Systematic Reviews of Interventions.2222. Green S, Higgins JPT. Preparing a Cochrane Review. Cochrane Handbook for Systematic Reviews of Interventions. Hoboken: John Wiley & Sons; 2008. p. 11-30. Standardized mean difference (SMD) was used as an overall effect measure. The studies were weighted by inverse variance, and a random-effects model was chosen owing to the heterogeneity of the data. Inconsistency (I2), chi-square (χ2), and tau-square tests were performed to test for heterogeneity. A p-value less than 0.05 was considered statistically significant; I2 > 50% was considered indicative of substantial heterogeneity in the studies.2222. Green S, Higgins JPT. Preparing a Cochrane Review. Cochrane Handbook for Systematic Reviews of Interventions. Hoboken: John Wiley & Sons; 2008. p. 11-30.

Sensitivity analysis

To examine the effect of a single study on the overall effect, a leave-one-out analysis was conducted. We also excluded an outlying study to examine the pooled effect and to account for heterogeneity.

Publication bias analysis

Egger’s test and a funnel plot were employed to assess publication bias in the included studies.

Results

Study characteristics

Following screening, a total of 34 studies were assessed for eligibility and six studies were chosen for inclusion in the meta-analysis. Detailed methodology and reasons for exclusion are presented in the PRISMA flow diagram ( Figure 3 ). The characteristics of included studies and clinical data for both MDD and healthy control groups are presented in Tables 1 , 2 , and 3 . The serum PAI-1 values are shown in Table 4 .

Table 1
Characteristics of the studies included in the meta-analysis
Table 2
Characteristics of the populations in the studies included
Table 3
- Basic clinical data for the subjects included in the meta-analysis
Table 4
Mean serum PAI-1 levels used in the meta-analysis

Quality assessment

Following the NOS scoring categories, two studies were of high quality and four studies were of moderate quality ( Table 5 ). According to the NIH-SQAT guidelines and after interrater consensus, two2121. Malan L, Mashele N, Malan NT, Harvey BH, Potgieter JC, Van Rooyen JM. Depression symptoms facilitated fibrinolytic dysregulation and future coronary artery disease risk in a black male cohort. J Cardiovasc Nurs. 2017;32:401-8. , 2323. Pan A, Ye X, Franco OH, Li H, Yu Z, Wang J, et al. The association of depressive symptoms with inflammatory factors and adipokines in middle-aged and older Chinese. PloS One. 2008;3:e1392-e. of the included studies were considered to be of good quality (scored 7) and four2020. Eskandari F, Mistry S, Martinez PE, Torvik S, Kotila C, Sebring N, et al. Younger, premenopausal women with major depressive disorder have more abdominal fat and increased serum levels of prothrombotic factors: implications for greater cardiovascular risk. Metabolism. 2005;54:918-24. , 2424. Jiang H, Li X, Chen S, Lu N, Yue Y, Liang J, et al. Plasminogen activator inhibitor-1 in depression: results from animal and clinical studies. Sci Rep. 2016;6:30464.

25. Schroeder V, Borner U, Gutknecht S, Schmid J-P, Saner H, Kohler HP. Relation of depression to various markers of coagulation and fibrinolysis in patients with and without coronary artery disease. Eur J Cardiovasc Prev Rehabil. 2007;14:782-7.
- 2626. Lahlou-Laforet K, Alhenc-Gelas M, Pornin M, Bydlowski S, Seigneur E, Benetos A, et al. Relation of depressive mood to plasminogen activator inhibitor, tissue plasminogen activator, and fibrinogen levels in patients with versus without coronary heart disease. Am J Cardiol. 2006;97:1287-91. were of moderate quality (scored 6).

Table 5
Newcastle-Ottawa-Scale for quality assessment of included studies

Serum PAI-1 level

Six studies2020. Eskandari F, Mistry S, Martinez PE, Torvik S, Kotila C, Sebring N, et al. Younger, premenopausal women with major depressive disorder have more abdominal fat and increased serum levels of prothrombotic factors: implications for greater cardiovascular risk. Metabolism. 2005;54:918-24. , 2121. Malan L, Mashele N, Malan NT, Harvey BH, Potgieter JC, Van Rooyen JM. Depression symptoms facilitated fibrinolytic dysregulation and future coronary artery disease risk in a black male cohort. J Cardiovasc Nurs. 2017;32:401-8. , 2323. Pan A, Ye X, Franco OH, Li H, Yu Z, Wang J, et al. The association of depressive symptoms with inflammatory factors and adipokines in middle-aged and older Chinese. PloS One. 2008;3:e1392-e.

24. Jiang H, Li X, Chen S, Lu N, Yue Y, Liang J, et al. Plasminogen activator inhibitor-1 in depression: results from animal and clinical studies. Sci Rep. 2016;6:30464.

25. Schroeder V, Borner U, Gutknecht S, Schmid J-P, Saner H, Kohler HP. Relation of depression to various markers of coagulation and fibrinolysis in patients with and without coronary artery disease. Eur J Cardiovasc Prev Rehabil. 2007;14:782-7.
- 2626. Lahlou-Laforet K, Alhenc-Gelas M, Pornin M, Bydlowski S, Seigneur E, Benetos A, et al. Relation of depressive mood to plasminogen activator inhibitor, tissue plasminogen activator, and fibrinogen levels in patients with versus without coronary heart disease. Am J Cardiol. 2006;97:1287-91. that reported mean ± SD were included in the meta-analysis with a total of 507 MDD patients and 3,453 adjusted healthy controls, the overall SMD was 0.27 (95%CI 0.01-0.53); serum PAI-1 levels were 0.27 SDs higher in depression patients than controls. The test for overall effect was significant (z = 2.04, p = 0.04). Substantial heterogeneity was detected in the studies, since the I2 statistic was 72%, χ2 was 18.32 (p = 0.003) ( Figure 4 ).

Figure 4
- Forest plot of plasminogen activator inhibitor-1 (PAI-1) levels in major depressive disorder (MDD) patients compared to control groups; the right side represents higher serum PAI-1 in MDD patients, or lower levels in controls, the left side represents lower levels in MDD patients, or higher levels in controls. 95%CI = 95% confidence interval; df = degrees of freedom; I2 = inconsistency test; IV = inverse variance.

Sensitivity analysis

A leave-one-out analysis revealed that no single study affected the results significantly, as the SMD was still within the CI of the overall results following removal of each study. Eliminating some studies shifted the value to non-significant, where the CI intersects with 0, as shown in Figure 5 .

Figure 5
Forest plot of the leave-one-out analysis. 95%CI = 95% confidence interval.

We tried incorporating the 8:00 am measurements taken by Eskandari et al.,2020. Eskandari F, Mistry S, Martinez PE, Torvik S, Kotila C, Sebring N, et al. Younger, premenopausal women with major depressive disorder have more abdominal fat and increased serum levels of prothrombotic factors: implications for greater cardiovascular risk. Metabolism. 2005;54:918-24. to be consistent with other studies instead of averaging the 8:00 am and 8:00 pm measurements, but doing so did not remarkably affect the result (SMD 0.28, 95%CI 0.02-0.55, p = 0.04). Eliminating Pan et al.2323. Pan A, Ye X, Franco OH, Li H, Yu Z, Wang J, et al. The association of depressive symptoms with inflammatory factors and adipokines in middle-aged and older Chinese. PloS One. 2008;3:e1392-e. reduces the heterogeneity level from 74 to 11% and increases the overall effect (SMD 0.36, 95%CI 0.17-0.55, p = 0.0002). However, eliminating studies on the basis of heterogeneity is not recommended, since it may introduce bias (Cochrane Handbook Chapter 10, Section 10.10.3).2222. Green S, Higgins JPT. Preparing a Cochrane Review. Cochrane Handbook for Systematic Reviews of Interventions. Hoboken: John Wiley & Sons; 2008. p. 11-30.

Publication bias

Egger’s test for funnel plot asymmetry ( Figure 6 ) suggests presence of publication bias (p = 0.0002). However, the results of Egger’s test should be interpreted with care when a meta-analysis includes a small number of studies.2222. Green S, Higgins JPT. Preparing a Cochrane Review. Cochrane Handbook for Systematic Reviews of Interventions. Hoboken: John Wiley & Sons; 2008. p. 11-30.

Figure 6
Funnel plot test for publication bias using the effect measure and the standard error.

Discussion

Previous research has provided evidence that patients with MDD often have elevated serum PAI-1 levels.1111. Sherwin E, Sandhu KV, Dinan TG, Cryan JF. May the force be with you: the light and dark sides of the microbiota-gut-brain axis in neuropsychiatry. CNS Drugs. 2016;30:1019-41.

12. Segawa M, Morinobu S, Matsumoto T, Fuchikami M, Yamawaki S. Electroconvulsive seizure, but not imipramine, rapidly up-regulates pro-BDNF and t-PA, leading to mature BDNF production, in the rat hippocampus. Int J Neuropsychopharmacol. 2012;16:339-50.

13. Sartori CR, Vieira AS, Ferrari EM, Langone F, Tongiorgi E, Parada CA. The antidepressive effect of the physical exercise correlates with increased levels of mature BDNF, and proBDNF proteolytic cleavage-related genes, p11 and tPA. Neuroscience. 2011;180:9-18.
- 1414. Geiser F, Meier C, Wegener I, Imbierowicz K, Conrad R, Liedtke R, et al. Association between anxiety and factors of coagulation and fibrinolysis. Psychother Psychosom. 2008;77:377-83. PAI-1 is known for its inhibitory action on tPA.1515. Melchor JP, Strickland S. Tissue plasminogen activator in central nervous system physiology and pathology. Thromb Haemost. 2005;93:655-60. , 1616. Bahi A, Dreyer J-L. Hippocampus-specific deletion of tissue plasminogen activator “tPA” in adult mice impairs depression- and anxiety-like behaviors. Eur Neuropsychopharmacol. 2012;22:672-82. Inhibition of tPA predisposes to depressive symptoms due to involvement of BDNF.1515. Melchor JP, Strickland S. Tissue plasminogen activator in central nervous system physiology and pathology. Thromb Haemost. 2005;93:655-60. , 1616. Bahi A, Dreyer J-L. Hippocampus-specific deletion of tissue plasminogen activator “tPA” in adult mice impairs depression- and anxiety-like behaviors. Eur Neuropsychopharmacol. 2012;22:672-82. Mature BDNF is proteolytically cleaved from proBNDF by tPA and plasmin, which is itself the end product of tPA.1717. Pang PT, Teng HK, Zaitsev E, Woo NT, Sakata K, Zhen S, et al. Cleavage of proBDNF by tPA/plasmin is essential for long-term hippocampal plasticity. Science. 2004;306:487-91. Whereas proBDNF stimulates neuronal apoptosis and depression, mBDNF has anti-apoptotic properties.1717. Pang PT, Teng HK, Zaitsev E, Woo NT, Sakata K, Zhen S, et al. Cleavage of proBDNF by tPA/plasmin is essential for long-term hippocampal plasticity. Science. 2004;306:487-91. Physical exercise that has antidepressant effects causes elevation of tPA and mBDNF levels.1212. Segawa M, Morinobu S, Matsumoto T, Fuchikami M, Yamawaki S. Electroconvulsive seizure, but not imipramine, rapidly up-regulates pro-BDNF and t-PA, leading to mature BDNF production, in the rat hippocampus. Int J Neuropsychopharmacol. 2012;16:339-50. Failure of the conversion of proBDNF into mBDNF is associated with the pathogenesis of MDD. Mature BDNF is even implicated in the mechanism of action of selective serotonin reuptake inhibitor antidepressants, such as escitalopram.1818. Lu B, Pang PT, Woo NH. The yin and yang of neurotrophin action. Nature Rev Neurosci. 2005;6:603-14. Therefore, this study aimed to systematically examine and analyze the results reported in the literature about the impact of PAI-1 levels on depression. To the best of our knowledge, our study is the first systematic review and meta-analysis to assess the association between PAI-1 and MDD.

In this meta-analysis, six studies2020. Eskandari F, Mistry S, Martinez PE, Torvik S, Kotila C, Sebring N, et al. Younger, premenopausal women with major depressive disorder have more abdominal fat and increased serum levels of prothrombotic factors: implications for greater cardiovascular risk. Metabolism. 2005;54:918-24. , 2121. Malan L, Mashele N, Malan NT, Harvey BH, Potgieter JC, Van Rooyen JM. Depression symptoms facilitated fibrinolytic dysregulation and future coronary artery disease risk in a black male cohort. J Cardiovasc Nurs. 2017;32:401-8. , 2323. Pan A, Ye X, Franco OH, Li H, Yu Z, Wang J, et al. The association of depressive symptoms with inflammatory factors and adipokines in middle-aged and older Chinese. PloS One. 2008;3:e1392-e.

24. Jiang H, Li X, Chen S, Lu N, Yue Y, Liang J, et al. Plasminogen activator inhibitor-1 in depression: results from animal and clinical studies. Sci Rep. 2016;6:30464.

25. Schroeder V, Borner U, Gutknecht S, Schmid J-P, Saner H, Kohler HP. Relation of depression to various markers of coagulation and fibrinolysis in patients with and without coronary artery disease. Eur J Cardiovasc Prev Rehabil. 2007;14:782-7.
- 2626. Lahlou-Laforet K, Alhenc-Gelas M, Pornin M, Bydlowski S, Seigneur E, Benetos A, et al. Relation of depressive mood to plasminogen activator inhibitor, tissue plasminogen activator, and fibrinogen levels in patients with versus without coronary heart disease. Am J Cardiol. 2006;97:1287-91. were included, with a total of 3,960 participants (507 MDD patients and 3,453 controls). According to the results presented in the six studies included in the quantitative synthesis, serum PAI-1 levels were 0.27 SDs higher in MDD patients than in controls.

The six studies included in this meta-analysis focused on rating scales rather than a clinical diagnosis for defining depression. Furthermore, the six studies included did not all focus on the same subtype of depression, so that the criteria used for diagnosis were not homogenous. A large proportion of the patients with depression included in the studies suffered from cardiovascular diseases, such as coronary heart disease (CHD) in the study by Lahlou-Laforet et al.2626. Lahlou-Laforet K, Alhenc-Gelas M, Pornin M, Bydlowski S, Seigneur E, Benetos A, et al. Relation of depressive mood to plasminogen activator inhibitor, tissue plasminogen activator, and fibrinogen levels in patients with versus without coronary heart disease. Am J Cardiol. 2006;97:1287-91. and coronary artery disease (CAD) in the study by Schroeder et al.2525. Schroeder V, Borner U, Gutknecht S, Schmid J-P, Saner H, Kohler HP. Relation of depression to various markers of coagulation and fibrinolysis in patients with and without coronary artery disease. Eur J Cardiovasc Prev Rehabil. 2007;14:782-7. Furthermore, the included studies focused on specific age groups. Besides, differences in episodes, duration of illness, and illness severity among patients with MDD might be a potential confounding factor. Furthermore, PAI-1 levels are modulated by angiotensin, glucocorticoids, and aldosterone. However, the levels of these factors were not consistently screened in the six studies included. Jiang et al. highlighted that in their rodent depression data model, stress increases PAI-1 expression in the medial prefrontal cortex, and the hippocampus. Also, chronic escitalopram treatment downregulated PAI-1 expression in these brain subregions and decreased the active PAI-1 concentration in the serum, but not in the CSF in rodents,99. Krishnan V, Nestler EJ. The molecular neurobiology of depression. Nature. 2008;455:894-902. while it did not affect the PAI-1 concentrations in the serum of MDD patients.2525. Schroeder V, Borner U, Gutknecht S, Schmid J-P, Saner H, Kohler HP. Relation of depression to various markers of coagulation and fibrinolysis in patients with and without coronary artery disease. Eur J Cardiovasc Prev Rehabil. 2007;14:782-7. , 2626. Lahlou-Laforet K, Alhenc-Gelas M, Pornin M, Bydlowski S, Seigneur E, Benetos A, et al. Relation of depressive mood to plasminogen activator inhibitor, tissue plasminogen activator, and fibrinogen levels in patients with versus without coronary heart disease. Am J Cardiol. 2006;97:1287-91.

Many factors are known to affect PAI-1 expression, including obesity,22. Olesen J, Gustavsson A, Svensson M, Wittchen HU, Jönsson B. The economic cost of brain disorders in Europe. Eur J Neurol. 2011;19:155-62. sleep dysregulation,2727. Tsai S-J. Role of tissue-type plasminogen activator and plasminogen activator inhibitor-1 in psychological stress and depression. Oncotarget. 2017;8:113258-68. and hypothalamus-pituitary-adrenal (HPA) axis dysregulation44. Ownby RL, Crocco E, Acevedo A, John V, Loewenstein D. Depression and risk for Alzheimer disease: systematic review, meta-analysis, and metaregression analysis. Arch Gen Psychiatry. 2006;63:530-8. ( Figures 1 and 2 ). Also, female hormonal dysregulation affects PAI-1, which leads to an increase in the incidence of female depression.2323. Pan A, Ye X, Franco OH, Li H, Yu Z, Wang J, et al. The association of depressive symptoms with inflammatory factors and adipokines in middle-aged and older Chinese. PloS One. 2008;3:e1392-e. , 2828. Party H, Dujarrier C, Hébert M, Lenoir S, Martinez de Lizarrondo S, Delépée R, et al. Plasminogen activator inhibitor-1 (PAI-1) deficiency predisposes to depression and resistance to treatments. Acta Neuropathol Comm. 2019;7:153. Some pleiotropic compounds also affect PAI-1 activity, including metformin,2929. Velazquez EM, Mendoza SG, Wang P, Glueck CJ. Metformin therapy is associated with a decrease in plasma plasminogen activator inhibitor-1, lipoprotein(a), and immunoreactive insulin levels in patients with the polycystic ovary syndrome. Metabolism. 1997;46:454-7. resveratrol, and other antioxidants such as curcumin, ginko biloba, shikonin, and theaflavin by many different mechanisms.1313. Sartori CR, Vieira AS, Ferrari EM, Langone F, Tongiorgi E, Parada CA. The antidepressive effect of the physical exercise correlates with increased levels of mature BDNF, and proBDNF proteolytic cleavage-related genes, p11 and tPA. Neuroscience. 2011;180:9-18. , 3030. Gouda MM, Prabhu A, Bhandary YP. Curcumin alleviates IL-17A-mediated p53-PAI-1 expression in bleomycin-induced alveolar basal epithelial cells. J Cell Biochemistry. 2017;119:2222-30.

Pharmacological treatments available nowadays are useful, but unfortunately, around 30-40% of patients are resistant to such treatments.3131. Carvalho AF, Sharma MS, Brunoni AR, Vieta E, Fava GA. The safety, tolerability and risks associated with the use of newer generation antidepressant drugs: a critical review of the literature. Psychother Psychosom. 2016;85:270-88. , 3232. Lang UE, Borgwardt S. Molecular mechanisms of depression: perspectives on new treatment strategies. Cell Physiol Biochem. 2013;31:761-77. Besides, antidepressants could cause side effects.2929. Velazquez EM, Mendoza SG, Wang P, Glueck CJ. Metformin therapy is associated with a decrease in plasma plasminogen activator inhibitor-1, lipoprotein(a), and immunoreactive insulin levels in patients with the polycystic ovary syndrome. Metabolism. 1997;46:454-7. Party et al. introduced a new model for depression using PAI knockout mice, which showed resistance to antidepressant therapy.2828. Party H, Dujarrier C, Hébert M, Lenoir S, Martinez de Lizarrondo S, Delépée R, et al. Plasminogen activator inhibitor-1 (PAI-1) deficiency predisposes to depression and resistance to treatments. Acta Neuropathol Comm. 2019;7:153.

Depression is known to be associated with alteration of PAI-1 protein, blood coagulation, and fibrinolysis.3333. Rao JS, Chen M, Festoff BW. Plasminogen activator inhibitor 1, the primary regulator of fibrinolysis, in normal human cerebrospinal fluid. J Neurosci Res. 1993;34:340-5. Tsai et al. concluded that since PAI-1 dysregulation might be a biomarker for MDD, drugs that could decrease PAI-1 levels might help treat depression.2727. Tsai S-J. Role of tissue-type plasminogen activator and plasminogen activator inhibitor-1 in psychological stress and depression. Oncotarget. 2017;8:113258-68. Furthermore, PAI-1 may be a mediator in which MDD could precipitate CVD development via BDNF metabolism, adiposity, sleep dysregulation, and alteration of the hypothalamic-pituitary-adrenal (HPA)-axis.3434. Tosur Z, Green D, De Chavez PJ, Knutson KL, Goldberger JJ, Zee P, et al. The association between sleep characteristics and prothrombotic markers in a population-based sample: Chicago Area Sleep Study. Sleep Med. 2014;15:973-8.

Further studies on the relation between PAI and MDD should include larger samples of patients with MDD. Besides, it is warranted to standardize measurement of PAI-1 and other variables. More studies should focus on measuring PAI-1 levels in cerebrospinal fluid ( CSF). Measurements of PAI-1 in serum and CSF would probably provide more reliable results. Intake of antidepressants might interfere with the results, as antidepressant treatment might influence PAI-1 levels.3535. Cattaneo A, Bocchio-Chiavetto L, Zanardini R, Milanesi E, Placentino A, Gennarelli M. Reduced peripheral brain-derived neurotrophic factor mRNA levels are normalized by antidepressant treatment. Int J Neuropsychopharmacol. 2009;13:103. For example, in the study by Jiang et al.,2424. Jiang H, Li X, Chen S, Lu N, Yue Y, Liang J, et al. Plasminogen activator inhibitor-1 in depression: results from animal and clinical studies. Sci Rep. 2016;6:30464. escitalopram treatment significantly decreased PAI-1 levels in serum, but not in CSF. It is currently unclear whether PAI-1 can cross the blood-brain barrier,3434. Tosur Z, Green D, De Chavez PJ, Knutson KL, Goldberger JJ, Zee P, et al. The association between sleep characteristics and prothrombotic markers in a population-based sample: Chicago Area Sleep Study. Sleep Med. 2014;15:973-8. despite its presence in certain areas of the brain and the CSF.3333. Rao JS, Chen M, Festoff BW. Plasminogen activator inhibitor 1, the primary regulator of fibrinolysis, in normal human cerebrospinal fluid. J Neurosci Res. 1993;34:340-5.

Despite the intensive search of the current literature and careful data extraction, this review still has limitations. Some studies focused only on one gender: Eskandari et al. examined only females,2020. Eskandari F, Mistry S, Martinez PE, Torvik S, Kotila C, Sebring N, et al. Younger, premenopausal women with major depressive disorder have more abdominal fat and increased serum levels of prothrombotic factors: implications for greater cardiovascular risk. Metabolism. 2005;54:918-24. while Lahlou-Laforet examined only males.2626. Lahlou-Laforet K, Alhenc-Gelas M, Pornin M, Bydlowski S, Seigneur E, Benetos A, et al. Relation of depressive mood to plasminogen activator inhibitor, tissue plasminogen activator, and fibrinogen levels in patients with versus without coronary heart disease. Am J Cardiol. 2006;97:1287-91. Eskandari et al. even focused only on premenopausal females.2020. Eskandari F, Mistry S, Martinez PE, Torvik S, Kotila C, Sebring N, et al. Younger, premenopausal women with major depressive disorder have more abdominal fat and increased serum levels of prothrombotic factors: implications for greater cardiovascular risk. Metabolism. 2005;54:918-24. Several confounding factors were present in the Eskandari et al. study; patients continued their antidepressant medication, which might be a confounding factor. Lahlou-Laforet et al.’s study included confounding factors such as smoking, hypertension, triglyceride concentration, and body mass index.2626. Lahlou-Laforet K, Alhenc-Gelas M, Pornin M, Bydlowski S, Seigneur E, Benetos A, et al. Relation of depressive mood to plasminogen activator inhibitor, tissue plasminogen activator, and fibrinogen levels in patients with versus without coronary heart disease. Am J Cardiol. 2006;97:1287-91. It is worth mentioning that each study focused on certain coagulation factors including PAI-1; the coagulation factors that were studied varied between the six studies. Furthermore, Malan et al. focused only on members of the black African race2121. Malan L, Mashele N, Malan NT, Harvey BH, Potgieter JC, Van Rooyen JM. Depression symptoms facilitated fibrinolytic dysregulation and future coronary artery disease risk in a black male cohort. J Cardiovasc Nurs. 2017;32:401-8. and Pan et al. focused solely on the Chinese population,2323. Pan A, Ye X, Franco OH, Li H, Yu Z, Wang J, et al. The association of depressive symptoms with inflammatory factors and adipokines in middle-aged and older Chinese. PloS One. 2008;3:e1392-e. while the other studies probably involved various races. Also, Malan et al. measured fasting PAI-1 levels,2121. Malan L, Mashele N, Malan NT, Harvey BH, Potgieter JC, Van Rooyen JM. Depression symptoms facilitated fibrinolytic dysregulation and future coronary artery disease risk in a black male cohort. J Cardiovasc Nurs. 2017;32:401-8. while the other studies did not mention whether measurements were in a fasting state or not. Furthermore, data heterogeneity and publication bias were detected, and the limited number of studies still poses a main concern.

Conclusion

In conclusion, this systematic review and meta-analysis revealed that elevated PAI-1 is associated with MDD, however heterogeneity, publication bias, and the limited number of studies should be taken into consideration when interpreting the result. More extensive prospective clinical studies are required to thoroughly examine its clinical correlation and validate the clinical significance of these observations.

References

  • 1
    Andrade L, Caraveo-Anduaga JJ, Berglund P, Bijl RV, De Graaf R, Vollebergh W, et al. The epidemiology of major depressive episodes: results from the International Consortium of Psychiatric Epidemiology (ICPE) Surveys. Int J Meth Psychiatr Res. 2003;12:3-21.
  • 2
    Olesen J, Gustavsson A, Svensson M, Wittchen HU, Jönsson B. The economic cost of brain disorders in Europe. Eur J Neurol. 2011;19:155-62.
  • 3
    Sobieraj M, Williams J, Marley J, Ryan P. The impact of depression on the physical health of family members. Br J Gen Pract. 1998;48:1653-5.
  • 4
    Ownby RL, Crocco E, Acevedo A, John V, Loewenstein D. Depression and risk for Alzheimer disease: systematic review, meta-analysis, and metaregression analysis. Arch Gen Psychiatry. 2006;63:530-8.
  • 5
    Dhar AK, Barton DA. Depression and the link with cardiovascular disease. Front Psychiatry. 2016;7:33.
  • 6
    Moylan S, Maes M, Wray NR, Berk M. The neuroprogressive nature of major depressive disorder: pathways to disease evolution and resistance, and therapeutic implications. Mol Psychiatry. 2012;18:595-606.
  • 7
    Tolentino JC, Schmidt SL. DSM-5 criteria and depression severity: implications for clinical practice. Front Psychiatry. 2018;9:450.
  • 8
    Belmaker RH, Agam G. Major depressive disorder. New Engl J Med. 2008;358:55-68.
  • 9
    Krishnan V, Nestler EJ. The molecular neurobiology of depression. Nature. 2008;455:894-902.
  • 10
    Harper DG, Jensen JE, Ravichandran C, Perlis RH, Fava M, Renshaw PF, et al. Tissue type-specific bioenergetic abnormalities in adults with major depression. Neuropsychopharmacology. 2017;42:876-85.
  • 11
    Sherwin E, Sandhu KV, Dinan TG, Cryan JF. May the force be with you: the light and dark sides of the microbiota-gut-brain axis in neuropsychiatry. CNS Drugs. 2016;30:1019-41.
  • 12
    Segawa M, Morinobu S, Matsumoto T, Fuchikami M, Yamawaki S. Electroconvulsive seizure, but not imipramine, rapidly up-regulates pro-BDNF and t-PA, leading to mature BDNF production, in the rat hippocampus. Int J Neuropsychopharmacol. 2012;16:339-50.
  • 13
    Sartori CR, Vieira AS, Ferrari EM, Langone F, Tongiorgi E, Parada CA. The antidepressive effect of the physical exercise correlates with increased levels of mature BDNF, and proBDNF proteolytic cleavage-related genes, p11 and tPA. Neuroscience. 2011;180:9-18.
  • 14
    Geiser F, Meier C, Wegener I, Imbierowicz K, Conrad R, Liedtke R, et al. Association between anxiety and factors of coagulation and fibrinolysis. Psychother Psychosom. 2008;77:377-83.
  • 15
    Melchor JP, Strickland S. Tissue plasminogen activator in central nervous system physiology and pathology. Thromb Haemost. 2005;93:655-60.
  • 16
    Bahi A, Dreyer J-L. Hippocampus-specific deletion of tissue plasminogen activator “tPA” in adult mice impairs depression- and anxiety-like behaviors. Eur Neuropsychopharmacol. 2012;22:672-82.
  • 17
    Pang PT, Teng HK, Zaitsev E, Woo NT, Sakata K, Zhen S, et al. Cleavage of proBDNF by tPA/plasmin is essential for long-term hippocampal plasticity. Science. 2004;306:487-91.
  • 18
    Lu B, Pang PT, Woo NH. The yin and yang of neurotrophin action. Nature Rev Neurosci. 2005;6:603-14.
  • 19
    McGrath S, Zhao X, Steele R, Thombs BD, Benedetti A, Levis B, et al. Estimating the sample mean and standard deviation from commonly reported quantiles in meta-analysis. Stat Meth Med Res. 2020;29:2520-37.
  • 20
    Eskandari F, Mistry S, Martinez PE, Torvik S, Kotila C, Sebring N, et al. Younger, premenopausal women with major depressive disorder have more abdominal fat and increased serum levels of prothrombotic factors: implications for greater cardiovascular risk. Metabolism. 2005;54:918-24.
  • 21
    Malan L, Mashele N, Malan NT, Harvey BH, Potgieter JC, Van Rooyen JM. Depression symptoms facilitated fibrinolytic dysregulation and future coronary artery disease risk in a black male cohort. J Cardiovasc Nurs. 2017;32:401-8.
  • 22
    Green S, Higgins JPT. Preparing a Cochrane Review. Cochrane Handbook for Systematic Reviews of Interventions. Hoboken: John Wiley & Sons; 2008. p. 11-30.
  • 23
    Pan A, Ye X, Franco OH, Li H, Yu Z, Wang J, et al. The association of depressive symptoms with inflammatory factors and adipokines in middle-aged and older Chinese. PloS One. 2008;3:e1392-e.
  • 24
    Jiang H, Li X, Chen S, Lu N, Yue Y, Liang J, et al. Plasminogen activator inhibitor-1 in depression: results from animal and clinical studies. Sci Rep. 2016;6:30464.
  • 25
    Schroeder V, Borner U, Gutknecht S, Schmid J-P, Saner H, Kohler HP. Relation of depression to various markers of coagulation and fibrinolysis in patients with and without coronary artery disease. Eur J Cardiovasc Prev Rehabil. 2007;14:782-7.
  • 26
    Lahlou-Laforet K, Alhenc-Gelas M, Pornin M, Bydlowski S, Seigneur E, Benetos A, et al. Relation of depressive mood to plasminogen activator inhibitor, tissue plasminogen activator, and fibrinogen levels in patients with versus without coronary heart disease. Am J Cardiol. 2006;97:1287-91.
  • 27
    Tsai S-J. Role of tissue-type plasminogen activator and plasminogen activator inhibitor-1 in psychological stress and depression. Oncotarget. 2017;8:113258-68.
  • 28
    Party H, Dujarrier C, Hébert M, Lenoir S, Martinez de Lizarrondo S, Delépée R, et al. Plasminogen activator inhibitor-1 (PAI-1) deficiency predisposes to depression and resistance to treatments. Acta Neuropathol Comm. 2019;7:153.
  • 29
    Velazquez EM, Mendoza SG, Wang P, Glueck CJ. Metformin therapy is associated with a decrease in plasma plasminogen activator inhibitor-1, lipoprotein(a), and immunoreactive insulin levels in patients with the polycystic ovary syndrome. Metabolism. 1997;46:454-7.
  • 30
    Gouda MM, Prabhu A, Bhandary YP. Curcumin alleviates IL-17A-mediated p53-PAI-1 expression in bleomycin-induced alveolar basal epithelial cells. J Cell Biochemistry. 2017;119:2222-30.
  • 31
    Carvalho AF, Sharma MS, Brunoni AR, Vieta E, Fava GA. The safety, tolerability and risks associated with the use of newer generation antidepressant drugs: a critical review of the literature. Psychother Psychosom. 2016;85:270-88.
  • 32
    Lang UE, Borgwardt S. Molecular mechanisms of depression: perspectives on new treatment strategies. Cell Physiol Biochem. 2013;31:761-77.
  • 33
    Rao JS, Chen M, Festoff BW. Plasminogen activator inhibitor 1, the primary regulator of fibrinolysis, in normal human cerebrospinal fluid. J Neurosci Res. 1993;34:340-5.
  • 34
    Tosur Z, Green D, De Chavez PJ, Knutson KL, Goldberger JJ, Zee P, et al. The association between sleep characteristics and prothrombotic markers in a population-based sample: Chicago Area Sleep Study. Sleep Med. 2014;15:973-8.
  • 35
    Cattaneo A, Bocchio-Chiavetto L, Zanardini R, Milanesi E, Placentino A, Gennarelli M. Reduced peripheral brain-derived neurotrophic factor mRNA levels are normalized by antidepressant treatment. Int J Neuropsychopharmacol. 2009;13:103.

Publication Dates

  • Publication in this collection
    28 Aug 2023
  • Date of issue
    2023

History

  • Received
    21 July 2021
  • Accepted
    09 Nov 2021
Associação de Psiquiatria do Rio Grande do Sul Av. Ipiranga, 5311/202, 90610-001 Porto Alegre RS/ Brasil, Tel./Fax: (55 51) 3024 4846 - Porto Alegre - RS - Brazil
E-mail: trends@aprs.org.br