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Increased serum matrix metalloproteinase-9 (MMP-9) levels in young patients during bipolar depression
Journal of Affective Disorders 146 (2013) 286–289
Contents lists available at SciVerse ScienceDirect
Journal of Affective Disorders journal homepage: www.elsevier.com/locate/jad
Brief report
Increased serum matrix metalloproteinase-9 (MMP-9) levels in young patients during bipolar depression Janusz K. Rybakowski a,n, Agnieszka Remlinger-Molenda a, Aleksandra Czech-Kucharska a, Marlena Wojcicka b, Michal Michalak c, Jacek Losy b a
Department of Adult Psychiatry, Poznan University of Medical Sciences, Poznan, Poland Department of Clinical Neuroimmunology, Poznan University of Medical Sciences, Poznan, Poland c Department of Computer Science and Statistics, Poznan University of Medical Sciences, Poznan, Poland b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 25 February 2012 Received in revised form 16 July 2012 Accepted 16 July 2012 Available online 2 August 2012
Background: Matrix metalloproteinase-9 (MMP-9) is an enzyme implicated in a number of pathological conditions such as cardiovascular disease, cancer, and neuropsychiatric disorders. Increased blood levels of MMP-9 were found in cancer, heart disease and migraine. Molecular-genetic studies demonstrated an association of functional polymorphism of MMP-9 gene with predisposition to schizophrenia and bipolar illness. In this first study of serum MMP-9 in psychiatric illness, we estimated it in patients with bipolar mood disorder both during depression or mania as well as during immediate remission after these episodes. Methods: The study was performed on 54 in-patients with bipolar mood disorder (19 males, 35 females), aged 427 14 years. Thirty were studied during acute episode and immediate remission after depression, and 24 during acute episode and immediate remission after mania. The control group consisted of 29 subjects (15 males, 14 females) aged 40 7 11 years. Serum MMP-9 was estimated by ELISA. Results: In patients with bipolar illness, a significant correlation of MMP-9 levels was obtained with age. Younger patients with depression (below or equal 45 years of age), both during acute episode and in remission after depression had significantly higher MMP-9 levels compared to those with acute episode and remission after mania and control subjects. Limitations: Relatively small number of patients, who were receiving different antidepressant, antipsychotic and mood stabilizing drugs that might have influenced MMP-9 levels. Conclusions: Increased levels of serum MMP-9 during depression in young patients may indicate this phenomenon as a possible biochemical marker for staging of bipolar disorder. & 2012 Elsevier B.V. All rights reserved.
Keywords: Matrix metalloproteinase-9 Serum levels Bipolar mood disorder Mania Depression Remission
1. Introduction Matrix metalloproteinases are a large family of extracellularly acting endopeptidases, the substrates of which are proteins of the extracellular matrix and adhesion proteins (Strenlicht and Werb, 2001). Among them, matrix metalloproteinase-9 (MMP-9) has been implicated in a number of pathological conditions, including cardiovascular disease, cancer, and neuropsychiatric disorders. Recently, a review article on a mediating role of the MMP-9 in these conditions was published (Rybakowski, 2009). Elevated levels of blood MMP-9 were demonstrated in a number of cardiovascular illnesses, such as coronary heart disease n Correspondence to: Department of Adult Psychiatry, Poznan University of Medical Sciences, ul.Szpitalna 27/33, 60-572 Poznan, Poland. Tel.: þ48 61 8475 087; fax: þ 48 61 8480 392. E-mail address: [email protected] (J.K. Rybakowski).
0165-0327/$ - see front matter & 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jad.2012.07.019
(Konstantino et al., 2009), atherosclerosis (Olson et al., 2008) and hypertension (Dhingra et al., 2009), and in each of these conditions they were associated with a higher risk of disease progression. Similarly, elevated levels of MMP-9 were associated with worse prognosis of neoplastic illnesses such as endometrial polyps (Erdemoglu et al., 2008), breast cancer (Wu et al., 2008) and pulmonary lymphangio-leomyomatosis (Odajima et al., 2009). Elevated levels of blood MMP-9 were also demonstrated in neurological illnesses such as multiple sclerosis (Benesova et al., 2009) and migraine (Imamura et al., 2008). Recent molecular genetic studies of the functional 1562 C/T polymorphism of the MMP-9 gene performed by our group demonstrated an association of the polymorphism with a predisposition to schizophrenia (Rybakowski et al., 2009a) and bipolar mood disorder (Rybakowski et al., 2009b). Additionally, in bipolar illness this polymorphism was associated with a performance on cognitive tests (Rybakowski et al., 2009c). Corresponding findings
J.K. Rybakowski et al. / Journal of Affective Disorders 146 (2013) 286–289
were obtained in a study of Domenici et al. (2010), where, using focused proteomic approach, MMP-9 was found to be a plasma protein biomarker for depression. Blood levels of MMP-9 in psychiatric illnesses have not been studied so far. In view of the above findings showing a possible role of MMP-9 in mood disorders, we attempted to estimate serum MMP-9 in patients with bipolar mood disorder both during depression or mania as well as during immediate remission after these episodes.
2. Subjects and methods 2.1. Patients The study was performed on 54 in-patients with bipolar mood disorder (19 males, 35 females), with a mean age of 42714 years, treated at the Department of Adult Psychiatry, University of Medical Sciences in Poznan. Consensus diagnosis by at least two psychiatrists was made for each patient, according to DSM-IV criteria (SCID; First et al., 1996). The mean age of onset of illness was 26711 years and the mean duration of the illness was 1579 years. Within bipolar patients, 30 (9 male, 21 female) were studied during acute episode of depression and immediate remission after depression, and 24 (10 male, 14 female) were studied during acute episode of mania and immediate remission after mania. The intensity of depression was assessed by means of the 17-item Hamilton Depression Rating Scale (HDRS; Hamilton, 1960). The criterion for acute episode was Z18 points and that of remission was r7 points on this scale. The mean period between two assessments was 59 728 day. The intensity of mania was assessed by means of the Young Mania Rating Scale (Young et al., 1978). The criterion for acute manic episode was Z20 points and that of remission was r8 points on this scale. The mean period between two assessments was 51 737days. Both during acute episode, as well as in remission, all patients were receiving various antidepressant, antipsychotic and mood stabilizing drugs. 2.2. Control group The control group consisted of 29 subjects (15 males, 14 females) aged 40 711 years. Control subjects were healthy volunteers without any present or past psychiatric history. Also, they did not have any autoimmune conditions as well as any acute or chronic somatic illnesses which could influence MMP-9 activity in 4 weeks prior to the study. After complete description of the study to all patients and control subjects, written informed consent was obtained from all of them. The study was approved by the Bioethics Committee, Poznan University of Medical Sciences.
287
2.3. MMP-9 determinations Fasting venous blood was drawn for MMP-9 determination. The assay of serum MMP-9 was performed using enzyme-linked immunosorbent assay (ELISA), R&D Quantikine System.
2.4. Statistical methods Calculations were performed using the Statistica version 7.1 statistical package. Distribution of the results was tested with the Shapiro–Wilk test. Since the results of MMP-9 were not normally distributed, the non-parametric statistical tests were employed. Comparisons of two groups were performed by the Mann–Whitney test and for correlations, the Spearman test was used. Statistical significance was set at po0.05.
3. Results In patients with bipolar illness, a significant correlation of MMP-9 levels was obtained with age during acute episode (p o0.05), and a trend in such direction was found during remission (p o0.01). In the control group, such correlation was not significant (p ¼0.13). There were no gender differences in MMP-9 levels in patients with bipolar illness both during acute episode (p ¼1) and in remission (p¼0.77) as well as in control subjects (p¼0.31). Following the finding on a possible age-dependence of MMP-9 results, the comparison of serum MMP-9 levels was done in younger ( r45) and older group ( 445) both in bipolar patients and in control subjects. This cut-off age was chosen as being close to the mean age of patients studied. The results are depicted in Table 1. Younger patients with depression ( r45 years of age), both during acute episode and in remission after depression, had significantly higher MMP-9 levels compared to those with acute episode and remission after mania and control subjects. Comparing patients in different age groups it was found that both in depression and in mania the MMP-9 values were higher in patients r45 years of age compared to those above 45 years, both during acute episode and in remission, reaching statistical significance in the acute episode of depression (p¼ 0.004). The results in control subjects were numerically higher but did not reach the level of statistical significance. We have found an inverse correlation between MMP-9 level and the duration of illness which was not significant for the whole group, either for acute episode (r ¼ 0.219; p¼0.111) or remission (r ¼ 0.179; p ¼0.196). However, there was a trend for significant negative correlation (r¼ 0.347; p¼0.061) between MMP-9 levels during acute depressive episode and the duration of bipolar illness.
Table 1 Serum MMP concentrations (ng/ml) in two age-related groups of bipolar patients during acute episode of depression or mania and in remission after the episode as well as in control subjects. Values are given as mean 7SD. Depression N ¼ 30
r45 years 445 years
a b
Mania N ¼ 24
Control subjects N ¼29
Acute episode
Remission
Acute episode
Remission
N ¼12 1286 7845a N ¼18 554 7435
N ¼ 12 1134 7 557b N ¼ 18 705 7 757
N ¼19 616 7462 N ¼5 413 7152
N ¼ 19 525 7 409 N¼5 362 7 248
N ¼20 577 7 346 N ¼9 511 7 220
Significant difference vs. acute episode of mania (p¼ 0.020), vs. remission after mania (p ¼ 0.002), and vs. control subjects (p ¼0.031), Mann–Whitney test. Significant difference vs. acute episode of mania (p ¼0.009), vs. remission after mania (p ¼0.006), and vs. control subjects (p ¼ 0.011), Mann–Whitney test.
288
J.K. Rybakowski et al. / Journal of Affective Disorders 146 (2013) 286–289
We have also found an inverse correlation of MMP-9 level with the number of episodes which was significant for MMP-9 in remission after mania in patients where the illness started with depressive episode (r ¼ 0.679; p¼ 0.044) and a trend for MMP-9 during depression in patients where the illness began with mania (r¼ 0.717; p ¼0.070).
4. Discussion This is the first attempt to measure blood MMP-9 levels in psychiatric patients. The main finding of our study is a significant elevation of serum MMP-9 levels in younger (equal or below 45 years of age) patients with depression in the course of bipolar mood disorder. This could corroborate a pathogenic role of MMP9 in bipolar mood disorder, previously demonstrated in molecular genetic studies (Rybakowski et al., 2009a). Concerning blood MMP-9 levels, such abnormality may be mainly connected with depressive episode and mostly expressed in patients with shorter duration of illness and with lower number of affective episodes. An association of MMP-9 with depression was previously observed in proteomic studies where MMP-9 was found to be a plasma protein biomarker for depression (Domenici et al., 2010). In a Swedish study including 402 participants recruited from middle-aged normal population, elevated plasma levels of MMP-9 were positively associated with symptoms of depression, assessed by means of the Center for Epidemiological Studies Depression Questionnaire (CED-S; Garvin et al., 2009). In recent years, staging concepts of the course of bipolar illness have been developed, with both neurobiological and therapeutic implications (Berk et al., 2007). Kapczinski et al. (2009) postulated a potential use of biochemical markers as an adjunctive tool for staging bipolar disorder. It has been suggested that decreased serum brain-derived neurotrophic factor (BDNF) and interleukin6 (IL-6) may be markers of a late stage of bipolar disorder (KauerSant’Anna et al., 2009). In connection with this, experimental studies have showed an effect of MMP-9 on Trk tyrosine kinase neurotrophin receptor (Jayanth et al., 2010). Also, an impact of MMP-9 on oxidative stress has been demonstrated (Volna et al., 2011) while the oxidant system impairment has also been implicated in staging of bipolar disorder (Andreazza et al., 2009). However, why an increase of serum MMP-9 at the early stages of bipolar illness is accompanying only depressive episodes and not manic ones is difficult to explain. In this respect, studies of patients during sustained remission after depression and mania would be helpful. Elevated serum levels of MMP-9 found by us in depressed patients in the course of bipolar mood disorder may correspond with such elevations occurring in pathological conditions which show an association with bipolar mood disorder. Japanese researchers have demonstrated increased plasma levels of MMP-9 in patients with migraine (Imamura et al., 2008) and Canadian authors found recently that 1/4 of bipolar patients may have co-morbid migraine (Ortiz et al., 2010). In view of the elevated MMP-9 levels shown in cardiovascular disease and cancer, it should be mentioned that the patients with bipolar mood disorder had higher risk for cardiovascular illness (Osby et al., 2001) and increased cancer morbidity (BarChana et al., 2008). In cancer and cardiovascular studies, higher increase in serum MMP-9 was associated with poorer prognosis, but was not correlated with the staging of the illness. Matrix metalloproteinase-9 plays a role in the processes of cellular growth modulation and tumorigenesis, involving activity of glycogen synthase kinase (GSK)-3 beta and tumor necrosis factor (TNF; Takada et al., 2004, Kelly et al., 2012). The genes for both these substances were investigated by our group for a
possible association with the predisposition to bipolar illness and such association of both TNF and GSK-3 beta with the predisposition to the illness was observed (Czerski et al., 2008; Szczepankiewicz et al., 2006). There are some limitations to our study. The first is a small number of patients, therefore, a confirmation of our results on a greater sample and by other investigators should be necessary. Secondly, the patients both during acute episode and in remission were receiving different antidepressant, antipsychotic and mood stabilizing drugs that might have influenced MMP-9 level. In recent experimental studies, some effects of antidepressants and mood-stabilizers such as lithium and valproate on MMP-9 system have been demonstrated (Benekareddy et al., 2008; Tsai et al., 2010). Bearing these limitations in mind, we believe that the results of our study may suggest a possible role of serum MMP-9 in the pathogenic processes of depression in the course of bipolar mood disorder. Furthermore, increased levels of serum MMP-9 during depression in young patients may indicate this phenomenon as a possible biochemical marker for staging of bipolar disorder. Role of funding source The study was supported by own research funds of the Department of Adult psychiatry, Poznan University of Medical Sciences.
Conflict of interest All authors declare no conflict of interest that could influence their work.
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Jayanth, P., Amith, S.R., Gee, K., Szewczuk, M.R., 2010. Neu1 sialidase and matrix metalloproteinase-9 cross-talk is essential for neurotrophin activation of Trk receptors and cellular signaling. Cellular Signalling 22, 1193–1205. Kapczinski, F., Dias, V.V., Kauer-Sant’Anna, M., Brietzke, E., Vasquez, G.H., Vieta, E., Berk, M., 2009. The potential use of biomarkers as an adjunctive tool for staging bipolar disorder. Progress in Neuro-Psychopharmacology and Biological Psychiatry 33, 1366–1371. Kauer-Sant’Anna, M., Kapczinski, F., Andreazza, A.C., Bond, D.J., Lam, R.W., Young, L.T., Yatham, L.N., 2009. Brain-derived neurotrophic factor and inflammatory markers in patients with early- vs. late-stage bipolar disorder. International Journal of Neuropsychopharmacology 12, 447–458. Kelly, E.A., Liu, L.Y., Esnault, S., Quinchia Johnson, B.H., Jarjour, N.N., 2012. Potent synergistic effect of IL-3 and TNF on matrix metalloproteinase 9 generation by human eosinophils. Cytokine, Epub ahead of print. Konstantino, Y., Nguyen, T.T., Wolk, R., Aiello, R.J., Terra, S.G., Fryburg, D.A., 2009. Potential implications of matrix metalloproteinase-9 in assessment and treatment of coronary artery disease. Biomarkers: Biochemical Indicators of Exposure, Response, and Susceptibility to Chemicals 14, 118–129. Odajima, N., Betsuyaku, T., Nasuhara, Y., Inoue, H., Seyama, K., Nishimura, M., 2009. Matrix metalloproteinases in blood from patients with LAM. Respiratory Medicine 103, 124–129. Olson, F.J., Schmidt, C., Gummesson, A., Sigurdardottir, V., Hulthe, J., Wiklund, O., Fagerberg, B., 2008. Circulating matrix metalloproteinase 9 levels in relation to sampling methods, femoral and carotid atherosclerosis. Journal of Internal Medicine 263, 626–635. Ortiz, A., Cervantes, P., Zlotnik, G, van de Velde, C., Slaney, C., Garnham, J., Turecki, G., O’Donovan, C., Alda, M., 2010. Cross-prevalence of migraine and bipolar disorder. Bipolar Disorders 12, 397–403. Osby, U., Brandt, L., Correia, N., Ekbom, A., Sparen, P., 2001. Excess mortality in bipolar and unipolar disorder in Sweden. Archives of General Psychiatry 58, 844. Rybakowski, J.K., 2009. Matrix metalloproteinase-9 (MMP9)—a mediating enzyme in cardiovascular disease, cancer, and neuropsychiatric disorders. Cardiovascular Psychiatry and Neurology 2009, 904836.
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Contents lists available at SciVerse ScienceDirect
Journal of Affective Disorders journal homepage: www.elsevier.com/locate/jad
Brief report
Increased serum matrix metalloproteinase-9 (MMP-9) levels in young patients during bipolar depression Janusz K. Rybakowski a,n, Agnieszka Remlinger-Molenda a, Aleksandra Czech-Kucharska a, Marlena Wojcicka b, Michal Michalak c, Jacek Losy b a
Department of Adult Psychiatry, Poznan University of Medical Sciences, Poznan, Poland Department of Clinical Neuroimmunology, Poznan University of Medical Sciences, Poznan, Poland c Department of Computer Science and Statistics, Poznan University of Medical Sciences, Poznan, Poland b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 25 February 2012 Received in revised form 16 July 2012 Accepted 16 July 2012 Available online 2 August 2012
Background: Matrix metalloproteinase-9 (MMP-9) is an enzyme implicated in a number of pathological conditions such as cardiovascular disease, cancer, and neuropsychiatric disorders. Increased blood levels of MMP-9 were found in cancer, heart disease and migraine. Molecular-genetic studies demonstrated an association of functional polymorphism of MMP-9 gene with predisposition to schizophrenia and bipolar illness. In this first study of serum MMP-9 in psychiatric illness, we estimated it in patients with bipolar mood disorder both during depression or mania as well as during immediate remission after these episodes. Methods: The study was performed on 54 in-patients with bipolar mood disorder (19 males, 35 females), aged 427 14 years. Thirty were studied during acute episode and immediate remission after depression, and 24 during acute episode and immediate remission after mania. The control group consisted of 29 subjects (15 males, 14 females) aged 40 7 11 years. Serum MMP-9 was estimated by ELISA. Results: In patients with bipolar illness, a significant correlation of MMP-9 levels was obtained with age. Younger patients with depression (below or equal 45 years of age), both during acute episode and in remission after depression had significantly higher MMP-9 levels compared to those with acute episode and remission after mania and control subjects. Limitations: Relatively small number of patients, who were receiving different antidepressant, antipsychotic and mood stabilizing drugs that might have influenced MMP-9 levels. Conclusions: Increased levels of serum MMP-9 during depression in young patients may indicate this phenomenon as a possible biochemical marker for staging of bipolar disorder. & 2012 Elsevier B.V. All rights reserved.
Keywords: Matrix metalloproteinase-9 Serum levels Bipolar mood disorder Mania Depression Remission
1. Introduction Matrix metalloproteinases are a large family of extracellularly acting endopeptidases, the substrates of which are proteins of the extracellular matrix and adhesion proteins (Strenlicht and Werb, 2001). Among them, matrix metalloproteinase-9 (MMP-9) has been implicated in a number of pathological conditions, including cardiovascular disease, cancer, and neuropsychiatric disorders. Recently, a review article on a mediating role of the MMP-9 in these conditions was published (Rybakowski, 2009). Elevated levels of blood MMP-9 were demonstrated in a number of cardiovascular illnesses, such as coronary heart disease n Correspondence to: Department of Adult Psychiatry, Poznan University of Medical Sciences, ul.Szpitalna 27/33, 60-572 Poznan, Poland. Tel.: þ48 61 8475 087; fax: þ 48 61 8480 392. E-mail address: [email protected] (J.K. Rybakowski).
0165-0327/$ - see front matter & 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jad.2012.07.019
(Konstantino et al., 2009), atherosclerosis (Olson et al., 2008) and hypertension (Dhingra et al., 2009), and in each of these conditions they were associated with a higher risk of disease progression. Similarly, elevated levels of MMP-9 were associated with worse prognosis of neoplastic illnesses such as endometrial polyps (Erdemoglu et al., 2008), breast cancer (Wu et al., 2008) and pulmonary lymphangio-leomyomatosis (Odajima et al., 2009). Elevated levels of blood MMP-9 were also demonstrated in neurological illnesses such as multiple sclerosis (Benesova et al., 2009) and migraine (Imamura et al., 2008). Recent molecular genetic studies of the functional 1562 C/T polymorphism of the MMP-9 gene performed by our group demonstrated an association of the polymorphism with a predisposition to schizophrenia (Rybakowski et al., 2009a) and bipolar mood disorder (Rybakowski et al., 2009b). Additionally, in bipolar illness this polymorphism was associated with a performance on cognitive tests (Rybakowski et al., 2009c). Corresponding findings
J.K. Rybakowski et al. / Journal of Affective Disorders 146 (2013) 286–289
were obtained in a study of Domenici et al. (2010), where, using focused proteomic approach, MMP-9 was found to be a plasma protein biomarker for depression. Blood levels of MMP-9 in psychiatric illnesses have not been studied so far. In view of the above findings showing a possible role of MMP-9 in mood disorders, we attempted to estimate serum MMP-9 in patients with bipolar mood disorder both during depression or mania as well as during immediate remission after these episodes.
2. Subjects and methods 2.1. Patients The study was performed on 54 in-patients with bipolar mood disorder (19 males, 35 females), with a mean age of 42714 years, treated at the Department of Adult Psychiatry, University of Medical Sciences in Poznan. Consensus diagnosis by at least two psychiatrists was made for each patient, according to DSM-IV criteria (SCID; First et al., 1996). The mean age of onset of illness was 26711 years and the mean duration of the illness was 1579 years. Within bipolar patients, 30 (9 male, 21 female) were studied during acute episode of depression and immediate remission after depression, and 24 (10 male, 14 female) were studied during acute episode of mania and immediate remission after mania. The intensity of depression was assessed by means of the 17-item Hamilton Depression Rating Scale (HDRS; Hamilton, 1960). The criterion for acute episode was Z18 points and that of remission was r7 points on this scale. The mean period between two assessments was 59 728 day. The intensity of mania was assessed by means of the Young Mania Rating Scale (Young et al., 1978). The criterion for acute manic episode was Z20 points and that of remission was r8 points on this scale. The mean period between two assessments was 51 737days. Both during acute episode, as well as in remission, all patients were receiving various antidepressant, antipsychotic and mood stabilizing drugs. 2.2. Control group The control group consisted of 29 subjects (15 males, 14 females) aged 40 711 years. Control subjects were healthy volunteers without any present or past psychiatric history. Also, they did not have any autoimmune conditions as well as any acute or chronic somatic illnesses which could influence MMP-9 activity in 4 weeks prior to the study. After complete description of the study to all patients and control subjects, written informed consent was obtained from all of them. The study was approved by the Bioethics Committee, Poznan University of Medical Sciences.
287
2.3. MMP-9 determinations Fasting venous blood was drawn for MMP-9 determination. The assay of serum MMP-9 was performed using enzyme-linked immunosorbent assay (ELISA), R&D Quantikine System.
2.4. Statistical methods Calculations were performed using the Statistica version 7.1 statistical package. Distribution of the results was tested with the Shapiro–Wilk test. Since the results of MMP-9 were not normally distributed, the non-parametric statistical tests were employed. Comparisons of two groups were performed by the Mann–Whitney test and for correlations, the Spearman test was used. Statistical significance was set at po0.05.
3. Results In patients with bipolar illness, a significant correlation of MMP-9 levels was obtained with age during acute episode (p o0.05), and a trend in such direction was found during remission (p o0.01). In the control group, such correlation was not significant (p ¼0.13). There were no gender differences in MMP-9 levels in patients with bipolar illness both during acute episode (p ¼1) and in remission (p¼0.77) as well as in control subjects (p¼0.31). Following the finding on a possible age-dependence of MMP-9 results, the comparison of serum MMP-9 levels was done in younger ( r45) and older group ( 445) both in bipolar patients and in control subjects. This cut-off age was chosen as being close to the mean age of patients studied. The results are depicted in Table 1. Younger patients with depression ( r45 years of age), both during acute episode and in remission after depression, had significantly higher MMP-9 levels compared to those with acute episode and remission after mania and control subjects. Comparing patients in different age groups it was found that both in depression and in mania the MMP-9 values were higher in patients r45 years of age compared to those above 45 years, both during acute episode and in remission, reaching statistical significance in the acute episode of depression (p¼ 0.004). The results in control subjects were numerically higher but did not reach the level of statistical significance. We have found an inverse correlation between MMP-9 level and the duration of illness which was not significant for the whole group, either for acute episode (r ¼ 0.219; p¼0.111) or remission (r ¼ 0.179; p ¼0.196). However, there was a trend for significant negative correlation (r¼ 0.347; p¼0.061) between MMP-9 levels during acute depressive episode and the duration of bipolar illness.
Table 1 Serum MMP concentrations (ng/ml) in two age-related groups of bipolar patients during acute episode of depression or mania and in remission after the episode as well as in control subjects. Values are given as mean 7SD. Depression N ¼ 30
r45 years 445 years
a b
Mania N ¼ 24
Control subjects N ¼29
Acute episode
Remission
Acute episode
Remission
N ¼12 1286 7845a N ¼18 554 7435
N ¼ 12 1134 7 557b N ¼ 18 705 7 757
N ¼19 616 7462 N ¼5 413 7152
N ¼ 19 525 7 409 N¼5 362 7 248
N ¼20 577 7 346 N ¼9 511 7 220
Significant difference vs. acute episode of mania (p¼ 0.020), vs. remission after mania (p ¼ 0.002), and vs. control subjects (p ¼0.031), Mann–Whitney test. Significant difference vs. acute episode of mania (p ¼0.009), vs. remission after mania (p ¼0.006), and vs. control subjects (p ¼ 0.011), Mann–Whitney test.
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We have also found an inverse correlation of MMP-9 level with the number of episodes which was significant for MMP-9 in remission after mania in patients where the illness started with depressive episode (r ¼ 0.679; p¼ 0.044) and a trend for MMP-9 during depression in patients where the illness began with mania (r¼ 0.717; p ¼0.070).
4. Discussion This is the first attempt to measure blood MMP-9 levels in psychiatric patients. The main finding of our study is a significant elevation of serum MMP-9 levels in younger (equal or below 45 years of age) patients with depression in the course of bipolar mood disorder. This could corroborate a pathogenic role of MMP9 in bipolar mood disorder, previously demonstrated in molecular genetic studies (Rybakowski et al., 2009a). Concerning blood MMP-9 levels, such abnormality may be mainly connected with depressive episode and mostly expressed in patients with shorter duration of illness and with lower number of affective episodes. An association of MMP-9 with depression was previously observed in proteomic studies where MMP-9 was found to be a plasma protein biomarker for depression (Domenici et al., 2010). In a Swedish study including 402 participants recruited from middle-aged normal population, elevated plasma levels of MMP-9 were positively associated with symptoms of depression, assessed by means of the Center for Epidemiological Studies Depression Questionnaire (CED-S; Garvin et al., 2009). In recent years, staging concepts of the course of bipolar illness have been developed, with both neurobiological and therapeutic implications (Berk et al., 2007). Kapczinski et al. (2009) postulated a potential use of biochemical markers as an adjunctive tool for staging bipolar disorder. It has been suggested that decreased serum brain-derived neurotrophic factor (BDNF) and interleukin6 (IL-6) may be markers of a late stage of bipolar disorder (KauerSant’Anna et al., 2009). In connection with this, experimental studies have showed an effect of MMP-9 on Trk tyrosine kinase neurotrophin receptor (Jayanth et al., 2010). Also, an impact of MMP-9 on oxidative stress has been demonstrated (Volna et al., 2011) while the oxidant system impairment has also been implicated in staging of bipolar disorder (Andreazza et al., 2009). However, why an increase of serum MMP-9 at the early stages of bipolar illness is accompanying only depressive episodes and not manic ones is difficult to explain. In this respect, studies of patients during sustained remission after depression and mania would be helpful. Elevated serum levels of MMP-9 found by us in depressed patients in the course of bipolar mood disorder may correspond with such elevations occurring in pathological conditions which show an association with bipolar mood disorder. Japanese researchers have demonstrated increased plasma levels of MMP-9 in patients with migraine (Imamura et al., 2008) and Canadian authors found recently that 1/4 of bipolar patients may have co-morbid migraine (Ortiz et al., 2010). In view of the elevated MMP-9 levels shown in cardiovascular disease and cancer, it should be mentioned that the patients with bipolar mood disorder had higher risk for cardiovascular illness (Osby et al., 2001) and increased cancer morbidity (BarChana et al., 2008). In cancer and cardiovascular studies, higher increase in serum MMP-9 was associated with poorer prognosis, but was not correlated with the staging of the illness. Matrix metalloproteinase-9 plays a role in the processes of cellular growth modulation and tumorigenesis, involving activity of glycogen synthase kinase (GSK)-3 beta and tumor necrosis factor (TNF; Takada et al., 2004, Kelly et al., 2012). The genes for both these substances were investigated by our group for a
possible association with the predisposition to bipolar illness and such association of both TNF and GSK-3 beta with the predisposition to the illness was observed (Czerski et al., 2008; Szczepankiewicz et al., 2006). There are some limitations to our study. The first is a small number of patients, therefore, a confirmation of our results on a greater sample and by other investigators should be necessary. Secondly, the patients both during acute episode and in remission were receiving different antidepressant, antipsychotic and mood stabilizing drugs that might have influenced MMP-9 level. In recent experimental studies, some effects of antidepressants and mood-stabilizers such as lithium and valproate on MMP-9 system have been demonstrated (Benekareddy et al., 2008; Tsai et al., 2010). Bearing these limitations in mind, we believe that the results of our study may suggest a possible role of serum MMP-9 in the pathogenic processes of depression in the course of bipolar mood disorder. Furthermore, increased levels of serum MMP-9 during depression in young patients may indicate this phenomenon as a possible biochemical marker for staging of bipolar disorder. Role of funding source The study was supported by own research funds of the Department of Adult psychiatry, Poznan University of Medical Sciences.
Conflict of interest All authors declare no conflict of interest that could influence their work.
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