- Email: [email protected]
The relevance of oxidative stress status in first episode and recurrent depression
Journal of Affective Disorders 143 (2012) 34–38
Contents lists available at SciVerse ScienceDirect
Journal of Affective Disorders journal homepage: www.elsevier.com/locate/jad
Research report
The relevance of oxidative stress status in first episode and recurrent depression Cristinel Stefanescu a, Alin Ciobica b,n a ‘‘
Gr. T. Popa’’ University of Medicine and Pharmacy, 16 Universitatii Street, 700115, Iasi, Romania Alexandru Ioan Cuza’’ University, Dept. of Biology, 11 Carol I Blvd., 700506, Iasi, Romania
b ‘‘
a r t i c l e i n f o
a b s t r a c t
Article history: Received 22 March 2012 Received in revised form 14 May 2012 Accepted 14 May 2012 Available online 25 July 2012
Oxidative and nitrosative stress (O&NS) could play an important role in the pathophysiology of major depression (MDD). The aim of the present work was to evaluate the specific activity of the main peripheral antioxidant defences (superoxide dismutase—SOD and glutathione peroxidase—GPX) and the level of malondialdehyde—MDA (a lipid peroxidation maker), in depressed patients, as compared to an age-matched control group. Also, we were interested to see if there are any differences between first episode vs. recurrent depression groups, in terms of oxidative stress markers. Additionally, we want it to investigate the effects of different antidepressant medication (mirtazapine, venlafaxine, tianeptine and escitalopram) on oxidative status of depressed patients. Our results showed an increased oxidative stress status in the serum of patients with MDD, expressed by a significant decrease of both SOD and GPX specific activities and a significant increase of the lipid peroxidation marker MDA, as compared to the control group. When we analyzed the oxidative stress status in depressed patients based on chronicity we observed significant decrease of SOD and GPX specific activities in recurrent depression group, as compared to the first episode group. Moreover, a very significant increase in MDA concentration was observed in recurrent depression patients, as compared to the first episode group. Our work provides additional evidences of increased oxidative stress in MDD, expressed by altered antioxidant enzyme activity and increased levels of lipid peroxidation. Also, it seems that subclassifying depression into different subtypes, based on chronicity, can predict differences in the levels of some various oxidative stress markers. & 2012 Elsevier B.V. All rights reserved.
Keywords: Major depression disorder Oxidative stress First episode and recurrent depression
1. Introduction Lately there is a growing amount of evidences that major depression (MDD) is an inflammatory disorder, as showed mainly by the increased levels of pro-inflammatory cytokines, e.g. interleukin-1b, interleukin-6 or tumor necrosis factor-a (Maes et al., 2012). In this way, according to the so-called cytokine hypothesis, depression would be due to a stress-related increased production of pro-inflammatory cytokines that, in turn, would lead to increased oxidative and nitrosative damage (Maes, 2008; Catena-Dell’Osso et al., 2011). Also, decreased levels of antioxidants/antioxidant enzymes may cause greater inflammatory responsivity (Kobrosly et al., 2010). These aspects are also sustained by reports stating increased levels of reactive oxygen species (ROS) (Tsuboi et al., 2006), combined with lowered levels of some antioxidants like vitamin E, coenzyme Q10, alfa-tocopherol, ascorbic acid, zinc or glutathione in MDD (Maes et al., 2011), as well as some alterations of the antioxidant enzymes such as superoxide dismutase-SOD
n
Corresponding author. Tel.: þ40 751 218 264;fax þ 40 232 201 472. E-mail address: [email protected] (A. Ciobica).
0165-0327/$ - see front matter & 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jad.2012.05.022
and glutathione peroxidase-GPX (Kodydkova´ et al., 2009; Sarandol et al., 2007). In this way, it is possible for the pathways of oxidative stress to underpin the pathophysiology of MDD and moreover it seems that the main oxidative stress markers could represent key aspects of MDD, predicting even the chronicity of the disease (Moylan et al., 2012; Ga"ecki et al., 2009a). Considering these aspects, the aim of this work was to evaluate the specific activity of the main antioxidant defences (SOD and GPX) and also the concentration of a lipid peroxidation marker (malondialdehyde-MDA) in MDD patients, as compared to an agematched control group. Moreover, we were interested to see if the classification of depressed patients, based on chronicity, will result in any differences of oxidative stress markers concentrations. Additionally, we want it to investigate the effects of different antidepressant medication on oxidative status of MDD patients.
2. Material and methods Thirty-one patients with MDD according to DSM-IV (APA, (1994)) treated in the Socola Hospital were recruited. The diagnoses were made using a structured clinical interview.
C. Stefanescu, A. Ciobica / Journal of Affective Disorders 143 (2012) 34–38
The mean age of the 20 female (64.5%) and 11 male (35.5%) patients was 47.577.9 years at initial assessment. One group of depressed participants (n ¼15) was comprised of individuals (9 female-60% and 6 male-40%) who were presenting for assessment for the first time and had no past treatment history (first episode group-FE;mean age 44.66 76.8). The second group of patients included individuals who had extensive illness histories (n ¼16, 11 female and 5 male), having experienced three or more previous episodes of MDD (recurrent group-R;mean age 50.4478.9). In addition, psychiatric symptoms were assessed using Hamilton Rating Scale for Depression (HRSD; Hamilton, 1960). The mean score for the depressed patients was 21.675.6, with an average HRSD of 23.476.4 for the first episode group and 19.674.9 for the recurrent group. Mean duration of current depressive episode was 26.3720.35 weeks. Average age of onset was 41.8 79.1 years, mean duration of illness was 7.176.1 years and mean number of episodes (including the current one) was 2.672.38. All patients were receiving antidepressant medication at the time of the examination. In this way, within the first episode patients (n¼15), 8 were on mirtazapine (30 mg/day) and 7 on venlafaxine (75 mg/day), while from the recurrent group (n¼ 16), 6 patients were receiving tianeptine (37,5 mg/day), 5 were receiving escitalopram (10 mg/day) and 5 were on venlafaxine (150 mg/day). On average, patients had been treated with antidepressants for 18.54 725.3 weeks. Exclusion criteria for all participants were represented by: history of cardiovascular and cerebrovascular disease, hepatic and/ or renal diseases, diabetes mellitus, hypothyroidism, malignancies, alcohol consumption (430 g/day) and supplementation by vitamins, polyunsaturated fatty acids and/or antioxidants. No patient was diagnosed with other psychiatric comorbidity. For comparison, 20 healthy age (46.3 77.8 years) and sex (13 female, 7 male-65% vs. 35%) matched subjects, without a history of psychiatric disorder were recruited. Healthy controls were free from medication and had no symptoms or medical history of a mental health disorder. Their HRSD was 2.171.6. Analysis of covariance (Table 1) showed that patients with a first episode of major depression and recurrent depression did not differ significantly from healthy comparison subjects with respect to age, gender and smoking habits. We also observed no significant differences between first episode and recurrent group in the duration of the current episode and duration of the medication. The study was conducted according to provisions of the Helsinki Declaration and the local committee approved the study. All the patients signed the informed consent. Blood samples were collected before breakfast, allowed to clot, centrifuged and stored at 40 1C until measurement. Determinations of SOD, GPX and MDA were performed as previously described (Padurariu et al., 2010). The precision of the biochemical estimations was analyzed by determining the inter-assay and intra-assay values.
35
We report an intra-assay coefficient of 7.8% for SOD, 8.2% for GPX and 9.3% for MDA. Regarding the inter-assay coefficients, these were 8.9% for SOD, 8.8% for GPX and 13.4% for MDA. The results for antioxidant enzymes activity and MDA level were analyzed using one-way ANOVA. All results are expressed as mean7SEM. Post hoc analyses were performed using Tukey’s honestly significant difference test in order to compare the first episode/recurrent groups and the treatment groups. F values for which Po0.05 were regarded as statistically significant.
3. Results Initial analysis of our results included all MDD patients, regardless of the depression subtype or their treatment. Our analysis showed an increased oxidative stress status in patients with MDD, expressed by a significant decrease of both SOD (F(1,49)¼25, po0.0001) and GPX (F(1,49)¼15, p¼0.0003) specific activities, as compared to the control group (Fig. 1A/B). Additionally, a significant increase of the lipid peroxidation marker MDA (F(1,49)¼15, p¼ 0.0002) was also observed in patients with MDD, as compared to controls (Fig. 1C). When we analyzed the oxidative stress status in MDD patients based on chronicity, we observed a significant decrease of SOD specific activity in both the group of patients with the first episode of depression (F(1,33)¼6, p ¼0.022), as well as in the group with recurrent depression (F(1,34)¼ 114, p o0.0001), as compared to controls (Fig. 2A). Additionally, post-hoc analysis showed significant differences between the group of patients with the first episode of depression vs. recurrent depression (p ¼0.004). Also, a significant decrease of GPX specific activity was observed in the group with recurrent depression (F(1,34)¼17, p¼0.0002), as compared to controls, while the first episode group did not differ significantly (F(1,33)¼3, p¼0.09) from the healthy subjects (Fig. 2B). Importantly, post-hoc analysis revealed significant differences regarding the specific activity of GPX between the first episode group and recurrent depression group (po0.0001). Additionally, we noted an increase of MDA concentration in the group with recurrent depression, as compared to control (F(1,34)¼55, po0.0001) (Fig. 2C). Moreover, post-hoc analysis showed significant differences regarding the lipid peroxidation marker (MDA) between the group of patients with the first episode of depression and recurrent depression group (po0.0001). Regarding the treatment, in the case of the patients with the first episode of depression, we noted only a significant decrease in the specific activity of SOD in the patients treated with mirtazapine (F(1,26)¼31, po0.0001), as compared to the controls (Fig. 3A). Still, post-hoc analysis showed significant differences between first episode patients treated venlafaxine vs. those treated with mirtazapine, in both SOD specific activity (p ¼0.001) (Fig. 3A), as well as in MDA concentration (p¼0.037) (Fig. 3C).
Table 1 Demographic data in controls and patients with a first episode of major depression and recurrent depression.
Age (years) Gender (female/male) Current smokers (%) Duration of current episode (weeks) Duration of medication (weeks) a n
Controla (n¼20)
First episode groupa (n¼ 15)
Reccurent groupa (n¼ 16)
Fn
Pn
46.3 77.8 13/7 35 – –
44.66 76.8 9/6 37.5 24.84 718.6 15.95 721.5
50.447 8.9 11/5 26.66 27.72 722.1 20.977 29.1
1.96 0.12 0.21 0.11 0.31
0.153 0.884 0.808 0.745 0.582
Each value represents mean and standard deviation. Analysis of covariance for age, smoking status, duration of illness and dose.
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C. Stefanescu, A. Ciobica / Journal of Affective Disorders 143 (2012) 34–38
Fig. 1. Superoxide dismutase (SOD) specific activity (A), glutathione peroxidase (GPX) specific activity (B) and the levels of malondiyaldehide (MDA) (C) in the serum of control subjects and major depression disorder (MDD) patients. The values are mean 7 SEM (n ¼20 in control and 31 in MDD group). nnnp o 0.0003.
Regarding the effects of the treatment on the oxidative stress status in the case of the patients with recurrent depression, we observed a significant decrease of SOD specific activity in all 3 groups: escitalopram (F(1,23)¼30, po0.0001), tianeptine (F(1,24)¼ 133, po0.0001) and venlafaxine (F(1,23)¼84, po0.0001) (Fig. 4A), as well as a significant decrease of GPX specific activity in the case of escitalopram (F(1,23)¼ 6, p¼0.02), tianeptine (F(1,24)¼15, p¼0.0008), as compared to the control group (Fig. 4B). Regarding the concentration of MDA we also observed a significant increase in the patients treated with escitalopram (F(1,23)¼256, p o0.0001), tianeptine (F(1,24)¼16, p¼0.0005) and venlafaxine (F(1,23)¼23, po0.0001), as compared to the control group (Fig. 4C). Also, we compared the treated groups of patients with recurrent depression by using post-hoc analysis (detailed results in the legend of Fig. 4).
4. Discussion Our results provide additional evidences of increased oxidative stress in MDD expressed by altered serum antioxidant enzyme activity and increased levels of lipid peroxidation. In this way, previous studies regarding the oxidative stress markers in MDD reported similar aspects with decreased antioxidant
Fig. 2. Superoxide dismutase (SOD) specific activity (A), glutathione peroxidase (GPX) specific activity (B) and the levels of malondiyaldehide (MDA) (C) in the serum of control subjects and major depression disorder (MDD) patients, classified after the disease’s chronicity. The values are mean 7 SEM (n ¼20 in control, 15 in first episode group and 16 in recurrent group). np¼ 0.022, nnp ¼0.0002, nnn p o0.0001. For post-hoc analysis—# (first episode vs. recurrent): p ¼0.004 for SOD (A), p o 0.0001 for GPX (B) and p o 0.0001 for MDA (C).
enzyme GPX and increased levels of MDA (Ozcan et al., 2004; Sarandol et al., 2007). However, regarding the specific activity of SOD, most of the previous studies reported increased levels in MDD (Khanzode et al., 2003; Kodydkova´ et al., 2009; Ga"ecki et al., 2009a; Sarandol et al., 2007). Still, there are also isolated papers stating decrease SOD in MDD (Herken et al., 2007), as well as authors reporting no significant differences vs. controls (Srivastava et al., 2002). This could be perhaps explained by the fact that SOD is the first line of defense against oxidative stress development and decreased SOD and GPX activity may lead to an accumulation of H2O2. This could also stimulate the lipid peroxidation and protein oxidation processes, resulting in cellular deficits. In this way, an increased generation of oxygen and nitrogen reactive species in MDD might lead to a rapid consumption of plasma antioxidants. As depleted, the antioxidant systems cannot protect the organism against the proooxidative challenge and so in a vicious cycle in the patients with first episode of depression and then subsequently in the case of the recurrent depression, individuals may have an inadequate antioxidant enzymatic activity that is incapable of responding to increased free radical
C. Stefanescu, A. Ciobica / Journal of Affective Disorders 143 (2012) 34–38
Fig. 3. Superoxide dismutase (SOD) specific activity (A), glutathione peroxidase (GPX) specific activity (B) and the levels of malondiyaldehide (MDA) (C) in the serum of control subjects and first episode (FE) treated patients. The values are mean 7 SEM (n ¼20 in control, 8 in mirtazapine and 7 in venlafaxine group). nnn p o 0.0001. For post-hoc analysis—# (venlafaxine vs. mirtazapine): p ¼0.001 for SOD (A) and p ¼0.037 for MDA (C).
production, which could lead to some of the various pathological alterations from MDD. Similar aspects regarding the relevance of oxidative stress in the staging of MDD were also demonstrated by several authors (Moylan et al., 2012; Ga"ecki et al., 2009a). This will be also sustained by the progressive increase in the serum levels of MDA in the patients with the first episode of depression and those with recurrent depression, respectively. This finding also supports the idea that an increase of the oxidative processes (lipid peroxidation in this case) will generate, eventually, the fall of the enzymatic antioxidant protection, as we showed earlier. However, while it is somehow reasonable to argue that this decrease of SOD could be caused by the disease itself, our results mainly point to pharmacological effects as they show a significant increase of SOD specific activity in first-episode patients treated with mirtazapine. Still, the same decrease of SOD was also reported in recurrent patients treated with escitalopram, tianeptine and venlafaxine, as compared to controls. Interestingly enough, antioxidant activity was actually cited for mirtazapine (Tok et al., 2012), escitalopram (Shalaby et al.,2009), tianeptine (Quevedo et al., 2012) and venlafaxine (Eren et al., 2007). Regarding previous studies on the oxidative stress status in treated patients with MDD, the results showed no significant
37
Fig. 4. Superoxide dismutase (SOD) specific activity (A), glutathione peroxidase (GPX) specific activity (B) and the levels of malondiyaldehide (MDA) (C) in the serum of control subjects and treated patients with recurrent depression (R). The values are mean 7 SEM (n¼ 20 in control, 6 in tianeptine, 5 in escitalopram and 5 in venlafaxine group). np ¼0.02, nnp o0,0008, nnnpo 0.0001. For post-hoc analysis—a (escitalopram vs. venlafaxine): p¼ 0.02 for SOD (A), p ¼0.004 for GPX (B) and p o 0.0001 for MDA (C). # (escitalopram vs. tianeptine): p o 0.0001 for SOD (A) and po 0.0001 for MDA (C). b (tianeptine vs. venlafaxine): po 0.0001 for GPX (B).
changes in the oxidative stress makers after 3 months treatment with flouxetine (Ga"ecki et al., 2009a) or after venlafaxine and sertraline administration for 6 weeks (Sarandol et al., 2007). On the other side, the administration of selective SSRIs for 3 months resulted in a decrease to normal levels for oxidative stress parameters (Bilici et al., 2001), while a combined therapy with fluoxetine and acetylsalicylic acid generated a significant improvement of the oxidative stress markers (Ga"ecki et al., (2009b)). It seems that also the dosage used is influential, since it was demonstrated that the administration of different doses of flouxetine (10 mg or 20 mg-as in Galeki study-2009a) does not result in significant modifications of the oxidative stress markers, while a higher dose of 40 mg induced an increase in the antioxidant enzymes (Kim et al., 2007). There are of course several limitations to our study which include the relatively small size of the groups we used, the fact that patients were taking antidepressants for different lengths of time, as well as the lack of pre and post treatment measurements of oxidative stress markers.
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C. Stefanescu, A. Ciobica / Journal of Affective Disorders 143 (2012) 34–38
Our results provide additional evidences of increased oxidative stress status in MDD, as shown by alterations of antioxidant enzymes specific activities, as well as increased concentrations of MDA. Also, it seems that sub-classifying depression into different subtypes, based on chronicity, can predict differences in the levels of some various oxidative stress markers. Role of funding source Ciobica Alin is supported by a POSDRU grant /89/1.5/S/49944, Alexandru Ioan Cuza University, Iasi.
Conflict of interest None, except for the fact that Ciobica Alin is supported by a POSDRU Grant /89/1.5/S/49944, Alexandru Ioan Cuza University, Iasi.
Acknowledgments We thank Padurariu Manuela who kindly helped us with the organizational aspects at the Socola Hospital, Iasi, Romania.
References American Psychiatric Association-APA, 1994. Diagnostic and Statistical Manual of Mental Disorders, DSM-IV, Fourth Edition APA, Washington, DC. ¨ glu, M.A., Uydu, H.A., Bekaro˘glu, M., De˘ger, O., 2001. Bilici, M., Efe, H., Koro˘ Antioxidative enzyme activities and lipid peroxidation in major depression: alterations by antidepressant treatments. Journal of Affective Disorders 64, 43–51. Catena-Dell’Osso, M., Bellantuono, C., Consoli, G., Baroni, S., Rotella, F., Marazziti, D., 2011. Inflammatory and neurodegenerative pathways in depression: a new avenue for antidepressant development? Current Medicinal Chemistry 18, 245–255. Eren, I., Naziro˘glu, M., Demirdas-, A., Celik, O., U˘guz, A.C., Altunbas-ak, A., Ozmen, I., Uz, E., 2007. Venlafaxine modulates depression-induced oxidative stress in brain and medulla of rat. Neurochemical Research 32, 497–505. Ga"ecki, P., Szemraj, J., Bien´kiewicz, M., Zboralski, K., Ga"ecka, E., 2009b. Oxidative stress parameters after combined fluoxetine and acetylsalicylic acid therapy in depressive patients. Human Psychopharmacology 24, 277–286. Ga"ecki, P., Szemraj, J., Bien´kiewicz, M., Florkowski, A., Ga"ecka, E., 2009a. Lipid peroxidation and antioxidant protection in patients during acute depressive episodes and in remission after fluoxetine treatment. Pharmacological Reports 61, 436–447. Hamilton, M., 1960. A rating scale for depression. Journal of Neurology, Neurosurgery, and Psychiatry 23, 56–62. Herken, H., Gurel, A., Selek, S., 2007. Adenosine deaminase, nitric oxide, superoxide dismutase, and xanthine oxidase in patients with major depression: impact of antidepressant treatment. Archives of Medical Research 38, 247–252. Khanzode, S.D., Dakhale, G.N., Khanzode, S.S., Saoji, A., Palasodkar, R., 2003. Oxidative damage and major depression: the potential antioxidant action of selective serotonin re-uptake inhibitors. Redox Report 8, 365–370.
Kim, D., Li, H., Yoo, K., Lee, B., Hwan,g, I., Won, M., 2007. Effects of fluoxetine on ischemic cells and expressions in BDNF and some antioxidants in the gerbil hippocampus CA1 region induced by transient ischemia. Experimental Neurology 204, 748–758. Kobrosly, R., van Wijngaarden, E., 2010. Associations between immunologic, inflammatory, and oxidative stress markers with severity of depressive symptoms: an analysis of the 2005–2006 National Health and Nutrition Examination Survey. Neurotoxicology 31, 126–133. Kodydkova´, J., Va´vrova´, L., Zeman, M., Jira´k, R., Maca´sek, J., Stankova´, B., Tvrzicka´, E., Za´k, A., 2009. Antioxidative enzymes and increased oxidative stress in depressive women. Clinical Biochemistry 42, 1368–1374. Maes, M., Fiˇsar, Z., Medina, M., Scapagnini, G., Nowak, G., Berk, M., 2012. New drug targets in depression: inflammatory, cell-mediated immune, oxidative and nitrosative stress, mitochondrial, antioxidant, and neuroprogressive pathways. And new drug candidates-Nrf2 activators and GSK-3 inhibitors. Inflammopharmacology. Maes, M., 2008. The cytokine hypothesis of depression: inflammation, oxidative & nitrosative stress (IO&NS) and leaky gut as new targets for adjunctive treatments in depression. Neuroendocrinology Letters 29, 287–291. Maes, M., Galecki, P., Chang, Y.S., Berk, M., 2011. A review on the oxidative and nitrosative stress (O&NS) pathways in major depression and their possible contribution to the (neuro)degenerative processes in that illness. Progress in Neuro-Psychopharmacology & Biological Psychiatry 35, 676–692. Moylan, S., Maes, M., Wray, N.R., Berk, M., 2012. The neuroprogressive nature of major depressive disorder: pathways to disease evolution and resistance, and therapeutic implications. Molecular Psychiatry. Ozcan, M.E., Gulec, M., Ozerol, E., Polat, R., Akyol, O., 2004. Antioxidant enzyme activities and oxidative stress in affective disorders. International Clinical Psychopharmacology 19, 89–95. Padurariu, M., Ciobica, A., Hritcu, L., Stoica, B., Bild, W., Stefanescu, C., 2010. Changes of some oxidative stress markers in the serum of patients with mild cognitive impairment and Alzheimer’s disease. Neuroscience Letters 469, 6–10. Quevedo, J., Re´us, G., Abelaira, H., Ribeiro, K., Della, F., Bernardini, M., Steckert, A., Galant, L., Dal-Pizzol, F., 2012. Tianeptine treatment reverses increase on oxidative damage and decrease of antioxidant defense enzymes into the brain of rats submitted to the chronic mild stress model. 28th CINP World Congress of Neuropsychopharmacology. Sarandol, A., Sarandol, E., Eker, S.S., Erdinc, S., Vatansever, E., Kirli, S., 2007. Major depressive disorder is accompanied with oxidative stress: short-term antidepressant treatment does not alter oxidative-antioxidative systems. Human Psychopharmacology 22, 67–73. Shalaby, A., Kamal, S., 2009. Effect of Escitalopram on GABA level and anti-oxidant markers in prefrontal cortex and nucleus accumbens of chronic mild stressexposed albino rats. International Journal of Physiology, Pathophysiology and Pharmacology 1, 154–161. Srivastava, N., Barthwal, M.K., Dalal, P.K., Agarwal, A.K., Nag, D., Seth, P.K., Srimal, R.C., Dikshit, M., 2002. A study on nitric oxide, beta-adrenergic receptors and antioxidant status in the polymorphonuclear leukocytes from the patients of depression. Journal of Affective Disorders 72, 45–52. Tok, A., Sener, E., Albayrak, A., Cetin, N., Polat, B., Suleyman, B., Akcay, F., Suleyman, H., 2012. Effect of mirtazapine on oxidative stress created in rat kidneys by ischemia-reperfusion. Renal Failure 34, 103–110. Tsuboi, H., Tatsumi, A., Yamamoto, K., Kobayashi, F., Shimoi, K., Kinae, N., 2006. Possible connection among job stress, depressive symptoms, lipid modulation and antioxidants. Journal of Affective Disorders 91, 63–70.
Contents lists available at SciVerse ScienceDirect
Journal of Affective Disorders journal homepage: www.elsevier.com/locate/jad
Research report
The relevance of oxidative stress status in first episode and recurrent depression Cristinel Stefanescu a, Alin Ciobica b,n a ‘‘
Gr. T. Popa’’ University of Medicine and Pharmacy, 16 Universitatii Street, 700115, Iasi, Romania Alexandru Ioan Cuza’’ University, Dept. of Biology, 11 Carol I Blvd., 700506, Iasi, Romania
b ‘‘
a r t i c l e i n f o
a b s t r a c t
Article history: Received 22 March 2012 Received in revised form 14 May 2012 Accepted 14 May 2012 Available online 25 July 2012
Oxidative and nitrosative stress (O&NS) could play an important role in the pathophysiology of major depression (MDD). The aim of the present work was to evaluate the specific activity of the main peripheral antioxidant defences (superoxide dismutase—SOD and glutathione peroxidase—GPX) and the level of malondialdehyde—MDA (a lipid peroxidation maker), in depressed patients, as compared to an age-matched control group. Also, we were interested to see if there are any differences between first episode vs. recurrent depression groups, in terms of oxidative stress markers. Additionally, we want it to investigate the effects of different antidepressant medication (mirtazapine, venlafaxine, tianeptine and escitalopram) on oxidative status of depressed patients. Our results showed an increased oxidative stress status in the serum of patients with MDD, expressed by a significant decrease of both SOD and GPX specific activities and a significant increase of the lipid peroxidation marker MDA, as compared to the control group. When we analyzed the oxidative stress status in depressed patients based on chronicity we observed significant decrease of SOD and GPX specific activities in recurrent depression group, as compared to the first episode group. Moreover, a very significant increase in MDA concentration was observed in recurrent depression patients, as compared to the first episode group. Our work provides additional evidences of increased oxidative stress in MDD, expressed by altered antioxidant enzyme activity and increased levels of lipid peroxidation. Also, it seems that subclassifying depression into different subtypes, based on chronicity, can predict differences in the levels of some various oxidative stress markers. & 2012 Elsevier B.V. All rights reserved.
Keywords: Major depression disorder Oxidative stress First episode and recurrent depression
1. Introduction Lately there is a growing amount of evidences that major depression (MDD) is an inflammatory disorder, as showed mainly by the increased levels of pro-inflammatory cytokines, e.g. interleukin-1b, interleukin-6 or tumor necrosis factor-a (Maes et al., 2012). In this way, according to the so-called cytokine hypothesis, depression would be due to a stress-related increased production of pro-inflammatory cytokines that, in turn, would lead to increased oxidative and nitrosative damage (Maes, 2008; Catena-Dell’Osso et al., 2011). Also, decreased levels of antioxidants/antioxidant enzymes may cause greater inflammatory responsivity (Kobrosly et al., 2010). These aspects are also sustained by reports stating increased levels of reactive oxygen species (ROS) (Tsuboi et al., 2006), combined with lowered levels of some antioxidants like vitamin E, coenzyme Q10, alfa-tocopherol, ascorbic acid, zinc or glutathione in MDD (Maes et al., 2011), as well as some alterations of the antioxidant enzymes such as superoxide dismutase-SOD
n
Corresponding author. Tel.: þ40 751 218 264;fax þ 40 232 201 472. E-mail address: [email protected] (A. Ciobica).
0165-0327/$ - see front matter & 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jad.2012.05.022
and glutathione peroxidase-GPX (Kodydkova´ et al., 2009; Sarandol et al., 2007). In this way, it is possible for the pathways of oxidative stress to underpin the pathophysiology of MDD and moreover it seems that the main oxidative stress markers could represent key aspects of MDD, predicting even the chronicity of the disease (Moylan et al., 2012; Ga"ecki et al., 2009a). Considering these aspects, the aim of this work was to evaluate the specific activity of the main antioxidant defences (SOD and GPX) and also the concentration of a lipid peroxidation marker (malondialdehyde-MDA) in MDD patients, as compared to an agematched control group. Moreover, we were interested to see if the classification of depressed patients, based on chronicity, will result in any differences of oxidative stress markers concentrations. Additionally, we want it to investigate the effects of different antidepressant medication on oxidative status of MDD patients.
2. Material and methods Thirty-one patients with MDD according to DSM-IV (APA, (1994)) treated in the Socola Hospital were recruited. The diagnoses were made using a structured clinical interview.
C. Stefanescu, A. Ciobica / Journal of Affective Disorders 143 (2012) 34–38
The mean age of the 20 female (64.5%) and 11 male (35.5%) patients was 47.577.9 years at initial assessment. One group of depressed participants (n ¼15) was comprised of individuals (9 female-60% and 6 male-40%) who were presenting for assessment for the first time and had no past treatment history (first episode group-FE;mean age 44.66 76.8). The second group of patients included individuals who had extensive illness histories (n ¼16, 11 female and 5 male), having experienced three or more previous episodes of MDD (recurrent group-R;mean age 50.4478.9). In addition, psychiatric symptoms were assessed using Hamilton Rating Scale for Depression (HRSD; Hamilton, 1960). The mean score for the depressed patients was 21.675.6, with an average HRSD of 23.476.4 for the first episode group and 19.674.9 for the recurrent group. Mean duration of current depressive episode was 26.3720.35 weeks. Average age of onset was 41.8 79.1 years, mean duration of illness was 7.176.1 years and mean number of episodes (including the current one) was 2.672.38. All patients were receiving antidepressant medication at the time of the examination. In this way, within the first episode patients (n¼15), 8 were on mirtazapine (30 mg/day) and 7 on venlafaxine (75 mg/day), while from the recurrent group (n¼ 16), 6 patients were receiving tianeptine (37,5 mg/day), 5 were receiving escitalopram (10 mg/day) and 5 were on venlafaxine (150 mg/day). On average, patients had been treated with antidepressants for 18.54 725.3 weeks. Exclusion criteria for all participants were represented by: history of cardiovascular and cerebrovascular disease, hepatic and/ or renal diseases, diabetes mellitus, hypothyroidism, malignancies, alcohol consumption (430 g/day) and supplementation by vitamins, polyunsaturated fatty acids and/or antioxidants. No patient was diagnosed with other psychiatric comorbidity. For comparison, 20 healthy age (46.3 77.8 years) and sex (13 female, 7 male-65% vs. 35%) matched subjects, without a history of psychiatric disorder were recruited. Healthy controls were free from medication and had no symptoms or medical history of a mental health disorder. Their HRSD was 2.171.6. Analysis of covariance (Table 1) showed that patients with a first episode of major depression and recurrent depression did not differ significantly from healthy comparison subjects with respect to age, gender and smoking habits. We also observed no significant differences between first episode and recurrent group in the duration of the current episode and duration of the medication. The study was conducted according to provisions of the Helsinki Declaration and the local committee approved the study. All the patients signed the informed consent. Blood samples were collected before breakfast, allowed to clot, centrifuged and stored at 40 1C until measurement. Determinations of SOD, GPX and MDA were performed as previously described (Padurariu et al., 2010). The precision of the biochemical estimations was analyzed by determining the inter-assay and intra-assay values.
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We report an intra-assay coefficient of 7.8% for SOD, 8.2% for GPX and 9.3% for MDA. Regarding the inter-assay coefficients, these were 8.9% for SOD, 8.8% for GPX and 13.4% for MDA. The results for antioxidant enzymes activity and MDA level were analyzed using one-way ANOVA. All results are expressed as mean7SEM. Post hoc analyses were performed using Tukey’s honestly significant difference test in order to compare the first episode/recurrent groups and the treatment groups. F values for which Po0.05 were regarded as statistically significant.
3. Results Initial analysis of our results included all MDD patients, regardless of the depression subtype or their treatment. Our analysis showed an increased oxidative stress status in patients with MDD, expressed by a significant decrease of both SOD (F(1,49)¼25, po0.0001) and GPX (F(1,49)¼15, p¼0.0003) specific activities, as compared to the control group (Fig. 1A/B). Additionally, a significant increase of the lipid peroxidation marker MDA (F(1,49)¼15, p¼ 0.0002) was also observed in patients with MDD, as compared to controls (Fig. 1C). When we analyzed the oxidative stress status in MDD patients based on chronicity, we observed a significant decrease of SOD specific activity in both the group of patients with the first episode of depression (F(1,33)¼6, p ¼0.022), as well as in the group with recurrent depression (F(1,34)¼ 114, p o0.0001), as compared to controls (Fig. 2A). Additionally, post-hoc analysis showed significant differences between the group of patients with the first episode of depression vs. recurrent depression (p ¼0.004). Also, a significant decrease of GPX specific activity was observed in the group with recurrent depression (F(1,34)¼17, p¼0.0002), as compared to controls, while the first episode group did not differ significantly (F(1,33)¼3, p¼0.09) from the healthy subjects (Fig. 2B). Importantly, post-hoc analysis revealed significant differences regarding the specific activity of GPX between the first episode group and recurrent depression group (po0.0001). Additionally, we noted an increase of MDA concentration in the group with recurrent depression, as compared to control (F(1,34)¼55, po0.0001) (Fig. 2C). Moreover, post-hoc analysis showed significant differences regarding the lipid peroxidation marker (MDA) between the group of patients with the first episode of depression and recurrent depression group (po0.0001). Regarding the treatment, in the case of the patients with the first episode of depression, we noted only a significant decrease in the specific activity of SOD in the patients treated with mirtazapine (F(1,26)¼31, po0.0001), as compared to the controls (Fig. 3A). Still, post-hoc analysis showed significant differences between first episode patients treated venlafaxine vs. those treated with mirtazapine, in both SOD specific activity (p ¼0.001) (Fig. 3A), as well as in MDA concentration (p¼0.037) (Fig. 3C).
Table 1 Demographic data in controls and patients with a first episode of major depression and recurrent depression.
Age (years) Gender (female/male) Current smokers (%) Duration of current episode (weeks) Duration of medication (weeks) a n
Controla (n¼20)
First episode groupa (n¼ 15)
Reccurent groupa (n¼ 16)
Fn
Pn
46.3 77.8 13/7 35 – –
44.66 76.8 9/6 37.5 24.84 718.6 15.95 721.5
50.447 8.9 11/5 26.66 27.72 722.1 20.977 29.1
1.96 0.12 0.21 0.11 0.31
0.153 0.884 0.808 0.745 0.582
Each value represents mean and standard deviation. Analysis of covariance for age, smoking status, duration of illness and dose.
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Fig. 1. Superoxide dismutase (SOD) specific activity (A), glutathione peroxidase (GPX) specific activity (B) and the levels of malondiyaldehide (MDA) (C) in the serum of control subjects and major depression disorder (MDD) patients. The values are mean 7 SEM (n ¼20 in control and 31 in MDD group). nnnp o 0.0003.
Regarding the effects of the treatment on the oxidative stress status in the case of the patients with recurrent depression, we observed a significant decrease of SOD specific activity in all 3 groups: escitalopram (F(1,23)¼30, po0.0001), tianeptine (F(1,24)¼ 133, po0.0001) and venlafaxine (F(1,23)¼84, po0.0001) (Fig. 4A), as well as a significant decrease of GPX specific activity in the case of escitalopram (F(1,23)¼ 6, p¼0.02), tianeptine (F(1,24)¼15, p¼0.0008), as compared to the control group (Fig. 4B). Regarding the concentration of MDA we also observed a significant increase in the patients treated with escitalopram (F(1,23)¼256, p o0.0001), tianeptine (F(1,24)¼16, p¼0.0005) and venlafaxine (F(1,23)¼23, po0.0001), as compared to the control group (Fig. 4C). Also, we compared the treated groups of patients with recurrent depression by using post-hoc analysis (detailed results in the legend of Fig. 4).
4. Discussion Our results provide additional evidences of increased oxidative stress in MDD expressed by altered serum antioxidant enzyme activity and increased levels of lipid peroxidation. In this way, previous studies regarding the oxidative stress markers in MDD reported similar aspects with decreased antioxidant
Fig. 2. Superoxide dismutase (SOD) specific activity (A), glutathione peroxidase (GPX) specific activity (B) and the levels of malondiyaldehide (MDA) (C) in the serum of control subjects and major depression disorder (MDD) patients, classified after the disease’s chronicity. The values are mean 7 SEM (n ¼20 in control, 15 in first episode group and 16 in recurrent group). np¼ 0.022, nnp ¼0.0002, nnn p o0.0001. For post-hoc analysis—# (first episode vs. recurrent): p ¼0.004 for SOD (A), p o 0.0001 for GPX (B) and p o 0.0001 for MDA (C).
enzyme GPX and increased levels of MDA (Ozcan et al., 2004; Sarandol et al., 2007). However, regarding the specific activity of SOD, most of the previous studies reported increased levels in MDD (Khanzode et al., 2003; Kodydkova´ et al., 2009; Ga"ecki et al., 2009a; Sarandol et al., 2007). Still, there are also isolated papers stating decrease SOD in MDD (Herken et al., 2007), as well as authors reporting no significant differences vs. controls (Srivastava et al., 2002). This could be perhaps explained by the fact that SOD is the first line of defense against oxidative stress development and decreased SOD and GPX activity may lead to an accumulation of H2O2. This could also stimulate the lipid peroxidation and protein oxidation processes, resulting in cellular deficits. In this way, an increased generation of oxygen and nitrogen reactive species in MDD might lead to a rapid consumption of plasma antioxidants. As depleted, the antioxidant systems cannot protect the organism against the proooxidative challenge and so in a vicious cycle in the patients with first episode of depression and then subsequently in the case of the recurrent depression, individuals may have an inadequate antioxidant enzymatic activity that is incapable of responding to increased free radical
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Fig. 3. Superoxide dismutase (SOD) specific activity (A), glutathione peroxidase (GPX) specific activity (B) and the levels of malondiyaldehide (MDA) (C) in the serum of control subjects and first episode (FE) treated patients. The values are mean 7 SEM (n ¼20 in control, 8 in mirtazapine and 7 in venlafaxine group). nnn p o 0.0001. For post-hoc analysis—# (venlafaxine vs. mirtazapine): p ¼0.001 for SOD (A) and p ¼0.037 for MDA (C).
production, which could lead to some of the various pathological alterations from MDD. Similar aspects regarding the relevance of oxidative stress in the staging of MDD were also demonstrated by several authors (Moylan et al., 2012; Ga"ecki et al., 2009a). This will be also sustained by the progressive increase in the serum levels of MDA in the patients with the first episode of depression and those with recurrent depression, respectively. This finding also supports the idea that an increase of the oxidative processes (lipid peroxidation in this case) will generate, eventually, the fall of the enzymatic antioxidant protection, as we showed earlier. However, while it is somehow reasonable to argue that this decrease of SOD could be caused by the disease itself, our results mainly point to pharmacological effects as they show a significant increase of SOD specific activity in first-episode patients treated with mirtazapine. Still, the same decrease of SOD was also reported in recurrent patients treated with escitalopram, tianeptine and venlafaxine, as compared to controls. Interestingly enough, antioxidant activity was actually cited for mirtazapine (Tok et al., 2012), escitalopram (Shalaby et al.,2009), tianeptine (Quevedo et al., 2012) and venlafaxine (Eren et al., 2007). Regarding previous studies on the oxidative stress status in treated patients with MDD, the results showed no significant
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Fig. 4. Superoxide dismutase (SOD) specific activity (A), glutathione peroxidase (GPX) specific activity (B) and the levels of malondiyaldehide (MDA) (C) in the serum of control subjects and treated patients with recurrent depression (R). The values are mean 7 SEM (n¼ 20 in control, 6 in tianeptine, 5 in escitalopram and 5 in venlafaxine group). np ¼0.02, nnp o0,0008, nnnpo 0.0001. For post-hoc analysis—a (escitalopram vs. venlafaxine): p¼ 0.02 for SOD (A), p ¼0.004 for GPX (B) and p o 0.0001 for MDA (C). # (escitalopram vs. tianeptine): p o 0.0001 for SOD (A) and po 0.0001 for MDA (C). b (tianeptine vs. venlafaxine): po 0.0001 for GPX (B).
changes in the oxidative stress makers after 3 months treatment with flouxetine (Ga"ecki et al., 2009a) or after venlafaxine and sertraline administration for 6 weeks (Sarandol et al., 2007). On the other side, the administration of selective SSRIs for 3 months resulted in a decrease to normal levels for oxidative stress parameters (Bilici et al., 2001), while a combined therapy with fluoxetine and acetylsalicylic acid generated a significant improvement of the oxidative stress markers (Ga"ecki et al., (2009b)). It seems that also the dosage used is influential, since it was demonstrated that the administration of different doses of flouxetine (10 mg or 20 mg-as in Galeki study-2009a) does not result in significant modifications of the oxidative stress markers, while a higher dose of 40 mg induced an increase in the antioxidant enzymes (Kim et al., 2007). There are of course several limitations to our study which include the relatively small size of the groups we used, the fact that patients were taking antidepressants for different lengths of time, as well as the lack of pre and post treatment measurements of oxidative stress markers.
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Our results provide additional evidences of increased oxidative stress status in MDD, as shown by alterations of antioxidant enzymes specific activities, as well as increased concentrations of MDA. Also, it seems that sub-classifying depression into different subtypes, based on chronicity, can predict differences in the levels of some various oxidative stress markers. Role of funding source Ciobica Alin is supported by a POSDRU grant /89/1.5/S/49944, Alexandru Ioan Cuza University, Iasi.
Conflict of interest None, except for the fact that Ciobica Alin is supported by a POSDRU Grant /89/1.5/S/49944, Alexandru Ioan Cuza University, Iasi.
Acknowledgments We thank Padurariu Manuela who kindly helped us with the organizational aspects at the Socola Hospital, Iasi, Romania.
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