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Progress in Neuro-Psychopharmacology & Biological Psychiatry 31 (2007) 1023 – 1026 www.elsevier.com/locate/pnpbp
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Serum brain-derived neurotrophic factor level in dysthymia: A comparative study with major depressive disorder a
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Ömer Aydemir a,⁎, Artuner Deveci a , Oryal E. Taskin a , Fatma Taneli b , Aysen Esen-Danaci a Celal Bayar University Hospital, Department of Psychiatry, Manisa 45030 Turkey b Celal Bayar University, Department of Biochemistry, Manisa, Turkey
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Received 4 December 2006; received in revised form 22 February 2007; accepted 23 February 2007 Available online 6 March 2007
Abstract
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In this present work, it is aimed to demonstrate BDNF serum concentrations in patients with dysthymia and to compare them with BDNF serum concentrations in patients with major depressive disorder and healthy subjects. The study was carried out in Celal Bayar University Hospital, Manisa, Turkey. Seventeen patients with dysthymia, 24 patients with major depressive disorder and 26 subjects without any psychiatric diagnosis and any psychiatric treatment were included in the study. The severity of depression was assessed with 17-item HAM-D. All subjects were asked to give their written consent. Blood samples were collected at baseline. Serum BDNF was kept at −70 °C before testing, and assayed with an ELISA Kit (Promega; Madison, WI, USA), after dilution with the Block and Sample solution provided with the kit. The data were subjected to the analysis of variance. The BDNF serum concentrations of the dysthymia group (mean = 28.9 ± 9.2 ng/ml) were significantly higher than that of the major depressive disorder group (21.2 ± 11.3 ng/ml) (p = 0.002), and it was not different from the level of the control group (31.4 ± 8.8 ng/ml). BDNF serum concentrations and HAM-D score did not have any significant correlation in the dysthymia and major depression groups (r = −0.276, p = 0.086). The low level of BDNF in patients with dysthymic disorder seems to point out that BDNF changes in mood disorders are state-dependent and vary according to the severity of depressive episodes. © 2007 Elsevier Inc. All rights reserved.
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Keywords: BDNF; Dysthymic disorder; Major depressive disorder
1. Introduction
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Dysthymic disorder is a mild but chronic form of depression lasting at least 2 years and often much longer. Compared to patients with episodic major depressive disorder, patients with dysthymic disorder are less severely depressed at initial examination but exhibit higher level of symptoms in followups conducted 6–30 months later and almost 70% of the patients with dysthymic disorder meet the criteria for a mood disorder even after 5 years (Stein et al., 2000). Thus, some authors suggest dysthymia as a characterological or subaffective depression, while others try to prove the biological overlap between dysthymia and major depression. There are neurobiological studies trying to demonstrate the common features between major depression and dysthymia. Almost half of the patients with dysthymia show abnormal DST ⁎ Corresponding author. Tel./fax: 90 236 2530357. E-mail address:
[email protected] (Ö. Aydemir). 0278-5846/$ - see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.pnpbp.2007.02.013
and TRH-TSH test results (Rihmer and Szadoczky, 1993). In major depression, about half of the patients show nonsuppression in DST, and 20–30% of the patients have blunted TSH response to TRH (Thase, 2004); and these findings are similar to the findings in dysthymia. Furthermore, polysomnographic studies reveal a decrease of REM latency, an increase in REM sleep and an abnormality of the periodic leg movement (PLM) index in dysthymia (Saletu-Zyhlarz et al., 2001). When these sleep abnormalities in dysthymia are compared with the sleep structure in major depressive disorder, the EEG sleep data seem to favor the existence of a biological overlap between dysthymia and major depressive disorder (Arriaga et al., 1995). Also, psychopharmacological studies on dysthymia show the efficacy of antidepressant treatment in this group (Lima and Moncrieff, 2000). These neurobiological studies point out that dysthymia has many common neurobiological features with major depression. In recent years, several studies have implicated a major role for intracellular pathways regulating neuroplasticity and
Ö. Aydemir et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 31 (2007) 1023–1026
2. Methods
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2.3. Instruments
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The study was carried out in the Department of Psychiatry in Celal Bayar University Hospital, Manisa, Turkey, between February 2004 and May 2005.
assessments. BDNF serum concentrations were measured by a solid-phase sandwich, two-site, enzyme-linked immunoassay (ELISA), using the BDNF Emax Immunoassay System reagents (Promega, Madison, WI, USA) according to the manufacturer's instructions. In this procedure flat-bottomed 96-well plates were coated with anti-BDNF monoclonal antibody to bind soluble BDNF and the plates were incubated overnight at 4 °C. After washing the plates with wash buffer (Tris–HCl, pH 7.6) and blocking for nonspecific binding, the plates were incubated at 25 °C for 1 h without shaking and later washed once. BDNF standards and samples, in duplicate, were added to the appropriate wells and the plates incubated for 2 h at 25 °C. The second specific BDNF polyclonal antibody was added and incubated 2 h at 25 °C so that the captured BDNF binds the polyclonal antibody. After washing the amount of specifically bound polyclonal antibody is then detected using species-specific anti-IgY antibody conjugated to horseradish peroxidase as a tertiary reactant. Unbound conjugate is removed by washing and following incubation with a chromogenic substrate and stopping the reaction with 1 N hydrochloric acid the absorbencies were measured at 450 nm using an automatic ELISA microplate reader. Intra-assay precision (coefficient of variation CV) is 8.8% at 28.6 pg/ml; 2.9% at 53.3 pg/ml.
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neurodegeneration in the aetiology of mood disorders (Popoli et al., 2002). Accordingly, many different types of stress paradigms decrease the expression of brain-derived neurotrophic factor (BDNF) and other neurotrophic/growth factors in the hippocampus. The hippocampus is one of several limbic structures that have been implicated in mood disorders and has connections with the amygdala and prefrontal cortex; regions that are more directly involved in emotion and cognition and thereby contribute to other major symptoms of depression (Duman and Monteggia, 2006). BDNF serum concentrations are decreased in depressed and untreated patients and antidepressant treatment increases BDNF serum concentrations in correlation with achieved remission (Aydemir et al., 2005). With respect to these findings, BDNF is suggested to be one of the biological parameters for depression. In this present study, it is aimed to demonstrate the BDNF serum concentrations in patients with dysthymic disorder in comparison to the patients with major depression with the hypothesis that BDNF serum concentrations are decreased in patients with dysthymic disorder as in patients with major depressive disorder.
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2.1. Subjects
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Seventeen patients with a diagnosis of dysthymic disorder and 24 patients with a diagnosis of major depressive disorder participated in the study. Patients at the age between 18 and 65 years, without any history of other psychiatric disorder or physical/neurological disease were included in the study. Patients with dysthymic disorder have received no psychiatric treatment before, that is, they were drug-naïve. Patients with major depressive disorder were drug free for at least 1 year. In the major depressive disorder group, 19 (79.1%) patients were having their first episode; the other five (20.9%) patients were recurrent. In addition, 26 subjects without any lifetime psychiatric diagnosis and any lifetime psychiatric treatment were invited to the study. Patients were diagnosed with the Turkish version of SCID-CV (Ozkurkcugil et al., 1999) according to DSM-IV. All subjects were asked to give their written consent.
The severity of depression was evaluated with the 17-item Hamilton Depression Rating Scale (HAM-D). The structured interview for HAM-D developed by Williams et al. (2000) was used to provide a better interrater reliability. It was adapted into Turkish by Aydemir et al. (2006) and was shown to be reliable and valid in Turkish. 2.4. Statistical analysis For statistical analysis, data were subjected to the analysis of variance (ANOVA) for comparing the mean scores of the HAMD and the mean of the BDNF serum concentrations between the three groups with Tukey post hoc evaluation. The Pearson correlation test was performed for obtaining the correlation
Table 1 Demographic features, HAM-D scores and BDNF serum concentrations of the groups
2.2. BDNF assessment
Venous blood samples (5 ml) from the patients and normal controls were collected in anticoagulant-free tubes between 11:00 and 12:00 AM. They were kept at room temperature for 1 h followed by 1 h at 4 °C before serum was isolated. Samples were centrifuged at 4 °C (3000 rpm, for 15 min using a refrigerated centrifuge) and the sera transferred to a new set of polypropylene tubes. The sera were stored at − 70 °C for batch
Age (years) Gender Male Female Age of onset (years) Duration of illness (years) HAM-D BDNF (ng/ml)
Dysthymia (n = 17)
Major depression (n = 24)
Control (n = 26)
P
41.7 ± 10.4
33.9 ± 15.7
31.4 ± 5.9
0.032
1 (5.9%) 16 (94.1) 31.5 ± 10.2 10.9 ± 5.2
7 (29.2%) 17 (70.8%) 33.4 ± 12.9 2.5 ± 3.9
6 (23.1%) 20 (76.9%)
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11.1 ± 2.4 28.9 ± 9.2
21.0 ± 3.6 21.2 ± 11.3
2.3 ± 1.7 31.4 ± 8.8
b0.0001 0.002
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4.1. Stress and BDNF
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Dexamethasone Suppression Test (DST), catecholamines, and several other electroencephalogram (EEG) sleep variables, show more consistent differences between dysthymic disorder and major depressive disorder (Howland and Thase, 1991). In our study, in terms of BDNF serum concentrations, patients with dysthymia separated from patients with major depression and were not different from healthy controls.
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One possible explanation of our finding can be the relation between stress and dysthymia. When it is focused to the neurobiological parameters which cause difference between dysthymia and major depression, stress-related parameters, such as DST or catecholamines, are prominent (Howland and Thase, 1991). There were reports that stress can cause damage and atrophy of neurons in certain brain structures, most notably the hippocampus, which expresses high levels of receptors for glucocorticoids, the major stress-reactive adrenal steroid (Duman, 2004). A role for BDNF in the effects of stress and the response to antidepressant treatment is supported by studies demonstrating opposing regulation of this neurotrophic factor (Duman and Monteggia, 2006). Smith and colleagues were the first to demonstrate the role of neurotrophic factors in stress actions and stress decreases the expression of BDNF in the CA3 pyramidal cell layer and the dentate gyrus granule cell layer of the hippocampus (Smith et al., 1995). Further studies showed that BDNF expression is also down-regulated by other types of stress (Duman, 2004). However, there is one study that did not find an effect of chronic (21 days) restraint stress on BDNF (Kuroda and McEwen, 1998). The reason for this discrepancy is unclear but could be related to the period of time (21 h) after stress at which BDNF was assessed. Alternatively, there could be desensitization to the effects of repeated stress for 21 days (6 h/day) (Duman and Monteggia, 2006). As Hayden and Klein (2001) reported, chronic stress is one of the important predictors in the outcome of dysthymia. However, acute stressors may precipitate superimposed major depressive disorder episodes (double depression) in the course of dysthymic disorder (Moerk and Klein, 2000; Griffiths et al., 2000). Chronic stress in dysthymia can possibly cause desensitization which may be associated with the tendency of BDNF to remain unchanged. Therefore, BDNF changes can be assumed as state-dependent in mood disorders instead of being trait-dependent, and it seems to be one explanation why BDNF serum concentrations are unchanged in dysthymic disorder.
between HAM-D score and age, and BDNF serum concentrations in the two depressive patient groups.
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3. Results
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Fig. 1. Serum BDNF levels of the groups (ng/ml).
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4. Discussion
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Table 1 demonstrates age, gender, clinical characteristics, HAM-D scores and BDNF serum concentrations of the three study groups. The dysthymia group was significantly older than the major depression and control groups (F = 3.647, df = 2, p = 0.032). Since the groups separate in terms of age, the correlation between age and BDNF serum concentrations was calculated and it was not significant (r = 0.119, p = 0.457). Regarding the 17-item HAM-D, the major depression group had a significantly higher score than the dysthymia and control groups (F = 92.274, df = 1, p b 0.0001). The major depression group had a significantly lower BDNF serum concentrations than the dysthymia and control groups (F = 6.961, df = 2, p = 0.002) (Fig. 1). The BDNF serum concentrations and the mean HAM-D scores did not have any significant correlation in the dysthymia and major depression groups (r = − 0.276, p = 0.086).
This present work shows that the dysthymia group has a higher level of serum brain-derived neurotrophic factor (BDNF) than the major depression group but is not different from the control group. To our knowledge, this is the first study on BDNF serum concentrations in dysthymic disorder. Many studies on biological parameters to demonstrate the relation between dysthymic disorder and major depressive disorder have been performed. Studies of rapid eye movement (REM) latency, electrodermal activity, and the thyroid axis show similarities between dysthymic disorder and major depressive disorder; but other investigations, including the
4.2. Severity of depression and BDNF Another explanation is the difference of severity of depression between major depression and dysthymia, and its correlation with BDNF. In previous works, it is demonstrated that the severity of depression negatively correlates with the BDNF serum concentrations (Shimizu et al., 2003; Karege et al., 2002). However, in our study, the BDNF serum concentrations of the major depressive group and dysthymic
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group were not significantly correlated with the HAM-D scores though it was very close to significance (p = 0.086). Thus, since depression is less severe in dysthymic disorder than in major depressive disorder, there might be a difference between the two disorders in terms of BDNF serum concentrations.
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There are some limitations in this study. First, the number of the patients in the study groups, especially in the dysthymia group, is too small to generalize the results. These results should be repeated in wider groups of patients. Another limitation is measuring BDNF in serum since it is an indirect way to put the gene expression of BDNF forward. However, since Pan et al. (1998) demonstrated the ability of BDNF to cross blood–brain barrier; BDNF serum concentrations may reflect BDNF brain concentrations. Another limitation is the finding that no correlation was found among major depressive and dysthymic patients in regard to their HAM-D scores and BDNF levels. Because of the lack of variation both in the level of depression and in the BDNF serum concentrations, the correlation may be insignificant. Significant correlation between HAM-D scores and BDNF serum concentrations would be helpful in understanding the unchanged serum level of BDNF in dysthymic patients. Event though types of stress in depressive disorders are discussed, no determination and rating of stress were performed in this study for comparing the dysthymic and major depressive groups. Further studies with wider patient groups addressing all variables such as stress, other neurotrophic factors or depression severity at the same time should be conducted.
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4.3. Limitations
preliminary study. Prog Neuropsychopharmacol Biol Psychiatry 2005;29: 261–5. Aydemir O, Deveci A, Icelli I. Reliability and validity of the Turkish version of the Structured Interview Guide For Hamilton Depression Rating Scale Seasonal Affective Disorder. Psychiatry in Turkey, vol. 8. 2006. p. 18–21. [Turkish]. Duman RS. Role of neurotrophic factors in the etiology and treatment of mood disorders. Neuromolecular Med 2004;5:11–25. Duman RS, Monteggia LM. A neurotrophic model for stress-related mood disorders. Biol Psychiatry 2006;59:1116–27. Griffiths J, Ravindran AV, Merali Z, Anisman H. Dysthymia: neurochemical and behavioral perspectives. Mol Psychiatry 2000;5:242–61. Hayden EP, Klein DN. Outcome of dysthymic disorder at 5-year follow-up: the effect of familial psychopathology, early adversity, personality, comorbidity, and chronic stres. Am J Psychiatry 2001;158:1864–70. Howland RH, Thase ME. Biological studies of dysthymia. Biol Psychiatry 1991;30:283–304. Karege F, Perret G, Bondolfi G, Schwald M, Bertschy G, Aubry JM. Decreased serum brain-derived neurotrophic factor levels in depressed patients. Psychiatry Res 2002;109:143–8. Kuroda Y, McEwen BS. Effect of chronic restraint stress and tianeptine on growth factors, growth-associated protein-43 and microtubule-associated protein 2 mRNA expression in the rat hippocampus. Brain Res Mol Brain Res 1998;59:35–9. Lima MS, Moncrieff J. A comparison of drugs versus placebo for the treatment of dysthymia. Cochrane Database Syst Rev 2000;2:CD001130. Moerk KM, Klein DN. The development of major depressive episodes during the course of dysthymic and episodic major depressive disorders: a retrospective examination of life events. J Affect Disord 2000;58:117–23. Ozkurkcugil A, Aydemir O, Yildiz M, Esen-Danaci A, Koroglu E. Adaptation into Turkish and reliability study of Structured Interview for DSM-IV Axis I Disorders. J Drugs Ther 1999;12:233–6 [Turkish]. Popoli M, Gennarelli M, Racagni G. Modulation of synaptic plasticity by stress and antidepressants. Bipolar Disord 2002;4:166–82. Rihmer Z, Szadoczky E. Dexamethasone Suppression Test and TRH-TSH test in subaffective dysthymia and character-spectrum disorder. J Affect Disord 1993;28:287–91. Pan W, Banks WA, Fasold MB, Bluth J, Kastin AJ. Transport of brain-derived neurotrophic factor across the blood–brain barrier. Neuropharmacology 1998;37:1553–61. Saletu-Zyhlarz GM, Abu-Bakr MH, Anderer P, Semler B, Decker K, Parapatics S, et al. Insomnia related to dysthymia: polysomnographic and psychometric comparison with normal controls and acute therapeutic trials with trazodone. Neuropsychobiology 2001;44:139–49. Shimizu E, Hashimoto K, Okamura N, Koike K, Komatsu N, Kumakiri C, et al. Alterations of serum levels of brain-derived neurotrophic factor (BDNF) in depressed patients with or without antidepressants. Biol Psychiatry 2003;54:70–5. Smith MA, Makino S, Kvetnansky R, Post RM. Stres alters the express of brainderived neurotrophic factor and neurotrophins-3 mRNAs in the hippocampus. J Neurosci 1995;15:1768–77. Stein DN, Schwartz JE, Rose S, Leader JB. Five-year course and outcome of dysthymic disorder: a prospective, naturalistic follow-up study. Am J Psychiatry 2000;157:931–9. Thase ME. Mood disorders: neurobiology. In: Sadock BJ, Sadock VA, editors. Kaplan and Sadock's comprehensive textbook of psychiatry, 8th version. Philadelphia: Lippincott Williams & Wilkins; 2004. p. 1318–27. Williams JBW, Link MJ, Rosenthal NE, Amira L, Terman M. Structured interview guide for the Hamilton depression rating scale — seasonal affective disorder version, rev. New York: New York State Psychiatric Institute; 2000.
4.4. Conclusion
Acknowledgement
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The unchanged BDNF serum concentrations in patients with dysthymic disorder seem to point out that BDNF changes in mood disorders are state-dependent and vary according to the severity of depressive episodes. Further studies on stress-related mood disorders concerning BDNF and other neurotrophic factors will be elucidative.
References
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The authors wish to thank to Wyeth Turkey who partially supported this study by financing the laboratory kits.
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