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Elevated serum S100B protein in drug-free bipolar patients during first manic episode: a pilot study
European Neuropsychopharmacology 12 (2002) 269–272 www.elsevier.com / locate / euroneuro
Elevated serum S100B protein in drug-free bipolar patients during first manic episode: a pilot study R. Machado-Vieira a,b , D.R. Lara a,c , L.V.C. Portela a,d , C.A. Gonc¸alves a , J.C. Soares e , a,f a, F. Kapczinski , D.O. Souza * a
Department of Biochemistry, Institute of Basic Health Sciences, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600 -Anexo, 90035 -003 Porto Alegre, RS, Brazil b ´ Espırita Hospital of Porto Alegre, Porto Alegre, Brazil c ˆ ´ ˆ , Faculdade de Biociencias , PUC-RS, Porto Alegre, RS, Brazil Departamento de Ciencias Fisiologicas d ´ Laboratorio Municipal de Novo Hamburgo, Novo Hamburgo, RS, Brazil e Western Psychiatric Institute and Clinic, University of Pittsburgh Medical Center, Pittsburgh, PA, USA f ´ de Porto Alegre ( HCPA), Universidade Federal do Rio Grande do Sul, Department of Psychiatry, School of Medicine, Hospital de Clınicas Porto Alegre, Brazil Received 21 August 2001; received in revised form 26 February 2002; accepted 26 February 2002
Abstract S100B protein is a calcium-binding protein mostly derived from glial cells, which exerts trophic or toxic effects on neural cells depending on its concentration. Since serum S100B levels has been tested as a potential marker in neuropsychiatric disorders, and structural abnormalities on glial cells have been recently associated with bipolar disorder patients, we conducted this preliminary study to examine if S100B serum levels are altered during first manic episode. We quantitated S100B in serum of 40 subjects (20 unmedicated patients during manic episode and 20 healthy matched controls). The mean6S.D. values for S100B for bipolar subjects were 0.06560.068 mg / l and 0.01860.029 mg / l for healthy controls. Increased levels of S100B in bipolar mania was statistically significant (Wilcoxon signed ranks test, Z522.45, P50.01). These preliminary findings suggest that mania may increase the levels of S100B in serum of bipolar disorder patients, which could be related to adaptative neural mechanisms in bipolar mania. 2002 Elsevier Science B.V. All rights reserved. Keywords: Bipolar disorder; S100B protein; Mania; Serum; Mechanism of action; Glia
1. Introduction Bipolar disorder is an heterogeneous and heritable psychiatric disorder with neurobiological findings based on psychopharmacological, brain imaging, genetic and neurochemical studies. These findings include elevated intracellular calcium concentration in lymphocytes and platelets (Hough et al., 1999; Emamghoreishi et al., 1997) induced by serotonin (Okamoto et al., 1995), cell-mediated immunity activation (Tsai et al., 1999) and abnormalities on *Corresponding author. Tel.: 155-51-3316-5558; fax: 155-51-33165540. E-mail address: [email protected] (D.O. Souza).
serotonergic system genes (Vogt et al., 2000; Bellivier et al., 1998). Also, recent neuroimaging and histopathological studies in prefrontal cortex of bipolar postmortem patients have described reduced glial cells number (Drevets et al., 1998) and glial fibrillary acidic protein (GFAP) levels (Johnston-Wilson et al., 2000). Glial cells regulate many crucial processes related to physiological neuronal activity, including regulation of neurotransmitters and extracellular ions, glucose storage, and growth factors production (Laming et al., 2000). The S100B is a gliotrophic and neurotrophic calcium-binding protein, mostly produced and released by astrocytes in the central nervous system (CNS). Extracellular S100B has been shown to exert trophic effects on neural cells
0924-977X / 02 / $ – see front matter 2002 Elsevier Science B.V. All rights reserved. PII: S0924-977X( 02 )00029-9
270
R. Machado-Vieira et al. / European Neuropsychopharmacology 12 (2002) 269 – 272
(Schafer and Heizmann, 1996), but at higher levels may be toxic, stressing and inducing cell death by raising intracellular free calcium concentrations (Barger and Van Eldik, 1992). Regarding psychiatric disorders, elevation in serum S100B concentrations has been described both in drugtreated and drug-free schizophrenic patients (Wiesmann et al., 1999; Lara et al., 2001). Also, increased serum S100B concentration may represent a sensitive indicator of CNS damage (Persson et al., 1987) in acute ischemic stroke (Missler et al., 1997), Alzheimer disease (Griffin et al., 1989) and acute exacerbation of multiple sclerosis (Lamers et al., 1995). Moreover, transgenic mice with increased expression of S100B has been shown to be hyperactive (Gerlai and Roder, 1995), which is usually observed during manic states. While neurotrophic factors such as brain-derived neurotrophic factor (BDNF) has received much attention in mood research, little work has addressed the role of S100B. Thus, in order to examine the possible effects of mania on S100B turnover in serum, we conducted this study. We want to examine the hypothesis that mania would increase the relative content of serum S100B concentrations in drug-free bipolar disorder patients, as observed in untreated schizophrenia subjects (Lara et al., 2001).
2. Experimental Twenty drug-free for at least 9 months bipolar disorder patients (13 females and seven males, mean6S.D. age5 38.3612.6 years), including 16 drug-naive patients in the first manic episode were studied. After complete description of the study to subjects, written informed consent was obtained. They did not have any current medical problems, other psychiatric disorders or history of alcohol or drug use. Major clinical (systemic diseases) and psychiatric disorders comorbidities were excluded based on detailed clinical and psychiatric history, as well as chart reviews. All patients met DSM-IV diagnostic criteria for bipolar I disorder. Also, patients’ symptoms were assessed at day one (admission), using the Young Mania Rating Scale (YMRS) and the Brief Psychiatric Rating Scale (BPRS). Bipolar disorder patients were in acute mania and diagnosis was confirmed independently by two psychiatrists at the time they enrolled in the study. Patients in a mixed or depressive episode were excluded. Twenty healthy control subjects matched for age and gender (mean6S.D. age538.3612.2 years) were studied. They did not have any history of psychiatric disorders, substance abuse, current medical problems and did not have history of psychiatric disorders in first-degree relatives. We used the DSM-IV check-list to exclude psychiatric diagnosis in the matched controls group. Blood samples (10 ml) were collected using vacutainer system at admission room, in the first day of hospitaliza-
tion, serum was separated and kept frozen at 270 8C for no more than 6 months, until the assays were carried out. S100B protein concentrations were measured using an immunoluminometric assay (LIA-mat Sangtec 100— Sangtec Medical, Bromma, Sweden) in a Lumat LB9507 luminometer (EG&G Berthold). All determinations were carried out within the same experiment. The S100B standard curve was linear from 0.01 to 20 ng / ml and coefficient of variation of duplicate values was within 5%. As the data showed a skewed distribution, we took the more conservative approach and carried out a nonparametric analysis. The Wilcoxon test was used to compare nonparametrically distributed data. Correlations between YMRS and BPRS with S100B serum levels were performed using the Spearman rank order correlation test.
3. Results Patient characteristics are described in Table 1. Bipolar patients had significantly higher S100B levels in serum samples compared to healthy control subjects (mean6S.D.50.06560.068 mg / l, median50.044 and mean6S.D.50.01860.029 mg / l, median50.003, respectively; Z522,45, P50.014; see Table 1). No relationship with gender or age were found in this sample. Values lower than 0.001 were considered as 0.001 in the table. The mean ¨ length drug-free period of the non drug naıve bipolar patients was 14 months (between 9 and 24 months). There were no statistically significant differences between serum S100B levels and number of previous depressive episodes. S100B presented no correlation with BPRS (r50.569, P50.812) and with YMRS (r520.104, P50.66) scores (see Table 1).
4. Discussion Our preliminary findings are, to our knowledge, the first report that serum S100B levels may be increased in mania bipolar. The pathological mechanisms and correlation involved in the cross-regulation of central and peripheral levels of S100B remain unclear and should be further investigated and clarified in future studies. Nonetheless, despite minor peripheral sources cannot be ruled out as contributing sources for serum S100B, astrocytes have been proposed to represent the major source of S100B and elevations in serum levels could reflect cerebral injury or dysfunction (Missler et al., 1997). Also, studies suggest that this cytokine may induce a protective response on neural cells against an ongoing pathological process or alternatively, acting as a neurotoxic protein inducing apoptosis at higher levels (Schafer and Heizmann, 1996). Schizophrenia and bipolar disorder have been proposed to present similar neurobiological findings related to neurochemical, pharmacological and neuroimaging studies.
R. Machado-Vieira et al. / European Neuropsychopharmacology 12 (2002) 269 – 272
271
Table 1 Patient characteristics and serum S100B levels Patient No.
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 Mean
Gender
F F F F F F F F M M F F F F M M M M M M
Age (years)
Medication free period
BPRS score
YMRS score
54 60 48 52 39 58 40 41 32 35 29 29 22 24 24 23 32 58 36 31
10 months 1 year Naive 2 years Naive 9 months Naive Naive Naive Naive Naive Naive Naive Naive Naive Naive Naive Naive Naive Naive
46 42 39 41 54 66 60 58 44 53 49 38 47 34 38 44 52 42 47 50 47.268.2
38.3612.6
Increased serum S100B has been also described in schizophrenia (Wiesmann et al., 1999; Lara et al., 2001) and prominent reductions in glial cell number were found in subjects with familial bipolar disorder (Ongur et al., 1998; Rajkowska, 2000). In this study, we also found an overlap of low values between patients and controls. The distribution of values in the patient group shows a scatter up into higher levels with a high variance and a higher median value. Thus, we propose that the levels of protein could be also related to state variables. Furthermore, these results may not be specific or in any sense pathognomonic of mania. Individual changes in the physiology of any patient with mania may involve sleep disturbances, changes in pattern of food intake, increased time standing and a marked increase in motor activity. We suggest that any or all of these may contribute to what is observed in our preliminary study. Alternatively, astrocytes with high concentrations of S100B result in a potent activation of nitric oxide (NO) synthase and a subsequent generation of NO, an ubiquitous biological messenger molecule that can lead to astrocytic cell death in cultures (Hu et al., 1997). Changes on NO synthase activity has also been associated with psychological stress (Matsumoto et al., 1999), motor activity (Halcak et al., 2000), sexual regulation (Pfaus, 1999) and aggressivity (Demas et al., 1999). Despite the potential limitation of our current study due a lack of specificity of S100B levels in regard to pathophysiological changes in bipolar disorder, we suggest that changes on serotonergic system in bipolar patients (Hough et al., 1999; Emamghoreishi et al., 1997; Vogt et
Serum S100B (ng / ml) Patients
Controls
36 45 33 43 47 46 38 46 38 32 50 32 46 30 30 40 44 38 34 42
0.036 0.113 0.249 0.002 0.017 0.097 0.001 0.163 0.001 0.112 0.005 0.141 0.001 0.001 0.035 0.025 0.098 0.078 0.088 0.052
0.006 0.073 0.001 0.003 0.054 0.001 0.019 0.001 0.001 0.093 0.002 0.018 0.011 0.013 0.001 0.072 0.001 0.001 0.001 0.001
39.566.2
0.06560.068
0.01860.029
al., 2000; Bellivier et al., 1998) represent another possibility to explain our current findings. Genes encoding proteins involved in serotonergic metabolism, including some 5-HT and tryptophan hydroxylase genes (Vogt et al., 2000; Bellivier et al., 1998) are potential candidates in studies of susceptibility to bipolar disorder. Besides, atypical antipsychotics, including clozapine, olanzapine and risperidone, which block multiple 5-HT receptor subtypes, have been increasingly used in the treatment of mania (Soares, 2000). Also, recent studies performed on rodents and cell cultures show that S100B present a close relationship with serotonergic system. The protein mediates the trophic effects induced by serotonin (Nishi et al., 1996) and influences the maintenance of hippocampal synaptic connections controlled by serotonergic stimulation of astrocytes (Wilson et al., 1998). Also, expression of S100B protein decrease after treatment with tryptophan hydroxylase inhibitor (Azmitia et al., 1995) and increase with the selective inhibitor of serotonin uptake fluoxetine (Haring et al., 1993). In conclusion, a better understanding of mechanism of action and abnormalities in cytokines in the pathophysiology of bipolar mania, as already observed in depression (Lanquillon et al., 2000), may provide new therapeutic interventions for these patients.
Acknowledgements We are grateful to patients and staff from Hospital ´ Espırita de Porto Alegre, as well as the healthy volunteers.
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R. Machado-Vieira et al. / European Neuropsychopharmacology 12 (2002) 269 – 272
This project was financed by grants from PRONEX (No. 41960904), FAPERGS and FIPE.
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Muller, C., Roots, B., Ng, K., 2000. Neuronal–glial interactions and behaviour. Neurosci. Biobehav. Rev. 24, 295–340. Lanquillon, S., Krieg, J.C., Bening-Abu-Schach, U., Vedder, H., 2000. Cytokine production and treatment response in major depressive disorder. Neuropsychopharmacology 22, 370–379. Lara, D.R., Gama, C.S., Belmonte-de Abreu, P., Portela, L.V.C., Gonc¸alves, C.A., Fonseca, M., Hauck, S., Souza, D.O., 2001. Increased serum S100B protein in schizophrenia: a study in medicationfree patients. J. Psychiatr. Res. 35, 11–14. Matsumoto, K., Yobimoto, K., Huong, N.T., Abdel-Fattah, M., Van Hien, T., Watanabe, H., 1999. Psychological stress-induced enhancement of brain lipid peroxidation via nitric oxide systems and its modulation by anxiolytic and anxiogenic drugs in mice. Brain Res. 839, 74–84. Missler, U., Weismann, M., Friedrich, C., Kaps, M., 1997. S-100 protein and neuron-specific enolase concentrations in blood as indicators of infarction volume and prognosis in acute ischemic stroke. Stroke 28, 1956–1960. Nishi, M., Whitaker-Azmitia, P.M., Azmitia, E.C., 1996. Enhanced synaptophysin immunoreactivity in rat hippocampal culture by 5HT1A agonist, S100B, and corticosteroid receptor agonists. Synapse 23, 1–9. Okamoto, Y., Kagaya, A., Shinno, H., Motohashi, N., Yamawaki, S., 1995. Serotonin-induced platelet calcium mobilization is enhanced in mania. Life Sci. 56, 327–332. Ongur, D., Drevets, W.C., Price, J.L., 1998. Glial reduction in the subgenual prefrontal cortex in mood disorders. Proc. Natl. Acad. Sci. USA 95, 13290–13295. Persson, L., Hardemark, H.G., Gustafsson, J., Rundstrom, G., MendelHartvig, I., Esscher, T., Pahlman, S., 1987. S-100 protein and neuronspecific enolase in cerebrospinal fluid and serum: markers of cell damage in human central nervous system. Stroke 18, 911–918. Pfaus, J.G., 1999. Neurobiology of sexual behavior. Curr. Opin. Neurobiol. 9, 751–758. Rajkowska, G., 2000. Postmortem studies in mood disorders indicate altered numbers of neurons and glial cells. Biol. Psychiatry 48, 766–777. Schafer, B.W., Heizmann, C.W., 1996. The S100 family of EF-hand calcium-binding proteins: functions and pathology. Trends Biochem. Sci. 21, 134–140. Soares, J.C., 2000. Recent advances in the treatment of bipolar mania, depression, mixed states, and rapid cycling. Int. Clin. Psychopharmacol. 15, 183–196. Tsai, S.Y., Chen, K.P., Yang, Y.Y., Chen, C.C., Lee, J.C., Singh, V.K., Leu, S.J., 1999. Activation of indices of cell-mediated immunity in bipolar mania. Biol. Psychiatry 8, 989–994. Vogt, I.R., Shimron-Abarbanell, D., Neidt, H., Erdmann, J., Cichon, S., Schulze, T.G. et al., 2000. Investigation of the human serotonin 6 (5-HT6) receptor gene in bipolar affective disorder and schizophrenia. Am. J. Med. Genet. 96, 217–221. Wiesmann, M., Wandinger, K.P., Missler, U., Eckhoff, D., Rothermundt, M., Arolt, V., Kirchner, H., 1999. Elevated plasma levels of S100B protein in schizophrenic patients. Biol. Psychiatry 45, 1508–1511. Wilson, C.C., Faber, K.M., Haring, J.H., 1998. Serotonin regulates synaptic connections in the dentate molecular layer of adult rats via 5-HT1A receptors: evidence for a glial mechanism. Brain Res. 782, 235–239.
Elevated serum S100B protein in drug-free bipolar patients during first manic episode: a pilot study R. Machado-Vieira a,b , D.R. Lara a,c , L.V.C. Portela a,d , C.A. Gonc¸alves a , J.C. Soares e , a,f a, F. Kapczinski , D.O. Souza * a
Department of Biochemistry, Institute of Basic Health Sciences, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600 -Anexo, 90035 -003 Porto Alegre, RS, Brazil b ´ Espırita Hospital of Porto Alegre, Porto Alegre, Brazil c ˆ ´ ˆ , Faculdade de Biociencias , PUC-RS, Porto Alegre, RS, Brazil Departamento de Ciencias Fisiologicas d ´ Laboratorio Municipal de Novo Hamburgo, Novo Hamburgo, RS, Brazil e Western Psychiatric Institute and Clinic, University of Pittsburgh Medical Center, Pittsburgh, PA, USA f ´ de Porto Alegre ( HCPA), Universidade Federal do Rio Grande do Sul, Department of Psychiatry, School of Medicine, Hospital de Clınicas Porto Alegre, Brazil Received 21 August 2001; received in revised form 26 February 2002; accepted 26 February 2002
Abstract S100B protein is a calcium-binding protein mostly derived from glial cells, which exerts trophic or toxic effects on neural cells depending on its concentration. Since serum S100B levels has been tested as a potential marker in neuropsychiatric disorders, and structural abnormalities on glial cells have been recently associated with bipolar disorder patients, we conducted this preliminary study to examine if S100B serum levels are altered during first manic episode. We quantitated S100B in serum of 40 subjects (20 unmedicated patients during manic episode and 20 healthy matched controls). The mean6S.D. values for S100B for bipolar subjects were 0.06560.068 mg / l and 0.01860.029 mg / l for healthy controls. Increased levels of S100B in bipolar mania was statistically significant (Wilcoxon signed ranks test, Z522.45, P50.01). These preliminary findings suggest that mania may increase the levels of S100B in serum of bipolar disorder patients, which could be related to adaptative neural mechanisms in bipolar mania. 2002 Elsevier Science B.V. All rights reserved. Keywords: Bipolar disorder; S100B protein; Mania; Serum; Mechanism of action; Glia
1. Introduction Bipolar disorder is an heterogeneous and heritable psychiatric disorder with neurobiological findings based on psychopharmacological, brain imaging, genetic and neurochemical studies. These findings include elevated intracellular calcium concentration in lymphocytes and platelets (Hough et al., 1999; Emamghoreishi et al., 1997) induced by serotonin (Okamoto et al., 1995), cell-mediated immunity activation (Tsai et al., 1999) and abnormalities on *Corresponding author. Tel.: 155-51-3316-5558; fax: 155-51-33165540. E-mail address: [email protected] (D.O. Souza).
serotonergic system genes (Vogt et al., 2000; Bellivier et al., 1998). Also, recent neuroimaging and histopathological studies in prefrontal cortex of bipolar postmortem patients have described reduced glial cells number (Drevets et al., 1998) and glial fibrillary acidic protein (GFAP) levels (Johnston-Wilson et al., 2000). Glial cells regulate many crucial processes related to physiological neuronal activity, including regulation of neurotransmitters and extracellular ions, glucose storage, and growth factors production (Laming et al., 2000). The S100B is a gliotrophic and neurotrophic calcium-binding protein, mostly produced and released by astrocytes in the central nervous system (CNS). Extracellular S100B has been shown to exert trophic effects on neural cells
0924-977X / 02 / $ – see front matter 2002 Elsevier Science B.V. All rights reserved. PII: S0924-977X( 02 )00029-9
270
R. Machado-Vieira et al. / European Neuropsychopharmacology 12 (2002) 269 – 272
(Schafer and Heizmann, 1996), but at higher levels may be toxic, stressing and inducing cell death by raising intracellular free calcium concentrations (Barger and Van Eldik, 1992). Regarding psychiatric disorders, elevation in serum S100B concentrations has been described both in drugtreated and drug-free schizophrenic patients (Wiesmann et al., 1999; Lara et al., 2001). Also, increased serum S100B concentration may represent a sensitive indicator of CNS damage (Persson et al., 1987) in acute ischemic stroke (Missler et al., 1997), Alzheimer disease (Griffin et al., 1989) and acute exacerbation of multiple sclerosis (Lamers et al., 1995). Moreover, transgenic mice with increased expression of S100B has been shown to be hyperactive (Gerlai and Roder, 1995), which is usually observed during manic states. While neurotrophic factors such as brain-derived neurotrophic factor (BDNF) has received much attention in mood research, little work has addressed the role of S100B. Thus, in order to examine the possible effects of mania on S100B turnover in serum, we conducted this study. We want to examine the hypothesis that mania would increase the relative content of serum S100B concentrations in drug-free bipolar disorder patients, as observed in untreated schizophrenia subjects (Lara et al., 2001).
2. Experimental Twenty drug-free for at least 9 months bipolar disorder patients (13 females and seven males, mean6S.D. age5 38.3612.6 years), including 16 drug-naive patients in the first manic episode were studied. After complete description of the study to subjects, written informed consent was obtained. They did not have any current medical problems, other psychiatric disorders or history of alcohol or drug use. Major clinical (systemic diseases) and psychiatric disorders comorbidities were excluded based on detailed clinical and psychiatric history, as well as chart reviews. All patients met DSM-IV diagnostic criteria for bipolar I disorder. Also, patients’ symptoms were assessed at day one (admission), using the Young Mania Rating Scale (YMRS) and the Brief Psychiatric Rating Scale (BPRS). Bipolar disorder patients were in acute mania and diagnosis was confirmed independently by two psychiatrists at the time they enrolled in the study. Patients in a mixed or depressive episode were excluded. Twenty healthy control subjects matched for age and gender (mean6S.D. age538.3612.2 years) were studied. They did not have any history of psychiatric disorders, substance abuse, current medical problems and did not have history of psychiatric disorders in first-degree relatives. We used the DSM-IV check-list to exclude psychiatric diagnosis in the matched controls group. Blood samples (10 ml) were collected using vacutainer system at admission room, in the first day of hospitaliza-
tion, serum was separated and kept frozen at 270 8C for no more than 6 months, until the assays were carried out. S100B protein concentrations were measured using an immunoluminometric assay (LIA-mat Sangtec 100— Sangtec Medical, Bromma, Sweden) in a Lumat LB9507 luminometer (EG&G Berthold). All determinations were carried out within the same experiment. The S100B standard curve was linear from 0.01 to 20 ng / ml and coefficient of variation of duplicate values was within 5%. As the data showed a skewed distribution, we took the more conservative approach and carried out a nonparametric analysis. The Wilcoxon test was used to compare nonparametrically distributed data. Correlations between YMRS and BPRS with S100B serum levels were performed using the Spearman rank order correlation test.
3. Results Patient characteristics are described in Table 1. Bipolar patients had significantly higher S100B levels in serum samples compared to healthy control subjects (mean6S.D.50.06560.068 mg / l, median50.044 and mean6S.D.50.01860.029 mg / l, median50.003, respectively; Z522,45, P50.014; see Table 1). No relationship with gender or age were found in this sample. Values lower than 0.001 were considered as 0.001 in the table. The mean ¨ length drug-free period of the non drug naıve bipolar patients was 14 months (between 9 and 24 months). There were no statistically significant differences between serum S100B levels and number of previous depressive episodes. S100B presented no correlation with BPRS (r50.569, P50.812) and with YMRS (r520.104, P50.66) scores (see Table 1).
4. Discussion Our preliminary findings are, to our knowledge, the first report that serum S100B levels may be increased in mania bipolar. The pathological mechanisms and correlation involved in the cross-regulation of central and peripheral levels of S100B remain unclear and should be further investigated and clarified in future studies. Nonetheless, despite minor peripheral sources cannot be ruled out as contributing sources for serum S100B, astrocytes have been proposed to represent the major source of S100B and elevations in serum levels could reflect cerebral injury or dysfunction (Missler et al., 1997). Also, studies suggest that this cytokine may induce a protective response on neural cells against an ongoing pathological process or alternatively, acting as a neurotoxic protein inducing apoptosis at higher levels (Schafer and Heizmann, 1996). Schizophrenia and bipolar disorder have been proposed to present similar neurobiological findings related to neurochemical, pharmacological and neuroimaging studies.
R. Machado-Vieira et al. / European Neuropsychopharmacology 12 (2002) 269 – 272
271
Table 1 Patient characteristics and serum S100B levels Patient No.
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 Mean
Gender
F F F F F F F F M M F F F F M M M M M M
Age (years)
Medication free period
BPRS score
YMRS score
54 60 48 52 39 58 40 41 32 35 29 29 22 24 24 23 32 58 36 31
10 months 1 year Naive 2 years Naive 9 months Naive Naive Naive Naive Naive Naive Naive Naive Naive Naive Naive Naive Naive Naive
46 42 39 41 54 66 60 58 44 53 49 38 47 34 38 44 52 42 47 50 47.268.2
38.3612.6
Increased serum S100B has been also described in schizophrenia (Wiesmann et al., 1999; Lara et al., 2001) and prominent reductions in glial cell number were found in subjects with familial bipolar disorder (Ongur et al., 1998; Rajkowska, 2000). In this study, we also found an overlap of low values between patients and controls. The distribution of values in the patient group shows a scatter up into higher levels with a high variance and a higher median value. Thus, we propose that the levels of protein could be also related to state variables. Furthermore, these results may not be specific or in any sense pathognomonic of mania. Individual changes in the physiology of any patient with mania may involve sleep disturbances, changes in pattern of food intake, increased time standing and a marked increase in motor activity. We suggest that any or all of these may contribute to what is observed in our preliminary study. Alternatively, astrocytes with high concentrations of S100B result in a potent activation of nitric oxide (NO) synthase and a subsequent generation of NO, an ubiquitous biological messenger molecule that can lead to astrocytic cell death in cultures (Hu et al., 1997). Changes on NO synthase activity has also been associated with psychological stress (Matsumoto et al., 1999), motor activity (Halcak et al., 2000), sexual regulation (Pfaus, 1999) and aggressivity (Demas et al., 1999). Despite the potential limitation of our current study due a lack of specificity of S100B levels in regard to pathophysiological changes in bipolar disorder, we suggest that changes on serotonergic system in bipolar patients (Hough et al., 1999; Emamghoreishi et al., 1997; Vogt et
Serum S100B (ng / ml) Patients
Controls
36 45 33 43 47 46 38 46 38 32 50 32 46 30 30 40 44 38 34 42
0.036 0.113 0.249 0.002 0.017 0.097 0.001 0.163 0.001 0.112 0.005 0.141 0.001 0.001 0.035 0.025 0.098 0.078 0.088 0.052
0.006 0.073 0.001 0.003 0.054 0.001 0.019 0.001 0.001 0.093 0.002 0.018 0.011 0.013 0.001 0.072 0.001 0.001 0.001 0.001
39.566.2
0.06560.068
0.01860.029
al., 2000; Bellivier et al., 1998) represent another possibility to explain our current findings. Genes encoding proteins involved in serotonergic metabolism, including some 5-HT and tryptophan hydroxylase genes (Vogt et al., 2000; Bellivier et al., 1998) are potential candidates in studies of susceptibility to bipolar disorder. Besides, atypical antipsychotics, including clozapine, olanzapine and risperidone, which block multiple 5-HT receptor subtypes, have been increasingly used in the treatment of mania (Soares, 2000). Also, recent studies performed on rodents and cell cultures show that S100B present a close relationship with serotonergic system. The protein mediates the trophic effects induced by serotonin (Nishi et al., 1996) and influences the maintenance of hippocampal synaptic connections controlled by serotonergic stimulation of astrocytes (Wilson et al., 1998). Also, expression of S100B protein decrease after treatment with tryptophan hydroxylase inhibitor (Azmitia et al., 1995) and increase with the selective inhibitor of serotonin uptake fluoxetine (Haring et al., 1993). In conclusion, a better understanding of mechanism of action and abnormalities in cytokines in the pathophysiology of bipolar mania, as already observed in depression (Lanquillon et al., 2000), may provide new therapeutic interventions for these patients.
Acknowledgements We are grateful to patients and staff from Hospital ´ Espırita de Porto Alegre, as well as the healthy volunteers.
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This project was financed by grants from PRONEX (No. 41960904), FAPERGS and FIPE.
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