Acta Neuropsychiatrica 2015 All rights reserved DOI: 10.1017/neu.2015.5
© Scandinavian College of Neuropsychopharmacology 2015 ACTA NEUROPSYCHIATRICA
Serum levels of carcinoembryonic antigen (CEA) in patients with bipolar disorder Kaplan I, Bulut M, Atli A, Güneş M, Kaya MC, Çolpan L. Serum levels of carcinoembryonic antigen (CEA) in patients with bipolar disorder.
Ibrahim Kaplan1, Mahmut Bulut2, Abdullah Atli2, Mehmet Güneş2, Mehmet Cemal Kaya2, Leyla Çolpan1 1
Objective: Carcinoembryonic antigen (CEA) is an oncofetal glycoprotein that is widely used as a tumour marker in adenocarcinomas. However, several non-neoplastic conditions, including acute and chronic inflammation and other inflammation-related conditions, are characterised by increased CEA concentrations. Bipolar disorder (BD) ranks seventh among the worldwide burden of non-fatal diseases. Inflammatory biomarkers have been considered as one of the main key pillars of a multifactorial approach for prediction of BD in an at-risk population. BP is accompanied by activation of inflammatory, cell-mediated and negative immunoregulatory cytokines. Methods: We measured the levels of CEA in serum samples from 44 individuals with euthymic BP out-patients and 45 healthy controls. Patients were diagnosed according to the DSM-IV criteria. CEA was measured by an electrochemiluminescence immunoassay. Results: The mean serum CEA concentration was 2.36 ± 1.52 and 1.77 ± 0.98 µg/l in patients and controls, respectively. CEA levels were significantly increased in euthymic BP patients when compared with controls (p = 0.031). Conclusions: This study suggests that CEA is increased in BD and supports a role for immune activation in the core pathological mechanisms of BP. CEA levels may be a secondary marker for diagnosing BP.
Department of Biochemistry, Medical Faculty, Dicle University, Diyarbakır, Turkey; and 2 Department of Psychiatry, Medical Faculty, Dicle University, Diyarbakır, Turkey
Keywords: bipolar disorder; CEA; proinflammatory cytokines Ibrahim Kaplan, Department of Medical Biochemistry, Medical Faculty, Dicle University, Diyarbakır, Turkey. Tel: + 90 505 451 2025; Fax: + 90 412 248 8520; E-mail: [email protected] Accepted for publication January 15, 2015
Significance outcomes
∙ ∙
Immune system dysregulation and inflammation have a role in bipolar disorder and carcinoembryonic antigen stimulates monocytes and macrophages and cause the production of endothelial adhesion molecules and proinflammatory cytokines. Our study suggests that increased CEA is observed in individuals with bipolar disorder.
Limitations
In addition to measurement of CEA, not measurement of proinflammatory and anti-inflammatory marker is one of the limitation of our study. Introduction
Carcinoembryonic antigen (CEA) is an oncofetal glycoprotein, molecular weight 180 kDa, that is widely used as a tumour marker in adenocarcinomas,
especially in colorectal cancer (1). However, it is also expressed in normal mucosal cells (2). CEA also increases at some non-neoplastic conditions, such as chronic inflammatory disease, hepatic and renal failure, aging and smoking (3–5). In addition, increased CEA 1
Kaplan et al. levels have been shown in hypothyroidism, chronic obstructive pulmonary disease and obesity (6–8). The function of CEA has not been fully illuminated, but previous studies have reported that monocytes and macrophages are stimulated by CEA to trigger the production of endothelial adhesion molecules and proinflammatory cytokines (9,10). Bipolar disorder (BD), previously known as manicdepressive illness, has been ranked seventh among the worldwide. BP has a chronic and remitting nature characterised by periods of depression and periods of hypomania or mania in many patients (11). There are two types of BD. BD type I disorder has been defined as the presence of at least one manic episode; BD type II disorder has been defined as presence of at least one hypomanic episode along with the presence of one or more major depressive episodes (12). The accepted prevalence of BD ranges from 0.5% to 1.5%, but these rates may be as high as 10%, depending on which diagnostic criteria are adopted in recent epidemiological studies (13). Evidence from clinical studies showed that immune system dysregulation and inflammation have a role in BP (14). It is reasonable to suspect that elevated inflammatory cytokines partially contribute to the cognitive impairments in BD (15). Progressive structural, functional and biochemical changes in BD might be related to neurotransmitter changes, neurotrophic alterations, oxidative stress and inflammation. Mitochondrial dysfunction, free radical production, neurodegeneration and alterations of several neurotransmitters can occur due to the effects of inflammatory changes in BD (16,17). Inflammatory biomarkers have been considered as one of the main pillars of a multifactorial approach for estimation of BD in an at-risk population (18). Preclinical studies suggest that mood stabilisers such as lithium and valproic acid play a role in the modulation of neuroinflammatory processes, and this indicates a role for neuroinflammation in BD (19–21). It is shown that inflammatory processes played a role in the aetiology of BD. In addition, it is considered that CEA also increases the proinflammatory cytokines. Thus, we thought that CEA levels could be changed as an inflammatory marker in BD. The association between elevated CEA and BP has not previously been examined. Our aim in this study was to evaluate CEA levels as a marker of inflammation in BD. Methods
This study was approved by the Dicle University Ethical Committee. A total of 44 out-patients who agreed to participate in the study with type I BD, 2
diagnosed according to the DSM-IV criteria, having been in a euthymic phase for at least 3 months, and followed by the Dicle University, Department of Psychiatry Mood Disorder Unit were enrolled. Patients were between 18–65 years of age. Patients admitted in the Unit with a history of drug and alcohol abuse, chronic systemic diseases such as diabetes mellitus, morbid obesity, cancer, hypertension, etc., severe head injury or seizure disorders, or pregnant were excluded from the study. Patients who have comorbid psychiatric disorders and mental retardation were excluded from the study. The control group consisted of 45 healthy subjects. The control group was selected from healthy individuals who donate blood to the blood bank. The case and control groups had similar distributions in age, sex, body mass index and smoking status. Hamilton Depression Scale, the Young Mania Rating Scale and Clinical Global Impression Scale (CGI) were used in the patient group (22,23). Blood samples were obtained from the subjects in the morning after an overnight fast, centrifuged within 30 min at 2500 × g at 4°C for 10 min. Serum aliquots were prepared and stored at −80°C until analysis and the assays for variables analyzed in the current study were performed on the same day CEA values were measured in Dicle University, Medical Faculty Central Laboratory using electrochemiluminescence immunoassay (Roche Cobas e601). Assay precision was evaluated by testing two control concentrations of commercially available quality control materials. Statistical analysis
SPSS® for Windows 15.0 statistical program was used for statistical analysis. The Kolmogorov–Smirnov test was used to confirm that data within the ranges of normal distribution in both groups. A parametric test was employed for the variables in the normal distribution. The significance of differences between groups was estimated by Student’s t-test. χ2 test was used when comparing proportions. Differences were accepted as significant when p < 0.05. Bivariate comparisons were examined via Spearman correlation coefficients and values were corrected for ties. Results
The mean age was 31.90 ± 11.12 and 30.46 ± 7.38 years for patients and controls, respectively. The mean serum CEA level in BD was 2.36 ± 1.52 µg/l and in control was 1.77 ± 0.98 µg/l. CEA levels were significantly increased in euthymic BD patients when compared with controls (p = 0.031). Furthermore, while 49.4% of patients and 50.6% of control group
CEA levels in bipolar disorder patients Table 1. Sociodemographic variables and biochemical measurements of patients and controls
Gender Male Female Smoking status Yes No
CEA level (µg/l) Age Mean disease onset (years) Mean disease duration (years) HAM-D (mean ± SD) YMRS (mean ± SD) CGI
Patients [n (%)]
Controls [n (%)]
37 (84.1) 7 (15.9)
38 (84.4) 7 (15.6)
24 (54.5) 20 (45.5)
28 (62.2) 17 (37.8)
Mean ± SD
Mean ± SD
2.36 ± 1.52 31.90 ± 11.12 22.57 ± 9.21 9.36 ± 8.22 4.61 ± 4.35 1.95 ± 2.09 1.38 ± 0.62
1.77 ± 0.98 30.46 ± 7.38
t value
p value
0.722
0.596
0.302
2.196 0.722
0.031 0.472
CEA, carcinoembryonic antigen; CGI, Clinical Global Impression Scale; HAM-D, Hamilton Depression Scale; YMRS, Young Mania Rating Scale.
were smokers, there was no significant difference between the smoking status of patient and control groups (p = 0.302) (Table 1). There were no correlations between mean CEA levels and age, onset of disease and disease duration (p > 0.05). The sociodemographic variables are shown in Table 1. In all, 88.6% (n = 39) of patients were using antipsychotics, 93% (n = 41) were using mood stabilisers, and 20.5% (n = 9) were using the antidepressant; 4.5% (n = 2) of our patients were using first-generation antipsychotics, 75% (n = 33) secondgeneration antipsychotics, and 9% (n = 4) first- and second-generation combined antipsychotics drugs. Only six patients (13.6%) were using one psychiatric drug and 38 patients (86.4%) were using combined drugs. Control group was not using any drug. There was no statistically significant relationship between CEA levels and using these drugs (p > 0.05). Discussion
In this study we investigated the CEA levels in euthymic bipolar patients and this is the first study to examine CEA levels at BD. An oncofetal glycoprotein CEA, which is a member of the immunoglobulin superfamily, is a cell surface adhesion molecule. CEA is overexpressed in adenocarcinoma, especially in colorectal cancer. It is also expressed in normal mucosal cells. Elevated CEA levels can be seen in pancreatitis, inflammatory bowel disease, cirrhosis, biliary obstruction, peptic ulcer disease, hypothyroidism and cigarette smoking. The serum concentration is
© Scandinavian College of Neuropsychopharmacology 2015 ACTA NEUROPSYCHIATRICA
Serum levels of carcinoembryonic antigen (CEA) in patients with bipolar disorder Kaplan I, Bulut M, Atli A, Güneş M, Kaya MC, Çolpan L. Serum levels of carcinoembryonic antigen (CEA) in patients with bipolar disorder.
Ibrahim Kaplan1, Mahmut Bulut2, Abdullah Atli2, Mehmet Güneş2, Mehmet Cemal Kaya2, Leyla Çolpan1 1
Objective: Carcinoembryonic antigen (CEA) is an oncofetal glycoprotein that is widely used as a tumour marker in adenocarcinomas. However, several non-neoplastic conditions, including acute and chronic inflammation and other inflammation-related conditions, are characterised by increased CEA concentrations. Bipolar disorder (BD) ranks seventh among the worldwide burden of non-fatal diseases. Inflammatory biomarkers have been considered as one of the main key pillars of a multifactorial approach for prediction of BD in an at-risk population. BP is accompanied by activation of inflammatory, cell-mediated and negative immunoregulatory cytokines. Methods: We measured the levels of CEA in serum samples from 44 individuals with euthymic BP out-patients and 45 healthy controls. Patients were diagnosed according to the DSM-IV criteria. CEA was measured by an electrochemiluminescence immunoassay. Results: The mean serum CEA concentration was 2.36 ± 1.52 and 1.77 ± 0.98 µg/l in patients and controls, respectively. CEA levels were significantly increased in euthymic BP patients when compared with controls (p = 0.031). Conclusions: This study suggests that CEA is increased in BD and supports a role for immune activation in the core pathological mechanisms of BP. CEA levels may be a secondary marker for diagnosing BP.
Department of Biochemistry, Medical Faculty, Dicle University, Diyarbakır, Turkey; and 2 Department of Psychiatry, Medical Faculty, Dicle University, Diyarbakır, Turkey
Keywords: bipolar disorder; CEA; proinflammatory cytokines Ibrahim Kaplan, Department of Medical Biochemistry, Medical Faculty, Dicle University, Diyarbakır, Turkey. Tel: + 90 505 451 2025; Fax: + 90 412 248 8520; E-mail: [email protected] Accepted for publication January 15, 2015
Significance outcomes
∙ ∙
Immune system dysregulation and inflammation have a role in bipolar disorder and carcinoembryonic antigen stimulates monocytes and macrophages and cause the production of endothelial adhesion molecules and proinflammatory cytokines. Our study suggests that increased CEA is observed in individuals with bipolar disorder.
Limitations
In addition to measurement of CEA, not measurement of proinflammatory and anti-inflammatory marker is one of the limitation of our study. Introduction
Carcinoembryonic antigen (CEA) is an oncofetal glycoprotein, molecular weight 180 kDa, that is widely used as a tumour marker in adenocarcinomas,
especially in colorectal cancer (1). However, it is also expressed in normal mucosal cells (2). CEA also increases at some non-neoplastic conditions, such as chronic inflammatory disease, hepatic and renal failure, aging and smoking (3–5). In addition, increased CEA 1
Kaplan et al. levels have been shown in hypothyroidism, chronic obstructive pulmonary disease and obesity (6–8). The function of CEA has not been fully illuminated, but previous studies have reported that monocytes and macrophages are stimulated by CEA to trigger the production of endothelial adhesion molecules and proinflammatory cytokines (9,10). Bipolar disorder (BD), previously known as manicdepressive illness, has been ranked seventh among the worldwide. BP has a chronic and remitting nature characterised by periods of depression and periods of hypomania or mania in many patients (11). There are two types of BD. BD type I disorder has been defined as the presence of at least one manic episode; BD type II disorder has been defined as presence of at least one hypomanic episode along with the presence of one or more major depressive episodes (12). The accepted prevalence of BD ranges from 0.5% to 1.5%, but these rates may be as high as 10%, depending on which diagnostic criteria are adopted in recent epidemiological studies (13). Evidence from clinical studies showed that immune system dysregulation and inflammation have a role in BP (14). It is reasonable to suspect that elevated inflammatory cytokines partially contribute to the cognitive impairments in BD (15). Progressive structural, functional and biochemical changes in BD might be related to neurotransmitter changes, neurotrophic alterations, oxidative stress and inflammation. Mitochondrial dysfunction, free radical production, neurodegeneration and alterations of several neurotransmitters can occur due to the effects of inflammatory changes in BD (16,17). Inflammatory biomarkers have been considered as one of the main pillars of a multifactorial approach for estimation of BD in an at-risk population (18). Preclinical studies suggest that mood stabilisers such as lithium and valproic acid play a role in the modulation of neuroinflammatory processes, and this indicates a role for neuroinflammation in BD (19–21). It is shown that inflammatory processes played a role in the aetiology of BD. In addition, it is considered that CEA also increases the proinflammatory cytokines. Thus, we thought that CEA levels could be changed as an inflammatory marker in BD. The association between elevated CEA and BP has not previously been examined. Our aim in this study was to evaluate CEA levels as a marker of inflammation in BD. Methods
This study was approved by the Dicle University Ethical Committee. A total of 44 out-patients who agreed to participate in the study with type I BD, 2
diagnosed according to the DSM-IV criteria, having been in a euthymic phase for at least 3 months, and followed by the Dicle University, Department of Psychiatry Mood Disorder Unit were enrolled. Patients were between 18–65 years of age. Patients admitted in the Unit with a history of drug and alcohol abuse, chronic systemic diseases such as diabetes mellitus, morbid obesity, cancer, hypertension, etc., severe head injury or seizure disorders, or pregnant were excluded from the study. Patients who have comorbid psychiatric disorders and mental retardation were excluded from the study. The control group consisted of 45 healthy subjects. The control group was selected from healthy individuals who donate blood to the blood bank. The case and control groups had similar distributions in age, sex, body mass index and smoking status. Hamilton Depression Scale, the Young Mania Rating Scale and Clinical Global Impression Scale (CGI) were used in the patient group (22,23). Blood samples were obtained from the subjects in the morning after an overnight fast, centrifuged within 30 min at 2500 × g at 4°C for 10 min. Serum aliquots were prepared and stored at −80°C until analysis and the assays for variables analyzed in the current study were performed on the same day CEA values were measured in Dicle University, Medical Faculty Central Laboratory using electrochemiluminescence immunoassay (Roche Cobas e601). Assay precision was evaluated by testing two control concentrations of commercially available quality control materials. Statistical analysis
SPSS® for Windows 15.0 statistical program was used for statistical analysis. The Kolmogorov–Smirnov test was used to confirm that data within the ranges of normal distribution in both groups. A parametric test was employed for the variables in the normal distribution. The significance of differences between groups was estimated by Student’s t-test. χ2 test was used when comparing proportions. Differences were accepted as significant when p < 0.05. Bivariate comparisons were examined via Spearman correlation coefficients and values were corrected for ties. Results
The mean age was 31.90 ± 11.12 and 30.46 ± 7.38 years for patients and controls, respectively. The mean serum CEA level in BD was 2.36 ± 1.52 µg/l and in control was 1.77 ± 0.98 µg/l. CEA levels were significantly increased in euthymic BD patients when compared with controls (p = 0.031). Furthermore, while 49.4% of patients and 50.6% of control group
CEA levels in bipolar disorder patients Table 1. Sociodemographic variables and biochemical measurements of patients and controls
Gender Male Female Smoking status Yes No
CEA level (µg/l) Age Mean disease onset (years) Mean disease duration (years) HAM-D (mean ± SD) YMRS (mean ± SD) CGI
Patients [n (%)]
Controls [n (%)]
37 (84.1) 7 (15.9)
38 (84.4) 7 (15.6)
24 (54.5) 20 (45.5)
28 (62.2) 17 (37.8)
Mean ± SD
Mean ± SD
2.36 ± 1.52 31.90 ± 11.12 22.57 ± 9.21 9.36 ± 8.22 4.61 ± 4.35 1.95 ± 2.09 1.38 ± 0.62
1.77 ± 0.98 30.46 ± 7.38
t value
p value
0.722
0.596
0.302
2.196 0.722
0.031 0.472
CEA, carcinoembryonic antigen; CGI, Clinical Global Impression Scale; HAM-D, Hamilton Depression Scale; YMRS, Young Mania Rating Scale.
were smokers, there was no significant difference between the smoking status of patient and control groups (p = 0.302) (Table 1). There were no correlations between mean CEA levels and age, onset of disease and disease duration (p > 0.05). The sociodemographic variables are shown in Table 1. In all, 88.6% (n = 39) of patients were using antipsychotics, 93% (n = 41) were using mood stabilisers, and 20.5% (n = 9) were using the antidepressant; 4.5% (n = 2) of our patients were using first-generation antipsychotics, 75% (n = 33) secondgeneration antipsychotics, and 9% (n = 4) first- and second-generation combined antipsychotics drugs. Only six patients (13.6%) were using one psychiatric drug and 38 patients (86.4%) were using combined drugs. Control group was not using any drug. There was no statistically significant relationship between CEA levels and using these drugs (p > 0.05). Discussion
In this study we investigated the CEA levels in euthymic bipolar patients and this is the first study to examine CEA levels at BD. An oncofetal glycoprotein CEA, which is a member of the immunoglobulin superfamily, is a cell surface adhesion molecule. CEA is overexpressed in adenocarcinoma, especially in colorectal cancer. It is also expressed in normal mucosal cells. Elevated CEA levels can be seen in pancreatitis, inflammatory bowel disease, cirrhosis, biliary obstruction, peptic ulcer disease, hypothyroidism and cigarette smoking. The serum concentration is
