C-reactive protein levels and cognitive functions in patients with bipolar I disorder : Middle East Current Psychiatry

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C-reactive protein levels and cognitive functions in patients with bipolar I disorder

Mohamed, Amany E.a; Abdel Fattah, Nelly R.a; Youssef, Amira M.a; El-Masry, Nagda M.a; Abdel Fattah, Nermin R.b

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Middle East Current Psychiatry: July 2018 - Volume 25 - Issue 3 - p 135-140
doi: 10.1097/01.XME.0000534677.38455.46
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Abstract

Introduction

Bipolar disorder (BD) is a chronic, severe, and highly disabling illness, which is estimated to affect 1% of the population worldwide 1.

BD is associated with increased morbidity and mortality due to general medical conditions, such as cardiovascular disease, obesity, and diabetes mellitus, which are not simply a result of psychiatric symptoms or personal dysfunction 2. Recent studies have found that most bipolar patients have high rates of functional and cognitive impairment, contributing to the substantial psychosocial morbidity associated with the disorder 3. Although there has been a considerable increase in the understanding of the pathophysiological processes of BD, the underlying biology and common mechanisms of comorbid physical and psychiatric disorders remain largely unclear. There has been an increasing interest in the role of the immune and inflammatory systems in mood disorders. It has been demonstrated that mood episodes are associated with changes in cytokine profiles and acute-phase proteins such as immunoglobulin, complement proteins, factor B, and high-sensitivity C-reactive protein (hsCRP) 4. Cunha et al. 5 have reported C-reactive protein (CRP) abnormalities in individuals with BD and although there is evidence for an association of mania and elevated CRP levels, very few studies have evaluated BD patients in different phases of the illness and examined the possible association between elevated serum levels of CRP and severity of psychopathology and cognitive deficits among BD patients. So we conducted the present study to assess the serum levels of CRP in bipolar I disorder patients in different affective phases and evaluate the relation between serum levels of CRP and cognitive impairment in the remitted patients.

Patients and methods

Patients

This cross-sectional case–control observational study was conducted at the psychiatric outpatient clinic and inpatient ward of the Faculty of Medicine, and Medical Biochemistry Department of Faculty of Medicine, Zagazig University, Egypt during the period from July 2015-December 2015.

The study sample included two groups: the patients group consisted of 42 patients aged 18–49 years who were consecutively recruited from the outpatient clinic or the psychiatric ward of Zagazig University Hospitals with the diagnosis of bipolar I disorder according to Diagnostic and Statistical Manual of Mental Disorders-IV criteria and who were divided into three subgroups. Group I: bipolar I patients currently in a manic episode (n=14); group II: bipolar I patients currently in a depressive episode (n=14); group III: bipolar I patients currently in full remission (n=14).

Control group: 42 apparently healthy volunteers matched with patients by age, sex and socioeconomic level from the workers and employees working in Zagazig University Hospitals as well as relatives of nonpsychiatric patients admitted in the hospital with no family history of psychiatric illness.

Inclusion criteria

Age ranging from 18 to 65 years, both sexes, of all socioeconomic classes.

Exclusion criteria

Comorbid psychiatric disorder including substance abuse, history of any acute or chronic general medical condition, history of trauma or surgical intervention in the preceding 6 months, CRP concentration greater than 10 mg/l as they were assumed to represent an acute or chronic infection or inflammation, electroconvulsive therapy (ECT) done during the 3 months prior to inclusion in the remission group, and inability to read or write Arabic language.

Additional exclusion criteria for patients in remission:

  • History of head trauma.
  • History of gross neurological disorder, for example, epilepsy or brain tumor.
  • ECT done for at least 3 months prior to inclusion.
  • Inability to read and write Arabic language.
  • Suspected mental retardation.

The control group matched the same inclusion and exclusion criteria as the patients plus no history of psychiatric disorders.

Data collection and tools

Full psychiatric examination through a semistructured interview

The collection of data included demographic, clinical data [waist circumference, smoking, age of onset of the disease, duration of illness, number of episodes, number of admissions, number of ECT, psychotropic medications, and any substance abuse (types, duration, and severity)] and general medical examination using the sheet of the Department of Psychiatry, Zagazig University. This allowed each patient to receive psychiatric diagnosis of bipolar I disorder according to the Diagnostic and Statistical Manual of Mental Disorders-IV criteria.

Laboratory investigations

  • Routine laboratory investigations: complete blood count, liver and kidney functions, blood electrolytes.
  • Blood sampling and CRP measurements: blood samples (5 ml) in anticoagulant-free aliquot for each participant were collected by venipuncture. Complete clot formation had taken place before centrifugation 6. Serum samples were then stored at −80°C until the day of the analysis. Measurements were performed with the Roche/COBAS INTEGRA system 400, CRP (latex) high sensitive assay (Roche Diagnostics, Basel, Switzerland), a latex particle-enhanced immune turbid metric method, with a measurement range of 1.0–200 mg/l.

Psychometric assessment

  • Hamilton Depression Rating Scale (HDRS-17) 7: HDRS was developed during the late 1950s in response to the need for a standardized measure of the phenomenology of a depressive syndrome. Hamilton finally structured it in 1960. Since then it has become the most commonly used rating scale of depression and has been used as a basis for the construction of other scales. The scale contains 17 variables. The score on it ranges from 0 to 50 (0–7=normal, 8–13=mild depression, 14–18=moderate depression, 19–22=severe depression, ≥23=very severe depression).
  • Young Mania Rating Scale (YMRS) 8: the YMRS is one of the most frequently utilized rating scales to assess manic symptoms. The scale has 11 items and is based on the patient’s subjective report of his or her clinical condition over the previous 48 h. Additional information is based on clinical observations made during the course of the clinical interview. There are four items that are graded on a 0–8 scale (irritability, speech, thought content, and disruptive/aggressive behavior), whereas the remaining seven items are graded on a 0–4 scale. These four items are given twice the weight of the others to compensate for poor cooperation from severely ill patients. There are well-described anchor points for each grade of severity. The authors encourage the use of whole or half-point ratings once experience with the scale is acquired. Typical YMRS baseline scores can vary a lot. They depend on the patients’ clinical features such as mania (YMRS=12), depression (YMRS=3), or euthymic (YMRS=2). Strengths of the YMRS include its brevity, widely accepted use, and ease of administration.
  • Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) 9: only for the patients in the full remission (group III) to avoid the bias which may be caused by the effect of psychotic, manic, or depressive symptoms on the cognitive functions, for example, attention, concentration, and memory. The RBANS is composed of 12 subtests that can be combined into five domains (immediate memory, visuospatial/constructional, language, attention, delayed memory).

Further, a nonlinear transformation of the sum of the five index scores can be calculated.

The RBANS has two alternate forms that are psychometrically equivalent. These alternate forms contain different test items. In our study, we use the form A of the test. The RBANS appears to be a highly useful screening measure of cognitive functioning in patients with BD. The test is sensitive to the level and pattern of impairment typically observed in patients with severe mental illness is highly correlated with the standard measures of intelligence and memory, and is largely independent of symptom severity. It has also been used in previous studies of individuals with BD 10.

Administrative design

Informed consent was obtained from all participants and their legal guardians before inclusion in the study. The study was approved by the Ethics Committee of Zagazig University Hospital.

Statistical analysis

Data were checked, entered, and analyzed using SPSS version 11 (SPSS Inc., Chicago, Illinois, USA) 11. Data were expressed as mean±SD for quantitative variables, number and percentage for qualitative ones. Paired t-test, analysis of variance, χ2, Mann–Whitney U-test, Kruskal–Wallis H-test, and Pearson’s correlation coefficient were used when appropriate. P value less than 0.05 was considered to be statistically significant and those less than or equal to 0.001 as highly significant results 12.

Results

In the current study, there was no statistically significant difference between patients and healthy controls regarding sociodemographic factors (age, sex, education, occupation, marital status, and smoking state), which ensured that both groups are matched and possible confounding factors are eliminated as much as possible (Tables 1–8).

T1-7
Table 1:
Comparison between patients and controls regarding sociodemographic characteristics
T2-7
Table 2:
Comparison between patients (manic, depressed, remitted, and total) and controls regarding C-reactive protein levels
T3-7
Table 3:
Comparison between manic depressed and remitted patients regarding C-reactive protein levels
T4-7
Table 4:
Relation between C-reactive protein levels in patients and some sociodemographic variables
T5-7
Table 5:
Correlation between C-reactive protein levels and severity of mood symptoms
T6-7
Table 6:
Relation between C-reactive protein levels and treatment drug
T7-7
Table 7:
Cognitive functions among patients in full remission
T8-7
Table 8:
Correlation between C-reactive protein levels and cognitive function in fully remitted patients

Serum CRP levels were higher in patients than controls (3.7±3.3, 0.98±0.4) and the difference was highly significant (P<0.001). When we compare each affective group with the control group, the difference was still highly significant in patients than in controls. The highest level of CRP was detected in manic patients (4.8±4.5 mg/l), then remitted patients (3.5±2.6 mg/l) followed by the depressed patients (2.76±2.15 mg/l). But there was no statistically significant difference between manic, depressed, and remitted patients regarding CRP level.

There is no significant relation between hsCRP levels and sex, age, or smoking. There is a statistically highly significant correlation between hsCRP and waist circumference, while there is no significant correlation between hsCRP and clinical variables (age of onset, duration of illness, number of episodes, number of hospitalizations, and number of ECT sessions).

Also there was no statistically significant correlation between hsCRP levels and severity of mood symptoms, that is YMRS and HDRS. There was no statistically significant relation between hsCRP and any treatment group. Lithium-receiving patients had lower hsCRP levels than nonlithium-receiving patients although the difference was not statistically significant.

There was cognitive impairment in remitted bipolar patients as their mean scores in RBANS total scale was 67.1 which was 2 SD below the normal mean of the test (100). There was a statistically highly significant correlation between hsCRP and RBANS total, RBANS immediate memory, RBANS language, RBANS delayed memory, and significant correlation with RBANS attention but no significant correlation could be found between hsCRP and RBANS visuospatial/constructional subtest.

Discussion

There has been an increasing interest in the role of immune and inflammatory systems in mood disorders. Several studies have reported that patients with BD, across the different mood phases of the disease, have abnormal blood levels of several inflammatory markers as cytokines and CRP.

This study found that there was statistically significant elevation of CRP levels in BD patients (3.7±3.3) as compared with the control group (0.98±0.4). We also found that comparing every affective group separately with the control group, the difference was still significantly higher in patients than controls.

Our results are consistent with Dickerson et al. 13 who compared 122 outpatients with BD and165 control individuals. The researchers divided BD patients into two groups according to YMRS scoring. Those with YMRS greater than 6 had significantly higher CRP levels than healthy controls while those with YMRS scoring less than 6 did not differ from that of the controls. They concluded that these results suggest that outpatients with BD with mania symptoms have increased levels of CRP as compared with those without mania symptoms and with individuals without psychiatric disorders.

De Berardis et al. 14 also studied three affective groups of BD patients and found that the CRP levels were higher in both BD manic and depressive subgroups when compared with healthy controls. Recently Vuksan-Cusa et al. 15 also found that CRP was higher in BD than in healthy controls. It is worth mentioning that all BD patients in this study (n=60) were euthymic.

In contrast to our findings Hope et al. 16 reported that there were no significant differences in CRP levels between controls and BD patients. Also no significant differences were found in hsCRP across affective state groups, although the neutral mood group had relatively the highest levels of hsCRP. They gave one explanation of these findings by the possibility that genetic variants influencing serum levels of CR 17 have been unequally distributed in the affective state groups.

Finally, in the most recent meta-analysis conducted to estimate the size of association between the CRP levels and BD, including 11 studies and comprising 1618 participants, the overall CRP levels were significantly elevated in patients with BD versus controls. The CRP levels were significantly higher in manic and euthymic patients, but not in depressed patients with BD compared with controls. However, it is worth mentioning that the authors suggested that the lack of statistical significance of CRP levels in BD depressed group may be explained by the smaller sample size in this group 18.

In our study, no significant correlation could be detected between CRP level and age, sex, or smoking status in BD patients.

In agreement with our findings Hope et al. 16, found that hsCRP was not correlated with any of the possible confounding factors and Hornig et al. 19 found no association between CRP and sex or age. Dickerson et al. 13,20 reported that CRP was not significantly associated with age but with female sex.

Regarding CRP and smoking, Hope et al. 16 and Dickerson et al. 20 also found that smoking habits among the patients did not have any significant correlation with CRP, but surprisingly Tsai et al. 21, reported that the mean hsCRP level of nonsmoking patients in acute mania was significantly higher than that of smoking patients. The only variable that we found to be highly positively correlated with CRP level was the waist circumference, that is the more the waist circumference is, the higher is the CRP level and that was in agreement with others 15. Dickerson et al. 20 found that the levels of CRP were also positively associated with BMI (another marker of metabolic syndrome) in BD patients. In our study, no significant correlation could be found between CRP and both YMRS and HDRS scoring. This is in agreement with other studies 16 but in disagreement with Dickerson et al. 13 in which the CRP level was significantly associated with the YMRS and also with 6 out of 11 of its items (speech, appearance, irritability, language–thought disorder, content, and increased motor activity/energy) but not with other YMRS items (elevated mood, insight, sleep, and sexual interest) or HDRS. We did not find any effect of psychotropic medications (antipsychotics ‘typical and atypical’, lithium, other mood stabilizers, or antidepressants) on CRP levels although patients receiving lithium had lower median CRP levels than patients on nonlithium therapy (2.15 vs. 3 mg/l).

One study that investigated lithium augmentation to antidepressants in patients with refractory depression found that lithium augmentation may reduce CRP levels 22, whereas another study that assessed CRP levels in a mixed sample of bipolar I, bipolar II, and unipolar patients showed that those who were on lithium monotherapy were less likely to demonstrate increased levels of CRP 19.

We found a significant relationship between CRP levels and RBANS total, RBANS immediate memory, RBANS attention, RBANS language, and RBANS delayed memory which means poorer performance in these tests with elevation of CRP. However, we could not prove this association with RBANS visuospatial/constructional test. At present, research regarding the relationship between inflammatory response and cognitive performance in BD is extremely limited. Two studies only explored the association between peripheral proinflammatory cytokines and oxidative markers and cognitive performance in individuals diagnosed with BD.

In one of them, peripheral serum expression of the proinflammatory cytokine, TNF-α, was found to be negatively correlated with accuracy on the delayed memory component on the Rey Auditory Verbal Learning Test, in a study consisting of 54 medicated individuals diagnosed with euthymic (absence of a depressive or manic cycle) BD type I. Furthermore, the expression of two soluble tumor necrosis factor (TNF) receptors (sTNFr1 and sTNFr2) was higher in euthymic BD individuals as compared with healthy controls 23. It is noteworthy that BD patients and healthy individuals did not differ in terms of TNF-α levels. The authors concluded that this result may have been related to the fast degradation of TNF-α in peripheral tissues 23. Further, the elevated production of sTNF receptors may explain why cognitive deficits persist during the euthymic phase of BD 24,25.

The only study, to the best of our knowledge, which examined the association between elevated CRP levels and cognitive functioning in BD found that patients with a serum CRP level of above the 90th percentile of control levels had a 4.3-fold increased risk of having a low RBANS score, and those with a CRP level above the 75th percentile had a 3.1-fold increased risk. The only individual RBANS component significantly associated with high CRP levels was delayed memory, with patients above the 90th percentile of CRP levels being 3.96-fold more likely to have low scores in this test, relative to those with lower levels. However, patients scores for the RBANS components such as immediate memory, attention, and language showed significant and inverse linear correlations with CRP levels, as did their performance in the Trail Making Test A, which measures cognitive processing speed 20.

In addition to the proinflammatory response that may cause direct neuronal damage, raised CRP concentrations, by acting as a cardiovascular risk factor and causing cerebral atherosclerosis, may result in cerebral macroangiopathy (i.e. large observable stroke) or cerebral microangiopathy (i.e. leucoaraiosis). Both types of lesions disrupt the integrity of frontal subcortical circuits and are responsible for the development of cognitive impairment and dementia 26,27.

Limitations

First, the small sample size is mostly due to a cultural issue concerning seeking psychiatric help during the course of the disease.

Second, since our findings were based on cross-sectional rather than randomized or longitudinal data, the directionality of the association between CRP and BD cannot be clearly inferred. It is possible that inflammation, which is known to be associated with increased levels of CRP, might lead to BD. In contrast, BD symptoms, acting as a stimulus for inflammatory response, might predict CRP levels.

Third, CRP alterations in BD do not necessarily reflect an underlying pathophysiologic process and may be secondary to alterations in biological pathway or presence of comorbidities.

Finally, we cannot rule out that other confounding/moderator variables which are not examined in our study, such as health-related behaviors (i.e. diet and physical activity), chronic diseases, psychological stress and sleep.

Acknowledgements

The authors acknowledge all the participants of this study for their cooperation. They also thank the Department of Psychiatry and The Department of Medical Biochemistry, Faculty of Medicine, Zagazig University.

A.E.M., N.R.A.F., and A.M.Y. selected the research theme and designed the framework for the study; A.E.M., N.R.A.F., and N.M.E. collected the clinical data of bipolar patients; N.M.E. and A.M.Y. performed psychometric assessment for all the study participants; N.R.A.F. did the laboratory assessment; all the authors were involved in analyzing the data and drafting the paper; N.R.A.F. did the final review of the manuscript and submitted it for publication.

Conflicts of interest

There are no conflicts of interest.

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Keywords:

bipolar I disorder; cognitive function; C-reactive protein; depressed phase; euthymic phase; manic phase

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