1

Örebro University

School of Medical Sciences

Degree project, 30 ECTS

6 Jan 2016

Bipolar disorder and routine clinical

biomarkers of inflammation:

a systematic review

Version 1

Author: Ida Bark, Bachelor of Medicine

Supervisor: Julia Sabet, PhD

Örebro, Sweden

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Table of content

1. Abstract p. 3

2. Abbreviations p. 4

3. Introduction p. 5

4. Methods and materials p. 8

4.1 Eligibility criteria p. 8

4.2 Information search p. 9

4.3 Ethics p. 10

5. Results p. 11

5.1 Study selection p. 11

5.2 Study characteristics p. 11

5.3 Comparisons of inflammatory markers p. 17

5.3.1 C-reactive protein p. 17

5.3.2 Leukocyte count p. 17

5.3.3 Neutrophil count / percentage p. 17

5.3.4 Lymphocyte count / percentage p. 17

5.3.5 Platelet count p. 18

5.3.6 Monocyte percentage p. 18

5.3.7 Ratios p. 18

5.3.8 Difference between BD mood states p. 18

5.4 Quality assessment of included studies p.19

6. Discussion p. 20

7. Conclusion p. 22

8. References p. 23

Appendix 1 p. 29

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1. Abstract

Introduction: Bipolar Disorder (BD) is a chronic psychiatric illness associated with

psychiatric and medical co-morbidity as well as an unhealthy life-style. Increasing evidence

points towards a link between BD and inflammation and/or immune dysfunction.

Our aim was to review studies investigating inflammation in patients with BD using

inflammatory markers commonly used in everyday clinical practice.

Methods: We conducted a systematic review of studies comparing BD-patients with a control

group regarding inflammatory markers in peripheral blood. Searches were made in PubMed

and PsycInfo and articles were selected for full-text reading based on evaluation of abstract.

Results: Forty-five articles were selected for full-text reading and of these, 24 were included

in the review. Several studies showed significantly elevated levels in the BD group for CRP,

leukocytes and neutrophils while decreased levels were found for lymphocytes, although

other studies could not show a significant difference.

Conclusion: This review provides further support for a link between BD and inflammation,

although the direction of causality remains unclear, and points toward lymphocyte count /

percentage as a promising marker for further studies. Our opinion is that inflammation in the

future might become one useful piece of the puzzle that is caring for and treating patients with

bipolar disorder.

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2. Abbreviations

BD = Bipolar disorder

BMI = Body mass index

CI = Confidence interval

COX-2 = Cyclooxygenase-2

CRP = C-reactive protein

ESR = Estimated sedimentation rate

hsCRP = High sensitivity C-reactive protein

IL = Interleukin

NLR = Neutrophil - lymphocyte ratio

PLR = Platelet - lymphocyte ratio

SBU = ”Statens beredning för medicinsk och social utvärdering” (swe)

SD = Standard deviation

SEM = Standard error of the mean

TNF-α = Tumor necrosis factor alpha

WBC = White blood cell

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3. Introduction

Bipolar disorder (BD) is a chronic psychiatric illness with a prevalence of 1-4.4% depending

on country and whether sub-threshold BD is included. The onset of the disease most

commonly occurs in late adolescence or young adulthood and the disease is associated with a

substantial economic and psychosocial burden [1].

BD is characterized by recurrent mood episodes, both depressed and manic, with intermittent

periods of neutral mood, called euthymia.

A mood episode can also be characterized as “with mixed features” meaning an episode of

mania/hypomania or depression but with symptoms of the other state as well [2].

BD is classified as BD type I or BD type II according to DSM-V. The main difference is that

mania is present in BD type I, while persons with BD type II only experience hypomania.

Both mania and hypomania are characterized by an “elevated, expansive or irritable mood”,

but what differentiates them is that mania is associated with a marked impairment in

functioning, requires hospitalization, or includes psychotic features.

If any of the criteria for BD type I or II are not met, a physician may diagnose a patient with

“Other specified/Unspecified Bipolar and Related Disorders” [2].

Despite the focus on mania/hypomania in BD, several studies show that bipolar patients spend

a significantly greater time depressed than manic or hypomanic. It is also the depressed state

that is associated with the greatest risk of suicide [1].

Patients with BD experience a high level of co-morbidity, both psychiatric and medical [1].

It has been shown that the all-cause mortality rate among patients with BD is about twice as

high as that of the general population. Some of this excess mortality is explained by a high

rate of suicide and other violent deaths. A meta-analysis by Hayes et al. estimated the

standardized mortality ratio for suicide to be 14.44 (95% CI 12.43-16.78) [3].

Despite this, most patients with BD do not die of suicide. A Swedish study found that suicide

and other external causes (accidents and homicide) only accounted for 18 % of deaths

whereas cardiovascular disorders (CVD) accounted for 38% [4]. The same study concluded

that “persons with BD died of CVD approximately 10 years early” compared to the general

population [4].

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This excess mortality from physical illness may have several explanations. One cause might

be the unhealthy lifestyle of many persons with BD.

For example, among persons with BD, the prevalence of smoking is approximately 2 to 3

times that of the general population [5]. Persons with BD also have a higher rate of metabolic

syndrome than the general population [2].

In addition to the unhealthy lifestyle, evidence also points toward the presence of a low-grade

inflammation and an immune dysfunction in individuals with BD [6].

Two recent meta-analyses have examined the levels of cytokines in individuals with BD [7,8].

Both studies showed elevated levels of several cytokines and cytokine receptors, both pro-

inflammatory cytokines such as TNF-α and anti-inflammatory cytokine IL-4.

The brain is protected from the peripheral blood, so cytokines can’t freely access and

subsequently affect the brain. They can however, reach and/or impact the brain in a number of

ways, for ex via active transport, via leaky parts of the blood-brain barrier or by stimulation of

peripheral afferent nerves [9].

Another meta-analysis from 2013 found that the acute-phase protein C-reactive protein (CRP)

was elevated in BD subjects compared to controls [10].

The relationship between inflammation and mental disorders may go both ways, but there is

evidence that inflammation can cause depression. Wright et al. showed that healthy

individuals who were injected with a typhoid vaccine had increased levels of IL-6 and

experienced a decrease in mood [11].

Another study by Alavi et al. showed that treatment with pegylated interferon against hepatitis

C led to the development of new-onset depression in 35% of participants [12].

Because of the potential relationship between inflammation and mental illness, anti-

inflammatory agents may also play a part in the treatment of such diseases.

One study, albeit small, showed that the COX-2 inhibitor Celecoxib, in combination with

antidepressant Reboxetine, gave a significantly greater improvement in depressed patients

compared to Reboxetine alone [13].

Another study that investigated Etanercept, a soluble TNF-α receptor, as therapy for psoriasis,

found that this inhibitor of TNF-α action also reduced depression in these patients - an effect

that was not clearly associated with improvement in skin and joint symptoms [14].

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The association between BD and inflammation is complicated by several factors, for example

the increased prevalence of metabolic syndrome [2]. Metabolic syndrome has been shown to

lead to elevated levels of both CRP and leukocytes, with central obesity being the component

most strongly associated with the elevation of these inflammatory markers [15].

One of the most used substances in the treatment for BD, lithium, adds further complexity to

the question of the immune system in BD. Lithium is known to cause an increase in

granulocytes, while reducing the number of lymphocytes. Though lithium inhibits T-

lymphocyte production, it actually enhances the activity of T-cells [16].

Individuals who suffer from BD seem to follow a downward path during their illness. This

process has been called neuro-progression and is characterized by increasing cognitive

impairment, shorter intervals between mood episodes and decreased likelihood of responding

to treatment [17]. This process seems to be linked, at least in part, to the number of mood

episodes experienced by the individual (F) [18].

Inflammation is one of the factors that have been implicated in this process [17], and

inflammatory biomarkers such as cytokines may be used in the staging of BD, as proposed by

Kapczinski et al. [18].

The aim of this systematic review is to compare persons diagnosed with Bipolar disorder with

the general population and also between different BD mood states, regarding concentrations

of inflammatory markers used in everyday clinical practice. This is done to present further

evidence of the link between BD and inflammation, and provide a foundation and direction

for further research.

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4. Materials and methods

The primary objective was the comparison of persons diagnosed with BD with the general

population (represented by a control group). Studies were elected based on the criteria below.

A secondary objective was to compare groups of BD patients between the three main mood

states (mania/hypomania, depression and euthymia) using studies already included based on

the inclusion criteria for the primary objective.

4.1. Eligibility criteria

Inclusion criteria:

1) Original observational studies

2) Studies comparing individuals diagnosed with Bipolar

Disorder, with a control group representing the general

non-BD population, also accepting control groups

described as “healthy” or “normal”. Studies investigating

additional groups besides BD, such as schizophrenia or

major depression, were not excluded but the results from

these groups are not reviewed.

3) Comparison made for any of the inflammatory markers

presented in figure 1. All markers are characterized by

being measured in peripheral blood and available in

everyday clinical practice.

4) Studies comparing levels of the above-mentioned

inflammatory markers and stating statistical significance.

5) English language studies

Exclusion criteria:

1) Duplicate studies

2) In vitro studies

3) Non human studies

4) Studies with a mixed patient group including individuals with disorders other than BD, if

the group is not also divided and presented as distinct groups.

5) Studies without an available abstract

Figure 1. Biomarkers included in the review

Inflammatory markers included:

CRP (including hsCRP)

ESR

Total platelet count

Total leukocyte count

Lymphocytes total count or

percentage as part of WBC

differential count

Neutrophil total count or percentage

as part of WBC differential count

Monocyte total count or percentage

as part of WBC differential count

Lymphocyte/Neutrophil ratio and

additional ratios between the above

cell populations.

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4.2. Information search

Studies were identified by searching the databases PubMed and PsycInfo. A test search was

also made in Cochrane but this yielded very few results and Cochrane was therefore not used.

The first search in PubMed was performed on 6 Oct 2015 in the following way:

“Bipolar disorders AND C-reactive protein OR CRP OR hsCRP OR ESR OR Estimated

sedimentation rate OR leukocyte* OR monocyte* OR lymphocyte* OR neutrophil* OR

platelet* OR trombocyte*”

In addition a filter was used for English language and human studies.

A further search in PubMed was performed on 19 Oct 2015 for Bipolar Disorder AND

granulocyte* since this term was missing in the first search. With filters for human studies

and English language, this yielded 15 articles, none of which were selected for full text

reading.

The first search in PsycInfo was performed on 19 Oct 2015 in the following way:

Bipolar disorder AND C-reactive protein OR CRP OR hsCRP OR ESR OR Estimated

sedimentation rate OR leukocyte* OR monocyte* OR lymphocyte* OR neutrophil* OR

platelet* OR thrombocyte* OR granulocyte*. Filters were used for English language and

human studies.

From the results obtained in the above searches, articles were selected for full-text reading by

reading the abstracts.

Reference lists of selected full text articles were hand searched to find additional articles and a

second search, using the same search terms and criteria, was performed in both databases on

20 Nov 2015 to identify recently published articles.

The results of the search and the selection process are presented in figure 2.

In the case of studies that were not easily excluded or included, these were discussed with the

supervisor.

Three studies by Hope et al [19-21] used the same sample. Of these, two [19,20] made unique

comparisons and were included with only these unique comparisons reviewed. The third [21]

was excluded.

Two studies by Bai et al [22,23] also used the same sample but made unique comparisons and

were therefore included.

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One study [24] was part observational and part interventional. This study was included but

only the observational part was used.

No study investigated ESR, and this marker is therefore discussed no further.

All studies included in the review were assessed for quality, using a form adapted by the

author from SBU’s form for evaluation of observational studies [25] . The form is presented

in appendix 1.

Three of the studies included in the review were also assessed by the supervisor, to evaluate

the work of the author.

4.3. Ethics

No new data were used in this review, all data have previously been published.

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5. Results

5.1. Study selection

The search in PubMed yielded 687 articles and the search in PsycInfo yielded 412 articles.

After selection from abstracts and exclusion of duplicates, 45 articles remained for full text

evaluation [19,20,22-24,26-65]. One additional article for full-text evaluation was identified

from scanning references [66] and 1 article was identified in the updated search [21] (for

details see figure 2).

Of these 47 studies read in full text, 23 were excluded. Seven studies were excluded because

they lacked a control group [32,38,42,48,51,61,65]. Ten studies were excluded because they

did not investigate any of the markers selected for this review or they did not compare the

markers between BD-patients and controls [27,37,41,43,49,50,53-55,57]. Three studies were

excluded because the BD population was mixed with other populations for the comparison

[39,52,66]. One study was excluded because it did not include a BD group [28]. One study

did not report statistical significance for the comparison [62]. One study used the same

population and comparison as an already included study [21].

After exclusion, 24 studies remained for inclusion in the review [19,20,22-24,26,29-31,33-

36,40,44-47,56,58-60,63,64].

5.2. Study characteristics

All studies are presented in detail in table 1.

Seven of the studies were conducted in Taiwan [22,23,45,46,56,58,59]; 4 in the USA

[33,35,36,44]; 3 studies each in Turkey [29,47,60] and Brazil [30,31,40]; 2 each in Norway

[19,20] and Italy [24,34]; and 1 each in Egypt [26], South Africa [63] and Sweden [64].

Three of the studies were published before the year 2000 [33,44,64], 9 between 2000-09

[19,24,26,31,34,35,45,46,63], and 12 after 2010 [20,22,23,29,30,36,40,47,56,58-60]. Four of

the studies used only male participants [33,46,47,56].

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Figure 2. Flowchart of article selection process.

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Table 1. Study characteristics. 1 Group definitions are the same as used in the original study.

2 Arrows

show whether levels are elevated or decreased in the BD population. NLR = Neutrophil-Lymphocyte

Ratio, PLR = Platelet-Lymphocyte Ratio, SD = Standard Deviation, SEM = Standard Error of the

Mean, CI = Confidence Interval

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15

16

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5.3. Comparisons of inflammatory markers

5.3.1 C-reactive protein

C-reactive protein (CRP) was investigated in 18 studies [19,20,22,23,30,31,34-36,40,44-

46,56,58-60,63], containing 38 comparisons between BD-patients and controls. Of these

comparisons, 18 showed a statistically significant difference, with elevated levels in the BD

groups, and 1 was close to achieving significance.

Of the comparisons, 10 were done between manic patients and controls, and 7 of these

showed statistical significance. Eight comparisons were done between depressed patients and

controls, 2 of which showed significance; and 8 comparisons were done between euthymic

patients and controls, 3 of which showed significance.

5.3.2 Leukocyte count

Leukocyte count was investigated in 7 studies [26,29,33,40,58,59,64], containing 9

comparisons between BD-patients and controls. Of these comparisons, 1 showed a significant

elevation in the BD group and 1 was close to achieving significance.

5.3.3 Neutrophil count / percentage

Neutrophil count and/or percentage was investigated in 5 studies [29,33,47,58,59], containing

7 comparisons. Of these comparisons, 3 showed a significant elevation in the BD groups and

1 was close to achieving significance.

5.3.4 Lymphocyte count / percentage

Lymphocyte count and/or percentage was investigated in 7 studies [26,29,33,47,58,59,64],

containing 10 comparisons. Of these comparisons, 6 showed a significant decrease in the BD

group.

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5.3.5 Platelet count

Platelet count was investigated in 6 studies [24,29,40,47,58,59], containing 9 comparisons,

none of which showed a statistically significant difference.

5.3.6 Monocyte percentage

Monocyte percentage was investigated in 2 studies [58,59], containing 2 comparisons, none of

which showed a statistically significant difference.

5.3.7 Ratios

Neutrophil-lymphocyte ratio was investigated in 2 studies [29,47], containing 3 comparisons,

all of which showed a significant elevation in the BD groups.

Platelet-lymphocyte ratio was investigated in 1 study [47], containing 2 comparisons, both of

which showed a significant elevation in the BD groups.

5.3.8 Difference between BD mood states

Eight studies investigated differences between mood states for several markers

[20,22,30,31,34,40,47,59].

Seven studies contained comparisons of CRP; 6 comparisons between manic and euthymic, 3

of which showed a significant elevation in the manic group; 5 comparisons between manic

and depressed, 2 of which showed a significant elevation in the manic group; and 6

comparisons between depressed and euthymic, 1 of which showed a significant elevation in

the depressed group.

Two studies compared mood states for several markers other than CRP, none of which were

significant.

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5.4. Quality assessment of included studies

The results of the quality assessment are presented in table 2. The results of the assessment

showed great variability between studies. While the majority of studies used populations that

were similar regarding age and sex, only a minority also adjusted for BMI. No studies could

declare any conflicts of interest.

Table 2. Results from quality assessment. See also appendix 1.

1a 1b 1ci 1cii 2 3a 3b 3c 4a 4b

Bai et al, 2015 [23] (-) 1 0 0 0 1 0 0 1 1

Cakir et al, 2015 [29] 1 1 0 0 1 1 1 0 1 1

Kalelioglu et al, 2015 [47] (-) 1 1 1 1 1 1 0 1 1

Uyanik et al, 2015 [60] (-) 1 0 0 1 0 1 0 1 1

Bai et al, 2014 [22] (-) 1 1 1 0 1 1 0 1 1

Tsai et al, 2014 [59] 1 1 0 1 1 1 1 1 1 1

Chiarani et al, 2013 [30] (-) 1 0 1 0 0 0 0 1 1

Dickerson et al, 2013 [36] 1 0 1 1 0 0 0 0 1 1

Fontoura et al, 2012 [40] (-) 1 0 0 0 0 0 0 1 1

Tsai et al, 2012 [58] (-) 1 0 0 1 1 1 1 1 1

Hope et al, 2011 [20] 1 1 0 0 1 0 0 0 1 1

Su et al, 2011 [56] 1 1 0 0 1 1 0 0 1 1

Hope et al, 2009 [19] 1 1 1 0 1 0 0 0 1 1

Cunha et al, 2008 [31] (-) 1 0 0 0 1 0 0 1 1

De Berardis et al, 2008 [34] 1 1 0 0 1 1 1 0 1 1

Dickerson et al, 2007 [35] 1 0 1 0 0 0 0 0 1 1

Huang et al, 2007 [45] 1 0 0 0 1 1 1 0 1 1

Hung et al, 2007 [46] 1 1 0 0 0 1 0 0 1 1

Abeer et al, 2006 [26] 1 1 0 0 1 0 0 0 1 1

De Berardis et al, 2003 [24] (-) 1 0 0 1 0 0 0 1 1

Wadee et al, 2002 [63] (-) 1 0 0 0 0 0 0 1 1

Hornig et al, 1998 [44] 1 0 1 0 1 0 0 1 1 1

Darko et al, 1988 [33] (-) 1 0 0 1 0 1 0 1 1

Wahlin et al, 1984 [64] 1 (-) 0 0 0 0 0 0 1 1

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6. Discussion

Most studies included in this review investigated CRP and several of them could demonstrate

elevated levels in the BD population compared to controls, supporting the theory that BD is

associated with inflammation. Elevated levels in the BD population could also be

demonstrated for total leukocytes and neutrophil percentage / total count in some studies,

while no studies could demonstrate any significant change for platelets or monocytes. The

only marker associated with decreased levels in the BD population was lymphocytes, and

there was a larger proportion of significant comparisons for lymphocytes than for most other

markers. The ratios including lymphocytes also showed a statistically significant difference

between groups; both NLR and PLR were elevated in the BD group compared to controls,

which, in the case of NLR, might be explained both by elevated levels of neutrophils and

decreased levels of lymphocytes, giving this marker the potential of being useful in future

studies of inflammation in BD. Unfortunately, there were few studies investigating

lymphocytes.

The difference in lymphocytes is in line with previous meta-analyses demonstrating changes

in the levels of cytokines, since lymphocytes are a major contributor of cytokines in the body,

although the production of cytokines is not only depending on the number of cells but also the

amount of cytokines produced by each cell [7,8].

There was a larger proportion of significant comparisons when considering groups with only

manic patients, suggesting that mania might be the state with the strongest link to

inflammation, a finding that has not been clearly shown by earlier meta-analyses [7,8].

The meta-analysis by Dargél et al. concerning CRP in BD included 11 studies, 9 of which

were also included in our study [10]. We have been able to include 4 studies investigating

CRP that were published after the meta-analysis, all of which showed significantly elevated

levels for one or several comparisons. This supports the finding in the meta-analysis of

elevated levels of CRP among BD patients.

One strength in this review is that we were able to include more studies compared to the meta-

analysis. The reason for this is that the review methodology has less demands on homogeneity

between studies. The disadvantage of this is that the studies are not easily comparable because

of differences in several areas. Many studies focus on subgroups of patients regarding mood

state and treatment. Some studies also used median or percentage above a cut-off value

instead of mean and standard deviation.

21

To our knowledge, there is no meta-analysis or systematic review regarding any of the other

markers included besides CRP. This systematic review may therefore serve to point to

markers that could be used for future studies looking at changes in inflammatory markers in

patients with bipolar disorder.

The link between inflammation and BD is complicated by several factors, for example

obesity, medication and co-occurring medical illness with elements of inflammation. If the

aim is to identify potential causes of BD, an ideal study would adjust for all these factors, and

use a control group without additional complicating variables. One such aspect that is

complicating the comparison between BD patients and controls is that several studies use

control groups made up of hospital staff. While these controls are close to the patients in time

and place, they have demanding occupations that involve irregular working hours and

possibly large amounts of both physical and psychological stress, all of which could

potentially affect inflammatory markers.

If instead inflammation is considered as important for these patients regardless of the specific

cause, it is of less importance which factor is the major contributor.

One major question is that of causality, determining whether inflammation is a cause or an

effect of BD. The current review is composed mainly of cross-sectional studies, making it

difficult to say anything about the causality and the temporal relationship between

inflammation and BD.

It is not likely that inflammatory markers will ever be used in the diagnosis of BD, since there

is already a well established system for diagnosing psychiatric illnesses using the DSM

manual, but they might serve to point to the potential link between BD and inflammation - a

link that may explain some parts of the disease, for example co-morbidity and neuro-

progression. BD is a chronic illness that is often present during the majority of the patients’

lifetime, so even a low-grade inflammation has the potential to affect the individual.

It should be of great interest to consider all parts of the disease and the life of the patient in

the treatment, not only focusing on the mental disability itself but also trying to improve the

situation regarding co-morbidity and unhealthy lifestyle. And it is in this comprehensive view

that inflammation may play a part.

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7. Conclusion

Several studies showed a significant difference between BD patients and controls for several

markers while other studies could not find any statistically significant difference. The major

contribution of our work is to provide a foundation for further research in this area, pointing

towards inflammatory markers that may be of importance in the development and treatment of

the illness.

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29

Appendix 1

Form for quality assessment modified from SBUs form for evaluation of observational studies

[25].

All questions are answered "yes", "no" or "unclear" and presented in table 2.

Yes = 1

No = 0

Unclear = (-)

If the study has several comparisons and these comparisons have varying quality, the

questions will be answered in favor of the study. For ex: If question 3c) would be 1 for CRP

and 0 for neutrophils, the question may be answered with 1.

1. Selection bias

a) Was the compared groups (BD and control) similar regarding time and place ( mod. from

SBU A1a)

b)Was the composition of the compared groups (BD and control) sufficiently alike at the start

of the study / before adjustment? (SBU A1 b)

Regarding age and sex

c) Have adjustment for differences in baseline values been done (SBU A1 c)

i. Regarding age and sex

ii. Regarding BMI

2. Treatment bias (mod. from SBU A2)

a) Have the authors minimized differences between the groups (BD and control) regarding

factors that may act pro- or anti-inflammatory? (For example anti-inflammatory medication or

occurrence of known inflammatory diseases)

30

3. Detection bias (mod from SBU A3)

a) Have the blood samples been obtained in the same way in all groups regarding fasting

state?

b) Have the blood samples been obtained in the same way in all groups regarding time of day

for sampling

c) Have the samples from all participants been analyzed in the same assay? (Eliminating inter-

assay variability)1

4. Other considerations

a) Is there, based on information given by the authors, a low or non-existent risk that the

results have been influenced by any conflicts of interest? (SBU A6 a)

b) Is there, based on information given by the authors, a low or non-existent risk that the

results have been influenced by any financial support? (SBU A6 b)

1 = This should only be possible for CRP since the blood samples for analyses of blood cell

populations can’t be stored.

31

Letter of intent

Jan 6, 2015

Corresponding author:

Ida Bark

Bachelor degree, major in medicine

Örebro University, Sweden

I am sending my manuscript titled Bipolar disorder and routine clinical biomarkers of

inflammation: a systematic review for consideration.

This paper is a systematic review concerning the levels of inflammation in patients with

bipolar disorder as compared with healthy controls. The markers included were chosen based

on availability as they are all used in everyday routine clinical work.

Studies were identified in PubMed and PsycInfo, and 24 original articles were included in the

final review. This is a larger sample compared to the recent meta-analysis by Dargél et al

investigating levels of C-reactive protein.

This review also has the advantage of including several markers that were investigated in only

a few articles, thereby presenting possible future areas of research.

Besides the marker CRP, that constitutes the majority of the comparisons included in this

review, the results point toward a biomarker that should be further investigated in the future -

lymphocyte count.

I hope to hear from you as soon as possible.

Sincerely

Ida Bark

32

Ethical considerations

This review does not contain any original data since the material used is already published.

This means that no participants have been exposed to any discomfort or any risks as a result

of this study, but this review and other research in the same area may still have consequences

for patients with Bipolar disorder in the future.

If inflammatory markers play a part in the diagnosis and treatment of bipolar patients in the

future, samples will have to be taken from patients.

The analyses used in this review have the advantage of being performed on peripheral blood,

drawn by venipuncture. For most people, this is regarded as an acceptable amount of

discomfort, but for some it may be accompanied by emotional stress.

For many patients, the stress can be reduced by simply taking the samples at the same time as

other samples, for example during the periodic check-ups of lithium-treated patients.

If these biomarkers were ever to be used in the treatment of these patients, it would be so for a

reason, and in that case a small discomfort should be an acceptable price to pay for a better

treatment of both mental and physical illness.

Another concern is the potentially increased cost and work-load for the health-care system.

The biomarkers in this review are chosen based on their routine use in clinical practice. The

tests should be able to be ordered from any hospital laboratory at a low cost and are therefore

ideal in this respect.

33

Press release

Bipolär sjukdom är en kronisk psykisk sjukdom som innebär stora besvär för den som

drabbas, både psykiskt och fysiskt. Bipolär sjukdom är nämligen associerad med ökad

belastning av andra sjukdomar samt med en ohälsosam livsstil, t ex ökad förekomst av

rökning och övervikt.

Det finns forskning som tyder på att bipolär sjukdom har ett samband med inflammation, och

syftet med vårt arbete är därför att ytterligare kartlägga och styrka detta samband. Vi har

sammanställt redan publicerade vetenskapliga artiklar som undersöker sambandet mellan

bipolär sjukdom och inflammation. Dessa artiklar mäter nivåerna av rutinmässigt använda

blodprover, s k markörer, hos bipolära patienter och jämför dessa med en frisk kontrollgrupp.

Resultatet av vårt arbete tyder på att flera olika markörer som mäter inflammation påverkas

vid bipolär sjukdom, även om resultatet inte är entydigt. Ytterligare forskning inom området

behövs för att utreda hur detta samband ser ut samt hitta den markör som bäst speglar

sambandet. Vårt hopp är att sambandet mellan inflammation och bipolär sjukdom i framtiden

ska utnyttjas i den sammansatta bedömningen och behandlingen av patienter med bipolär

sjukdom, både vad gäller den psykiska sjukdomen i sig samt övriga aspekter av patienternas

hälsa. Detta för att hjälpa patienter till en högre livskvalitet och ett längre, hälsosammare liv.