Biochemical and Biophysical Research Communications xxx (2018) 1e6

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Biochemical and Biophysical Research Communications

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Increased cerebrospinal fluid complement C5 levels in major

depressive disorder and schizophrenia
Takashi Ishii a, c, Kotaro Hattori a, b, Tomoko Miyakawa a, b, Kentaro Watanabe a,
Shinsuke Hidese a, Daimei Sasayama a, g, Miho Ota a, Toshiya Teraishi a, Hiroaki Hori a, e,
Sumiko Yoshida b, f, Akihiko Nunomura c, Kazuyuki Nakagome d, Hiroshi Kunugi a, *
a
Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan
b
Medical Genome Center, National Center of Neurology and Psychiatry, Tokyo, Japan
c
Department of Neuropsychiatry, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan
d
National Institute of Mental Health, National Center of Neurology and Psychiatry, Tokyo, Japan
e
Department of Adult Mental Health, National Institute of Mental Health, National Center of Neurology and Psychiatry, Tokyo, Japan
f
National Center of Neurology and Psychiatry Hospital, Tokyo, Japan
g
Department of Psychiatry, Shinshu University School of Medicine, Matsumoto, Japan

a r t i c l e i n f o a b s t r a c t

Article history: Inflammation has been implicated in a variety of psychiatric disorders. We aimed to determine whether
Received 31 January 2018 levels of complement C5 protein in the cerebrospinal fluid (CSF), which may reflect activation of the
Accepted 15 February 2018 complement system in the brain, are altered in patients with major psychiatric disorders. Additionally,
Available online xxx
we examined possible associations of CSF C5 levels with clinical variables. Subjects comprised 89 pa-
tients with major depressive disorder (MDD), 66 patients with bipolar disorder (BPD), 96 patients with
Keywords:
schizophrenia, and 117 healthy controls, matched for age, sex, and ethnicity (Japanese). Diagnosis was
Cerebrospinal fluid
made according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, criteria. CSF C5
Complement C5
Schizophrenia
levels were measured by enzyme-linked immunosorbent assay. CSF C5 levels were significantly
Bipolar disorder increased in the patients with MDD (p < 0.001) and in the patients with schizophrenia (p ¼ 0.001),
Major depressive disorder compared with the healthy controls. The rate of individuals with an “abnormally high C5 level” (i.e.,
Body mass index above the 95th percentile value of the control subjects) was significantly increased in all psychiatric
groups, relative to the control group (all p < 0.01). Older age, male sex, and greater body mass index
tended to associate with higher C5 levels. There was a significantly positive correlation between C5 levels
and chlorpromazine-equivalent dose in the patients with schizophrenia. Thus, we found, for the first
time, elevated C5 levels in the CSF of patients with major psychiatric disorders. Our results suggest that
the activated complement system may contribute to neurological pathogenesis in a portion of patients
with major psychiatric disorders.
© 2018 Elsevier Inc. All rights reserved.

1. Introduction investigation of the cerebrospinal fluid (CSF) might be one of the

Current diagnostic systems for mental disorders rely upon the
presentation of signs and symptoms, and thus do not adequately
reflect the relevant neurobiological and behavioral systems [1].
There is an urgent need to elucidate molecular basis of mental
disorders and to develop biomarkers that allow classification of
psychiatric disorders based on the pathophysiology. In this context,
* Corresponding author. 4-1-1, Ogawahigashi, Kodaira, Tokyo, 187-8502, Japan.
E-mail address: hkunugi@ncnp.go.jp (H. Kunugi).
most promising approaches to detect molecules that contribute to
the pathophysiology of psychiatric diseases within the brain, as CSF
is in contact with the brain interstitial fluid over the surfaces of
ventricles, brain, and spinal cord; therefore, molecules released
from brain cells can directly diffuse into the CSF. Indeed, CSF bio-
markers have already been established for some neurological dis-
eases, such as tau, phosphorylated tau, and b-amyloid proteins,
which diagnose Alzheimer's disease with a high (~90%) sensitivity
and specificity [2].
There is a growing amount of evidence that supports increased
levels of pro-inflammatory cytokines in the blood of patients with

https://doi.org/10.1016/j.bbrc.2018.02.131
0006-291X/© 2018 Elsevier Inc. All rights reserved.

Please cite this article in press as: T. Ishii, et al., Increased cerebrospinal fluid complement C5 levels in major depressive disorder and
schizophrenia, Biochemical and Biophysical Research Communications (2018), https://doi.org/10.1016/j.bbrc.2018.02.131
2 T. Ishii et al. / Biochemical and Biophysical Research Communications xxx (2018) 1e6
Abbreviations
BBB blood-brain barrier
BMI body mass index
BPD bipolar disorder
CNS central nervous system
CPeq chlorpromazine-equivalent dose
CSF cerebrospinal fluid
ELISA enzyme-linked immunosorbent assay
GRID-HAMD-17 GRID-Hamilton Depression Rating Scale, 17-
item version
IL-6 interleukin-6
IMIeq imipramine-equivalent dose
MDD major depressive disorder
MINI Mini International Neuropsychiatric Interview
PANSS Positive and Negative Syndrome Scale
YMRS Young Mania Rating Scale
schizophrenia and major depressive disorder (MDD) [3,4]. We
previously reported increased interleukin-6 (IL-6) levels in the
blood of patients with schizophrenia [4]. Contrary to the traditional
view that the brain is an immunologically privileged site that is
shielded behind the blood-brain barrier (BBB), studies in the past
20 years have uncovered complex interactions among the immune
system, systemic inflammation, and brain functions, which can lead
to changes in mood, cognition, and behavior [5]. As stated above,
we have reported increased IL-6 in the CSF of patients with
schizophrenia, as well as in patients with MDD, relative to healthy
controls [6]; these findings were further supported by a recent
meta-analysis [7]. Additionally, we have reported increased CSF
fibrinogen levels in patients with MDD [2]. Fibrinogen is a coagu-
lation factor which activates microglia, thereby inducing neuro-
inflammation and negatively affecting the brain [8].
A major aspect of the innate immune system is the complement
system. In general, complement activation occurs via four path-
ways: the classical, alternative, mannan-binding lectin, and
extrinsic protease pathways [9,10]. These pathways converge upon
the cleavage of complement C5 into complement fragments C5a
and C5b by C5 convertase, which is the final step of the comple-
ment activation. C5a is the most potent and stable of the anaphy-
latoxins, while C5b is an initial element in the formation of the
membrane attack complex. Notably, the complement system also
plays a role in synapse elimination/pruning, which is essential to
the development of a precise neuronal network [11,12]. A recent
study on adult Swedish twins enriched for schizophrenia reported
that peripheral messenger RNA (mRNA) expression levels of two
complement genes (C5, SERPING1) in peripheral blood mono-
nuclear cells were associated with decreased superior frontal
cortical thickness, which may be involved in the pathogenesis of
schizophrenia [13]. A number of studies, including ours, have re-
ported structural and functional changes in volume, gray matter,
white matter, and functional activity, within the frontal lobe of
schizophrenia patients [14,15]. Since C5 is involved in the final step
of the activation of the complement system, we hypothesized that
C5 levels would be altered in the brain of patients with
schizophrenia.
The aim of the present study was to determine whether CSF
complement C5 levels were altered in patients with major psy-
chiatric disorders, i.e., MDD, bipolar disorder (BPD), and
schizophrenia, compared with healthy controls. We further
examined the possible association of CSF C5 levels with clinical
variables.
Please cite this article in press as: T. Ishii, et al., Increased cerebrospinal fluid complement C5 levels in major depressive disorder and
schizophrenia, Biochemical and Biophysical Research Communications (2018), https://doi.org/10.1016/j.bbrc.2018.02.131
2. Material and methods
2.1. Participants
Subjects comprised 89 patients with MDD (age: 43.8 ± 10.4
years; 43 males), 66 patients with BPD (43.7 ± 12.3; 32 males), 96
patients with schizophrenia (40.1 ± 10.3; 58 males), and 117
healthy controls (42.5 ± 15.3; 66 males), matched for age, sex, and
ethnicity (Japanese). Patients with BPD included 23 patients with
bipolar I and 43 with bipolar II disorder. All participants were
recruited at the National Center of Neurology and Psychiatry
(NCNP), Tokyo, Japan, via advertising at the NCNP hospital, on our
website, and in local free magazines. All participants underwent a
structured interview using the Japanese version of the Mini Inter-
national Neuropsychiatric Interview (MINI) [16], administered by a
trained psychologist or board-certificated psychiatrist. Diagnosis
was made according to the Diagnostic and Statistical Manual of
Mental Disorders, 4th edition Criteria (American Psychiatric Asso-
ciation, 1994), on the basis of the MINI, additional unstructured
interviews, and medical record (if available). Healthy controls were
volunteers without a current or past history of contact with psy-
chiatric services. Participants were excluded if they had a medical
history of central nervous system (CNS) diseases, severe head
injury, substance abuse, or mental retardation. The study protocol
was approved by the ethics committee at the NCNP; the study was
conducted according to the Declaration of Helsinki (World Medical
Association, 2000). Written informed consent was obtained from
every participant.
2.2. Clinical assessments
The Positive and Negative Syndrome Scale (PANSS) was used to
assess symptoms in patients with schizophrenia [17]. The GRID-
Hamilton Depression Rating Scale, 17-item version (GRID-HAMD-
17), was used to evaluate depressive symptoms in patients with
MDD or BPD [18]. The Young Mania Rating Scale (YMRS) was used
to evaluate manic symptoms in patients with BPD [19]. Daily doses
of antipsychotics were converted into chlorpromazine-equivalent
doses (CPeqs) and doses of antidepressants were converted into
imipramine-equivalent doses (IMIeqs), using the published guide-
lines [20]. The status of medication use was recorded at the time of
lumbar puncture.
2.3. Lumbar puncture
After neurologic examinations, each participant underwent
local anesthesia, followed by a lumbar puncture at the L3-4 or L4-5
interspace using an atraumatic pencil point needle (Universe 22G,
75 mm, Unisis Corp., Tokyo, Japan). CSF was collected using a low
protein absorption tube (PROTEOSAVE SS 15 mL Conical tube,
Sumitomo Bakelite Co., Tokyo, Japan) and immediately placed on
ice. The CSF was centrifuged (4000  g for 10 min) at 4  C, then the
supernatant was dispensed into 0.5 mL aliquots in low protein
absorption tubes (PROTEOSAVE SS 1.5 mL Slim tube, Sumitomo
Bakelite Co.) and stored in a deep freezer (80  C) until use.
2.4. Enzyme-linked immunosorbent assay (ELISA)
We used a Human Complement C5 ELISA Kit (ab125963, Abcam
Japan, Tokyo, Japan). The CSF samples were diluted 1:100, using the
diluent attached to the kit. Prior to the experiment, the experi-
menter (T.I) validated the reproducibility of the ELISA at a level of
4% coefficient of variation, using the kit.
 T. Ishii et al. / Biochemical and Biophysical Research Communications xxx (2018) 1e6 3

2.5. Statistical analysis
All statistical analyses were performed using the Statistical
Package for the Social Sciences version 24.0 (IBM Japan, Ltd., Tokyo,
Japan). Data are reported as mean ± standard deviation (SD).
Continuous variables were compared among more than two groups
of the patients and/or controls via analysis of variance. Categorical
variables were compared between the patients and controls via the
chi-squared test. Differences in C5 levels among the diagnostic
groups were compared by analysis of covariance (ANCOVA), con-
trolling for age and sex, and using the Bonferroni correction. The
Pearson product-moment correlation was calculated to examine
associations between CSF C5 levels and clinical variables within
each diagnostic group. Three samples that showed a negative value,
upon detection by optical density, were excluded from the analyses.
Statistical significance was defined as a p-value of <0.05.
3. Results
C5 levels than female subjects in each diagnostic group. BMI posi-
tively correlated with C5 levels in the patients with MDD, those
with BPD, and the controls. We performed ANCOVA analysis on the
subjects (N ¼ 307), in which C5 level was an dependent variable,
sex and diagnosis were factors, and age and BMI were covariates. In
this analysis, we found significant effects of age (F ¼ 11.8, df ¼ 1,
p ¼ 0.001), sex (F ¼ 35.2, df ¼ 1, p < 0.001), BMI (F ¼ 8.37, df ¼ 1,
p ¼ 0.004), and diagnosis (F ¼ 4.58, df ¼ 3, p ¼ 0.004) on C5 levels.
Post-hoc analyses revealed that C5 levels were significantly
increased in patients with MDD (p ¼ 0.001), and in patients with
schizophrenia (p ¼ 0.003), but not in patients with BPD (p ¼ 0.18).
As shown in Table 3, scores on HAMD-17, YMRS, or PANSS
(including its subscales) showed no significant correlation with CSF
C5 levels. There was a significantly positive correlation between
CPeq and C5 levels in the patients with schizophrenia (p ¼ 0.002,
Fig. 2). No significant correlation was detected between IMIeq and
C5 levels in MDD or BPD patients.

Clinical features of the participants are shown in Table 1. There 4. Discussion

were no significant differences between each diagnostic group and
the healthy control group in terms of age or sex distribution. The
body mass index (BMI) in the patients with schizophrenia was
significantly higher than the BMI in the controls.
3.1. C5 levels in diagnostic groups
CSF C5 levels for the diagnostic groups are shown in Table 2 and
Fig. 1. ANCOVA analysis, controlled for age and sex, revealed that
CSF C5 levels were significantly increased in the patients with MDD
(p < 0.001) and schizophrenia (p ¼ 0.001), but not in the patients
with BPD (p ¼ 0.09), relative to the controls. When an “abnormally
high C5 level” was defined as 424.0 ng/mL or higher, according to
the 95th percentile value of the control group, individuals with this
abnormally high C5 level were significantly more common in all of
the included psychiatric groups, relative to the controls (all
p < 0.01; Table 2).
3.2. Relationships of C5 levels with clinical variables
Table 3 shows correlations between CSF complement C5 levels
and multiple clinical variables. There was a significantly positive
correlation between C5 levels and age in the patients with BPD, as
well as in the controls. Male subjects tended to exhibit higher CSF
To our knowledge, this is the first report of increased CSF C5
levels in patients with major psychiatric disorders. C5 levels were
significantly increased in the patients with MDD and in the patients
with schizophrenia, compared with the healthy controls. The rate
of individuals with an “abnormally high C5 level” was higher in all
psychiatric groups than it was in the healthy controls. Older age,
male sex, and greater BMI tended to associate with higher C5 levels.
There was a significantly positive correlation between C5 levels and
CPeq in the patients with schizophrenia.
There are two possible mechanisms that may explain the
increased CSF C5 levels in the patients with MDD and in the pa-
tients with schizophrenia. First, an increased permeability of the
BBB may have permitted increased transition of the C5 molecule
from the peripheral blood to the brain. There is some evidence that
the albumin CSF-to-serum ratio, a marker for BBB permeability, was
increased in the patients with MDD and in the patients with
schizophrenia [21,22]. Another biomarker for BBB permeability is
the serum S100B protein, which is produced mainly by astrocytes
and oligodendrocytes. Several previous studies revealed that pa-
tients with MDD exhibit increased serum S100B levels [23,24];
however, conflicting reports stated that there was no significant
association between serum S100B and depression severity [25,26].
Regarding schizophrenia, two meta-analyses determined that
serum or plasma S100B levels were consistently increased in

Table 1
Clinical characteristics of the participants.

Controls (n ¼ 117) Major depressive disorder (n ¼ 89) Bipolar disorder (n ¼ 66) Schizophrenia (n ¼ 96)

Mean ± SD Mean ± SD vs. Controls Mean ± SD vs. Controls Mean ± SD vs. Controls

Age (years) 42.5 ± 15.3 43.8 ± 10.4 F ¼ 0.44, df ¼ 1, p ¼ 0.51 43.7 ± 12.3 F ¼ 0.28, df ¼ 1, p ¼ 0.60 40.1 ± 10.3 F ¼ 1.72, df ¼ 1, p ¼ 0.19
Sexy, male (%)Sexy, male (%) 66 (56.4) 43 (48.3) c2 ¼ 1.33, df ¼ 1, p ¼ 0.26 32 (48.5) c2 ¼ 1.07, df ¼ 1, p ¼ 0.36 58 (60.4) c2 ¼ 0.35, df ¼ 1, p ¼ 0.58
BMI (kg/m2)BMI (kg/m2) 22.6 ± 3.4 22.5 ± 3.3 F ¼ 0.07, df ¼ 1, p ¼ 0.79 23.9 ± 4.8 F ¼ 3.87, df ¼ 1, p ¼ 0.05 24.5 ± 5.5 F ¼ 7.87, df ¼ 1, p ¼ 0.006
CPeq (mg/day) 39.7 ± 126.5 114.2 ± 260.7 533.3 ± 516.6
IMIeq (mg/day) 68.0 ± 119.3 33.5 ± 83.5 14.4 ± 43.4
PANSS
total 60.9 ± 16.0
positive 14.1 ± 5.1
negative 16.2 ± 5.2
general 30.6 ± 8.8
HAMD-17
S88 16.6 ± 6.8 14.9 ± 5.1
<88 3.5 ± 2.5 3.6 ± 2.5
YMRS 6.3 ± 7.5

SD: standard deviation; BMI: body mass index; CPeq: chlorpromazine-equivalent dose; IMIeq: imipramine-equivalent dose; PANSS: Positive and Negative, Syndrome Scale;
HAMD-17: 17-item version of the Hamilton Depression Rating Scale; YMRS: Young Mania Rating Scale; y: number of males.

Please cite this article in press as: T. Ishii, et al., Increased cerebrospinal fluid complement C5 levels in major depressive disorder and
schizophrenia, Biochemical and Biophysical Research Communications (2018), https://doi.org/10.1016/j.bbrc.2018.02.131
4 T. Ishii et al. / Biochemical and Biophysical Research Communications xxx (2018) 1e6

Table 2
Comparison of cerebrospinal fluid complement C5 levels and frequency of abnormally high C5 concentration between patients and controls.

Cerebrospinal fluid C5 levels The number of patients with abnomally high C5

levels

n Mean ± SD (ng/mL) vs. Controls vs. Controls

Controls 117 218.7 ± 111.1 5 (4.3%)

Major depressive disorder 89 317.7 ± 221.1 F ¼ 7.93, df ¼ 3, yp < 0.001 22 (24.7%) c2 ¼ 18.6, df ¼ 1, p < 0.001
Bipolar disorder 66 278.3 ± 190.7 F ¼ 7.93, df ¼ 3, yp ¼ 0.09 11 (16.7%) c2 ¼ 8.1, df ¼ 1, p ¼ 0.006
Schizophrenia 96 306.6 ± 204.7 F ¼ 7.93, df ¼ 3, yp ¼ 0.001 20 (20.8%) c2 ¼ 14.0, df ¼ 1, p < 0.001
An “abnormally high C5 level” was defined as 424.0 ng/mL or higher, according to the 95th percentile value of the control group. y: ANCOVA controlling for age and sex.

ng/mL
p = 0.001
p < 0.001
ng/mL r=0.31
p=0.002

Fig. 2. Correlation between cerebrospinal fluid (CSF) C5 levels and chlorpromazine-

n = 117 n = 89 n = 66 n = 96
Fig. 1. Cerebrospinal fluid (CSF) complement C5 levels in healthy controls (CONT), as
well as in patients with major depressive disorder (MDD), bipolar disorder (BPD), and
schizophrenia (SCH).
patients with the disorder [27]. Second, since human CNS cells
produce components of the complement system under the
appropriate stimulatory conditions [10], increased production of C5
in the brain may contribute to the observed increase in CSF C5
levels, both in the patients with MDD and in the patients with
equivalent doses (CPeqs) in the patients with schizophrenia.
In the patients with schizophrenia, there was a significant, but weakly positive, cor-
relation between CSF C5 levels and CPeq.
schizophrenia. Although complement synthesis in the human brain
is regarded as generally low or non-detectable under normal con-
ditions [10], increased CSF C5a levels were reported in a study of
patients with neuromyelitis optica; conversely, their serum C5a
levels were unaltered [9].
We observed a positive correlation between C5 levels and
antipsychotic medication doses in the patients with schizophrenia,
which suggests that antipsychotics may increase C5 levels in the
brain. Animal model and in vitro studies indicate that

Table 3
Correlations between cerebrospinal fluid complement C5 levels and multiple clinical variables.

Controls (n ¼ 117) MDD (n ¼ 89) Bipolar disorder Schizophrenia

(n ¼ 66) (n ¼ 96)

r p r p r p r p

Age (years) 0.38 <0.001 0.04 0.71 0.41 0.001 0.12 0.24
Sex 0.17 0.07 0.33 0.002 0.27 0.03 0.31 0.002
BMI$ (kg/m2) 0.36 <0.001 0.27 0.02 0.32 0.01 0.11 0.33
HAMD-17 0.04 0.72 0.14 0.29
YMRS 0.19 0.16
PANSS
total 0.08 0.47
positive 0.09 0.40
negative 0.06 0.55
general 0.12 0.24
CPeq (mg/day) 0.02 0.87 0.31 0.002
IMIeq (mg/day) 0.13 0.22 0.15 0.23

MDD: major depressive disorder; BMI: body mass index; HAMD-17: 17-item version of the Hamilton, Depression Rating Scale; YMRS: Young Mania
Rating Scale; PANSS: Positive and Negative Syndrome; CPeq:: chlorpromazine-equivalent dose; IMIeq: imipramine-equivalent dose; Significant p-
values are shown in bold cases. $: BMI data were missing for 61 subjects (16.6%).

Please cite this article in press as: T. Ishii, et al., Increased cerebrospinal fluid complement C5 levels in major depressive disorder and
schizophrenia, Biochemical and Biophysical Research Communications (2018), https://doi.org/10.1016/j.bbrc.2018.02.131
 T. Ishii et al. / Biochemical and Biophysical Research Communications xxx (2018) 1e6
antipsychotics might negatively affect the BBB [28,29]: antipsy-
chotics may induce cytotoxic effects and apoptosis of BBB endo-
thelial cells, with a concomitant impairment of barrier functionality
[28]. In a manner consistent with this proposed medication effect,
chronic antipsychotic treatment resulted in an increased density of
microglia in the rat brain [29].
Increased CSF C5 levels may lead to microglial migration and
activation, thereby altering immune conditions and inducing neu-
roinflammation in the CNS. Microglial migration is diminished in
the complement C5a receptor knockout mouse [30], consistent
with these findings, C5a-peptide vaccines reduced microglial acti-
vation and neuroinflammation [31]. From a developmental
perspective, increased CSF C5 levels may contribute to
complement-mediating synapse pruning, especially in adoles-
cence. Peripheral mRNA expression levels of C5 were associated
with superior frontal cortical thickness in patients with schizo-
phrenia [13]. Moreover, structural alteration of C4, which is located
upstream of C5, has been suggested to induce synapse pruning [11].
Interestingly, BMI positively correlated with C5 levels in patients
with MDD, patients with BPD, and healthy controls. The mecha-
nism of this correlation is unclear; however, several lines of evi-
dence suggest that obesity may promote neuroinflammation and
BBB hyperpermeability. Further, obesity appears to cause low-
grade chronic inflammation in peripheral tissues and blood circu-
lation [32,33]. These previous studies did not evaluate neuro-
inflammation, but a separate report suggests that chronic
inflammation correlates with BBB hyperpermeability in certain
conditions related to the presence of CSF abnormalities [34].
Indeed, a high fat diet in mice induces neuroinflammation via BBB
disruption at the hippocampus [35]. Those findings are especially
interesting in the context of MDD pathophysiology, as obesity in-
creases the risk of depression [36]; in a related manner, patients
with MDD carry a significantly higher risk of developing obesity,
relative to health individuals [37], and neuroinflammation has
repeatedly been reported in MDD [2,38,39]. Future basic research
should evaluate the effect of obesity on neuroinflammation and CSF
markers, including in the context of medication. CSF C5 levels may
reflect the pathophysiology of a subset of mental diseases.
Although, in the present study, there was no association between
CSF C5 levels and symptom scores (or scores of subscales) in each
psychiatric group, a thorough investigation of the symptoms, brain
imaging and physiological tests of high C5 patients is required in a
future study.
As novel treatment options for high C5 patients, C5, C5a, C5aR
(induces microglia migration), and CD59 (inhibits membrane attack
complex formation) may be promising targets to inhibit the com-
plement cascade [40].
In the present study, the patients were biased towards milder
forms of mental illness and the majority of patients were medi-
cated. CSF was, therefore, collected in a “real-world setting”.
Notably, the number of bipolar subjects was relatively small.
CSF C5 levels were significantly increased in the patients with
MDD and schizophrenia, compared with the healthy controls. The
rate of individuals with an “abnormally high C5 level” was
increased in all psychiatric groups, relative to the health controls.
Our results suggest that the activated complement system may
contribute to neurological pathogenesis in a portion of patients
with major psychiatric disorders.
Conflicts-of-Interest
The authors declare that they have no conflict of interest.
Please cite this article in press as: T. Ishii, et al., Increased cerebrospinal fluid complement C5 levels in major depressive disorder and
schizophrenia, Biochemical and Biophysical Research Communications (2018), https://doi.org/10.1016/j.bbrc.2018.02.131
5
Funding
This study was supported by Intramural Research Grants for
Neurological and Psychiatric Disorders at NCNP [grant number 27-
1] (H.K.), Strategic Research Program for Brain Sciences from Japan
Agency for Medical Research and development (AMED) [grant
number 16dm0107100h001] (H.K.), and Health and Labor Sciences
Research Grants for Comprehensive Research on Persons with
Disabilities from AMED [grant number 15dK0310061h001] (H.K.).
These funding sources were involved only in the financial support.
There was a significant increase in C5 levels in the patients with
MDD (p < 0.001) and schizophrenia (p ¼ 0.001), compared with the
healthy controls. Horizontal solid lines indicate the mean values of
the diagnostic groups. The dotted line indicates the 95th percentile
value of the control group (424.0 ng/mL).
Acknowledgements
We thank Mr. Ikki Ishida, Ms. Junko Matsuo, Ms. Moeko Hiraishi,
Ms. Yuuki Yokota, Mr. Ryo Matsmura, Ms. Tomoko Kurashimo, Ms.
Naoko Ishihara, Mr. Takahiro Tomizawa, and Ms. Chie Kimizuka for
their assistance in recruitment and clinical assessments of partici-
pants. We also thank Ms. Misao Nakano and Mr. Shokichi Tajima for
their sample management.
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