3V\FKRQHXURHQGRFULQRORJ\²

Contents lists available at ScienceDirect

Psychoneuroendocrinology
journal homepage: www.elsevier.com/locate/psyneuen

Depression and fatigue in multiple sclerosis: Relation to exposure to violence 7

and cerebrospinal fluid immunomarkers
⁎
Philip Brennera, , Mathias Granqvistb, Johan Königssonc, Faiez Al Nimerb, Fredrik Piehlb,
Jussi Jokinena,c
a
Division of Psychiatry, Department of Clinical Neuroscience, Karolinska Institutet, SE-171 77 Stockholm, Sweden
b
Division of Neurology, Department of Clinical Neuroscience, Karolinska Institutet, SE-171 77 Stockholm, Sweden
c
Department of Clinical Sciences, Umeå University, SE-901 87, Umeå, Sweden

A R T I C L E I N F O A B S T R A C T

Keywords: Multiple sclerosis (MS) is a neuroinflammatory condition characterized by chronic dysregulation of immune
Multiple sclerosis responses leading to repeated episodes of inflammation in the central nervous system. Depression and fatigue are
Interleukins common among MS patients, even in early disease phases, and the disease course can be negatively affected by
Depression stressful events. IL-6 and IL-8 have been associated with depression and stressful life events in non-MS patients.
Fatigue
The aim of this study was to examine the relationships between depression, fatigue, and exposure to violence,
Stress
Disability
with IL-6 and IL-8 levels in the cerebrospinal fluid (CSF) of MS patients. Levels of IL-6 and -8 were analyzed in
the CSF of 47 patients with relapsing-remitting MS. Correlations between IL-6 and IL-8 levels and self-rated
depression and fatigue symptoms, as well as clinician-rated history of being exposed to interpersonal violence,
were analyzed with correction for age, sex and MS disability status. IL-6 correlated significantly (p < 0.05) with
depressive symptoms (adjusted Spearman’s ρ = 0.39), fatigue (ρ = 0.39), and exposure to violence in adult life
(ρ = 0.35). Depression correlated with both fatigue and being exposed to violence. Associations were not present
among patients exposed to disease modifying drugs. In exploratory analyses, the relationship between exposure
to violence and IL-6 was non-significant when controlled for depression. Further research should focus on re-
plication of these results, as well as exploring the impact of stressful life events on immune regulation and the
clinical characteristics and prognosis of MS patients.

1. Introduction
Multiple sclerosis (MS) is an autoimmune central nervous system
(CNS) disease that can give rise to a wide spectrum of symptoms, in-
cluding affection of mood, behavior, and cognition. Clinically sig-
nificant symptoms of depression, as well as the formalized diagnosis of
major depressive disorder (MDD), are common among MS patients
(Brenner et al., 2014; Marrie et al., 2015) with a recent systematic re-
view reporting a prevalence of 35% for symptoms and 21% for diag-
nosis (Boeschoten et al., 2017). Depression and MS appear to have a
complex relationship, where common background factors such as stress
may exist, but where depression also may be secondary to the MS
disease (Arnett et al., 2008). At least part of the underlying variance in
this association seems to be explained not by psychosocial factors or
coping with disability, but by MS disease activity in itself (Feinstein
et al., 2004). However, several criteria in the MDD diagnosis such as
restlessness, fatigue, or sleeping problems are also frequently found
among MS patients without depression, and the distinction from the
syndrome of MDD may be difficult (Patten, 2010).
MS fatigue, a sensation of physical and mental energy depletion that
limits normal activities, is also common and rated as one of the most
disabling symptoms by patients (Shah, 2009). While distinct from de-
pression, symptoms do overlap and are highly correlated even when
somatic depressive symptoms are omitted (Bakshi et al., 2000;
Kroencke et al., 2000). Causality, if it exists, is complex, as depression
can predict later fatigue and fatigue can predict later depression (Brown
et al., 2009).
Cytokines are signaling proteins central for the immune responses
and as such central to the pathogenesis of MS in several ways (Amedei
et al., 2012). MS patients have elevated serum levels of both pro- and
anti-inflammatory cytokines compared to healthy subjects (Martins
et al., 2011). The advancement of multiplex immunoassays seen in later
years has led to several mapping studies of cytokines and chemokines in
the cerebrospinal fluid (CSF) of MS patients. These studies have shown

⁎
Corresponding author at: Department of Clinical Neuroscience, Karolinska Institutet, Centre for Psychiatry Research, Karolinska Unversitetsjukhuset R5:00, SE-171 76 Stockholm,
Sweden.
E-mail address: philip.brenner@ki.se (P. Brenner).

https://doi.org/10.1016/j.psyneuen.2018.01.002
Received 3 October 2017; Received in revised form 2 January 2018; Accepted 3 January 2018
‹(OVHYLHU/WG$OOULJKWVUHVHUYHG
P. Brenner et al.
varied and often conflicting results regarding both detectability and
dysregulation compared to healthy controls, as well as for specificity for
MS clinical disease course (Burman et al., 2014; Edwards et al., 2011;
Matsushita et al., 2013). This probably reflects a current lack of
knowledge in several areas regarding the mechanisms, variation and
detectability of individual cytokines, but also the technical limitations
of current analysis platforms. Among a large panel of cytokines re-
ported in MS, interleukin-6 (IL-6) and −8 (IL-8) are among the most
consistently up-regulated.
IL-6 plays an important role for adaptive and innate immune re-
sponses. It has been implicated both in specific immune processes, such
as differentiation of Th17 cells, but also in general systemic effects, such
as sickness behavior (Scheller et al., 2011). CSF levels of IL-6 have been
reported in several MS materials, however, still with variable results
(Malmestrom et al., 2006; Uzawa et al., 2009). IL-8 is a molecule with
both cytokine and chemokine-like functions and mainly implicated in
innate immune activation processes (Qazi et al., 2011). Detection of
CSF IL-8 shows results that are somewhat more consistent and IL-8 has
recently been suggested as a biomarker for MS progression
(Matejcikova et al., 2015; Rossi et al., 2015). In non-MS subjects, both
depressive symptoms and MDD have been rather consistently linked to
upregulation of IL-6 and IL-8 in both blood (Baune et al., 2012;
Marsland et al., 2007) and in CSF (Dowlati et al., 2010; Kern et al.,
2014).
Being exposed to violence as a child or adult seems to increase the
sensitivity for developing psychiatric disorders, including depression
and suicidality (Devries et al., 2013; Heim and Nemeroff, 2001). Vio-
lence is a more specific type of event than the concepts of stress or
trauma, and may be less sensitive to recall bias (Lalande and Bonanno,
2011). MS patients have a higher risk than healthy controls for having
experienced childhood trauma – although not physical abuse – which is
associated with number of relapses, but not with disability (Spitzer
et al., 2012). A recent meta-analysis also saw an association with MS
onset for some types of violent physical trauma in case-control studies,
but not in cohort studies (Lunny et al., 2014), and the authors con-
cluded that further study using validated instruments specifying type of
trauma was needed. A growing body of evidence suggests that neu-
roinflammatory adaptations mediate this connection, including in-
creasing levels of proinflammatory cytokines (Cattaneo et al., 2015).
Patients with posttraumatic stress disorder (PTSD), where exposure to a
life-threatening event is mandatory for diagnosis, show upregulation of
proinflammatory cytokines, including IL-6, in blood (Lindqvist et al.,
2017). Thus, IL-6 and -8 have been implicated both in psychiatric
conditions in non-MS subjects and as inflammatory markers in MS.
However, studies examining the relation between these cytokines and
psychiatric symptoms in MS patients are rare.
The aims of this study were to examine the association between CSF
expression of IL-6 and IL-8 and a) symptoms of depression, and b)
symptoms of fatigue, and c) being exposed to violence as a child or
adult, in a clinical cohort of MS patients.
2. Materials and methods
2.1. Subjects
During the study recruiting period of May 2012 to June 2014, all
consecutive relapsing remitting MS (RRMS) patients at the MS out-
patient clinic at the Karolinska University Hospital, Solna who met the
following criteria were asked to participate in the study: 1. A recent CSF
examination for clinical purposes, allowing for an interview session
within 90 days of sampling. 2. Being 18–55 years of age. 3. Recent (≤2
years) MS diagnosis, or a current switch in drug treatment regime due
to relapse and/or side effects. Patients switching treatment could still
be treated with their current drug at time of sampling. 4. No known
major somatic or psychiatric diagnoses besides MS. 5. No psychiatric or
psychotropic medication, including glucocorticoids, within 90 days of

3V\FKRQHXURHQGRFULQRORJ\²
Inclusion criteria:
RRMS <2 years, or current
therapy switch due to
e acer a on/side e ects
18-55 years old
CSF sampled in clinical
prac ce
No main other psychiatric or
soma c condi on
Yes (n=102)
No psychotropic drugs
No
g 3)
Yes (n=70)
Consents to study
par cipa on, available for
interview 0 days a er CSF
sampling
Yes (n=47)
Study cohort
Fig. 1. Study recruitment flow chart. RRMS = Relapsing remitting multiple sclerosis,
CSF = cerebrospinal fluid.
SSRIs = Selective serotonin reuptake inhibitors, TCAs = tricyclic antidepressants.
sampling. The MS clinic serves a population-based uptake area that
includes the central-northern part of Stockholm County corresponding
to about 40% of the entire population of approximately 2 million.
Forty-seven subjects who met the criteria and gave informed con-
sent were included in the study. A recruitment flow chart is shown in
Fig. 1. Written informed consent was obtained from all patients
and the study was approved by the Regional Ethical Vetting Board
of Stockholm (Diary Number: 2012/352- 31/4).
2.2. Clinical measurements and covariates
During a single session, participants were subject to two semi-
structured clinical interviews conducted by a trained psychiatrist. The
Karolinska Interpersonal Violence Scale (KIVS) (Jokinen et al., 2010)
includes four subscales, each ranging from 0 to 5, measuring exposure
to/used interpersonal violence as a child (6–14 years old) or adult (15
years of age or older). Violence exposure ranges from occasional, low-
grade violence (1) up to repeated, serious battering or harm (5). The
KIVS has a good interrater reliability (Jokinen et al., 2010). The MINI
International Neuropsychiatric Interview (M.I.N.I.) version 6.0.0.b
(Sheehan et al., 1998), uses DSM-IV (Diagnostic and Statistical Manual
of Mental Disorders, 4th edition) (Association and DSM-IV., 1994)
criteria to screen for and clinically validate psychiatric diagnoses, in-
cluding MDD.
The subjects also filled out the Montgomery-Åsberg Depression
Rating Scale, self-report version; (MADRS-S)(Montgomery and Asberg,
1979), which is a nine item questionnaire for rating of depressive
symptoms according to the DSM criteria for MDD. In order not to
confound depressive symptoms with common MS-related symptoms
such as fatigue or sleeping problems, the five cognitive items in the
MADRS-S scale (covering the symptoms depressed mood, anxiety,
pessimism, loss of interest and suicidality) were separated for analysis.
The Modified Fatigue Impact Scale (MFIS) is modified version of the
Fatigue Impact Scale (Fisk et al., 1994) and is a widely used instrument
for measuring MS fatigue. Disability was rated at the time of CSF
sampling with the Expanded Disability Status Scale (EDSS) (Kurtzke,
1983) by a trained neurologist.
P. Brenner et al. 3V\FKRQHXURHQGRFULQRORJ\²

2.3. Laboratory analysis Table 1

Cohort characteristics. Values are medians with ranges if not otherwise stated.
CSF samples were collected through lumbar puncture using Sprotte®
n 47
spinal needles. The CSF was collected in plastic tubes and centrifuged at Women (%) 31 (66)
2442 rcf for 10 min. The supernatant was aliquoted and frozen at Age 34 (19, 52)
−70 °C within one hour of sampling. Years since MS diagnosis 0 (0, 11)
Cytokines IL-6 and IL-8 were analyzed from previously unthawed No of relapses 2 (1, 7)
Months since relapse 2 (0, 119)
CSF supernatants using ELISA kits from R&D systems® (Quantikine® Relapse < 3 months (n, %) 28 (60)
ELISA; MN, USA) according to the manufacturer’s protocol. Briefly, DMT naive (n, %) 30 (64)
standards were reconstituted and serially diluted. Undiluted CSF sam- Current DMT (n, %)a 12 (26)
ples, standards and negative controls were added to 96 well pre coated No of DMTs tried 0 (0, 3)
IL-6 (pg/ml) 3.5 (0.7, 65)
plates in duplicates after prior addition of assay diluent in equal
IL-8 (pg/ml) 47 (16, 90)
quantity to all wells. After incubation, wells were thrice rinsed with Current major depression (n, %) 6 (13)
wash buffer, decanted and blotted against clean paper towels. EDSS score 2 (0, 5)
Interleukin conjugates were added, plates were covered with adhesive MADRS-S 7 (0, 29)
strips and left to incubate. The wash step was repeated as described MADRS-S cognitive subscale 3 (0, 23)
MFIS 15 (0, 58)
above. Substrate solution was added and plates were kept protected KIVS exposure to violence 0 (0, 6)
from light at room temperature for color development, which was then " as child 0 (0, 4)
abrogated by adding stop solution. Plates were read using a microplate " as adult 0 (0, 4)
reader (Spectramax® plus 384, Molecular devices, CA, USA) set to
450 nm. Results were acquired and analyzed using SoftMax Pro (version DMT = Disease modifying treatment; IL = Interleukin; MS = Multiple
Sclerosis; EDSS = Expanded Disability Status Scale; MADRS-S = Montgomery-
6.2.1, Molecular devices, CA, USA).
Asberg Depression Rating Scale, Self Report version; MFIS = Multiple Sclerosis
Fatigue Impact Scale; KIVS = Karolinska Interpersonal Violence Scale.
2.4. Statistical analysis a
Interferon-β = 7, teriflunomide = 1, rituximab = 1, glatiramer
acetate = 1, natalizumab = 1, recent humologous stem cell transplanta-
First, descriptive analyses of the variables were performed. Second, tion = 1.
non-parametric tests for the distribution of the covariates were per-
formed for group comparisons between men and women, patients with EDSS ≤3 (n = 42), all significant associations remained intact except
and without current disease modifying treatment, patients with and for between IL-6 and MADRS-S total score, although the association
without current relapse, and patients with and without MDD. Third, with the MADRS-S cognitive subscale remained intact.
unadjusted as well as partial (adjusted for sex, age and EDSS score) two- In post hoc analyses showed in Table 4, the relationships between IL-
tailed nonparametric correlation analyses were performed on IL-6 and 6 and the psychiatric instruments were explored adjusted for each
IL-8, respectively, vs. age, EDSS score, MADRS-S score, MFIS score, and other. Depression was still correlated with IL-6 when adjusted for the
the KIVS total score and two subscales measuring exposure to inter- KIVS scales, but the KIVS scales were not when controlled for depres-
personal violence. sion Neither fatigue nor depression scales correlated with IL-6 when
For sensitivity, analyses were also performed in the subgroups of controlled for each other, due to the high correlation between the
patients who were DMT naive and with EDSS ≤3. All analyses which scales.
included MADRS-S were rerun with the score for MADRS-S cognitive
subscale. All analyses were performed in SPSS (v23.0, IBM Corp.). 4. Discussion

3. Results
Subject characteristics are shown in Table 1. In general, the subjects
were recently diagnosed with MS, without current active treatment,
and had low EDSS and psychiatric instrument scores. Six subjects (13%)
were diagnosed with MDD based on the M.I.N.I.-interview. No statis-
tically significant group differences were found for any covariate when
compared by sex, current DMT, relapse < 3 months, or EDSS ≤3, ex-
cept for MFIS scores being higher among women (median 20 vs 6,
p = 0.040).
Table 2 shows the unadjusted correlations between all parameters.
Age correlated with exposure to violence as a child, while EDSS cor-
related significantly with the depression scores. Table 3 shows the
correlations when adjusted for age, sex and EDSS score. Although IL-6
and −8 showed a moderate inverse correlation with each other, only
IL-6 levels were associated with the psychiatric ratings. MADRS-S, and
its cognitive subscale, correlated strongly with MFIS and moderately
with KIVS. Although the child- and adulthood subscales of KIVS cor-
related strongly with each other, only the adulthood subscale was as-
sociated with IL-6 and depression. When the partial correlations were
performed in the subgroup of patients who were DMT naive (n = 30),
IL-6 was still significantly associated with MADRS-S (p = 0.002) but
only borderline significant with the KIVS adulthood scale (p = 0.064).
Among patients with current or previous DMT (n = 17), no associations
between IL and MADRS-S were found, but an association between KIVS
adult score and IL-6 was significant (p = 0.018). Among patients with
The main finding of this study was that CSF expression of IL-6, but
not IL-8, was associated with self-rated depression and fatigue, as well
as with having been exposed to adult violence, in MS patients. As as-
sociations differed somewhat among DMT naïve and non-naïve pa-
tients, a possible modifying role of MS treatment on the involved im-
mune mechanisms should be considered. On one hand, an effective
treatment could affect the patients' mood positively and reduce stress,
but on the other hand, side effects of some DMTs may include depres-
sion and fatigue (Walther and Hohlfeld, 1999). Median scores for ex-
posure to violence were low in this study, and their high correlation
with depressive symptoms may reflect recall bias. Although the asso-
ciation with IL-6 was not significant when controlled for depression,
and comparisons to non-MS patients should only be made with caution,
the relationship is supported by the existing literature on stressful
events and changes in IL-6 regulation in non-MS subjects both periph-
erally (Bob et al., 2010; Rohleder et al., 2012) and centrally (Lindqvist
et al., 2017). There is also a possible connection with the established
association between stressful life events and MS exacerbations (Mohr
et al., 2004). Importantly, IL-6 levels have been suggested to also in-
crease sensitivity to stress (Virtanen et al., 2015), which theoretically
could imply a central role in both activation and maintenance of a stress
cycle. In MS patients, the ability to handle stressful events, or “coping”,
has been negatively linked to such varied outcomes as depression (Lode
et al., 2009), cognitive impairment (Ukueberuwa and Arnett, 2014),
and unemployment (Strober and Arnett, 2015). We do not know if or
how exposure to interpersonal violence, especially of the low-grade


P. Brenner et al. 3V\FKRQHXURHQGRFULQRORJ\²

Table 2
Unadjusted non-parametric correlations between inflammatory markers, psychiatric ratings and covariates. Multiple sclerosis patients n = 47.

IL-6 IL-8 EDSS MADRS-S MADRS-S cognitive MFIS KIVS exposed " as child " as adult

*
Age 0.05 −0.12 0.19 −0.05 −0.16 −0.05 −0.31 −0.17 −0.21
IL-6 −0.35* 0.13 0.41** 0.38* 0.44** 0.14 0.33* 0.29
IL-8 0.09 −0.09 −0.15 −0.17 0.14 0.01 0.05
EDSS 0.39** 0.30* 0.27 0.15 0.13 0.22
MADRS-S 0.90** 0.67** 0.30* 0.25 0.37*
MADRS-S cognitive 0.65** 0.41** 0.23 0.41**
MFIS 0.14 0.13 0.14
KIVS exposed 0.80** 0.85**
" as child 0.80**

Correlation coefficent is Spearman's ρ. IL = Interleukin; MS = Multiple Sclerosis; EDSS = Expanded Disability Status Scale; MADRS-S = Montgomery-Asberg Depression Rating Scale,
Self Report version; MFIS = Multiple Sclerosis Fatigue Impact Scale; KIVS = Karolinska Interpersonal Violence Scale.
* Significant at the 0.05 level (2-tailed).
** Significant at the 0.01 level (2-tailed).

type most common in this study, differs from other kinds of stress re- Table 4
garding these mechanisms. Interestingly, although the KIVS subscales Partial, nonparametric correlations between Interleukin-6 and psychiatric symptom
were highly correlated, this study did not find an association between scales.

IL-6 levels and exposure to violence in childhood. The connection be-
tween early life adversity and inflammatory markers, including IL-6,
has been reported in several studies (Miller and Chen, 2010; Tietjen
et al., 2012), but findings are not consistent (Coelho et al., 2014).
The association between external adverse events and an immune
marker shown here in MS patients has previously been reported in
psychiatric populations, such as patients with MDD (Slavich and Irwin,
2014), and among somatic disorders such as rheumatoid arthritis
(Roupe van der Voort et al., 2000) and migraine (Tietjen et al., 2012).
For MS patients, this could have potential implications. For example,
informative biomarkers are warranted for diagnostic, prognostic or
therapeutic purposes (Housley et al., 2015), and could also be used for
treatment decisions (Harris and Sadiq, 2014). If there is an association
between external stressful events and immune system regulatory me-
chanisms as demonstrated in this study, it suggests that potential im-
mune system biomarkers must be evaluated only when known inter-
actions between psychiatric symptoms and stressful events are
considered in order not to bias their interpretation. The clinical utility
of CSF IL as biomarkers is most likely limited due to practical con-
siderations and unknown factors regulating robustness of testing and
variability due to current relapses or DMT. The negative correlation
seen here between IL-6 and IL-8 may be due a type I error, but of the
studies which have examined associations between CSF interleukins,
results have differed (Kern et al., 2014; Lindqvist et al., 2009). This may
reflect the different roles of interleukins in the immune system, but also
a problem of robusticity in sampling procedures.
The strengths of this study include a well characterized population-
based cohort of MS patients, measures of both a clinical diagnosis of
MDD and self-rated depression symptoms, measures of life-time stress
exposure, and the adjustment for current disability. However, there are
IL-6
Also adjusted KIVS adult MFIS MADRS-S
for:
MADRS-S 0.33* −0.04
KIVS, exposure to violence as 0.33* 0.26
an adult
MFIS 0.43* 0.26
All analyses are adjusted for age and sex. Correlation coefficent is Spearman's ρ.
IL = Interleukin; MS = Multiple Sclerosis; EDSS = Expanded Disability Status Scale;
MADRS-S = Montgomery-Asberg Depression Rating Scale, Self Report version;
MFIS = Multiple Sclerosis Fatigue Impact Scale; KIVS = Karolinska Interpersonal
Violence Scale, exposed.
* Significant at p < 0.05 (2-tailed).
also several weaknesses, such as that CSF sampling was not standar-
dized (i.e. regarding time of day, not performed the same day as the
psychiatric evaluation), and that the sample size was not sufficiently
large to provide enough power to detect all effects using regression
models with several covariates. The selection criteria for inclusion in
the study intended to reflect two prioritized groups of patients who
would also typically leave CSF samples in clinical practice; recently
diagnosed, relatively drug naïve patients, as well as patients who have
experienced treatment failure. This introduced some heterogeneity in
the sample regarding clinical course and treatment history. In addition,
the exclusion of subjects with a known major psychiatric diagnosis and
with psychotropic medication may have increased the validity of the
demonstrated associations with interleukins, but decreased the gen-
eralizability of the results – depression is more common in the MS
population in general than in this cohort consisting of younger and

Table 3
Partial. non-parametric correlations between inflammatory markers and psychiatric ratings. Adjusted for age. sex and EDSS.

IL-8 MADRS-S MADRS-S cognitive MFIS KIVS exposed " as child " as adult

IL-6 −0.37* 0.39* 0.38* 0.43** 0.31* 0.17 0.35*

IL-8 −0.16 −0.23 −0.23 −0.016 0.084 −0.032
MADRS-S 0.88*** 0.60*** 0.38* 0.25 0.32*
MADRS-S cognitive 0.56*** 0.43** 0.22 0.43**
MFIS 0.18 0.18 0.12
KIVS exposed 0.77*** 0.84***
" as child 0.34*

Correlation coefficent is Spearman's ρ. IL = Interleukin; MS = Multiple Sclerosis; EDSS = Expanded Disability Status Scale; MADRS-S = Montgomery-Asberg Depression Rating Scale.
Self Report version; MFIS = Multiple Sclerosis Fatigue Impact Scale; KIVS = Karolinska Interpersonal Violence Scale.
* Correlation is significant at the 0.05 level (2-tailed).
** Correlation is significant at the 0.01 level (2-tailed).
*** Correlation is significant at the 0.001 level (2-tailed).


P. Brenner et al.
relatively newly diagnosed patients. Indeed, considering previous stu-
dies on the prevalence of depression among recently diagnosed MS
patients (Janssens et al., 2003) and patients with exacerbations (Moore
et al., 2012), the rate in this cohort was unexpectedly low.
The implications for patients with longer disease duration is un-
certain. An important subject for further study is to investigate the re-
lation between stressful events, inflammatory response and long term
MS prognosis, especially since there is some evidence that such events
are associated with exacerbations in MS disease activity (Mohr et al.,
2004). The molecular basis remains to be determined, but may include
both effects mediated by adaptive, innate and glucocorticoid responses
(Mohr and Pelletier, 2006).
Lastly, this study did not include a comparison group, as the purpose
was to specifically examine these associations in MS patients. In re-
plication studies, however, groups of interest include both healthy
subjects and patients with other forms of inflammatory diseases with
psychiatric comorbidity, e.g. progressive forms of MS and systemic
lupus erythematosus, as well as patients with non-inflammatory neu-
rological diseases. MS patients and controls – healthy or with in-
flammatory and non-inflammatory CNS disease – could be compared
regarding history of exposure to violence and other premorbid stressful
life events in relation to depression and immunological parameters
involved.
5. Conclusion
We here replicate and extend earlier findings of an association be-
tween CSF IL-6 levels with depressive symptoms and exposure to vio-
lence in adult life also to RRMS patients. Further research is warranted
to replicate these findings, to investigate the role of DMT and its side
effects in the interaction between MS severity, immune mechanisms
and behavioral symptoms, and to explore the association between life
events and neuroinflammatory regulation in MS patients.
Disclosures
PB has received speaker’s fees from Novartis and unrestricted re-
search funding from Janssen AG. FP has received unrestricted academic
research grants from Biogen, Genzyme and Novartis, and his depart-
ment has received travel support and/or compensation for lectures
and/or participation in advisory boards from Biogen, Genzyme, Merck
Serono, Novartis, Roche and Teva, which have been exclusively used
for the support of research activities.
Author’s contributions
Study conceptualization: PB, FP, JJ. Data collection: PB, MG, FP, JK.
Laboratory analysis: MG, FAN, FP. Manuscript writing and review: PB,
MG, JK, FAN, FP, JJ.
Conflicts of interest
The authors declare no conflicts of interest.
Acknowledgements
Funding for this study was provided by research grants from
Genzyme, the Swedish Research Council (project numbers K2009-61P-
21304-04-4, K2009-61X-21305-01-1), the Gadelius Foundation, and
the Regional Agreement on Medical Training and Clinical Research
(ALF, PPG) between the Stockholm County Council and Karolinska
Institutet.
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