DEPRESSION AND ANXIETY 29: 32–38 (2012)

Research Article
PROINFLAMMATORY AND ‘‘RESILIENCY’’ PROTEINS
IN THE CSF OF PATIENTS WITH MAJOR DEPRESSION
Jose M. Martinez, M.A.,1 Amir Garakani, M.D.,1 Rachel Yehuda, Ph.D.,1,2 and Jack M. Gorman, M.D.3

Background: A number of studies have shown that elevated levels of

inflammatory cytokines may promote depression and suicidal ideation and that
neuroprotective peptides may decrease the response to stress and depression.
In this study, cerebrospinal fluid (CSF) levels of three inflammatory cytokines
(IL-1, IL-6, and tumor necrosis factor a (TNFa)) and two putative ‘‘resiliency’’
neuropeptides (brain-derived neurotrophic factor (BDNF) and neuropeptide Y
(NPY)) were compared between patients with depression and healthy controls.
Methods: Eighteen patients with major depression and 25 healthy controls
underwent a lumbar puncture; CSF samples were withdrawn and assayed for
IL-1, IL-6, TNFa, BDNF, and NPY levels. Patients with depression were then
entered into an 8-week treatment protocol and had repeated lumbar puncture
procedures post-treatment. Results: Contrary to prediction, we found that at
baseline depressed patients had higher CSF NPY concentration compared to the
normal comparison group. Within the depressed patients, we found several
statistically significant correlations between elevated CSF cytokine levels and
clinical severity. Conclusion: Despite the small sample size, given the challenges
in obtaining CSF from patients with depression these data are of interest in
confirming some aspects of the inflammatory hypothesis of depression.
Depression and Anxiety 29:32–38, 2012. r 2011 Wiley-Liss, Inc.

Key words: cytokines; brain-derived neurotrophic factor; cerebrospinal fluid;

neuropeptide Y; depression

neuropeptide. For example, in a sample of 256 patients

INTRODUCTION
A number of recent studies have suggested that
activation of the immune system may be involved in the
pathophysiology of major depression and of suicidal
behavior.[1–4] At the same time, several neuropeptides
have been linked to resiliency against stress and are
conceived therefore to confer antidepressant effects.
Among these are neuropeptide Y (NPY) and brain-
derived neurotrophic factor (BDNF). NPY is widely
present throughout the CNS and binds to at least four
different receptors.[5] Many clinical and preclinical
studies have found a role for NPY in the regulation of
emotional behavior and stress response.[6] Infusion of
NPY directly into the rat hippocampus produced
antidepressant-like effects (Ishida et al., 2007).[7] It
has been suggested that NPY opposes the anxiogenic
effects of CRH in the rodent brain.[8]
The role of NPY in human depression is somewhat
less clear, but may be illuminated when attention is
paid to polymorphisms in the gene encoding the
with depression, the presence of a less active NPY
allele was associated with failure to respond to
antidepressant therapy and to increased activation of
the bilateral amygdala during presentation of fearful
1
Department of Psychiatry, Mount Sinai School of Medicine,
New York, New York
2
James J Peters Veterans Affairs Bronx, New York
3
Riverdale Behavioral Health Consultants, Bronx, New York
The authors disclose the following financial relationships within the
past 3 years: Contract grant sponsor: National Institutes of Health
(NIH); Contract grant numbers: R01-MH58808; K08-MH6701.
Correspondence to: Jose M. Martinez, Department of Psychiatry,
Mount Sinai School of Medicine, One Gustave L. Levy Place,
New York, NY 10029. E-mail: jose.martinez@mssm.edu
Received for publication 29 January 2011; Revised 28 June 2011;
Accepted 5 July 2011
DOI 10.1002/da.20876
Published online in Wiley Online Library (wileyonlinelibrary.com).

r 2011 Wiley-Liss, Inc.

2 Research Article: Cytokines,Martinez
ResiliencyetProteins
faces, particularly among those patients with ‘‘anxious
depression.’’[9] Frisch et al.[10] measured NPY-positive
neuron density in 34 patients with epilepsy undergoing
temporal lobe surgery. They found a positive correla-
tion between NPY neuron density and depression and
anxiety scores in the basolateral amygdala. NPY has
also been linked to alcohol dependence and may
represent a link between emotional behavior and the
propensity for alcoholism.[11]
In studies of human cerebrospinal fluid (CSF), NPY
is reduced in depressed patients and increases with
antidepressant therapy.[12–14] Men with combat-related
PTSD had lower CSF NPY concentrations than
normal volunteers.[15] In a sample of six patients,
Nikisch and Mathé[16] reported an increase in CSF
NPY level and reduction in corticotropin-releasing
hormone (CRH) level following electroconvulsive
therapy. Olsson et al.[17] in a small sample of 7 of 13
inpatients with depression (after a recent suicide
attempt) being treated with an antidepressant, reported
a significant decrease in CSF NPY between their
second and third lumbar punctures and a decrease in
CSF substance P across the patient group.
Similarly, BDNF has been shown to induce anti-
depressant-like effects in laboratory animals and to be
reduced in the serum of depressed patients.[18,19] Chen
et al.[20] showed that BDNF concentrations were
increased in postmortem brains of depressed patients
who had been treated with antidepressants compared to
those who had not received antidepressants. Another
postmortem study found reduced BDNF mRNA level
in the prefrontal cortex and hippocampus of subjects
who had committed suicide.[21] A number of studies
have shown that antidepressant therapy increases
serum BDNF levels.[18,22] The relationship between
brain, CSF, and blood levels of BDNF is likely to be
complex. Elfving et al.[23] compared BDNF levels
between two strains of mice: the Flinders Sensitive
Line (FSL), considered to be a genetic model of
depression, and the Flinders Resistant Line (FRL).
FSL mice had higher serum, lower hippocampal, and
similar CSF BDNF levels compared to FRL mice. CSF
BDNF concentration has been reported in other
CNS diseases. Compared to normal controls, CSF
BDNF levels were found to be increased in patients
with Parkinson’s disease,[24] decreased in patients with
Alzheimer’s disease[25] and equivalent in patients with
PTSD[26] and amyotrophic lateral sclerosis.[27] To our
knowledge, there is only one known published study of
CSF BDNF concentrations in patients with depression,
a report that evaluated the CSF levels of BDNF, IL-6
and corticosterone in patients with MDD and Parkin-
son’s Disease and patients with PD or MDD alone.[28]
They reported lower levels of IL-6 and BDNF in
patients with comorbid PD and MDD compared to
those with PD alone after the PD/MDD group and
MDD group received 12 weeks of citalopram (the
patients with PD alone did not receive citalopram).
Those with MDD alone were reported to have an
Depression and Anxiety
al. and Major Depression 33
increase in CSF BDNF after the treatment with
citalopram and their pretreatment levels of BDNF
and IL-6 were higher than those with comorbid PD
and MDD.
Until the past several decades, the central nervous
system was often conceived as immunological indolent
or ‘‘spared.’’ It is now clear that this is far from true.
Major advances have been made in understanding the
biology of the brain’s main immunological cell-type,
the microglia cell.[29] Microglia serve mainly to protect
neurons and other glial cells from toxic and infectious
agents. However, microglia cells are activated by pain
and peripheral immune stimulation and when activated
can release inflammatory cytokines directly into the
brain. Hence, stress that affects both the central and
peripheral nervous systems is capable of resulting in
microglial activation and increased central cytokine
levels. Both animal and clinical data suggest that
immune system activation may be an important aspect
in the pathophysiology of depression.
A prevailing hypothesis is that peripheral immune
activation triggers cytokine synthesis and release,
which then provokes activation of brain neurotrans-
mitter and neuroendocrine systems that contribute to
depression.[30,31] This hypothesis rests in part on
several reports of immune system activation during
stress in animals and humans and in depressed patients.
Immune system activation by lipopolysaccharide injec-
tion increases inflammatory cytokine levels and causes
a syndrome of behavioral despair in laboratory
rodents.[32] Inflammatory cytokines may alter hippo-
campal plasticity in experimental animals.[33] Slavich
et al.[34] recently reported that a social-threat task
increased both IL-6 and TNF-a in a group of 124
normal volunteer subjects. Serum levels of IL-6
increased more in response to the Trier Social Stress
Test in men with major depression and a history of
early life stress than in normal volunteers.[35] IL-6
levels also increased more during the Trier test in
nondepressed adults with a history of childhood
maltreatment compared to adults with no such early
life history.[36]
It is unclear to what degree findings of increased
peripheral levels of inflammatory cytokines in de-
pressed patients are related to chronic stress versus
depression itself. For example, in one study IL-6 levels
were increased only in patients with major depression
and post-traumatic stress disorder but not in patients
with major depressive disorder alone.[37] On the other
hand, serum levels of the anti-inflammatory marker
IL-1 receptor antagonist were also found in a group
with elevated depression symptoms.[38] Treatment with
antidepressant medication has been shown to reduce
levels of inflammatory cytokines,[39,40] and this effect
may only occur in patients whose depression responds
to medication.[41] In fact, response to SSRI antidepres-
sants may in part be mediated by polymorphisms on
the gene encoding IL-6.[42] Both depression[43] and
elevated serum levels of IL-1 and TNF-a[44] may be
Depression and Anxiety
34 Research Article: Cytokines,Martinez
ResiliencyetProteins
risk factors for Alzheimer’s disease. Elevated inflam-
matory markers may be independent contributors to
the excess in cardiovascular disease morbidity seen in
some studies of patients with depression.[45]
There has been considerable discussion in the
literature about potential mechanisms by which per-
ipheral cytokines may influence the central nervous
system. Cytokines cannot by themselves cross the
blood–brain barrier.[46] However, several hypotheses
have been advanced to explain the relationship between
the peripheral and central immune systems,[46–48]
including: (1) Passive transport through areas of the
brain that lack a blood–brain barrier; (2) activation by
peripheral cytokines of receptors on pathways that
signal the synthesis and release of cytokines by the
CNS, such as those on the vagus nerve that terminate
in the NTS. Cytokines are known to be secreted de
novo in the brain by microglia, astrocytes and, under
some circumstances, neurons; (3) binding of peripheral
cytokines to receptors in the brain vascular endothe-
lium, triggering the release of secondary messengers
that provoke a central immune response; (4) release
from peripheral macrophages that can traverse the
blood–brain barrier; (5) transport of peripheral cyto-
kines into the brain by active carriers; and (6) activation
of CRH containing terminals located outside the
blood–brain barrier that can then lead to increased
CRH activity within the brain.
Only a few studies have examined cytokines in the
CSF of patients with depression. Over a decade ago, a
study involving 13 unmedicated hospitalized patients
with depression and 10 normal volunteers found that
IL-1b levels were higher in the CSF of depressed
patients, but IL-6 levels were lower and there was no
difference between groups in TNF-a level (Levine
et al., 1999). Lindqvist et al. (2009) found elevated CSF
IL-6 levels in suicide attempters compared to normal
controls and a significant positive correlation between
MADRS scores and CSF IL-6 levels in the patients.
Interestingly, in this study there was no relationship
between serum and CSF cytokine levels. Bonne et al.
(in press) found no significant difference of pretreat-
ment concentrations of CSF corticotrophic-releasing
factor, IL-6, BDNF, or substance P in chronic PTSD
patients compared to healthy controls, post-treatment
CSF measures did not change significantly. A recent
report from Brundin et al. at the Lund University that
is as yet unpublished found ‘‘high levels of inflamma-
tion-related substances (cytokines) inyspinal fluid’’ of
patients ‘‘who had been diagnosed with major depres-
sion or who had made violent suicide attempts’’ (URL:
http://www.fiercebiotech.com/press-releases/biologi-
cal-changes-suicidal-patients).
In this study, we took advantage of unused CSF
samples from a study originally designed to investigate
the role of the thyroid hormone transport protein
transthyretin to compare the levels of three inflamma-
tory cytokines (IL-1, IL-6, and TNF-a) and two
putatively protective neuropeptides (brain-derived
Depression and Anxiety
al. and Major Depression 3
neurotrophic factor and NPY) between patients with
major depression both before and after antidepressant
therapy and a normal comparison sample. We sought
to measure both cytokines and ‘‘resiliency peptides’’
(BDNF and NPY) in CSF with the expectation that the
former would be elevated in patients with depression
compared to healthy controls and that the latter would
be lower.
MATERIALS AND METHODS
Subjects for this study were patients with DSM-IIIR defined major
depressive disorder and comparison subjects with no current
psychiatric illness. All subjects underwent a thorough medical
evaluation prior to baseline testing. This included a physical
examination, neurological examination with visualization of the
fundi; blood tests for routine chemistries, T3, T4, TSH, CBC, and
pregnancy test; urinalysis; urine screen for substances of abuse and
EKG. All subjects had a psychiatric evaluation and SCID to confirm
r
diagnosis.
In addition to meeting major depression criteria, depressed
subjects had to have a Hamilton Depression Rating Scale score of
greater than 15, indicating at least moderate severity. Exclusion
criteria for the depressed patient group were history of bipolar
disorder or schizophrenia, history in the past year of substance abuse
or dependence, panic disorder, obsessive compulsive disorder or
eating disorder, any history of thyroid disease, significant medical
disorders or use of medications that may distort study measures,
significant history of clinical depression that is treatment refractory
and unlikely to respond to standard clinical care and pregnant
women. Healthy controls needed to have a Hamilton Depression
Scale score of less than 8. Healthy controls were excluded if they met
a history of major depressive disorder, bipolar disorder, schizo-
phrenia, panic disorder, obsessive compulsive disorder, eating
disorder, or substance use disorder, any history of thyroid disease
or use of thyroid medication, significant medical disorder or the use
of medication that would distort study measures and pregnant
women.
All subjects were maintained free of psychotropic medication for
2 weeks (6 weeks for fluoxetine) prior to study. As-needed use of
benzodiazepine anxiolytics or hypnotics, such as zolpidem and chloral
hydrate, was permitted.
After 2 weeks of being medication-free and after an overnight fast,
a lumbar puncture was performed between the hours of 8 and 9 a.m.
Ten cc. of CSF were withdrawn and aliquoted in 1 cc portions. CSF
aliquots were stored at 701C until assay. Patients with depression
were then entered in the 8-week treatment protocol.
Standards enzyme-linked immunosorbent assay (ELISA) were
used with a lower limit of detection around 10–15 pg/ml, translating
to roughly an absorbance of 0.01. If a level was not detected it was
recorded as zero. Assays were run in a blinded fashion so that the
identities of the samples (patient or control) were not known.
All patients were started on extended release venlafaxine 37.5 mg
daily. Treatment consisted of a fixed flexible dose regimen with a
minimum target dose of 225 mg per day and a maximum dose of
375 mg. Dose escalation above 225 mg daily occurred after 4 weeks
for patients who were nonresponsive at this dose. For patients who
did not tolerate 225 mg daily, we permitted dose reduction to 150 mg
daily. The following rating scales and measures were obtained weekly
throughout the study: the Hamilton Depression Rating Scale,
Clinical Global Severity Scale, and Clinical Global Improvement
(CGI) Scale. Suicide ideation occurring in the 2 weeks preceding the
lumbar puncture procedure was measured using the Scale for Suicide
Depression and Anxiety
4 Research Article: Cytokines,Martinez
ResiliencyetProteins
al. and Major Depression 35

Ideation (SSI).[49] Suicide attempt was defined as a self-destructive act t 5 2.9, df 5 22.0, Po.007). There were no statisti-
with some degree of intent to end one’s life. Details of suicide cally significant differences at baseline between groups
attempts, including documentation of the number, method, and for BDNF, IL-1, IL 5 6, or TNF-a (Table 2).
lethality rating of attempts, were recorded using the Columbia After 8 weeks of treatment with venlafaxine patients
Suicide History Form.[50] At the conclusion of the 8-week treatment with depression experienced statistically significant
protocol and while still taking venlafaxine, the patients underwent
improvements in HAMD, CGS, and SSI scale scores
repeated lumbar puncture and blood draw for all measures listed
during baseline testing. (Table 1). However, there were no significant changes
The differences between patients and comparison subjects for all between pre- and post-treatment time points in any of
continuous measures were calculated using standard t-tests or the CSF measures (Table 3).
Mann–Whitney U Test. Differences within the patient group between Correlation coefficients between clinical severity and
the pre- and post-treatment tests were calculated using Wilcoxon CSF measures showed that among patients at baseline
Signed Rank Test. Correlations were calculated using Pearson’s there were statistically significant positive correlations
coefficients. Significance levels were set at Po.05, two tailed. Sample between CSF IL-1 concentration and history of suicide
sizes vary for the different measures because of missing data. attempts (r 5 .53, P 5.041, N 5 15) and between CSF
The research was approved by the Internal Review Boards of BDNF concentration and SSI score (r 5 .62, P 5.033,
Columbia University and Mount Sinai School of Medicine and all
N 5 12). After treatment there were significant positive
subjects signed written, informed consent forms prior to participation.
correlations between CSF IL-6 concentration and SSI
scale (r 5 .85, P 5.008, N 5 8) and between CSF TNFa
concentration and SSI scale (r 5 .81, P 5.008, N 5 9).
RESULTS Finally, there was a significant positive correlation
The 18 patients with major depression included 8 between baseline CSF TNFa and post-treatment CGI
males and 10 females with a mean age of 40.4 years score (r 5 .68, P 5.030, N 5 10).
(710.0), while the 25 nondepressed comparison
subjects included 13 males and 12 females with a mean
age of 29.9 years (76.7). The difference in age between TABLE 1. Comparison of behavioral measures pre- and
the two groups was statistically significant (t 5 4.1, post-treatment
df 5 41, Po.00). Body Mass Index between the two
groups was not significantly different (healthy controls Pre- Post- Paired
had a mean BMI 5 24.4 and MDD patients had a mean Variable treatment treatment sample test
BMI of 24.1). None of the healthy control subject HAM-D 19.273.8 10.674.3 t 5 5.78; Po.001; df 5 12
smoked, among the depressed patients two were CGS 4.370.5 3.371.4 t 5 2.87; Po.015; df 5 11
light smokers (less than 10 cigarettes/day, 2 were Suicide index 1.872.4 0.771.4 t 5 2.42; Po.032; df 5 12
moderate smokers (between 10 and 20 cigarettes/day)
and the remainder did not smoke. At baseline, CGS, Clinical Global Severity Scale; HAMD, Hamilton Depression
depressed patients had mean scores on the Hamilton Scale.
Depression Scale (HAMD), Clinical Global Severity
Scale (CGS), and SSI of 19.273.8 (N 5 13), 4.370.50
TABLE 2. Comparison of baseline biological variables
(N 5 12), and 1.872.3 (n 5 13), respectively (Table 1). between depressed patients and controls
After treatment with venlafaxine, the patients CGI
scale score was mean 2.3370.99, n 5 12. Of these 12, VariablePatients Healthy controls Mann–Whitney U test
two had no clinical change, two experienced only
minimal improvement, and eight met criteria for BDNF 4.2871.88 4.8672.22 NS
IL-1 0.07370.022 0.06470.004 NS
improvement by CGI criteria of much better or very
IL-6 0.06670.010 0.06070.007 NS
much better (two or one). TNF-a 0.10570.113 0.09570.057 NS
At baseline, before antidepressant treatment, de- NPY 176.13747.26 137.66724.14 Po.031
pressed patients (N 5 16) had significantly higher CSF
concentration of NPY than comparison subjects BDNF, brain-derived neurotrophic factor; IL, interleukin; TNF,
(N 5 17) (176.1747.3 pg/ml versus 137.7724.1 pg/ml; tumor necrosis factor; NPY, neuropeptide Y.

TABLE 3. Comparison of pre- and post-treatment biological measures in depressed patients

Variable Pre-treatment Post-treatment Wilcoxon signed ranks test

BDNF (n 5 12) 4.0372.030 4.4972.005 NS

IL-1 (n 5 9) 0.07870.027 0.06970.012 NS
IL-6 (n 5 8) 0.05970.004 0.09170.070 NS
TNF-a (n 5 9) 0.07870.035 0.07570.023 NS
NPY (n 5 10) 187.01740.23 179.68753.97 NS

BDNF, brain-derived neurotrophic factor; IL, interleukin; TNF, tumor necrosis factor; NPY, neuropeptide Y.

Depression and Anxiety Depression and Anxiety

36 Research Article: Cytokines,Martinez
ResiliencyetProteins
DISCUSSION
The study reported here has many obvious short-
comings, primary among which are the small sample
size, the fluctuating sample sizes among various
measures because of missing data, and the lack of a
second lumbar puncture from the normal comparison
subjects, which would have enabled us to have a better
picture of whether there was any ‘‘normalization’’ of
CSF indices in patients following antidepressant
treatment. It is also never clear to what extent the
level of any neuropeptide or neurotransmitter in the
CSF reflects its actual activity at critical synaptic and
cellular levels. Finally, there is a statistically significant,
nearly 10-year age difference between patients and
comparison subjects. Although this may affect the
results we obtained in the comparison of baseline NPY
concentrations between the two groups, it should not
be relevant to the significant correlations we observed
within the patient group.
Nevertheless, given the well-known difficulties of
obtaining CSF samples from patients with psychiatric
illnesses, we believe that these data are worth reporting,
even though some of the results are not in the predicted
direction. First, we found an unexpectedly higher CSF
NPY concentration in patients than comparison
subjects at baseline and did not detect any significant
increase in NPY concentration with antidepressant
treatment as has been reported before. Although these
data support the notion that NPY may be involved in
the pathophysiology of depression, they are equivocal
as to its role in promoting ‘‘resiliency.’’ One could, of
course, speculate that higher NPY levels in depressed
patients represent an adaptive change to the illness.
Similarly, the positive correlation between baseline
CSF BDNF concentration and severity of suicidal
ideation appears, like our NPY finding, to be the
opposite of what would be expected if BDNF is indeed
a ‘‘resiliency’’ neuropeptide.
Second, we found several positive correlations
between CSF inflammatory cytokine concentrations
and clinical measures. The significant correlations
must be taken into context with the fact that we
preformed multiple tests of correlation, most of which
were not statistically significant. The relationship
between baseline IL-1 concentration and history of
suicide attempts appears to be in keeping with the
general notion that inflammatory cytokines are asso-
ciated with severity of depression and suicidal idea-
tion.[51] Similarly, the significant correlations between
IL-6 and TNFa concentrations collected from patients
at the second lumbar puncture when they had been
receiving venlafaxine and score on the suicidal ideation
scale are also compatible with the inflammatory
cytokine theory, although it is unclear why these same
relationships were not statistically significant at base-
line, before treatment.
Third, the significant positive correlation between
baseline TNFa concentration and post-treatment CGI
Depression and Anxiety
al. and Major Depression 5
suggest that the former is a predictor of poor treat-
ment outcome, as high CSF TNFa before treat-
ment predicted poorer response to antidepressant
medication.
CONCLUSION
Although some of the findings from these analyses of
CSF indices in depressed patients may seem counter-
intuitive, in general they support the hypotheses that
inflammatory cytokines may play a role in depression
and that both NPY and BDNF are dysregulated in
patients with depression. These appear to be research
avenues well worth pursuing.
Acknowledgments. The authors acknowledge
Dr. Lloyd Mayer, for his help with the assay of CSF
samples. The authors declare that they have no
r interest relevant to this manuscript.
conflicting
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