Association of Interleukin-6 and Other Biologic Variables
with Depression in Older People Living in thkommunity
Andrew N. Dentino, MD,' Carl F. Pieper, DrPH,' K. Murali K. Rao, MD,* Mark S. Currie, MD,*
Tamara Harris, MD, MS,f Dan G. Blazer, MD,* and Harvey Jay Cohen, MD'
OBJECTIVES: The prevalence of depression increases with
age, as does the prevalence of higher levels of the cytokine
interleukin-6 (IL-6). This analysis was performed to deter-
mine the association between increased levels of this cytokine
and depression in a population-based sample.
DESIGN: Cross-sectional cohort study.
SETTING: Rural and urban counties in North Carolina.
PARTICIPANTS: Community-dwelling older people.
MEASUREMENTS: The association between IL-6 and other
biologic variables with self-report depression was examined
in 1686 persons aged 70 years and older in the third in-person
survey wave (1991) of the Duke Established Population for
Epidemiologic Studies of the Elderly (EPESE).Bivariate asso-
ciations were established by the Spearman correlation, ad-
justed for age. A stepwise linear logistic regression model was
used to derive a final model to assess multivariable effects on
CES-D scores.
RESULTS: Depression was correlated with IL-6 (P = . O l l ) ,
D-Dimer (P = .017), alpha-1-globulin (P = .023), alpha-2-
globulin (P = .002), and beta globulin (P = .012). After
controlling for age, race, and gender, IL-6 levels remained the
only biologic variable significantly associated with depres-
sion (P = .035).
CONCLUSION These data suggest that the inflammatory
marker, IL-6, is associated with depression in older people in
this cross-sectional study. These results are compatible with
the hypothesis of cytokine (IL-6) stimulation in geriatric
From the 'Center for the Study of Aging and Human Development, Claude D.
Pepper Older Americans Independence Center, Duke University Medical Center,
Durham, North Carolina, and the Geriatric Research Education and Clinical
Center (CRECC),Veterans Administration Medical Center, Durham, North
Carolina; and the +Epidemiology, Demography, and Biometry Program, Na-
tional Institute on Aging, Bethesda, Maryland.
The research upon which this publication was based was performed pursuant to
Contract No. NO1 AC-1-2102 with the National Institute on Aging in support
of Established Populations for Epidemiologic Studies of the Elderly (Duke). It
was also supported, in part, by the National Institutes of Health, National Insti-
tute on Aging, Claude D. Pepper Older Americans independence Centers, Grant
no. 5 P60 AG11268.
The content of this publication does not necessarily reflect the views or policies
of the U.S. Department of Health and Human Services.
Address correspondence to Harvey Jay Cohen, MD, Box 3003, Duke University
Medical Center, Durham, N C 27710.
JAGS 4E6-11,1999
0 1999 by the American Geriatrics Society
depression as part of an overall immunoendocrine dysregu-
lation. J Am Geriatr SOC476-11, 1999.
M ajor (or clinical) depression is among the most com-
mon medical conditions of the population,' with a
diagnosable depressive spectrum disorder affecting up to
one-eighth of the US population at some point during their
lives, including up to 20% of US women? It is one of the
major components of comorbidity in the context of a medical
i l l n e ~ sit, ~is diagnosed in 25 to 40% of the new patients of all
ages presenting to primary care providers," and it is a major
contributor to the nation's overall social cost because of lost
work and decreased productivity.'
Depression is an important health problem in older
people. Its prevalence is greater in older than in younger
persons, and older depressives have greater medical comor-
bidity, pain, and functional limitations when compared with
younger depressives.6 A frequent accompanying symptom of
major depression, substantial weight loss, may be more dan-
gerous in older people' because this weight loss may indicate
an increased risk of malnutrition, adverse medication inter-
actions and toxicity, infection, and death.8
The inflammatory cytokines, primarily macrophage
products that were first identified as part of the acute phase
response to bacterial infection but have been shown to be
associated with other health conditions common in old age,'
have been shown to possess multisystemic effects." These
may include fever, lethargy, slow wave sleep, anorexia, and
corticotropin-releasing hormone production." It is notable
that these are the same pathophysiologic phenomena seen
commonly during the development and maintenance of the
symptoms of depression.12
These effects are believed to occur through stimulation of
the hypothalamic-pituitary-adrenal (HPA) axis, with IL-6
having stimulatory effects on each of these three organs
independently and in seriesl3-I6 (Figure 1).Furthermore, it is
also known that stress is a strong inducer of these cyto-
kines." In clinical samples, positive correlations with depres-
sion have been noted both in assays of subjects' circulating
cytokine levels and in culture supernatant assays of mitogen-
stimulated peripheral leukocytes cultured in vitro from af-
fected individual^.'^^'^^'^ Other indicators of inflammation
associated with depression include C-reactive protein, the
white blood cell transferrin, the globulins, haptoglo-
0002-8614/99/$3.50
IAGS IANUARY 1999-VOL. 47. NO. 1 IL-G AND DEPRESSION IN OLDER COMMUNITY DWELLERS 7

METHODS
Sample
The general description of the study sample has been
reported elsewhere.24 Begun in 1985, the Duke (or Piedmont)
EPESE has created a longitudinal database for the study of
TNF CRH community-dwelling older people. It comprises individuals
(+I living in a five-county area surrounding and including
Durham, North Carolina, in a mix of near equal proportions
of urbadrural and black/white participants. The first survey,
XRT
in 1985-1986, resulted in a sample of 4162 s~bjects.~’ Par-
BDz EIC SMT TNF
ticipants received in-person interviews every 3 years, with
RU486 E-BDz-1 yearly telephone interviews taking place between each in-
person wave of the survey. The entire EPESE survey instru-
ment covers a wide variety of personal health and well-being
MPhaee ITUTTARY characteristics, personal medical history inventory, and life-
style questions, as well as various physical measures such as
ACTH weight and blood press~re.~’
In 1992, during the third in-person follow-up wave of
(-) (+) the Piedmont EPESE, 2569 remaining living cohort members
IL-2 ANTI-CRH LPS were visited in their homes, and requests were made for
TNF IL-8 IND XRT informed consent to draw blood. Of these study participants,
CRII 269 persons were deemed to require proxies for their contin-
RU486 ued participation in the overall EPESE study (the vast major-
ity due to cognitive impairment). Their blood was not drawn,
and these persons were excluded further from this analysis.
Of the remaining 2300 persons who were deemed not to
require proxies (and were, therefore, able to provide con-
LPS, TNF, ACTH, STRESS
sent), 573 (24.9%)did not have blood drawn (due to sub-
ject’s refusal, unusable samples, or presence of a disease
condition precluding phlebotomy). The non-blood draw
CORTISOL ~ older (mean age 77.5 vs
group, as described e l s e ~ h e r e ?was
Figurc 1.Immunoendocrine dysregulatory, or Positive Feedback, 76.6 years, respectively), contained more women (78.0 vs
model of major depression. Abbreviations: LPS = lipopolysac- 65.0%) and blacks (57.8 vs 52.3%),and had poorer Instru-
charide; XRT = ionizing radiation; cachectic dz. = cachectic mental Activities of Daily Living (IADL) and self-rated health
diseases; RU486 = mifepristone; DEX = dexamethasone; scores (percentages not shown). However, this group was not
IND = indomethacin; EIC = eicosanoids; BDZ = benzodiaz- different from the final sample regarding education (8.8 vs 9.0
epines; E=BDZ-I = endogenous benzodiazepine inhibitor; years) or percentage of persons with cognitive impairment
SMT = somatostatin; HTH = hypothalamus; CRH = (12.4 vs 15.0%) or depression (8.8 vs 10.2%).24
corticotropin-relasing hormone; ANTI-CRH = anti- Of the 1727 individuals who did consent to have their
corticotropin-relasing hormone; IMIP = imipramine; TNF =
tumor necrosis factor; HYPOGLY = hypoglycemia; ACTH = blood drawn (of whom 65% were female, and 53% were
adrenocorticotropic hormone; IL-1 = interleukin-1; IL-2 = black), 41 persons (2.7%of this total, of whom 65% were
interleukin-2; IL-6 = interleukin-6. female, and 72% were black) did not answer all questions
pertaining to the modified CES-D1.26 used in the EPESE. This
left 1686 subjects (97.6% of this total, of whom 65% were
female and 52% were black) with complete demographic,
bin, albumin, serum total protein, prolactin, cortisoIy1’ and blood, and depression data. This group included 287 white
tryptophan.21 men, 303 black men, 519 white women, and 577 black
The Duke Established Populations for Epidemiologic women.
Studies of the Elderly (EPESE) is a randomly selected,
population-based At the time of the sixth Mcasurcs
follow-up survey of the study, blood samples were drawn Demographic and medical variables included weight
from 1727 consenting members of this cohort. This allowed change, body mass index, self-rated health, life satisfaction,
for an assessment of the associations between biomarkers, current smoking status, and history of cancer, arthritis, myocar-
aging, medical status, and functional status issues in this dial infarction, cerebrovascular accident, diabetes mellitus, hip
group of older people. In this population, IL-6 increases with fracture, any fracture, and hypertension. Self-reported weight
age and is associated with poorer health and functional change was analyzed on the basis of self-reported weight at the
status.z4 third in-person survey minus self-reported weight at the first
The primary hypothesis of this study was that IL-6, a in-person survey. Functional status instruments included the
proinflammatory cytokine, and other markers of inflamma- Katz, Rosow-Breslau, Nagi, and Instrumental Activities of Daily
tion (white blood cell count, albumin, globulins, D-Dimer) Living measures, as reported in previous studies on this co-
would be associated positively with depression. h ~ r t . ~ ~The
. ‘ ~Short Portable Mental Status Questionnaire
8 DENTINOETAL. JANUARY 1999-VOL. 47, NO. 1 JAGS

(SPMSQ)was the measure of cognitive function, with a cutoff of ~ ~~

three errors indicative of significant cognitive Table G i v a r i a t e S t a t i s t i c s f o r Selected Variables, Duke

The CES-D score, a self-report index of depressive symp- EPESE, 1991
toms developed by the Center for Epidemiologic Studies of Standard
the National Institute of Mental was used as the Variable Mean Deviation
outcome variable for depression. A modified version of this
instrument (using only yesho responses) was employed for Age (years)* 77.6 5.41
this geriatric sample.’ A value of 9 on this instrument was Education (years)* 9.01 4.04
used as the cutoff point for dichotomization into depressed (modified)’ CES-D score** 2.81 3.50
versus nondepressed groups. The continuous variable of the SPMSQ score 1.69 1.76
CES-D score was also used for some analyses. IL-6 (pg/mL) 2.98 7.20
Biological variables included: IL-6; D-dimer; plasma D-Dimer (ng/mL) 300.24 393.23
protein electrophoretic profile of: globulin fractions alphal, Protein (g/dL) 6.59 2.19
alpha,, beta and gamma; albumin; a1bumin:globulin ratio; Albumin (g/dL) 4.01 0.80
total protein; and hematologic measures (hemoglobin, white Alpha-1-globulin (gs/dL) 0.30 0.1 7
blood cell count with differential and platelet count). Alpha-2-globulin (gs/dL) 0.73 0.1 8
Beta-globulin (gs/dL) 1.oo 0.20
Laboratory Methods for Measurement of Gamma-globulin (g/dL) 1.02 0.41
Biologic Variables White cell count (x1000 cells/mm3) 5.93 3.20
For biologic variable measurements, blood was collected Neutrophils ( X l 000 cells/mm3) 3.53 1.97
in EDTA-containing vacutainer tubes, placed on ice, and Lymphocytes (x1000 cells/mm3) 1.77 0.99
taken to the laboratory where it was centrifuged and the Basophils (X 1000 cells/mm3) 0.30 0.05
plasma promptly frozen at -70°C in .5 mL a l i q ~ o t s . 2Albu-
~ Eosinophils ( X l 000 cells/mm3) 0.16 0.14
min and globulins were measured by rotein electrophoresis, Monocytes (x1000 cells/mm3) 0.38 0.1 8
and D-Dimer by ELISA (DimertesJM Stripwell EIA Kit,
note 1: *n = 1732; **n = 1681;all others: n = 1727.
American Diagnostica, Greenwich, CT), as described previ- note 2: ‘after a value indicates P < .OS; **indicatesP < .01;***indicatesP <
White blood counts were measured using a coulter .001.
counter at Nichols Institute (San Juan Capistrano, CA).
Plasma IL-6 was measured by ELISA (Quantikine, R&D
Systems, Minneapolis, MN)?4*29 alpha-2- and beta-globulins. Despite a large sample, no other
biologic variable was significantly associated with depres-
Analytic Techniques
sion. Several other study variables were also significantly
All statistical analyses employed the SAS Statistical Pack- positively correlated with depression, including the medical
age (Cary, NC).31 Univariate (descriptive) statistics were first histories of stroke, fracture, and arthritis. The physical mea-
derived for the population under study. Bivariate relation- sure of diastolic blood pressure was significantly negatively
ships of the demographic, medical and biological variables correlated with depression, as were all functional status mea-
were then related to the continuous CES-D variable by Spear- sures and personal well-being and self-rated health indices.
man rank correlation coefficients. If any bivariate relation- Table 3 shows the results of the stepwise linear logistic
ship was statistically significant, it was then entered into regression model. This final model for CES-D scores showed
subsequent multivariable analyses. A stepwise linear logistic independent significant positive associations with female gen-
regression was then derived with variables allowed to enter at der ( P = .0010) and log IL-6 ( P = .042) and significant
an alpha of .05.” Age, sex, and race were controlled in this negative associations with education (P = .0001), self-rated
modeling. Since IL-6 showed a strong right-sided skew, a health (P = .OOOl), life satisfaction (P = .0001), Nagi score
logarithmic transformation of this variable was performed. ( P = .0001), and Katz ADL score ( P = .0169).
All biologic variables other than the categorized transforma-
tions of IL-6 were analyzed as continuous variables. , High IL-6 Levels and Depression in the Presence of
Weight Loss
RESULTS
Weight loss is common both in depression and in older
General Results people, regardless of depression.8 In order to look at the
Table 1 presents the means and standard deviations for specificity of the depression, IL-6, weight loss relationship,
the variables in this study. The bivariate (uncontrolled) rela- we performed secondary analyses of the association between
tionships between depression and other study variables are depression and high IL-6 levels with respect to subjects’
presented in Table 2. In this sample, 148 persons overall (9% weight changes between surveys. In this sample (Table 4), of
of total) met the criteria for depression by CES-D (score those having determinations of depression, self-reported
greater than 8 of 20). Age, but not race, was associated weight loss, and IL-6,955 lost weight, and 731 maintained or
significantly with the presence of clinical depression. Gender gained weight between the two surveys. Among those who
was associated significantly with depression, with a higher had lost weight, 22% of the subjects with high IL-6 (>5
proportion of women than men endorsing nine or more pg/mL) were depressed compared with 12% of those with
symptoms on the modified CES-D ( P = .0076). lower IL-6 ( P = .01). Among those who had maintained their
As can be seen in Table 2, several biological variables weight, there was no significant difference in the percentage
were significantly positively correlated with depression in the of those who were depressed in the high (10%)or low (8.5%)
bivariate analyses, including IL-6, D-Dimer, alpha-1-, IL-6 groups.
JAGS JANUARY 1999-VOL. 47, NO. 1 IL-6 AND DEPRESSION IN OLDER COMMUNITY DWELLERS 9

Table 2. Correlations With Depressiont in the North Carolina Table 3. Stepwise Linear Logistic Regression on CES-Dt Scores:
EPESE Dataset Final Model'

Correlation with CES-Dt

Depression Variable (Odds Ratio)
Variable (Spearman's rho)
Age 1.005
Demographic Gender (female) 1.684**
Age (years) 0.06* Race (black) 1.098
Race 0.02 Education 0.912"**
Gender 0.07** Log IL-6 1.377
Education -0.1 o*** Self-rated health 0.404"*
BioIogic Life satisfaction 0.273***
loglL6 (pg/mL) 0.06* Nagi score 0.51 O***
D-Dimer (ng/mL) 0.06* Katz ADL score 0.663*
Protein (g/dL) -0.01
note 1: age, sex and race included in all m o d e h g .
Albumin (g/dL) 0.04 note 2: 'after a value indicates P < .05; "indicates P < .Ol; ***indicates P <
Alpha-1 -globulin (g/dL) 0.06* .001.
Alpha-2-globulin (g/dL) 0.07'" note 3: t = modificd C E - D Scores 2 9.
Beta-globulin (g/dL) 0.06*
Gamma-globulin (g/dL) 0.04
White blood cells (per mm3) 0.01 Table 4. Weight Loss, Depression, and IL-6
Polys (per mm3) 0.01
Lost Weight Maintained Weight
Lymphocytes (per mm3) -0.03
% Depressed (n) % Depressed (n)
Basophils (per mm3) -0.01 _ _ _ ~ ~

Eosinophils (per mm3) -0.01 Hi 11-6 B 5.0 pg/mL 22% (88) 10% (60)
Monocytes (per mm3) 0.01 Lo IL-6 < 5.0 pg/mL 12% (867) 8.5% (671)
Medical History P = .010 P = .638
Heart attack 0.05
Stroke 0.05*
Cancer -0.02
Broken hip 0.03 the relationship of plasma IL-6, D-dimer, and other blood
Broken bone 0.06* markers with depressive symptoms in a population-based
Diabetes -0.02 sample. Other health-related associations of depression were
Arthritis 0.1o*** chosen because of the number of reports suggesting immuno-
High blood pressure 0.04 logic links with depression when accompanied by weight
Weight loss (last year) -0.02 loss.
Smoker (current) -0.0001 In our study, the cytokine interleukin-6 was associated
Physical measurements independently with depression, i.e., high IL-6 levels were
Blood pressure (mmHg) associated with depression. These results are consistent with
Systolic -0.02 other studies of cytokines and acute phase reactants and
Diastolic -0.06* * ~ ~ -et~ al.
d e p r e ~ s i o n . ' ~Seidel ~ employed whole blood assays,
Body Mass Index -0.01 at time zero and at 6 weeks after initiating antidepressant
Self-ratingdfunctional status treatment, and found that mitogen-induction of interleukins
Self-health rating -0.23*** in patients was increased at time zero over controls and
Life satisfaction rating -0.21*** decreased over time with treatment.I2 Maes et al., in a series
Katz ADL score -0.1 5*** of reports on this topic, have found increased interleukin and
InstrumentalADL score -0.10"** certain acute phase protein levels in various subsets of de-
Nagi score -0.18*** pressed individuals. Strikingly, these investigators have cor-
Rosow-Breslau score -0.20*** related with increases in interleukins along the worsening
Mental status spectrum of affective illness, from minor depression to major
SPMSQ score 0.1 1*** depression to major depression with melancholia. This adds
Cognitive impairment (from SPMSQ) 0.06* further support to the hypothesis that certain subjects with
melancholia may possess quantifiable immunoendocrine dys-
t = modified CES-D' zz 9. regulation, causing various somatic symptoms commonly
note: *after a value indicates P < .05;**indicates P < .01; "*indicates P <
,001. found in this d i ~ o r d e r . ~ ~ - ~ ~
However, all of the above studies were in clinical (pa-
tient) populations. The study presented here is the first
DISCUSSION community-based report associating IL-6 and depressive
Various biologic markers, including proinflammatory symptoms in older people. The pathophysiologic mechanism
cytokines, white blood cell count, albumin, the globulins, and postulated for this association (Figure I), similar to that of
other blood markers,12J8*20*21 have been hypothesized to be clinical studies, is one of an immunoendocrine dysregulated
associated with depression. This report is the first to explore state, wherein stress causes excess IL-6 production, which in
10 DENTINOETAL.
turn incites CRH production, resulting in HPA system acti-
vation and hypercortisolemia, which may contribute to de-
pression by an as yet undetermined impact on particular
neural pathways. This hyperfunctional adrenal state then
drives even greater elaboration of T-lymphocyte and macro-
phage products such as TNF, IL-1 and IL-6, which further
drives the ‘forward feedback‘ aspect of this cycle.37 This
dysregulated state may not be operative in all cases of depres-
sion; however, recent reports have looked at “HPA overac-
tive” versus “HPA nonhyperactive” depressed patients (for
example utilizing the combined dexamethasone suppression
test/CRH stimulation test protocol):’ who respond differ-
ently to traditional antidepressant treatment (for example
tricyclic antidepressants). These HPA overactive patients
might also be that subgroup of persons within a depressed
population who possess high IL-6 levels because IL-6 is a
primary inducer of CRH. We have previously suggested that
new therapies directed to reduction of IL-6 level might be
useful in the treatment of depre~sion.~’
It is interesting in this regard that we recently reported
that higher levels of religious activity, which have been asso-
ciated with lower levels of depression, are also independently
associated with lower levels of IL-6.39 It is also possible that
depressive symptoms are precipitated by biologic disorders
associated with IL-6 elevation, such as subclinical inflamma-
tion and multifactorial functional decline. Moreover, since
these are not mutually exclusive of age-related immunologic
dysregulation discussed above, both mechanisms may play an
important role.
Another suggestion that subpopulations of persons with
depression may be affected differentially is found in our
report of the stronger association between depression and
high IL-6 levels in persons with weight loss than in those
without weight loss. Furthermore, there was no association
between weight loss and depression, which suggests against
IL-6 being a surrogate marker for weight loss attributable to
other causes, in depressives in this sample. The independent
bivariate association between high IL-6 levels and weight loss
is in agreement with the consensus of the current literature on
this to pi^."*^' Additionally, as there may be many causes for
weight loss in an older p o p ~ l a t i o nthe
, ~ ~lack
~ of an indepen-
dent bivariate association between depression and weight
loss is not unanticipated. However, the significant comple-
mentary association between depression and high IL-6 in
persons with weight loss, though not in persons who main-
tained their weight in this study, suggests that high IL-6 levels
may be more specific to these depressed individuals with
weight loss than to depressives in general.
The somatic equivalents of major depression, especially
in older people, are protean and comprise some of the most
frequent major symptomatic determinants of this diagnosis,
most notably in the realm of melancholia?’ Weight loss in
and of itself is well known to be a very strong independent
predictor of mortality in older people,’ with major depres-
sion being the primary cause for weight loss in one commu-
nity nursing home ample.^ Cytokines have been linked to
weight loss. Experimentally, for example, a continuous infu-
sion of intravenous TNF (also known as cachectin), another
proinflammatory cytokine, leads to anorexia, weight loss,
edema, loss of body protein, lipid, and cell mass, and lethal-
ity.13 Biochemical effects of the inflammatory cytokines in-
clude (in the short term) hyperglycemia, hypertriglyceride-
mia, and l i p o g e n e s i ~ , ~with
~ - ~ ~increases in protein
JANUARY 1999-VOL. 47, NO. 1 JAGS
and decreases in cellular levels of certain amino
acids such as tyrosine, a precursor of neurotransmitter^?^ A
postulated physiologic basis for the role of high IL-6 levels in
certain depressions might, therefore, be caused by its effect on
weight loss.
This study has limitations. While the EPESE dataset has
provided a very rich source of epidemiologic information in
regard to the parameters affecting health, disease, and func-
tional statusz4 in older people, the analysis presented here is
cross-sectional, and, thus, cause and effect relationships can-
not be proven. The IL-6 and other biological measures were
determined at only one point in time, though our previous
studies have indicated that these measures may be quite
stable.29 This report does not show the degree of association
between aging and depression, which had been reported in
previous waves of the study.’ This may be due to the survi-
vorship of this cohort itself (with only approximately one-
third of the original 4162 subjects remaining in this study’s
sample), to an attenuation in the psychologic symptom en-
dorsements of depression in the “0ld-0ld’’ (median age in this
sample 76 years), or to the stronger impact of functional
status in this now older
This study is the first report in a community-dwelling
sample of older people of the association of the inflammatory
cytokine IL-6 with depression. This study’s results may be
one clue to the potential importance of this biologic relation-
ship in the etiology of this illness.
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