Association of depressive disorders, depression characteristics and antidepressant medication with inflammation

Abstract

Growing evidence suggests that immune dysregulation may be involved in depressive disorders, but the exact nature of this association is still unknown and may be restricted to specific subgroups. This study examines the association between depressive disorders, depression characteristics and antidepressant medication with inflammation in a large cohort of controls and depressed persons, taking possible sex differences and important confounding factors into account. Persons (18-65 years) with a current (N=1132) or remitted (N=789) depressive disorder according to DSM-IV criteria and healthy controls (N=494) were selected from the Netherlands Study of Depression and Anxiety. Assessments included clinical characteristics (severity, duration and age of onset), use of antidepressant medication and inflammatory markers (C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α)). After adjustment for sociodemographics, currently depressed men, but not women, had higher levels of CRP (1.33 versus 0.92 mg l ^-1 , P<0.001, Cohen's d=0.32) and IL-6 (0.88 versus 0.72 pg ml^-1 , P=0.01, Cohen's d=0.23) than non-depressed peers. Associations reduced after considering lifestyle and disease indicators -- especially body mass index -- but remained significant for CRP. After full adjustment, highest inflammation levels were found in depressed men with an older age of depression onset (CRP, TNF-α). Furthermore, inflammation was increased in men using serotonin-norepinephrine reuptake inhibitors (CRP, IL-6) and in men and women using tri- or tetracyclic antidepressants (CRP), but decreased among men using selective serotonin reuptake inhibitors (IL-6). In conclusion, elevated inflammation was confirmed in depressed men, especially those with a late-onset depression. Specific antidepressants may differ in their effects on inflammation.

Citation: Transl Psychiatry (2012) 2, e79, doi:10.1038/tp.2012.8

& 2012 Macmillan Publishers Limited All rights reserved 2158-3188/12 http://www.nature.com/tp

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Association of depressive disorders, depression characteristics and antidepressant medication with inammation

N Vogelzangs1, HE Duivis2, ATF Beekman1, C Kluft3, J Neuteboom3, W Hoogendijk4, JH Smit1, P de Jonge5 and BWJH Penninx1,5,6,7

Growing evidence suggests that immune dysregulation may be involved in depressive disorders, but the exact nature of this association is still unknown and may be restricted to specic subgroups. This study examines the association between depressive disorders, depression characteristics and antidepressant medication with inammation in a large cohort of controls and depressed persons, taking possible sex differences and important confounding factors into account. Persons (1865 years) with a current (N 1132) or remitted (N 789) depressive disorder according to DSM-IV criteria and healthy controls (N 494)

were selected from the Netherlands Study of Depression and Anxiety. Assessments included clinical characteristics (severity, duration and age of onset), use of antidepressant medication and inammatory markers (C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-a)). After adjustment for sociodemographics, currently depressed men, but not women, had higher levels of CRP (1.33 versus 0.92 mg l 1, Po0.001, Cohens d 0.32) and IL-6 (0.88 versus 0.72 pg ml 1, P 0.01,

Cohens d 0.23) than non-depressed peers. Associations reduced after considering lifestyle and disease indicators

especially body mass index but remained signicant for CRP. After full adjustment, highest inammation levels were found in depressed men with an older age of depression onset (CRP, TNF-a). Furthermore, inammation was increased in men using serotoninnorepinephrine reuptake inhibitors (CRP, IL-6) and in men and women using tri- or tetracyclic antidepressants (CRP), but decreased among men using selective serotonin reuptake inhibitors (IL-6). In conclusion, elevated inammation was conrmed in depressed men, especially those with a late-onset depression. Specic antidepressants may differ in their effects on inammation.

Translational Psychiatry (2012) 2, e79; doi:http://dx.doi.org/10.1038/tp.2012.8

Web End =10.1038/tp.2012.8 ; published online 21 February 2012

Introduction

Depression is a complex heterogeneous disorder, which may need a similarly heterogeneous offer of treatment possibilities. Currently available antidepressant medications largely target monoamine pathways, but treatment of depression is only effective in about a third to a half of patients.1,2

Identication of additional pathophysiological pathways involved in depression (subtypes) is needed to guide the development of alternative treatment strategies. Increasing interest has been directed to immune dysregulation in depression. Recently, two meta-analyses have shown that inammatory marker levels such as C-reactive protein (CRP), interleukin (IL)-6 and tumor necrosis factor alpha (TNF-a)

are increased in depressed persons compared with non-depressed subjects.3,4

Although the results of these meta-analyses are promising, the evidence for immune dysregulation in depression is not conclusive. A substantial portion of studies included in these

meta-analyses did not adequately adjust for possible confounding factors. The association between depression and inammation appeared much smaller, although still present, in studies adjusting for body mass index (BMI).4 The effect estimate after a more complete adjustment (including several lifestyle and disease factors) is not entirely clear. Also, most of the larger studies examining depression and inammation have used depressive symptoms questionnaires instead of assessing psychiatric diagnoses by means of clinical interviews. The former is much more prone to confounding by somatic health as a person can score high on these questionnaires based on having many physical complaints. Furthermore, a large part of previous studies has been conducted within older populations. More studies within younger age samples are therefore needed.

Next to these general limitations, meta-analyses have found very large heterogeneity across studies.3,4 It is plausible

that immune dysregulation is not generally present in depression, but restricted to particular subgroups of

1Department of Psychiatry and EMGO Institute for Health and Care Research, VU University Medical Center, Amsterdam, The Netherlands; 2Center of Research on Psychology in Somatic Diseases, Tilburg University, Tilburg, The Netherlands; 3Good Biomarker Sciences, Leiden, The Netherlands; 4Department of Psychiatry, Erasmus Medical Center, Rotterdam, The Netherlands; 5Department of Psychiatry, University Medical Center Groningen, Groningen, The Netherlands; 6Department of Psychiatry, Leiden University Medical Center, Leiden, The Netherlands and 7Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The NetherlandsCorrespondence: Dr N Vogelzangs, Department of Psychiatry and EMGO Institute for Health and Care Research, VU University Medical Center, AJ Ernststraat 1187, Amsterdam 1081 HL, The Netherlands.

E-mails: mailto:[email protected]

Web End [email protected] and mailto:[email protected]

Web End [email protected] Keywords: antidepressants; cohort study; depression characteristics; depressive disorder; inammation

Received 13 October 2011; revised 23 December 2011; accepted 8 January 2012

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depressed persons. Several factors that could inuence the depressioninammation relationship need further investigation to help delineate the depressed person with immune dysregulation. This is important to give direction to whom new treatment strategies could be targeted.

First, sex differences might exist, but results are thus far inconsistent. Stronger, weaker or similar effects have been found for women compared with men for different inamma-tory markers.4,5 Inammation levels uctuate throughout female life according to hormonal changes owing to phase of menstrual cycle, use of hormonal contraceptives, meno-pause and use of estrogens,68 which might inuence the relationship between depression and inammation.

Second, it is largely unknown whether specic depression characteristics indicate immune dysregulation.3 In line with a dose-response assumption, more severe and/or more chronic disorders can be hypothesized to show the most inammation.9,10 In addition, late-onset depression has been associated with family history of vascular disease7 and atherosclerosis.11,12 As immune dysregulation is critically involved in vascular disease,13 it can be hypothesized that increased inammation is specically present in those with late-onset depressive disorders.

Third, antidepressant medication might inuence inammation levels and this effect might differ across type of medication. As summarized by Miller et al.,14 several studies showed that antidepressant treatment, mainly selective serotonin reuptake inhibitors, was associated with decreases in inammatory markers. In contrast, recent results of two large studies suggest that use of antidepressants, mainly tricyclic antidepressants (TCA), is associated with elevated inammation levels.15

To address the issues raised above, the rst aim of the present study was to examine the association between diagnosed depressive disorders and inammatory markers (CRP, IL-6 and TNF-a), using a large and relatively young cohort of depressed persons and controls, taking possible sex differences and important confounding factors into account. The second aim was to investigate whether specic depression characteristics (severity, duration and age of onset) could further delineate the depressed person with increased inammation. Lastly, possible effects of (specic types of) antidepressant medication on inammation levels were examined.

Subjects and methods

Sample. The Netherlands Study of Depression and Anxiety (NESDA) is an ongoing cohort study designed to investigate the long-term course and consequences of depressive and anxiety disorders. Participants were 18 to 65 years old at baseline assessment in 20042007 and were recruited from the community (19%), general practice (54%) and secondary mental health care (27%). A total of 2981 persons were included, consisting of persons with a current or past depressive and/or anxiety disorder and healthy controls. A detailed description of the NESDA study design and sampling procedures can be found elsewhere.16 The

research protocol was approved by the Ethical Committee

of participating universities, and after complete description of the study all respondents provided written informed consent.

During the baseline interview, presence of depressive disorder (major depressive disorder, dysthymia) and anxiety disorder (social phobia, generalized anxiety disorder, panic disorder and agoraphobia) was established using the Composite Interview Diagnostic Instrument (CIDI) according to DSM-IV criteria.17 The CIDI is a highly reliable and valid instrument for assessing depressive and anxiety disorders18

and was administered by specially trained research staff. In addition, the severity of depression was measured in all participants using the 28-item self-report Inventory of Depressive Symptoms (IDS).19 For the present analyses we selected persons with a current (that is, past 6 months; N 1158) or remitted (lifetime, but not current; N 815)

depressive disorder and healthy controls without any lifetime depressive or anxiety disorder and an IDS score below 14 (N 506). Of these 2479 persons, 64 were excluded because

of missing information on inammatory markers, leaving a sample of 2415 persons for the present study. Persons with missing data on inammation did not differ from included persons in terms of sex, age, years of education and depressive disorder status.

Inammatory markers. Markers of inammation were assessed at the baseline NESDA measurement and included CRP, IL-6 and TNF-a. Fasting blood samples of

NESDA participants were obtained in the morning around 0800 hours and kept frozen at 70 1C. CRP and IL-6 were

assayed at the Clinical Chemistry department of the VU University Medical Center. High-sensitivity plasma levels of CRP were measured in duplicate by an in-house ELISA based on puried protein and polyclonal anti-CRP antibodies (Dako, Glostrup, Denmark). Intra- and inter-assay coefcients of variation were 5% and 10%, respectively. Plasma IL-6 levels were measured in duplicate by a high sensitivity ELISA (PeliKine Compact ELISA, Sanquin, Amsterdam, The Netherlands). Intra- and inter-assay coefcients of variation were 8% and 12%, respectively. Plasma TNF-a levels were assayed in duplicate at Good

Biomarker Science (Leiden, The Netherlands), using a high-sensitivity solid phase ELISA (Quantikine HS Human TNF-a

Immunoassay, R&D systems, Minneapolis, MN, USA). Intraand inter-assay coefcients of variation were 10% and 15%, respectively.

Depression characteristics. Next to CIDI depressive disorder diagnosis, depression characteristics included depressive symptoms severity as measured by the IDS, and depressive symptoms duration, using the Life Chart method,20 in which a detailed account of the presence of depressive symptoms during the past 4 years was assessed. From this, the percent of time patients reported depressive symptoms was computed. Additionally, age of depression onset was derived from the CIDI interview.

Antidepressant medication. Medication use was assessed based on drug container inspection of all drugs used in the past month and classied according to the World Health Organization Anatomical Therapeutic Chemical

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classication.21 Antidepressant medication was only considered when taken on a regular basis (at least 50% of the time) and included selective serotonin reuptake inhibitors (SSRI; N06AB), serotoninnorepinephrine reuptake inhibitors (SNRI; N06AX16 and N06AX21), TCA (N06AA) and tetracyclic antidepressants (TeCA; N06AX03, N06AX05 and N06AX11).

Covariates. Sociodemographic characteristics included age, sex and years of education. As lifestyle characteristics can be associated with both depression and inammation, smoking status (never, former and current; assessed by self-report), alcohol intake (o1, 114 (women) / 121 (men), 414 (women)/421 (men) drinks per week; based on general guidelines that are used in health organizations in the

Netherlands22 and as used in other studies23), BMI (weight in kilograms divided by height in meters squared) and physical activity (measured with the International Physical Activity Questionnaire24 in MET-minutes (ratio of energy expenditure during activity compared with rest times the number of minutes performing the activity) per week) were assessed. In addition, several disease related covariates were taken into account including presence of cardiovascular disease (assessed by self-report supported by appropriate medication use (see ref. 25 for detailed description), presence of diabetes (fasting plasma glucose level X7.0 mmol l 1 or use of anti-diabetic medication (A10)), and the number of other self-reported chronic diseases for which persons received treatment (including lung disease, osteoarthritis or rheumatic disease, cancer, ulcer, intestinal problem, liver disease, epilepsy and thyroid gland disease). As suggested by Howren et al.,4 to control for possible medication effects, we assessed statin use (C10AA, C10B) and use of systemic anti-inammatory medication (M01A, M01B, A07EB and A07EC). In women, we additionally assessed use of sex hormones (self-reported use of oral contraceptives or ATC code G03), self-reported menstrual cycle phase (menstrual (03 days since start last menstruation), follicular (413 days), luteal (1432 days)) and self-reported postmenopausal status (yes/no).

Statistical analyses. All analyses were conducted using SPSS version 15.0 statistical software (SPSS Inc., Chicago, IL, USA). Differences in baseline characteristics across sex were tested for statistical signicance using w2-statistics for dichotomous and categorical variables and independent t-tests and MannWhitney U-tests for normally and non-normally distributed continuous variables. For subsequent analyses, CRP, IL-6 and TNF-a were ln-transformed to normalize distributions and presented back-transformed.

Associations between baseline characteristics and inammatory markers were tested using independent samples t-tests for dichotomous variables, one-way analyses of variance for categorical variables and Pearsons correlations for continuous variables.

Associations between depressive disorders and inamma-tory markers were examined using analyses of (co)variance and (adjusted) means across depression groups (no, remitted and current) were presented. To take the effects of important confounding factors into account, three different models were

tested: unadjusted, adjusted for sociodemographics (sex, age and education) and additionally adjusted for lifestyle and disease (smoking status, alcohol intake, BMI, physical activity, cardiovascular disease, diabetes, number of other chronic diseases, statins and anti-inammatory medication). To investigate possible sex differences, we tested for sex interactions by including a sex-depressive disorder interaction term. When present, analyses were repeated sex stratied. For signicant associations, Cohens d was calculated in order to assess effect size.

To test whether specic depression characteristics were related to elevated inammation levels, we performed linear regression analyses for each depression characteristic within the sample of persons with a current depressive disorder. Sex interactions were again tested and if present, shown sex stratied.

To investigate possible effects of antidepressant medications, adjusted means of inammation levels across different medication groups were calculated using analyses of covariance and presented sex stratied in case sex interaction was present.

Results

Baseline characteristics of the total sample and for men (N 800) and women (N 1615) separately are shown in

Table 1. Women were younger, less often smokers, more often non-drinkers, had a lower BMI, less often cardiovascular disease or diabetes and less often used statins than men. In addition, women had higher levels of CRP, but lower levels of IL-6 and TNF-a than men. In men, older age, less education, smoking, heavy or non-drinking, higher BMI, lower physical activity, cardiovascular disease, diabetes, higher number of other chronic diseases, statin use and use of anti-inamma-tory medication were associated with higher levels of at least one of the inammatory markers (data not shown). In women, similar associations were found, except for smoking, heavy drinking, and physical activity. The Pearsons correlations between inammatory markers were modest, likely reecting only partial biological overlap, and somewhat higher in men (CRP-IL-6: r 0.40; CRP-TNF-a: r 0.22; IL-6TNF-a:

r 0.17) than in women (CRP-IL-6: r 0.28; CRP-TNF-a:

r 0.10; IL-6TNF-a: r 0.09).

Table 2 shows (adjusted) mean inammation levels across depression groups (controls, remitted and current depressive disorder) based on analyses of (co) variance. In the total sample, current depressive disorders were signicantly associated with higher levels of CRP and IL-6 in the unadjusted model. After additional adjustment for sociodemographics, lifestyle and disease factors, these associations disappeared. No associations were found for TNF-a. For current depressive disorders, sex interactions were found for

CRP (P-interactiono0.001) and IL-6 (P-interaction 0.009),

but not TNF-a (P-interaction 0.99).

In men, after adjustment for sociodemographics, a current depressive disorder was associated with higher CRP levels(1.33 versus 0.92 mg l 1, Po0.001, Cohens d 0.32) and

IL-6 levels (0.88 versus 0.72 pg ml 1, P 0.01, Cohens

d 0.23). Even after full adjustment for lifestyle and disease

factors, men with a current depressive disorder had higher

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Table 1 Baseline characteristics

Total sample (N 2415)

Men (N 800)

Women (N 1615)

Pa

SociodemographicsAge (years), mean (s.d.) 41.8 (12.9) 43.7 (12.6) 40.9 (12.9) o0.001 Education (years), mean (s.d.) 12.2 (3.3) 12.0 (3.3) 12.2 (3.3) 0.12

Lifestyle and DiseaseSmoking status 0.003 Never, % 27.9 23.5 30.1Former, % 32.7 34.3 31.9Current, % 39.4 42.3 38.0

Alcohol intake o0.001 o1 Drink a week, % 32.9 22.9 37.8114 (women) / 121 (men) drinks a week, % 55.9 66.5 50.7414 (women) / 421 (men) drinks a week, % 11.2 10.6 11.5

Body mass index, mean (s.d.) 25.7 (5.1) 26.3 (4.6) 25.4 (5.3) o0.001 Physical activity (MET-min per week), mean (s.d.) 3673 (3026) 3758 (3324) 3630 (2867) 0.36

Cardiovascular disease, % 5.6 9.4 3.8 o0.001

Diabetes, % 4.9 7.8 3.5 o0.001

Number of other chronic diseases, mean (s.d.) 0.4 (0.7) 0.4 (0.7) 0.4 (0.7) 0.11 Statin use, % 6.6 10.9 4.5 o0.001

Anti-inammatory medication use, % 4.2 4.0 4.3 0.75

Depression characteristicsDepressive disorder 0.004 Controls, % 20.5 24.1 18.6Remitted depressive disorder, % 32.7 29.8 34.1Current depressive disorder, % 46.9 46.1 47.2

Within currently depressed cases (N 1132)

Severity (IDS score), mean (s.d.) 32.5 (12.2) 32.9 (12.6) 32.3 (12.1) 0.46 Duration (% of time depressed), mean (s.d.) 38.5 (30.3) 40.9 (31.6) 37.4 (29.6) 0.07 Age of depression onset (years), mean (s.d.) 27.1 (12.5) 29.7 (13.3) 25.9 (11.8) o0.001

Antidepressant use 0.13No antidepressant, % 57.2 57.5 57.1 SSRI, % 28.8 25.7 30.3 SNRI, % 7.2 9.5 6.2 TCA, % 3.8 3.5 3.9 TeCA, % 2.9 3.8 2.5

Inammatory markersC-reactive protein (mg l 1), median (IQR) 1.22 (0.543.02) 1.09 (0.512.67) 1.30 (0.563.21) 0.001 Interleukin-6 (pg ml 1), median (IQR) 0.76 (0.501.25) 0.81 (0.531.36) 0.72 (0.491.19) 0.003 Tumor necrosis factor-alpha (pg ml 1), median (IQR) 0.80 (0.601.10) 0.80 (0.601.10) 0.70 (0.601.10) 0.001

Abbreviations: IDS, inventory of depressive symptoms; IQR, interquartile range; s.d., standard deviation; SSRI, selective serotonin reuptake inhibitor; SNRI, serotoninnorepinephrine reuptake inhibitor; TCA, tricyclic antidepressant; TeCA, tetracyclic antidepressant.

aBased on w2-test for dichotomous and categorical variables, and independent samples t-test for continuous variables testing the difference between men and women; for inammatory markers the MannWhitney U-test was used.

CRP levels compared with controls (1.29 versus 1.04 mg l 1,

P 0.02, Cohens d 0.21), and marginally higher IL-6 levels

(0.87 versus 0.76 pg ml 1, P 0.10, Cohens d 0.15). No

associations with TNF-a were found in men. Overall, BMI weakened the associations most, followed by number of other chronic diseases. Smoking status, alcohol use and physical activity weakened associations slightly further. Adjustment for cardiovascular disease, diabetes, statins and anti-inamma-tory medication hardly affected associations.

In women, depressive disorders were not associated with inammatory markers before or after adjustment. Although sex hormone use, menstrual cycle phase and postmenopausal status were strongly associated with inammation levels, additional adjustment for these factors did not change the results for women. Also, there were no signicant postmenopausal status-depression interactions in the associations with inammation levels (all P40.40) suggesting that associations

between depression and inammation appeared absent in both premenopausal (N 1076) and postmenopausal women

(N 539).

To investigate whether specic depression characteristics (severity, duration and age of onset) were associated with higher inammation levels, linear regression analyses were performed within the subgroup of currently depressed persons (N 1132; Table 3). Women with more severe

depressive symptoms had higher levels of TNF-a. No associations were found for duration of depressive symptoms. Men with an older age of depression onset had higher levels of CRP and TNF-a than those with a younger age of depression onset.

Lastly, the association between antidepressant medication use and inammation levels was examined. To incorporate possible differences in depression severity between persons who were or were not using antidepressants, we selected a

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Table 2 Adjusted mean inammation levels across depression groups

Controls Remitted depressive disorder Current depressive disorder

Mean (s.e.) P Mean (s.e.) P Mean (s.e.) P

CRP, mg l 1, a

Total sample N 494 N 789 N 1132

Unadjusted 1.09 (1.06) Ref 1.25 (1.04) 0.05 1.40 (1.04) o0.001 Adjustedb 1.17 (1.06) Ref 1.24 (1.04) 0.38 1.36 (1.04) 0.02

Adjustedc 1.27 (1.05) Ref 1.26 (1.04) 0.91 1.30 (1.03) 0.66 Men N 193 N 238 N 369

Unadjusted 0.83 (1.09) Ref 1.14 (1.08) 0.005 1.36 (1.06) o0.001 Adjustedb 0.92 (1.08) Ref 1.09 (1.08) 0.13 1.33 (1.06) o0.001

Adjustedc 1.04 (1.08) Ref 1.03 (1.07) 0.96 1.29 (1.06) 0.02 Women N 301 N 551 N 763

Unadjusted 1.29 (1.07) Ref 1.30 (1.05) 0.94 1.42 (1.05) 0.29 Adjustedb 1.36 (1.07) Ref 1.34 (1.05) 0.82 1.36 (1.05) 0.96 Adjustedc 1.45 (1.07) Ref 1.38 (1.05) 0.57 1.30 (1.04) 0.16

IL-6, pg ml 1, a

Total sample N 494 N 789 N 1132

Unadjusted 0.72 (1.04) Ref 0.75 (1.03) 0.49 0.80 (1.03) 0.04 Adjustedb 0.74 (1.04) Ref 0.74 (1.03) 0.88 0.79 (1.03) 0.24 Adjustedc 0.78 (1.04) Ref 0.74 (1.03) 0.42 0.77 (1.03) 0.91

Men N 193 N 238 N 369

Unadjusted 0.68 (1.07) Ref 0.82 (1.06) 0.03 0.89 (1.05) 0.001 Adjustedb 0.72 (1.07) Ref 0.80 (1.06) 0.20 0.88 (1.05) 0.01 Adjustedc 0.76 (1.07) Ref 0.78 (1.06) 0.72 0.87 (1.05) 0.10

Women N 301 N 551 N 763

Unadjusted 0.74 (1.06) Ref 0.71 (1.04) 0.55 0.75 (1.04) 0.86 Adjustedb 0.77 (1.06) Ref 0.71 (1.04) 0.22 0.75 (1.03) 0.63 Adjustedc 0.80 (1.06) Ref 0.72 (1.04) 0.13 0.73 (1.03) 0.14

TNF-a, pg ml 1, aTotal sample N 494 N 789 N 1132

Unadjusted 0.82 (1.03) Ref 0.82 (1.02) 0.99 0.86 (1.02) 0.23 Adjustedb 0.84 (1.03) Ref 0.82 (1.02) 0.60 0.85 (1.02) 0.59 Adjustedc 0.85 (1.03) Ref 0.82 (1.02) 0.43 0.84 (1.02) 0.78

Men N 193 N 238 N 369

Unadjusted 0.84 (1.04) Ref 0.84 (1.04) 0.90 0.87 (1.03) 0.41 Adjustedb 0.85 (1.04) Ref 0.83 (1.04) 0.65 0.87 (1.03) 0.70 Adjustedc 0.88 (1.04) Ref 0.83 (1.04) 0.33 0.86 (1.03) 0.69

Women N 301 N 551 N 763

Unadjusted 0.81 (1.04) Ref 0.81 (1.03) 0.97 0.85 (1.02) 0.34 Adjustedb 0.83 (1.04) Ref 0.81 (1.03) 0.76 0.84 (1.02) 0.74 Adjustedc 0.84 (1.04) Ref 0.82 (1.03) 0.70 0.83 (1.02) 0.90

Abbreviations: CRP, C-reactive protein; IL-6, interleukin-6; TNF-a, tumor necrosis factor-alpha.

aTo normalize distributions CRP, IL-6 and TNF-a were ln-transformed; for interpretation purposes presented means were back transformed.

bBased on analyses of (co)variance; adjusted for sex, age and education.

cAdditionally adjusted for smoking status, alcohol intake, body mass index, physical activity, cardiovascular disease, diabetes, number of other chronic diseases, statins and anti-inammatory medication.

Table 3 Associationa of depression characteristics with inammatory markers in persons with current depressive disorders (N 1132)

CRPb IL-6b TNF-ab

Depression characteristic b P b P b P

Severity (IDS score) 0.020 0.47 0.038 0.22 0.040 0.20

Men 0.048 0.36

Women 0.085 0.02 Duration of depressive symptoms 0.005 0.87 0.017 0.58 0.012 0.70

Age of depression onset 0.064 0.04 0.002 0.95 0.043 0.22

Men 0.140 0.003 0.149 0.004 Women 0.016 0.67 0.025 0.55

Abbreviations: CRP, C-reactive protein; IDS, inventory of depressive symptoms; IL-6, interleukin-6; TNF-a, tumor necrosis factor-alpha.

aBased on linear regression analyses adjusted for (sex), age, education, smoking status, alcohol intake, body mass index, physical activity, cardiovascular disease, diabetes, number of other chronic diseases, statins, anti-inammatory medication; sex-specic associations are shown in case P sex interaction p0.05.

bCRP, IL-6 and TNF-a were ln-transformed to normalize distributions.

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control group of medication-free depressed persons with a current diagnosis and an IDS score X25 (N 426). In this

medication-free reference group the mean IDS score was comparable to the other medication groups. As effects of TCA and TeCA users were comparable, they were grouped together to increase numbers. Sex interactions in the association between antidepressant medication group (no medication, SSRI, SNRI and TCA/TeCA) and inammatory markers were found (CRP: P-interaction 0.06, IL-6:

P-interaction 0.02; TNF-a: P-interaction 0.90). Therefore,

Figure 1 shows adjusted mean inammation levels comparing antidepressant users with medication-free persons, for men and women separately. Increased levels of CRP were found for men using SNRI (1.98 versus 1.21 mg l 1, P 0.02,

Cohens d 0.44) or TCA/TeCA (2.05 versus 1.21 mg l 1,

P 0.02, Cohens d 0.48) as compared with medication-

free depressed men. A trend for higher CRP in TCA/TeCA users was also found for women (2.10 versus 1.53 mg l 1,

P 0.08, Cohens d 0.28). In men only, IL-6 levels were

lower in SSRI users (0.70 versus 0.91 pg ml 1, P 0.02,

Cohens d 0.32) and considerably increased in SNRI

users (1.37 versus 0.91 pg ml 1, P 0.01, Cohens d 0.49)

compared with medication-free depressed men. No associations were found for TNF-a. For comparison, inammation levels in persons with cardiovascular disease were1.84 mg l 1 for CRP and 1.06 pg ml 1 for IL-6, suggesting that the putative effects of antidepressant medication are at least of similar magnitude as having cardiovascular disease. As antidepressant medication effects were found, we checked whether these inuenced the ndings from Tables 2 and 3, but results remained similar after additional adjustment for antidepressant medication group.

Discussion

The present study examined the association between depressive disorders, depression characteristics and anti-depressant medication with inammation in a large cohort of depressed persons and controls. After taking a large set of possibly confounding factors into account, it was found that men with current depressive disorders had higher levels of CRP, and marginally higher levels of IL-6, but not of TNF-a.

No overall associations were found in women. Increased inammation was in particular found in depressed men with an older age of depression onset (CRP, TNF-a). Users of SNRI (men only), TCA and TeCA had increased levels of CRP and IL-6, whereas men using SSRI had signicantly lower levels of IL-6.

Our results conrm previous ndings of immune dysregulation in depressed persons.3,4 In men, effect sizes for current depression were small to moderate for both CRP and IL-6. These effect sizes are comparable to those reported by the meta-analysis of Howren,4 in which stronger effects were found for studies using clinical interviews compared with studies using self-report questionnaires. Compared with symptom questionnaires, a depressive disorder diagnosis is less confounded by somatic health problems. Together with the fact that our results were elaborately adjusted for possibly confounding factors, our ndings suggest a true relationship between depression and inammation in men.

[afii9825]

Figure 1 Adjusted mean inammatory levels across medication groups and sex based on analyses of covariance (ANCOVA) adjusted for age, education, smoking status, alcohol intake, body mass index (BMI), physical activity, cardiovascular disease, diabetes, number of other chronic diseases, statins and anti-inammatory medication; to normalize distributions C-reactive protein (CRP), Interleukin-6 (IL-6) and Tumor necrosis factor-alpha (TNF-a) were ln-transformed, for interpretation purposes presented means were back transformed. Abbreviations: IDS, inventory of depressive symptoms score; SNRI, serotoninnorepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant; TeCA, tetracyclic antidepressant. 1Current depressive disorder and IDS X25 without medication use ( reference); only signicant differences from reference are

shown: *Po0.10; **Po0.05.

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No clear associations between depression and inammation were found in women. This is in line with results from another large and relatively young cohort study in which history of depression was associated with CRP levels in men, but not women.5 Hormonal changes throughout female life due to phase of menstrual cycle, use of hormonal contraceptives, menopause and use of estrogens greatly impact on inammation levels,68 which could confound a clear association between depression and inammation. However, in our study, associations between depression and inammation appeared absent in both pre- and post-menopausal women and adjusting for several hormonal factors did not change our ndings. Another explanation might be that in women, psychosocial factors have a larger role in depression and therefore override the effects of biological factors. For instance, insufcient social support and stressful life events have been found to pose a greater risk for depression among women compared with men.26,27

Results of increased inammation were particularly present in men with late-onset depression. In contrast, characteristics that are more often associated with an early age of onset, such as higher severity and longer duration, were not consistently associated with increased inammation. Interesting to note is that women in our study also had an earlier age of depression onset compared with men. A distinct etiology in late-onset versus early-onset depression was also found by Kendler et al.28 This study showed that depression with an early age of onset was associated with a family history of depression, whereas late-onset depression was associated with a family history of vascular disease. Also, subclinical vascular dysregulations, such as atherosclerosis, have been found to relate to late-onset depression.11,12 These ndings

are in line with the vascular depression hypothesis, which suggests that vascular damage in the brain predisposes to late-onset depression.29 As immune dysregulation is critically involved in vascular disease,13 this vascular damage could be the result of increased inammation.

Instead of inammatory or vascular, the true etiology of depression in this subgroup of men with late-onset depression might have a metabolic nature. Several studies have conrmed an association between CRP, IL-6 and TNF-a with the metabolic syndrome and visceral fat depots release cytokines.30 The metabolic syndrome and in particular visceral fat have been bidirectionally associated with depression in late life,31,32 specically in men. Men possess higher amounts of visceral fat compared with women and are therefore more likely to experience related inammation and depression. Involvement of metabolic processes is further supported by our nding that the association between depression and inammation in particular decreased after adjustment for BMI.

Several biological mechanisms could further explain the relationship between depression and inammation. Depression has been associated with dysregulation of important stress systems of the human body, that is, the hypothalamus pituitaryadrenal-axis33 and the autonomic nervous system.34 Although the hypothalamuspituitaryadrenal-axis in normal situations should temper inammatory reactions, prolonged hyperactivity of the hypothalamuspituitaryadrenal-axis could result in blunted anti-inammatory responses to

glucocorticoids resulting in increased inammation.35,36 In

addition, both decreased parasympathetic37 as well as

increased sympathetic nervous system activity38 have been associated with increased inammation. Furthermore, proinammatory cytokines might inhibit hippocampal neurogenesis,39 which could lead to a reduced hippocampal volume,40 which is also seen in depression.41 Also, several inammatory markers have been shown to promote indoleamine-2,3-dioxygenase activation,42 which catalyzes tryptophan, the precursor of serotonin, to kynurenine, thereby indirectly reducing the availability of serotonin.43 Lastly, specic genes might underlie both increased inammation and depression, as several inammation-related genes have been associated with susceptibility to major depression.44

Our study also shows that inammation levels differ across persons using different types of antidepressant medication. The highest inammation levels were found in men using SNRI, TCA or TeCA, while IL-6 levels in men using SSRI were lower compared with medication-free depressed men. Interesting to note is that the rst three classes of medication have a combined serotonergic/noradrenergic effect, whereas SSRI act purely serotonergic. Earlier studies found decreases in inammatory marker levels after antidepressant treatment, mainly SSRI (see ref. 14 for an overview), whereas two recent large studies found that use of antidepressants, mainly TCA, was associated with elevated inammation levels.15 Possibly, noradrenergic effects are driving increased inammation mechanisms. Noradrenaline is a part of the human stress response and has been suggested to potentiate cytokine production.45 Use of SNRI, TCA and TeCA has also been observed to disturb functioning of autonomic nervous system,46 blood pressure47 and the metabolic syndrome.48 Although it is possible that persons using SNRI, TCA or TeCA are in other ways different from SSRI users and medication-free depressed persons, we constructed our groups in such a way that depression severity levels were very comparable. In addition, we adjusted our analyses for a large set of covariates and have therefore taken possible differences in lifestyle or disease factors into account. On the other hand, evidence suggests that increased inammatory activity before treatment predicts non-response.49,50 Possi

bly, persons with elevated inammation did not respond to SSRI and were therefore prescribed SNRI, TCA or TeCA.

Associations found in this study were not always consistent across all inammatory markers. Correlations between inammatory markers were only modest and were highest between CRP and IL-6. Regulation of the immune system is rather complex and involves many different inammatory mechanisms. Most consistent ndings were found for CRP, which is a very general marker of inammation. IL-6 and TNF-a, on the other hand, only tap part of the immune system. This seems to suggest that inammation is indeed involved in depression, but it is still unclear which part of the immune system is most critically involved. Nonetheless, expected associations with covariates (for example, age, smoking, alcohol use, BMI, physical activity and somatic disease (medication)) were found for all inammatory markers.

What do the ndings of our study implicate with regard to treatment of depression? Considering the heterogeneity of depression and the fact that current treatment of depression is

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only effective in about a third to a half of patients,1,2 this

indicates that new treatments are needed for specic subgroups. Our nding of increased inammation in men with late-onset depression, together with previous ndings of high inammation indicating non-response to antidepressants,49,50

might suggest that this specic subgroup could benet from alternative treatments, with anti-inammatory medication being a likely candidate. Preliminary evidence from studies among patients treated with anti-inammatory agents for other indications suggests that these agents may have benecial effects on mood.51 One study found positive effects on mood in medically healthy, major depressed patients.52 On the other

hand we found, like others,14 that SSRI might have a benecial effect on inammation, suggesting that SSRI could be effective in depressed patients with immune dysregulation through this anti-inammatory effect. Furthermore, behavioral interventions, such as exercise, have been shown to normalize immune and metabolic dysregulation,53 as well as to improve depressive symptoms to some degree,54 and might therefore be an indicated treatment for a immune/metabolic depression subgroup. At this moment, these considerations for treatment implications are still very speculative. Follow-up (longitudinal) research should conrm and further delineate an inammatory (or metabolic) depression subtype, taking into account age, sex, depression characteristics and course. Experimental studies are needed to examine and compare the effects of different types of currently available antidepressants, anti-inammatory medication and behavioral (exercise) interventions on both immune/metabolic parameters and depression.

Our study has some important strengths such as a large sample size, assessment of multiple inammatory markers, clinical diagnoses of depression, adequate adjustment for potential confounders, the ability to examine the role of depression characteristics and antidepressant medication. However, some limitations need to be acknowledged. As our data are cross-sectional, we cannot make any inferences about the direction of the association. Longitudinal studies are needed to investigate whether immune dysregulation is a precursor or the result of depression (treatment), or whether this relationship is bidirectional. The few available prospective studies have shown contradicting results.9,55,56 Further, like

most other studies, we assessed circulating levels of inammatory markers, which show a high degree of intra-individual variation, which could explain the rather modest overall associations between depression and inammation in our study.

In conclusion, our study suggests that immune dysregulation has a role in a subgroup of depressed persons, in particular in men with a late-onset depression. Treatment trials should further examine the differential effects of different types of antidepressants on inammation. Whether a specic treatment strategy (SSRI, anti-inammatory drugs, exercise) is indicated for a subgroup of late-onset depressed patients with immune dysregulation needs to be further investigated, using longitudinal and experimental study designs.

Conict of interest

The authors declare no conict of interest.

Acknowledgements. The infrastructure for the NESDA study (http://www.nesda.nl

Web End =www.nesda.nl) is funded through the Geestkracht program of the Netherlands Organization for Health Research and Development (Zon-Mw, grant number 10-000-1002) and is supported by participating universities and mental health care organizations (VU University Medical Center, GGZ inGeest, Arkin, Leiden University Medical Center, GGZ Rivierduinen, University Medical Center Groningen, Lentis, GGZ Friesland, GGZ Drenthe, Institute for Quality of Health Care (IQ Healthcare), Netherlands Institute for Health Services Research (NIVEL) and Netherlands Institute of Mental Health and Addiction (Trimbos). Data analyses were supported through a fellowship (NV) from the EMGO Institute for Health and Care Research. Assaying of inammatory markers was supported by the Neuroscience Campus Amsterdam.

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