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Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2004-1667
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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 5 2522-2530
Copyright © 2005 by The Endocrine Society

Major Depression Is Associated with Significant Diurnal Elevations in Plasma Interleukin-6 Levels, a Shift of Its Circadian Rhythm, and Loss of Physiological Complexity in Its Secretion: Clinical Implications

Salvatore Alesci1, Pedro E. Martinez1, Sujata Kelkar, Ioannis Ilias, Donna S. Ronsaville, Samuel J. Listwak, Alejandro R. Ayala, Julio Licinio, Herman K. Gold, Mitchel A. Kling, George P. Chrousos and Philip W. Gold

Clinical Neuroendocrinology Branch (S.A., P.E.M., D.S.R., S.J.L., M.A.K., P.W.G.), National Institute of Mental Health, and Pediatric and Reproductive Endocrinology Branch (S.K., I.I., A.R.A., G.P.C.), National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892; Laboratory of Pharmacogenomics (J.L.), University of California, Los Angeles, Los Angeles, California 90095; and Cardiac Unit (H.K.G.), Massachusetts General Hospital, Boston, Massachusetts 02114

Address all correspondence and requests for reprints to: Salvatore Alesci, M.D., Ph.D., Clinical Neuroendocrinology Branch, National Institute of Mental Health, National Institutes of Health, 10 Center Drive, Building 10, Room 2D46, MSC 1284, Bethesda, Maryland 20892-1284. E-mail: alescisa{at}mail.nih.gov.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Background: Major depressive disorder (MDD) is associated with increased risk for premature coronary heart disease and bone loss. Single time measurements of plasma IL-6, a good predictor of future risk for both cardiovascular disease and osteoporosis, revealed significant elevations in depressed patients. The objective of this study was to rigorously compare plasma IL-6 levels, measured over 24 h, in MDD patients and healthy controls. Given the activating role of IL-6 on the hypothalamic-pituitary-adrenal (HPA) axis, and the relevance of its dysregulation in MDD, we also analyzed the relations between IL-6 and cortisol levels.

Methods: We studied nine patients and nine controls, individually matched by gender, age (±5 yr), body mass index (±2 kg/m2), and menstrual cycle phase. Diagnosis of MDD was confirmed by structured clinical interview based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Axis I diagnostic criteria. Self-reported mood ratings were assessed by multiple visual analog scales. The rhythmicity and complexity of IL-6 and cortisol secretion were tested by cosinor analyses, approximate entropy (ApEn) and cross-ApEn algorithms.

Results: MDD patients had significant mean IL-6 elevations from 1000–1200 h and at 1500 h (P ranging from <0.05 to <0.01) vs. controls. In addition, in MDD, the circadian rhythm of IL-6 was shifted by 12 h, and its physiological complexity was reduced, with no difference in the cross-ApEn of IL-6 and cortisol between the two groups, and significant time-lagged correlations only in the controls. IL-6 levels correlated significantly with mood ratings.

Conclusions: We report profound morning elevations of plasma IL-6 and a reversal of its circadian rhythm in MDD patients, in the absence of hypercortisolism. These findings may be relevant to the increased risk for coronary heart disease and bone loss in MDD.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
MAJOR DEPRESSIVE DISORDER (MDD) affects more than 30 million adults in the United States (1). For many patients, MDD is a lifetime disorder, characterized by multiple remissions and exacerbations. This psychiatric illness is accompanied not only by mental anguish but also by alterations in fundamental processes, endocrine programs for growth and reproduction, and activity of the hypothalamic-pituitary-adrenal (HPA) axis and sympathetic nervous system (2, 3, 4). A significant association between MDD and coronary heart disease, as well as osteoporosis, has been documented (5, 6, 7, 8, 9, 10). Yet the mechanisms underlying the long-term medical consequences of MDD have not yet been established.

IL-6 is a pleiotropic inflammatory cytokine that, in addition to its essential immune effects, exerts a plethora of neuroendocrine, hemostatic, and behavioral actions (11). IL-6 secretion is activated by the sympathetic and adrenomedullary nervous systems via ß-adrenergic receptors (11). Accordingly, exposure to physical and psychosocial stress in humans is accompanied by increased plasma IL-6 levels (12, 13). At the same time, IL-6 is a strong activator of the HPA axis and sympathetic nervous system (14, 15, 16, 17). IL-6 is a potent stimulus of the hepatic acute-phase response (18, 19, 20). Moreover, this cytokine can induce a prothrombotic state by increasing the expression of procoagulant factors, decreasing the levels of hemostatic inhibitors, and enhancing platelet production and endothelial cell activation (21). Thus, IL-6 plays a key role in the development of coronary heart disease in states associated with hypercytokinemia (22). In addition, IL-6 can modulate skeletal homeostasis by promoting osteoclastogenesis and up-regulating glucocorticoid receptor-binding sites in osteoblasts (23). Loss of estrogen-mediated inhibition of bone IL-6 production plays a key role in postmenopausal osteoporosis (24, 25). Finally, IL-6 is a major inducer of sickness behavior, characterized by profound fatigue, sleepiness, decreased motivation, social withdrawal and diffuse somatic manifestations, such as joint and muscle pain and headache (26, 27). Differently from most cytokines, which exert their actions primarily through paracrine and/or autocrine mechanisms, IL-6 is a circulating molecule with classic endocrine activity, whose plasma levels increase with age, are influenced by estrogens, and correlate with body mass index (BMI) (28, 29). In healthy individuals, IL-6 concentrations show a characteristic circadian pattern, with zenith during sleep hours, between 0100 and 0500 h, and nadir during morning hours, between 0800 and 1000 h; a secondary peak between 1700 and 1900 h has also been reported (30, 31, 32, 33).

Elevated levels of plasma IL-6, assessed by single morning measurements, have been previously reported in subjects with MDD (34, 35, 36). However, these reports overlooked the contribution of potential confounders, such as age, gender, and body composition, to this biological abnormality. Furthermore, they relied on a single-time-point measurement of IL-6, undermining important temporal considerations. To overcome these limitations, we compared plasma IL-6 levels, measured hourly around the clock, in patients with MDD and healthy controls, individually matched by gender, age, and BMI. Additionally, considering the relevance of HPA axis dysregulation in patients with MDD, and the activating role of IL-6 on the HPA axis, we also analyzed the relationship between IL-6 and cortisol secretion in our study groups.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Experimental subjects

Nine (five females and four males) depressed patients (age, 34.7 ± 9.5 yr; BMI, 26.0 ± 3.8 kg/m2, mean ± SD) and nine healthy subjects (age, 34.3 ± 8.9 yr; BMI, 25.8 ± 3.0 kg/m2), individually matched by gender, age (±5 yr), and BMI (±2 kg/m2), were enrolled in the study after obtaining written informed consent. Diagnosis of MDD was confirmed by structured clinical interview based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), Axis I diagnostic criteria. Patients with comorbid anxiety, eating disorders, substance abuse, or psychotic disorders were excluded.

Healthy volunteers, recruited through the National Institutes of Health normal volunteer program, had no past, present, or family history of major psychiatric disorders, and had never received any psychotropic drugs. Both depressed and normal subjects had been free of any infection, inflammation, and allergic reactions and had not been taking hormonal preparations (including glucocorticoids and estrogens) or other drugs known to affect the immune system, for at least 2 wk before the study. While on the study, healthy controls were medication-free, whereas depressed patients were allowed antidepressant treatment only for ethical reasons. Upon admission to the study unit, all participants had their medical history recorded and received a routine physical examination after informed consent was obtained. A battery of clinical tests (including urinalysis, complete blood count, renal and liver function tests, mineral panel, thyroid indices, chest x-ray, and electrocardiogram) were negative for abnormal findings. Individuals with a positive pregnancy or HIV test were excluded from the study. All of the recruited women were premenopausal and were studied only in the follicular phase of their menstrual cycle. During the course of the study, all participants were kept on a nutritionally balanced standardized diet, with 20% of total calories given at breakfast (0800 h; clock hour), 40% at lunch (1300 h), and 40% at dinner (1800 h). Subjects were not restricted in their water intake but were required to abstain from tobacco, alcohol, drugs, and strenuous physical activity. During the study, participants were active by day, with bed rest between 2200 and 0700 h. The study was approved by the National Institute of Mental Health Institutional Review Board and conducted in accordance with The Declaration of Helsinki guidelines.

Self-rated mood assessment by multiple visual analog scale (MVAS)

Subjects’ perception of current mood state was assessed by a 10-item VAS-based questionnaire, to allow self-report according to the DSM-IV criteria for MDD (Fig. 1Go). The VAS is a convenient, well-validated instrument used in behavioral sciences for both short-term mood assessment, and long-term mood monitoring. The typical VAS is a horizontal line of 100 mm in length anchored by two words at each end describing the extremes of the symptom in question. Subjects are asked to mark the line at the point they feel represents better their current perception of the symptom. The VAS score is determined by measuring the millimeters from the left end of the line to the point marked by the patients (37, 38). Our MVAS was designed to assess self-perception of the following feelings: sadness, withdrawal, guilt, tiredness, appetite, craving, concentration, self-esteem, suicidal thoughts, and physical discomfort (Fig. 1Go). MVAS was administered to the study subjects every hour between 0800 and 2300 h.



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  		FIG. 1. Layout of the MVAS used for self-rating mood assessment. Study subjects were asked to mark the 100-mm lines at the point they felt better represented their current perception of the correspondent feeling. VAS scores were determined by measuring the millimeters from the left end of the line to the point marked by the subject.

 
Blood collection

Twenty-four-hour blood sampling was performed serially between 0800 and 0800 h on the following day. A small catheter was inserted in the subjects’ forearm about 30 min before the first blood sample was withdrawn and connected through an iv line, perfused with normal saline solution (0.9% NaCl), to the venous/arterial blood management protection system (Baxter Health Care Corp., Edwards Critical Care Division, Irvine, CA). This device avoids mixing of blood samples with normal saline when undiluted blood is withdrawn from an inline sampling site; at the same time, it allows reinfusion of the serum/blood solution, retained in the system’s reservoir, to minimize fluid loss. Blood was collected into prechilled EDTA-containing tubes. After separation by centrifugation, plasma was immediately stored at –70 C until being thawed for assays.

IL-6 assay

IL-6 was measured in plasma samples collected between 0900 and 0700 h by a specific high-sensitivity solid-phase ELISA (R&D Systems, Minneapolis, MN). The intra- and interassay coefficients of variation ranged from 5.6–6.1% and from 7.5–10.4%, respectively. The lowest detection limit was 0.094 pg/ml (0.0123 IU/ml). Each determination was performed in duplicate, and average values were used for statistical analyses.

Cortisol assay

Cortisol was measured in plasma samples collected between 0830 and 0630 h by a chemiluminescence-based assay (Nichols Institute Diagnostics, San Juan Capistrano, CA). The interassay coefficients of variation were 18.3% at a dose level of 3.50 µg/dl (96.56 nmol/liter), 16.7% at a dose level of 6.35 µg/dl (175.33 nmol/liter), and 13.0% at a dose level of 10.26 µg/dl (283.07 nmol/liter). The lowest detection limit was 0.9 µg/dl (24.83 nmol/liter). Each determination was performed once, because our previous experience with this system had indicated that its reliability was sufficiently high to avoid duplicate measurements.

Data analyses

Individual IL-6 time series were initially displayed in chronograms (x-y plots) to inspect the data for patterns, trends, and/or outliers, followed by the testing of experimental data for normal distribution and equal variance. The log-transformed data were analyzed in a repeated-measures mixed model, with tests for the effect of group, time, and group-by-time interaction, using SAS PROC MIXED (SAS Institute Inc., Cary, NC). A significant interaction was followed by post hoc tests on least-square mean differences at each time. Between-group differences in IL-6 and cortisol daily minimum and maximum values and daily average change (i.e. the average difference between maximum and minimum values) were analyzed by unpaired Student’s t test. The level of statistical significance was set at P < 0.05.

The circadian rhythmicity of IL-6 secretion was tested by both single and multiple component cosinor analyses (39). Data were analyzed after transformation into percentages of mean values (40). A P value for the rejection of the zero amplitude assumption (i.e. no rhythm) was calculated, with rhythm detection considered statistically significant at P ≤ 0.05. Chronobiological parameters obtained from the best-fitting cosine curves included mesor (i.e. the mean level of the best-fitting cosine curve, representing an adjusted 24-h average), acrophase (i.e. the phase angle/time of peak of the best-fitting cosine curve with a single period), orthophase and bathyphase (i.e. the phase angle/time of peak and trough of the best-fitting cosine curve with two or more periods, respectively), and amplitude (i.e. half the difference between peak and trough of the best-fitting cosine curve) (39).

Time-ordered relationships between IL-6 and cortisol were analyzed by cross-correlation analyses. Cross-correlation was computed at various time lags covering the 24-h period, by leading or lagging the concentration-time series of IL-6 relative to the concentration-time series of cortisol. The mean of the coefficients of correlation Rx between IL-6 and cortisol concentration-time series at lag time x in depressed patients and controls was considered significant when exceeding zero by more than two times the SEM of the within-group mean correlation at that lag (two-tailed P < 0.05) (41).

The complexity of IL-6 secretion was analyzed with approximate entropy (ApEn) algorithms. ApEn is a measure of the orderliness/regularity of sequential measures, such as hormone time series. Lower ApEn values correspond to greater regularity (42). More technically, ApEn measures the log likelihood that runs of patterns in a time series, which are close together within a width of r (tolerance factor of the data sets) for m (length vector) contiguous observations, remain close together on subsequent incremental comparisons (43). Serial IL-6 data were assessed with ApEn algorithms using empirical statistics based on a Monte Carlo procedure (42). Input parameters were set at m = 1 and r = 35% SD of the individuals’ time series, values that are considered appropriate for the number of measurements in this time series (43). The ratio of the mean observed ApEn to random ApEn was calculated after shuffling the data with 1000 Monte Carlo cycles (44). The relation between the complexity of IL-6 and cortisol secretion was evaluated by cross-ApEn algorithms. Cross-ApEn is an inverse measure of the likelihood of predictability (or regularity) of two time series of data being in synchrony. For the implementation of cross-ApEn calculations, we used the same input parameters of m and r and the same procedures used to compute ApEn (44). Comparisons of ApEn and cross-ApEn between control and depressed subjects were tested for significance with the unpaired Student’s t test.

Correlations between daily (0900–2300 h) mean log-transformed IL-6 levels and MVAS scores were tested using Pearson’s correlations and linear regression.

Unless otherwise specified, all results are presented as mean ± SEM.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Significant diurnal increase of plasma IL-6 levels in MDD patients

Six (four females and two males) of nine patients met the DSM-IV criteria for current MDD; the remaining three patients (one female and two males) met the DSM-IV criteria for MDD in remission. Both depressed patients and healthy controls had significant daily variations in plasma IL-6 levels. In the repeated-measures analysis, the group-by-time interaction was significant (F21,328 = 1.92; P < 0.01), as a result of MDD patients showing higher IL-6 from 1000–1200 h and at 1500 h, but no significant differences at other times, compared with healthy controls. The greatest elevation was at noon [6.5 ± 1.3 vs. 2.7 ± 0.8 pg/ml (0.85 ± 0.17 vs. 0.35 ± 0.02 IU/ml); t = 3.15; P = 0.002] (Fig. 2AGo). Overall mean 24-h IL-6 levels did not differ significantly between depressed and controls [4.7 ± 0.7 vs. 3.4 ± 0.8 pg/ml (0.61 ± 0.09 vs. 0.44 ± 0.10 IU/ml); F1,16 = 1.51; P = 0.24]. IL-6 daily minimum values were also similar in the two groups [1.8 ± 0.3 vs. 1.6 ± 0.5 (0.23 ± 0.04 vs. 0.21 ± 0.06); P = 0.72). Daily maximum values and average change were greater in depressed subjects [9.6 ± 1.9 (1.25 ± 0.25) and 7.8 ± 1.8 (1.02 ± 0.23), respectively] than in healthy subjects [6.3 ± 0.9 (0.82 ± 0.12) and 4.6 ± 1.6 (0.60 ± 0.20), respectively), but these differences did not reach statistical significance (P = 0.13 and P = 0.12, respectively).



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  		FIG. 2. Mean chronograms of plasma IL-6 (A) and cortisol (B) levels measured over 24 h in patients with MDD and age-, gender-, and BMI-matched controls. A significant group-by-time interaction in repeated-measures ANOVA, followed by post hoc t tests at each time point, showed significant IL-6 elevation from 1000–1200 h and at 1500 h, and cortisol decrease from 2230–0030 h and at 0430 h in MDD patients, compared with controls. Results are presented as mean ± SEM in metric units (conversion factors to SI units: IL-6, 0.131; cortisol, 27.5862). *, P < 0.05; **, P < 0.01.

 
Because of the limited plasma sample availability in two subjects, we were able to measure cortisol only in eight depressed patients and matched controls. Significant daily variations in plasma cortisol levels were detected in both MDD and controls. In the repeated-measures analysis, the group-by-time interaction was significant (F22,260 = 2.00; P < 0.007), as a result of MDD patients showing lower cortisol from 2230–0030 h and at 0430 h, but similar values at other times, compared with healthy controls. Overall mean 24-h cortisol levels did not differ significantly between depressed patients and controls [5.84 ± 0.39 vs. 6.38 ± 0.39 µg/dl (161.1 ± 10.8 vs. 176.0 ± 10.8 nmol/liter); F1,12 = 3.69; P < 0.08]. In addition, depressed and control subjects did not differ significantly in cortisol daily minimum values [1.54 ± 0.27 vs. 2.21 ± 0.37 (42.5 ± 7.5 vs. 60.9 ± 10.2); P = 0.17], maximum values [12.9 ± 1.38 vs. 13.4 ± 0.65 (355.9 ± 38.0 vs. 369.7 ± 17.9); P = 0.74], or average change [11.3 ± 1.2 vs. 11.2 ± 0.5 (311.7 ± 33.1 vs. 309.0 ± 13.8); P = 0.91].

Phase-shift of the IL-6 circadian rhythm in MDD patients

Population mean cosinor analyses showed a phase shift of the IL-6 circadian rhythm in depressed subjects compared with controls. The orthophase of the best-fitting multiple component cosine curve was located at –6° (0024 h clock hour) in controls, and at –173° (1132 h) in depressed patients; the corresponding bathyphase values were –228° (1512 h) and –66° (0424 h) (Fig. 3AGo). The acrophase of the best-fitting 24-h single cosine curve was located at –38° (0231 h) in controls, with 95% confidence limits from –358° (2352 h) to –77° (0507 h) and amplitude of 13.6 ± 3.4%. The corresponding acrophase value in depressed patients was –207° (1348 h), with 95% confidence limits from –151° (1004 h) to –263° (1732 h) and amplitude of 16.6 ± 3.5% (Fig. 3BGo).



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  		FIG. 3. Population mean multiple-component cosinor analysis of the 24-h IL-6 (A) and cortisol (C) secretion showed a phase shift of the IL-6 circadian rhythm (but not of the cortisol rhythm) in MDD patients (red) compared with nondepressed controls (black), with orthophase in morning hours and bathyphase at nighttime (A). Confirmation and a more direct view of these findings was given by polar graphs of the 24-h IL-6 (B) and cortisol (D) best-fitting single cosine curve. The length of the vector represents the amplitude, whereas its orientation along the circular scale, in relation to the selected time/degree reference, represents the acrophase. The ellipse around the tip of the vector represents the 95% confidence region for the joint estimation of amplitude and acrophase.

 
In contrast to IL-6, population mean cosinor analyses indicated very similar cortisol circadian rhythms in MDD patients and controls. The orthophase of the best-fitting multiple component cosine curve, based on mean cortisol values at each time point, was located at –103° (0652 h) in controls and at –98° (0632 h) in depressed patients; the corresponding bathyphase values were –3° (0012 h) and –355° (2340 h) (Fig. 3CGo). The mean acrophase of the best-fitting 24-h single cosine curve was located at –135° (0900 h) in controls, with 95% confidence limits from –121° (0804 h) to –149° (0956 h) and amplitude of 49.0 ± 5.7%. The corresponding acrophase value in depressed patients was –150° (0959 h), with 95% confidence limits from –131° (0844 h) to –169° (1116 h) and amplitude of 47 ± 7.4% (Fig. 3DGo). In individual cosinor analyses, every subject had a significant cortisol cosinor pattern, and every control and six of eight MDD patients had cortisol orthophase between 0600 and 1000 h. However, the cosinor patterns of IL-6 secretion were by no means as regular as those of cortisol. Seven of eight controls, but only five of the eight depressed patients with cortisol measurements, had a significant daily rhythm in IL-6 (data not shown).

Loss of time-ordered relations between IL-6 and cortisol levels in MDD patients

A significant positive mean correlation was observed between IL-6 and cortisol in healthy subjects at lag times of –6 to –7 h, reflecting the IL-6 orthophase preceding that of cortisol by approximately 6 h (Fig. 4AGo). No significant lag correlation was observed in MDD patients (Fig. 4BGo).



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  		FIG. 4. Cross-correlation analysis of IL-6 and cortisol secretion in nondepressed (A) and MDD (B) subjects. The solid line represents the mean of the individual values of the correlation coefficients Rx for each subject at lag time x. The shaded area corresponds to 2 SEM below and above the zero of the within-group mean correlation at that lag and represents the limits of significance of the correlation (P = 0.05). At any lag time, a significant correlation is represented by falling of the solid line outside the shaded area.

 
Reduced complexity of IL-6 secretion in MDD patients

The ApEn of IL-6 time series was significantly lower in depressed patients than in controls (0.828 ± 0.029 vs. 0.963 ± 0.024; P < 0.05). The ratio of the observed ApEn to random ApEn values was also lower in depressed than in nondepressed subjects (0.839 ± 0.022 vs. 0.977 ± 0.025; P < 0.02). The ApEn of cortisol secretion was not significantly different in depressed patients and controls (0.876 ± 0.041 vs. 0.871 ± 0.043), although the ratio of the observed ApEn was significantly higher in the depressed compared with the nondepressed (0.811 ± 0.052 vs. 0.648 ± 0.048; P < 0.01). The cross-ApEn of IL-6 and cortisol was not different between patients with MDD and control subjects (0.982 ± 0.056 vs. 0.973 ± 0.070; P > 0.05); neither was the ratio of observed to random cross-ApEn (1.052 ± 0.064 vs. 1.042 ± 0.052; P > 0.05).

Significant correlations between IL-6 levels and MVAS scores

Only five MDD patients and matched controls completed the administered MVAS. Because of the small number of subjects, correlations between daily (0900–2300 h) mean IL-6 levels and MVAS scores were tested in the pooled subject population. IL-6 correlated significantly with concentration, guilt, sadness, self-esteem, suicidal thoughts, and tiredness (Fig. 5Go, A–F). A trend was observed for appetite (P = 0.07), whereas no significant correlations were found between IL-6 and craving for sweets/starches, withdrawal, and physical discomfort (data not shown). IL-6 remained significantly correlated with guilt, self-esteem, and suicidal thoughts after Bonferroni correction.



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  		FIG. 5. Correlations between daily (0900–2300 h) mean log-transformed plasma IL-6 levels and VAS scores for concentration (A), guilt (B), sadness (C), self-esteem (D), suicidal thoughts (E), and tiredness (F) in five MDD patients and matched controls. Note that for each measure, a lower VAS score denoted a worse feeling (see also Fig. 1Go). *, Correlations of IL-6 with guilt, self-esteem, and suicidal thoughts remained significant after Bonferroni correction.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
We have shown that, compared with nondepressed healthy subjects, patients with diagnosis of MDD had significantly increased morning levels of plasma IL-6, in the absence of morning cortisol abnormalities. Furthermore, the circadian pattern of IL-6 secretion was markedly different between MDD and control subjects, with virtually antithetical acrophases and loss of physiological complexity in the depressed patients, who, however, had normal cortisol rhythm. To avoid artifacts of age, gender, BMI, or phase of the menstrual cycle, every MDD patient was carefully matched to a control. Tight age matching was important, considering the significant increase of plasma IL-6 concentrations with age (28). Close BMI matching was also crucial, in light of the fact that in humans 30% or more of circulating IL-6 derives from the adipose tissue, and therefore IL-6 levels correlate closely with BMI (29). Matching all women enrolled in the study for phase of the menstrual cycle was also relevant, given the substantial influence of estrogens on IL-6 secretion (25).

Depressed patients have a doubling in the mortality and relative risk of premature coronary heart disease at any age, independent of smoking, excess body weight, hypertension, and other cardiac risk factors. Moreover, patients with coronary heart disease and MDD have a 2- to 3-fold increased risk for future cardiac events compared with patients with coronary heart disease but without MDD, independent of baseline cardiac dysfunction (5, 6, 7). Epidemiological studies have revealed that elevated concentrations of IL-6 are highly predictive of cardiovascular morbidity and mortality, independently of the traditional risk factors (22). In healthy men, for each quartile increase in plasma IL-6, there was a 38% increase in the risk of developing myocardial infarction. This relationship remained significant after adjustment for other cardiovascular risk factors, was present in all low-risk subgroups, including nonsmokers, and was stable over long periods of follow-up (45). We suggest that the substantial morning increase in plasma IL-6 levels might contribute to promote and hasten the premature development of cardiovascular disease in MDD patients by sustaining a proinflammatory and prothrombotic state. Thus, diurnal plasma IL-6 levels may correlate with future cardiovascular morbidity in MDD patients and predict its unfavorable outcome.

There is increasing evidence that MDD is an independent risk factor for osteopenia and osteoporosis (8, 9, 10). We previously reported that, compared with nondepressed healthy women matched by age, BMI, menopausal status, and ethnicity, women with a past or current history of MDD had significantly lower bone mineral density (BMD) (8). In women in the first decade of menopause, serum IL-6 is the single most important predictor of femoral bone loss, accounting for up to 34% of the total variability of change in BMD and with a predicted annual 1.34% decrease in total hip BMD per log unit increase in serum IL-6 (46). IL-6 serum levels are also a strong predictor of yearly femoral bone loss in patients with untreated hyperparathyroidism (47). Thus, IL-6 may be an important predictor and pathogenic factor in depression-associated bone loss.

In humans, peripheral IL-6 concentrations are related to the sleep-wake cycle. Different IL-6 zenith and nadir values in healthy individuals have been previously reported, sometimes by the same group, in independent studies. In most cases, a major IL-6 peak was detected during sleep hours, between 0100 and 0500 h, and a major trough during morning hours, between 0800 and 1000 h; a secondary peak between 1700 and 1900 h was also described (30, 31, 32, 33). In our study, the mean IL-6 zenith in healthy controls was around 0200 h, which is within the range of previously reported values, whereas the mean IL-6 nadir occurred at 1512 h rather than during morning hours; no secondary peaks were detected. This apparent discrepancy between our and previous findings may be related to differences in the gender and age distribution of the study subjects, as well as in the experimental design and control of the study conditions.

More importantly, our study revealed a 12-h shift in the circadian rhythm of IL-6 (but not in that of cortisol) in MDD patients compared with controls, with zenith during wake hours and nadir during sleep hours. Although the pathogenic significance of this phenomenon is unclear, an analogous, albeit chronobiologically different, phase shift in IL-6 secretion was described in chronic insomniacs, as well as in healthy individuals after sleep deprivation, and was linked to daylong fatigue and poor concentration (31, 32). Sleep abnormalities, frequently associated with MDD, and/or comorbid sleep disorder may have contributed to the morning elevations and phase shift of IL-6 secretion observed in our patients. Interestingly, a significant correlation of IL-6 levels with fatigue and poor concentration was found in our study. It is known that the neuropsychological and mood impairment of depressed patients is typically worse in the morning and improves in the evening (48). This circadian pattern may reflect the above described chronobiological abnormality in IL-6 secretion, which may be one component of a more generalized dysregulation of biological rhythms. Indeed, MDD has been previously linked to circadian alterations of various physiological parameters (49, 50). By disrupting phase relationships between biological mediators and creating conflicts between external time clues and internal set points, this dysrhythmia may impair motivation, cognition, alertness, and affect in depressed patients, requiring appropriate corrective chronotherapies.

MDD and the stress response share similar circuitries, mediators, and phenomena (2, 3, 4). Stressful experiences and negative emotions can directly stimulate the release of IL-6, a potent activator of the HPA axis and sympathetic nervous system, two key components of the stress system (12, 13, 14, 15, 16, 17). Our observation of increased and dysregulated IL-6 levels in patients with MDD, who did not manifest significant cortisol hypersecretion, indicate that increased morning IL-6 may be a more consistent marker of chronic stress than cortisol in MDD, even in patients who are in remission. Alternatively, it is conceivable that lifting the inhibitory effect of hypercortisolism on IL-6 secretion may allow increases in the circulating levels of this cytokine, which may thus appear more pronounced because of a state of relative hypocortisolism. The lower mean nighttime cortisol levels in our MDD patients might be explained by the fact that some of them were in remission. Longitudinal studies of patients with MDD before and after treatment may help clarify this issue.

Previous evaluation of time-ordered relations between IL-6 and cortisol secretion have shown significant time-lagged cross-correlations in a small group of patients with rheumatoid arthritis, as reported by Crofford et al. (41). Similar relations in healthy individuals could not be analyzed in that study, because of the unavailability of a high-sensitivity IL-6 assay. In contrast, the use of a highly sensitive assay in our study enabled us to investigate and compare time-ordered relations between IL-6 and cortisol in both MDD patients and controls. We found that in healthy subjects the IL-6 peak precedes that of cortisol by approximately 6 h. Although cross-correlations do not establish cause-effect relations, this finding may indirectly suggest that under physiological conditions, IL-6 may stimulate a delayed cortisol release by the adrenal gland. The time-ordered relation between IL-6 and cortisol secretion was lost in MDD subjects. Although this finding may be indicative of a lost or compromised interaction between the secretions of these two molecules, it may be simply related to the greater individual variability of the IL-6 rhythm observed in MDD patients compared with controls. Seven of the eight controls, but only five of the eight matched depressed patients with both cortisol and IL-6 measurements had a significant daily IL-6 rhythm. Furthermore, the IL-6 orthophase varied individually from 7 h before to 5 h after the cortisol orthophase.

The physiological complexity of IL-6 secretion was reduced in MDD patients, as shown by the lower ApEn of their IL-6 time series compared with that of controls. Loss of complexity in hormone secretion occurs in age-related changes and disease. In postmenopausal women, increase in circulating gonadotropin levels is accompanied by a decrease in ApEn of gonadotropin secretion (51). Similarly, primary hyperprolactinemia is associated with decreased ApEn of prolactin secretion (52). By analogy, the reduced irregularity of IL-6 secretion in MDD may be another sign of its abnormal secretory behavior and the lost capacity for fine-tuning in response to simultaneous changes in other systems. Although harder to interpret, the lack of differences in the cross-ApEn of IL-6 and cortisol between MDD patients and controls might point to the partially preserved integrity of an interactive physiological relationship between these two mediators, even in an altered state.

Behavioral changes similar to those described in MDD patients have been reported in pathological states associated with significant and prolonged IL-6 elevation, such as infectious and autoimmune diseases, and malignancies, as well as in healthy individuals and cancer patients after IL-6 administration (53, 54, 55). In our pooled population of MDD and nondepressed subjects, IL-6 levels correlated significantly with most of the negative feelings commonly associated with MDD, including guilt, low self-esteem, sadness, and suicidal thoughts. Thus, IL-6 oversecretion may contribute to maintain and amplify some of the maladaptive behavioral changes of MDD. This hypothesis remains to be tested separately in the two groups in a larger study.

In conclusion, we have shown profound dysregulation of IL-6 secretion in patients with diagnosis of MDD. This biological abnormality may provide a link between the psychoneuroendocrine dysfunctions of MDD and its heightened comorbidity with coronary heart disease and osteoporosis. The prognostic, clinical, and therapeutic relevance of our findings, in addition to a better understanding of their cellular and molecular mechanisms, deserve further investigation.


   Footnotes
 
First Published Online February 10, 2005

1 S.A. and P.E.M. contributed equally to this study. Back

Abbreviations: ApEn, Approximate entropy; BMD, bone mineral density; BMI, body mass index; DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; HPA, hypothalamic-pituitary-adrenal; MDD, major depressive disorder; MVAS, multiple visual analog scale.

Received August 19, 2004.

Accepted January 28, 2005.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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