Sleep disturbances and depressed mood: A harmful combination associated with increased leptin levels in women with normal weight

Biological Psychology 89 (2012) 163–169

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Sleep disturbances and depressed mood: A harmful combination associated with increased leptin levels in women with normal weight S. Häfner a,b,1 , J. Baumert a,1 , R.T. Emeny a,1 , M.E. Lacruz a,1 , B. Thorand a,1 , C. Herder c,1 , W. Koenig d,1 , R. Rupprecht b,1 , K.H. Ladwig a,e,∗,1 a

Helmholtz Zentrum München, German Research Center for Environmental Health, Institute of Epidemiology, 85764 Neuherberg, Germany Department of Psychiatry and Psychotherapy, Ludwig-Maximilian-University Munich, Munich, Germany c Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Duesseldorf, 40225 Duesseldorf, Germany d Department for Internal Medicine II – Cardiology, University Hospital 89081 Ulm, Germany e Department of Psychosomatic Medicine and Psychotherapy, University Hospital, Technical University, Munich, Germany b

a r t i c l e

i n f o

Article history: Received 21 September 2010 Accepted 7 October 2011 Available online 19 October 2011 Keywords: Leptin Depressed mood Sleep disturbances Gender and weight effects

a b s t r a c t Leptin, involved in energy regulation and contributor to cardiovascular disease, has been implicated to play a role in depression and sleep disturbances, two closely intertwined conditions. Previous results investigating leptin level alterations either in sleep disorders or in depression have been inconsistent. We investigate the association between leptin levels and the different combinations of depressed mood and sleep disturbances in 1369 subjects (706 men, 663 women), derived from the population-based MONIKA/KORA study. As leptin regulation is known to differ by sex and weight, analyses were performed in normal weight and overweight men and women separately. We found a highly significant association between leptin levels and the combination of depressed mood and sleep disturbances in normal-weight women (BMI ≤ 25) (p < 0.01). No associations were found in men and in overweight women. Our results suggest that leptin regulation in depressed mood and sleep disturbances very much depend on sex and weight. © 2011 Elsevier B.V. All rights reserved.

1. Introduction Depression is a recognized risk factor for coronary heart disease-related morbidity and mortality (Carney et al., 2004). Sleep disturbances have historically been added to the symptomatology of depression, but also, in the absence of depressive symptoms they have a harmful impact on metabolic and endocrine function (Spiegel et al., 1999, 2009) leading to an increased risk for obesity and cardiovascular disease (Hasler et al., 2004; Miller and Cappuccio, 2007). The adipose tissue derived hormone leptin, involved in energy regulation, and thought to contribute to cardiovascular disease (Romero-Corral et al., 2008; Soderberg et al., 1999; Wallace et al., 2001), has been investigated in both depression and sleep disorders. Previous studies in depression have yielded inconsistent

∗ Corresponding author at: German Research Center for Environmental Health, Institute of Epidemiology, Ingolstaedter Landstr. 1, 85764 Neuherberg, Germany. Tel.: +49 89 3187 3631; fax: +49 89 3187 3667. E-mail address: [email protected] (K.H. Ladwig). 1 For the MONICA/KORA Study Investigators. 0301-0511/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.biopsycho.2011.10.005

results with depression being associated with elevated (Antonijevic et al., 1998; Cizza et al., 2010; Rubin et al., 2002) as well as with decreased leptin levels (Jow et al., 2006; Kraus et al., 2001). The same inconsistency in results was found in studies investigating leptin in sleep disturbances and sleep curtailment. Sleep curtailment was found to be associated with decreased levels of leptin in one population-based study and in one small study investigating men (Spiegel et al., 2004; Taheri et al., 2004), whereas sleep curtailment in girls was found to be associated with increased leptin levels (Hitze et al., 2009). No difference of leptin levels was observed in sleep disturbances in men (Motivala et al., 2009). It is not unlikely that leptin regulation is involved in the pathomechanism that links sleep disturbances, as well as depression, with cardiovascular disease. To better understand the role of leptin in both conditions, we investigated whether sleep disturbances and depressed mood, alone or in combination, are associated with increased leptin levels. As leptin regulation is grossly disregulated in overweight individuals with an increase in leptin levels to the point of leptin resistance (Enriori et al., 2007; Knight et al., 2010), overweight and normal-weight individuals were analyzed separately.

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2. Research design and methods

variation were <10.0% (Karakas et al., 2010; Thorand et al., 2010). All analyses were run in a blinded fashion.

2.1. Settings The presented data were derived from the population-based MONICA Augsburg study (MONItoring of trends and determinants in CArdiovascular disease), conducted between 1984 and 1995 in the area of Augsburg, Southern Germany. The study was part of the multinational WHO MONICA project. Three independent crosssectional population-based surveys covering the city of Augsburg and the two adjacent countries were conducted in 1984/1985 (S1), 1989/1990 (S2) and 1994/1995 (S3) to estimate the prevalence and distribution of cardiovascular risk factors. A total number of 13,427 participants (6725 men, 6702 women) in the age range from 25 to 74 years were recruited. Two stage cluster sampling was applied (Lowel et al., 2005). Written informed consent was obtained from each study participant and the study was approved by the local authorities.

2.2. Study group Initially a case–cohort study (Thorand et al., 2005) was designed, in order to study the role of biomarkers in the development of CHD and type 2 diabetes. Out of the source population of 9531 eligible MONICA S1–S3 participants, aged 35–74 years with available blood sample at baseline, a subsample of 2225 participants (1206 men, 1019 women) was randomly selected, stratified by sex and survey. In this subsample, leptin levels as well as an array of biomarkers were assessed. In order to obtain a study population without chronic diseases, individuals with a history of stroke, myocardial infarction, diabetes, cancer and heart failure (n = 343) were excluded, leaving a data set of 1882 participants. Furthermore, participants with missing data on biomarkers and relevant covariates (n = 513) were excluded, leaving a final data set of n = 1369 (706 men, 663 women). This data set was used for cross sectional analyses. The survey numbers of men and women were 232/239, 292/229, 195/182 for S1, S2, and S3, respectively. The sample sizes for the subsample by survey were used together with the stratum-specific sizes of the 35–74 year old source population to compute sampling fractions. The inverse of the sampling fractions yielded the survey- and sex-specific sampling weights.

2.3. Assessment of metabolic covariates Participants underwent standardized medical examinations including collection of a nonfasting venous blood sample. Assessment procedures have been described elsewhere (Meisinger et al., 2002) Total serum cholesterol and HDL cholesterol were measured by enzymatic methods (CHOD-PAP, Boehringer Mannheim, Germany). CRP concentrations were measured using a high-sensitivity immunoradiometric assay (IRMA) (range 0.05–10 mg/dl) (men aged 45–64 years) or a high sensitivity latex-enhanced nephelometric assay run on a BN II analyser (DADE Behring, Marburg, Germany) (men aged 35–44 years and all women). Similar results were obtained when the same samples were analyzed by both methods (Khuseyinova et al., 2003). The intra- and inter-assay CVs of quality control tests sera for CRP was 4.0 and 12% for the IRMA and 2.5% and 5.1% for the nephelometric assay, respectively.

2.4. Assessment of leptin levels Serum leptin levels were determined using ELISAs from Mercodia, Uppsala, Sweden. The intra- and inter-assay coefficients of

2.5. Assessment of behavioural risk factors and psychosocial factors Information on behavioural risk factors was obtained in standardized personal interviews at the time of the respective survey (S1: 1984/1985, S2: 1989/1990, S3: 1994/1995), conducted by trained medical staff and a self administered questionnaire. Participants were asked to provide details on their health behaviours concerning smoking, alcohol consumption, physical activity and nutrition. In addition, information regarding a participant’s housing situation and income were assessed. Low income: Income was measured in classes (Mackenbach et al., 2005). Equivalent household income was calculated according to the formula used in the Luxembourg Income Study (Buhmann et al., 1988; Mackenbach et al., 1997). To make the incomes comparable, values were adjusted to the prices of 1995, with factors obtained from the German socio-economic panel monitor (Haisken-DeNew and Frick, 2007). The lowest income group comprised subjects whose household income was lower than or equal to 60% of the median, corresponding to the European Union definition of at-riskof-poverty threshold. 2.6. Assessment of psychosomatic factors Information about psychosomatic symptoms was acquired through a self-administered questionnaire. Somatic complaints were measured with the “von Zerssen’s symptom check list” (Zerssen, 1976). High somatic complaints were defined as having 7 or more symptoms out of a list of 24. Negative self perceived health was directly assessed by one item with a poor health condition indicated by the highest rating. Sleep disturbances were assessed by two separate 3-category interview questions, adopted from the Uppsala Sleep Inventory (Mallon et al., 2002), asking for difficulties initiating sleep (“Do you have trouble falling asleep?”) and for difficulties maintaining sleep (“Do you wake up during the night?”). The three possible answers were “sometimes”, “often” and “almost never”. Subjects who claimed to sometimes have difficulties falling asleep and maintaining sleep, or to often have difficulties falling asleep or/and maintaining sleep were combined into the category “sleep disturbances”. Depressive symptomatology was assessed by the DEpression and EXhaustion subscale (DEEX scale). The scale combines eight items (fatigability, tiredness, irritability, loss of energy, difficulty in concentrating, inner tension, nervousness, and anxiety) rated from 0 to 3, leading to a score of 24. Subjects in the top third of the depressive symptom distribution were considered as the index group with a depressed mood. Sex-specific cut-off points were applied (≥12 for women, and ≥10 for men) (Ladwig et al., 2004). 2.7. Statistical analysis Skewed variables (leptin, CRP, HDL-cholesterol, total cholesterol) were log-transformed to obtain a normal distribution. All analyses were then carried out with log-transformed variables. Means and proportions for baseline demographic characteristics, metabolic characteristics, behavioural risk factors and psychosomatic symptoms were computed using the categories “no depressed symptomatology, no sleep disturbances” (DS−, SD−), “depressed symptomatology, sleep disturbances” (DS+, SD−), “depressed symptomatology, no sleep disturbances” (DS+, SD−), “depressed symptomatology, sleep disturbances” (DS+, SD−). Differences in means were tested with ANOVA, differences in proportions were tested with 2 test.

S. Häfner et al. / Biological Psychology 89 (2012) 163–169

Because of significant sex differences in leptin levels (p < 0.001) all analyses were performed separately in men and women. First, a raw model was calculated to test for the association between leptin and sleep disturbances and depressed mood without accounting for effect modification. This model was adjusted for age, BMI and survey. Log-transformed leptin was used as outcome variable. Then, a second model was calculated to account for all possible effect modifications. The interaction terms DS × SD, SD × obesity, DS × obesity and DS × SD × obesity were included. The model was adjusted for age and survey. Then four different models of multiple linear regression were calculated to investigate the association of the four different combinations of sleep disturbances and depressed symptomatology with leptin levels. The category “no sleep disturbances, no depressed symptomatology” was taken as reference category. The first model was adjusted for age, survey and BMI. The second was additionally adjusted for clinical or metabolic variables (heart rate, systolic blood pressure, total cholesterol/HDL-cholesterol ratio and CRP), the third was additionally adjusted for behavioural and psychosocial factors (smoking, physical activity, alcohol intake, unhealthy diet and low income) and the fourth model was additionally adjusted for psychosomatic factors (somatic complaints and negative self-perceived health). Having found overweight to modify the effect of the combination of depressed symptomatology and sleep disturbances, we repeated the multiple linear regression analyses stratified by weight (BMI ≤ 25 kg/m2 versus BMI >25 kg/m2 ). Furthermore, linear regression analysis was conducted to calculate the correlation between log-transformed leptin and the cardiovascular risk factors systolic and diastolic blood pressure, heart rate, CRP, and cholesterol. Every linear regression analysis was adjusted for age, sex, and survey. Sex-specific means in the different groups were calculated in normal-weight individuals versus overweight individuals. Means were adjusted for age and survey. Differences between adjusted means of leptin levels in each risk group and the adjusted mean in the reference group were tested by t test. To test the assumption that different degrees of depressed symptomatology are the underlying cause for any effect of the combination of depressed mood and sleep disturbances compared to the effect of depressed mood alone, we tested for a dose–response relationship between depressive symptomatology and leptin levels in men and women using Pearson’s correlation coefficient between log-transformed leptin levels and a continuous measure of depressive symptomatology. For the dose–response analysis the sum of scores in the DEEX scale was used as a continuous measure. Because the data on sleep in this study is subjective, some biases on the categorization due to individual reports can be assumed. To check the precision of individual reports about sleeping difficulties, we reanalyzed data using a new categorization in which only individuals who complaint having often sleep disturbances were comprised in the group having sleep disturbances and individuals having almost never sleep disturbances were comprised to the group having no sleep disturbances. For all calculations sex- and survey-specific sampling weights were used. SAS (V9.1) was used for statistical analysis with a significance level of p < 0.05 (SAS Institute, Carey, North Carolina).

3. Results 3.1. Descriptive analysis Among 1369 subjects, a number of 609 subjects who were neither depressed nor suffered sleep disturbances comprised the “no sleep disturbances, not depressed” category. This group served as

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the reference group for the following three risk groups under investigation: a group of 252 subjects suffering sleep disturbances but without depressed mood, a group of 247 subjects with no sleep disturbances but depressed mood, and a group of 261 subjects suffering sleep disturbances as well as depressed mood. Characteristics of the study population divided by categories of different combinations of sleep disturbances and depressed mood are displayed in Table 1. Subjects with sleep disturbances, with or without depressed mood, were older than subjects without sleep disturbances and had higher levels of total cholesterol. Subjects of all three risk groups reported a higher level of somatic symptoms and perceived themselves to be less healthy compared to subjects without sleep disturbances and depressed mood with the highest proportion of subjects with somatic complaints and negative self-perceived health in the category “depressed mood, sleep disturbances”. Subjects in this group also reported to be less often physically active.

3.2. Association between leptin and depressed symptomatology and sleep disturbances Neither the association between depressed symptomatology and leptin levels (p = 0.52 in women, p = 0.17 in men), nor the association between sleep disturbances and leptin levels were significant (p = 0.08 in women, p = 0.81 in men). Data are not shown. 3.3. Interactions depressed symptomatology × sleep disturbances, depressed symptomatology × obesity, obesity × sleep disturbances and depressed symptomatology × sleep disturbances × obesity The interaction depressed symptomatology × sleep disturbances, depressed symptomatology × obesity, obesity × sleep disturbances and depressed mood × sleep disturbances × obesity were tested in a multiple regression adjusting for age and survey. The interaction terms depressed symptomatology × sleep disturbances × obesity (p = 0.02) and depressed × sleep disturbances were significant in women (p < 0.001) but not in men. In men, the interaction term sleep disturbances × obesity was significant (p = 0.04). Data are not shown.

3.4. Association between depressed symptomatology, sleep disturbances and the combination of both with leptin levels In the multiple linear regression analyses a significant association between the combination of depressed mood and sleep disturbances and leptin was found only in women in model 4 (Table 2).

3.5. Association between depressed symptomatology, sleep disturbances and the combination of both with leptin levels, stratified by obesity After stratifying women by weight (BMI ≤ 25 kg/m2 versus BMI > 25 kg/m2 ), the association between the combination of depressed mood and sleep disturbances and leptin levels became highly significant in women with a BMI ≤ 25 kg/m2 (p < 0.01), whereas no association was found in women with a BMI >25 kg/m2 (p = 0.98). Sleep disturbances or depressed mood alone was not associated with leptin levels. In men, stratification by weight (BMI ≤ 25 kg/m2 versus BMI > 25 kg/m2 ) did not yield any significant association between leptin and the different combinations of depressed mood and sleep disturbances. Data of the analysis of men after stratification by weight are not shown.

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Table 1 Characteristics of study subjects (n = 1369), data are shown for each category of combining sleep disturbances and depressed mood. No depressed mood, no sleep disturbances Subjects, number 609 49.4 ± 0.43 Age (years) Female (%) 48.3 BMI 26.80 ± 0.17 Clinical factors 73.8 ± 0.42 Heart rate 132.9 ± 0.73 Systolic BP (mmHG) 81.9 ± 0.43 Diastolic BP (mmHg) Metabolic variables 229.00 ± 1.01 Cholesterol (mg/dl)a 54.64 ± 1.01 HDL (mg/dl)a 1.31 ± 1.05 CRP (mg/l)a Leptina (ng/ml) Men 5.0 ± 1.05 Women 15.2 ± 1.05 Behavioural risk factors and psychosocial factors 27.9 Current smoker (%) >20 g/40 g Alcohol/day (%) 31.5 53.9 Physically inactive (%) Unhealthy diet (%) 34.5 18.5 Lowest income (%) Psychosomatic symptoms 25.5 High somatic complaints (%) 10.3 Negative self perceived health (%)

No depressed mood, sleep disturbances

Depressed mood, no sleep disturbances

Depressed mood, sleep disturbances,

252 52.7 ± 0.61 62.5 26.90 ± 0.26

247 49.7 ± 0.67 53.9 26.71 ± 0.26

261 52.3 ± 0.62 48.2 26.40 ± 0.24

<0.001 <0.01 0.48

73.0 ± 0.67 133.0 ± 1.15 82.0 ± 0.71

73.5 ± 0.67 131.3 ± 1.15 81.2 ± 0.71

73.6 ± 0.66 131.4 ± 1.29 81.2 ± 0.73

0.77 0.53 0.74

238.13 ± 1.01 56.67 ± 1.02 1.38 ± 1.07

226.35 ± 1.01 54.10 ± 1.02 1.20 ± 1.08

233.7 ± 1.01 56.1 ± 1.02 1.3 ± 1.07

<0.01 0.21 0.65

4.8 ± 1.08 17.1 ± 1.06

4.6 ± 1.07 15.0 ± 1.08

4.2 ± 1.08 17.1 ± 1.06

0.23 0.25

19.9 26.0 55.9 27.8 24.0

30.7 27.6 60.3 34.1 14.3

22.4 26.4 66.2 35.2 15.6

0.02 0.26 <0.001 0.23 0.30

47.6 17.9

76.8 28.8

86.5 42.4

<0.001 <0.001

p-value

Data are expressed as arithmetic means ± SE or as percentage, unless otherwise indicated. p-Value for comparison across the different categories using ANOVA for continous variables and 2 for categorical variables. a Geometric mean ± SE.

3.6. Correlation between leptin and cardiovascular risk factors Linear regression analysis between leptin and cardiovascular risk factors revealed a significant association between leptin and CRP (ˇ-estimate = 0.23, p < 0.0001) leptin and total cholesterol/HDL ratio (ˇ-estimate = 0.60, p < 0.0001). The association between leptin and systolic blood pressure, leptin and diastolic blood pressure and leptin and heart rate were also significant but ˇ-estimates were all <0.02.

3.6.1. Comparison of adjusted mean leptin levels In women with a BMI ≤ 25 the difference in mean leptin levels was highly significant (leptin levels in the group “not depressed, no sleep disturbances”: 8.99 (CI: 7.97–10.14) ng/ml, leptin levels in the group “depressed, sleep disturbances: 11.44 (CI 9.88–13.24) ng/ml, p < 0.01 (Fig. 1), whereas in women with a BMI > 25 no significant differences between groups were seen. In men there were no significant differences at all. Data are not shown.

Table 2 Multiple linear regression between leptin and the categories of different combinations of sleep disturbances and depressed mood.

Men Model 1a Model 2b Model 3c Model 4d Women Model 1a Model 2b Model 3c Model 4d Women, BMI ≤ 25 n Model 1a Model 2b Model 3c Model 4d Women, BMI > 25 n Model 1a Model 2b Model 3c Model 4d

Depressed mood, no sleep disturbances

No depressed mood, sleep disturbances

Depressed mood, sleep disturbances

ˇ-estimate (SE)

ˇ-estimate (SE)

ˇ-estimate (SE)

p-Value

p-Value

p-Value

−0.08 (0.06) −0.07 (0.07) −0.09 (0.06) −0.09 (0.07)

0.20 0.26 0.15 0.15

−0.03 (0.08) −0.01 (0.08) −0.02 (0.08) −0.02 (0.08)

0.72 0.95 0.82 0.82

−0.08 (0.06) −0.07 (0.06) −0.09 (0.07) −0.09 (0.08)

0.25 0.28 0.18 0.18

−0.002 (0.06) 0.01 (0.06) 0.00 (0.06) 0.02 (0.06)

0.98 0.88 1.00 0.76

0.05 (0.05) 0.03 (0.05) 0.05 (0.05) 0.06 (0.05)

0.34 0.55 0.34 0.26

0.11 (0.06) 0.11 (0.06) 0.11 (0.06) 0.14 (0.07)

0.05 0.06 0.07 0.04

62 0.02 (0.02) 0.04 (0.09) 0.03 (0.09) 0.08 (0.10)

0.79 0.69 0.74 0.44

57 0.10 (0.09) 0.08 (0.09) 0.10 (0.09) 0.11 (0.09)

0.25 0.35 0.26 0.20

59 0.25 (0.08) 0.25 (0.08) 0.23 (0.08) 0.32 (0.10)

<0.01 <0.01 <0.01 <0.01

87 −0.01 (0.08) 0 (0.08) 0.02 (0.08) −0.02 (0.08)

0.91 0.98 0.83 0.82

53 0 (0.07) 0 (0.07) 0.01 (0.07) −0.02 (0.07)

74 0.94 0.97 0.93 0.93

Reference category is the category “not depressed, no sleep disturbances”. a Model 1: adjusted to age, survey and BMI. b Model 2: adjusted to age, survey, BMI, heart rate, systolic blood pressure, cholesterol/HDL ratio and CRP. c Model 3: adjusted to age, survey, BMI, smoking, alcohol intake, physical activity, unhealthy diet and low income. d Model 4: adjusted to age, survey, BMI, somatic complaints and negative self-perceived health.

0 (0.08) 0.01 (0.08) 0 (0.08) 0 (0.09)

0.98 0.92 0.95 0.91

S. Häfner et al. / Biological Psychology 89 (2012) 163–169

Leptin in women

35,00 30,00

25,07

24,99

24,85

24,63

ng/ml

25,00

BMI ≤ 25 BMI >25

20,00 15,00 8,99

9,31

10,57

11,44**

10,00 5,00 0,00 no depressed depressed mood, no sleep mood, no sleep disturbances disturbances

no depressed mood, sleep disturbances

depressed mood, sleep disturbances

Fig. 1. Means of leptin levels in the groups of different combinations of sleep disturbances and depressed mood in women, adjusted for age and survey, subdivided in the groups normal-weight (BMI ≤ 25) and overweight (BMI > 25). Data are adjusted geometric means and 95% confidence intervals (CI). p-Values from t-test. Each category was compared with the reference category **p < 0.01.

3.6.2. Dose–response association between depressed mood and leptin levels The correlation between the continuous measure of depressed mood and leptin levels was not significant (all: p = 0.64, women: p = 0.92, men: p = 0.96). Data are not shown. 3.6.3. Reanalyzing data with different categories of sleep disturbances Reanalyzing the data comprising in the case group only subjects who expressed having often sleep disturbances, brought similar results. (ˇ-estimate model 1–4 for women being normal weight and suffering depressed mood and sleep disturbances: 0.21–0.34, p-value <0.05 to <0.01). The slightly reduced significance of the results is most probably caused by the smaller sizes of the groups. Data are not shown. 4. Discussion The novel finding of this large population-based study was that normal-weight women, suffering both depressed mood and sleep disturbances, had highly significantly elevated leptin levels, compared to non-depressed women with no sleep disturbances. Interestingly, in obese women with already elevated leptin levels the combination of depressed mood and sleep disturbances was not associated with a further increase of leptin levels. No association could be observed in men. The result could not be explained by differences in age, behaviour, psychosocial and psychosomatic factors. This is the first study to show that the combination of depressed mood and sleep disturbances is a condition with a potentially detrimental impact on health of normal-weight women, whereas sleep disturbances or depressed mood alone seem to be less harmful. Elevated leptin levels are known to increase the risk for cardiovascular events (Soderberg et al., 2009; Wolk et al., 2004). They are associated with sympathetic activation (Haynes et al., 1997), endothelial dysfunction (Knudson et al., 2008) and elevated cholesterol (Buettner et al., 2002). Leptin is also known to be a mediator of inflammatory response (Fernandez-Riejos et al., 2010; Viikari et al., 2007). In our data, leptin levels were positively correlated with the cardiovascular risk factors CRP and total cholesterol/HDL cholesterol ratio. Interestingly, neither depressed mood nor sleep disturbances alone were associated with increased leptin levels, but in combination they were. Sleep disturbances and depression are closely related. About 3 quarters of clinically depressed patients suffer

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sleep disturbances (Hamilton, 1989). Sleep disturbances often appear before other depression symptoms (Ohayon and Roth, 2003). Insomnia confers an increased risk for depression (Hohagen et al., 1993; Livingston et al., 2000; Perlis et al., 2006). Sleep disturbances in depressed elderly patients reduce the chance for improvement, as compared with depressed subjects with no insomnia (Pigeon et al., 2008). Sleep disturbances develop in response to stress (Morin et al., 2003). Stress induces a rise in cortisol levels and increases inflammatory parameters (LeMay et al., 1990; Zhou et al., 1993). Sleep disturbances additionally increase cortisol secretion and levels of proinflammatory cytokines (McEwen, 2006). Stress-related pathophysiological changes such as the rise in the concentrations of proinflammatory cytokines and glucocorticoids have been suggested to contribute to the behavioural changes associated with depression (Holsboer, 2000; Leonard, 2010). Stress, as well as sleep disruption are followed by a reduction of neurogenesis possibly representing the impaired hippocampal plasticity and contributing to the cognitive symptoms of depression (Lucassen et al., 2010). Depression is associated with sleep alterations in both ways insomnia and hypersomnia. It has been suggested that the diagnosis depression comprises several subtypes of depression. Atypical and melancholic subtypes of major depression may represent the extremes of a spectrum with atypical depression associated with hypersomnia and low cortisol levels and melancholic depression associated with insomnia and increased cortisol levels (Antonijevic, 2008). Leptin regulation is closely intertwined with the HPA axis. Increased glucocorticoid levels stimulate leptin synthesis and secretion (Dagogo-Jack et al., 1997; Newcomer et al., 1998). In consequence, subtypes with atypical features and hypersomnia might present with low leptin levels, whereas melancholic subtypes with insomnia might present with increased leptin levels. However, leptin regulation in overweight women as well as in men seems not to be altered in the condition of depressed mood and sleep disturbances. The underlying mechanism is unclear. Most likely, in overweight women, the already perturbated neuroendocrine system cannot react to stress anymore. The combination of adiposity and the absence of a stress-induced leptin-increase in women could also present a certain phenotype with a genetically caused dysregulation of leptin. It is known that gender plays an important role in leptin regulation. Circulating leptin levels are at least two times higher in women compared with men (Rosenbaum et al., 1996). This observation was confirmed in our study. The mechanism explaining the gender differences is still not completely understood. Estrogen is an effective leptin inducer similar to glucosteroids. Interestingly, steroid-induced secretion of leptin is greater in the adipose tissue of women compared to men (Casabiell et al., 1998). This might explain why elevated leptin levels are observed in women but not in men, who are depressed and suffer sleep disturbances. Preliminary data from earlier studies investigating gender differences of leptin levels in depression yielded conflicting results. Increased leptin levels were observed in depressed women compared to depressed men in two studies (Esel et al., 2005; Rubin et al., 2002), whereas decreased leptin levels were found in the cerebrospinal fluid of female suicide attempters with major depression compared to men (Westling et al., 2004). We have previously found elevated leptin levels in socially isolated and depressed men, whereas depressed, but socially integrated men tend to have lower leptin levels (Häfner et al., 2011). The combination of depressed mood and social isolation did not have any impact on leptin levels in women. Our previous findings together with the present findings suggest three important points: First, depressed mood alone is not a sufficient condition to be associated with leptin elevation, but has to occur with a second harmful stress-associated condition to exceed a certain threshold, where leptin levels start to rise. The consideration

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of different clinical features as well as environmental factors in the development of depression and their influence on biological markers might provide an opportunity to better distinguish between subtypes of depression (Antonijevic, 2008). Secondly, gender differences play an important role in leptin regulation and therefore should always be taken into account. Third, being overweight is associated with a dysregulation of leptin. Therefore, to better understand leptin regulation, we have to distinguish between normal-weight individuals and overweight individuals.

All funding sources had no further role in study design, in the collection, analysis and interpretation of data, in the writing of the report and in the decision to submit the paper.

4.1. Strengths and limitations

The authors are grateful for the commitment and involvement of all the study participants and for the work and dedication of the MONICA/KORA Augsburg Study staff. We thank Mercodia (Uppsala, Sweden) for providing the ELISA kits for the measurement of leptin free of charge.

Our study has several strengths and limitations which should be taken into account. The strengths are primarily its populationbased design and its large sample size. Detailed information on metabolic variables, lifestyle factors and psychosomatic complaints were available and could thus be considered as confounding factors. Depressed mood was assessed using the DEEX scale. The DEEX scale is not a questionnaire that comprises the whole pattern of symptoms in depression but focuses on symptoms that occur in “vital exhaustion” like reduced vitality and weakness. Items reflecting negative self-concepts, or feelings of guilt and distrust were not included, because the depressive symptoms depletion and tiredness rather than feelings of guilt and hopelessness have been found to be predictive for cardiovascular morbidity and mortality (Appels and Mulder, 1988; Kop et al., 2002; Schulz et al., 2000). In a former study it could be shown that the validity and reliability of the DEEX scale is promising (Ladwig et al., 2004). Due to the cross-sectional design leptin levels, BMI, depressed mood and sleep disturbances were only assessed once. To get a better understanding of the precise pathomechanism we need to follow-up the course of leptin levels, BMI, depressed mood and sleep disturbances in a long-term analysis. Unfortunately, we did not have any information on the history taking glucocorticoids, which are known to influence leptin levels. The assessment of sleep disturbances comprises neither the duration of sleep disturbances nor determines the severity of the sleeping disorder. Stress, sleep disturbances and depression are very closely intertwined. Longitudinal studies are needed to assess duration and severity of sleeping disorder, duration and severity of stress, onset and duration of depressive symptoms and a follow up of the biological parameters leptin, as well as cortisol and inflammatory cytokines. Finally, we can summarize that the combination of depressed mood and sleep disturbances is a serious condition in women with normal-weight, not only because there is a greater risk for treatment resistance and relapse, but also because of the increases in leptin levels, associated with the negative health consequences. Therefore, sleep disturbances in depression should be carefully observed and treated, particularly in women with normal-weight. Role of funding source The study was financed by the German Research Center for Environmental Health, Neuherberg, Germany and the German Federal Ministry of Education and Research (NGFN), Berlin, Germany. Additional support for this study was received from research grants from the German Research Foundation (TH-784/2-1 and TH784/2-2), by the European Foundation for the Study of Diabetes; the Federal Ministry of Health (Berlin, Germany); the Ministry of Innovation, Science, Research and Technology of the state North Rhine-Westphalia (Düsseldorf, Germany), and by additional funds provided by the University of Ulm, Germany and the German Diabetes Center.

Disclosure statement All other authors declare that they have no conflicts of interest.

Acknowledgements

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