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Depressive symptoms and autonomic nervous system dysfunction in an elderly population-based study: The PROOF study
Journal of Affective Disorders 143 (2012) 153–159
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Research report
Depressive symptoms and autonomic nervous system dysfunction in an elderly population-based study: The PROOF study Virginie Dauphinot a,b,n, Isabelle Rouch a,f, Michel P. Kossovsky c, Vincent Pichot d, Jean-Michel Dorey e, Pierre Krolak-Salmon a,b, Bernard Laurent a,f, Fre´de´ric Roche d, Jean-Claude Barthe´le´my d a
Research Memory Centre, hˆ opital des Charpennes, Lyon, France University Claude Bernard Lyon 1, Lyon, France c Department of Internal medicine, Rehabilitation and Geriatrics, University Hospitals of Geneva and University of Geneva, Geneva, Switzerland d Clinical and exercise physiology laboratory, University hospital, Saint-Etienne, France e Department of psychiatry, Hospital centre Le Vinatier, Bron, France f Neurology Department, EMI Inserm U342, University hospital, Saint-Etienne, France b
a r t i c l e i n f o
abstract
Article history: Received 27 November 2011 Received in revised form 16 May 2012 Accepted 16 May 2012 Available online 19 August 2012
Background: To assess the relationship between depressive symptoms, evaluated through self-reported history as well as current depressive symptoms, and impaired autonomic nervous system activity, evaluated by long-term heart rate variability and baroreflex sensitivity among elderly community residents, aged 65 years. Methods: Subjects from the Proof cohort Study were evaluated for depressive symptoms and self-reported history of depression at inclusion. Autonomic nervous system activity was assessed through 24-h heart rate variability and baroreflex sensitivity. Cross-sectional analyses were performed to study the relationship between the different status of depression and autonomic nervous system activity. Results: Among the 1011 Proof study participants, 823 subjects were included in the analyses. Current depressive symptoms were present among 67 subjects; history of depression was reported by 228 subjects. Psychoactive drugs were used by 59 subjects. Low frequency (p¼ 0.02), very low frequency (po0.01) and Low/High frequency ratio (po0.001) were lower among subjects with depressive symptoms and history of depression, independently of antidepressant treatment. The association remained significant for Low/High frequency ratio after adjustment for gender and physical activity (p¼ 0.004). Conclusion: Current depressive symptoms may be linked to autonomic nervous system lower performances. A possible long-term effect of depressive symptoms at middle-age may influence later-life autonomic nervous system activity. Our results highlight the importance of taking into account the depressive symptoms in the cardiovascular risk, even in the elderly. & 2012 Elsevier B.V. All rights reserved.
Keywords: Psychosocial Sympathetic nervous activity Aging
1. Introduction Depressive symptoms are known as a risk factor of cardiovascular morbidity and mortality (Lopez et al., 2006). Autonomic nervous system (ANS) dysfunction, evaluated through heart rate variability (HRV) and baroreflex sensitivity (BRS), is associated with depressive disorders in adult population, in cross-sectional studies (Broadley et al., 2005; Kemp et al., 2010; Licht et al., 2008). Depressive disorders are associated with a
n Corresponding author at: Virginie Dauphinot, hoˆ pital des Charpennes, 27 rue Gabriel Pe´ri, 69100 Villeurbanne, France. Tel: þ 33 472433114. E-mail address:
[email protected] (V. Dauphinot). 0165-0327/$ - see front matter & 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jad.2012.05.045
dysfunction of the hypothalamo-pituitary axis, inducing an increased secretion of cortisol, adrenalin and noradrenalin, eventually conducting to an increase of the sympathetic tone and a decrease of the parasympathetic tone of the ANS (Grippo and Johnson, 2002). This association may then contribute to the link between depression and cardiovascular and cerebrovascular mortality (Carney et al., 2005), since impairment of the ANS has been demonstrated to be highly predictive of such severe vascular clinical events (Tsuji et al., 1996). This association remains controversial since this statement has not been observed in studies supporting rather a decreased sympathetic tone among depressed subjects (Guinjoan et al., 1995; Williams et al., 1985). Also, the inconsistency between studies has highlighted the heterogenetity of the methods used to assess both ANS activity and depressive symptoms. Most of the previous studies assessed
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the relationship between major depressive disorders and shortterm HRV in adult subjects at different ages (Bar et al., 2004; Broadley et al., 2005; Licht et al., 2008). To our knowledge, no study has been carried out using long-term ANS measurements exclusively among elderly community residents of a same age, a population characterized by higher prevalence of depressive symptoms and cardiovascular comorbidities whereas the ANS activity decreases with age (Ranga R. Krishnan et al., 2002; Stein et al., 2009). In this study, we aimed at assessing whether self-reported history of depression and current depressive symptoms, were associated with impaired ANS activity, evaluated by long-term HRV recordings and BRS among a large elderly community population.
2. Methods 2.1. Study population and design The present study sample was selected from the PROOF study, a prospective observational cohort of 1011 age-matched subjects at baseline. The PROOF study was designed to assess the prognostic values of the ANS activity in the cardiovascular and cerebrovascular morbidity and mortality. The population was selected in 2001, from the electoral list of 65-year-old people living in the town of Saint-Etienne, France. Exclusion criteria of the PROOF study were previous cardiac disease (i.e.,: prior myocardial infarction, stroke, heart failure, atrial fibrillation, insulin-treated diabetes mellitus and cardiac pacemaker), a severe disease limiting life expectancy to 5 years or less, contraindication to brain MRI, living in an institution and intention to move during the next 2 years. The design of the PROOF study and description of the data has been previously published (Barthelemy et al., 2007; Dauphinot et al., 2009; Rouch et al., 2008). All subjects were assessed under standardised conditions and gave their informed written consent. In the present study, subjects with inconsistent or missing depression data were not included in the analysis. 2.2. Depressive symptoms Subjects were asked about history of depression: ‘Do you have a history of depression?’ In addition, current depressive symptoms were detected by the QD2A questionnaire, performed during a structured interview with a psychologist. The QD2A questionnaire is a self- evaluated inventory for depressive complaints, including 13 questions and assessing the severity of depressive symptoms (Pichot et al., 1984). This questionnaire is an abridged version and was initially developed using the Hopkins Symptoms check-list (Parloff et al., 1954), the Beck Depression Inventory (BDI) (Gallagher et al., 1982), the MMPI (Minnesota Multiphasic Personality Inventory) D scale (Gravitz, 1968; Hathaway and Briggs, 1957) and the Depressive symptom questionnaire of Zung (Zung et al., 1984). The threshold of 7 was previously defined to identify depressive subjects and was highly correlated to clinical diagnosis of depression (Guelfi, 1993). The anxiety disorders were assessed using the French version of Goldberg scale, which was associated with the psychiatric assessment (Goldberg et al., 1998). It consisted in a 9-item scale with scores ranging from 0 to 9. The subjects with a score higher than 4 were considered anxious (Goldberg et al., 1998). The use of benzodiazepine and other non depressive psychoactive medication was also collected. The current use of psychoactive medication for depressive symptoms was collected by subject’s report and was confirmed
by their physician’s prescription. Selective serotonin reuptake inhibitors (SSRI), tricyclic antidepressant (TCA), and other antidepressants were distinguished using the ATC (anatomical, therapeutically, chemical) code (WHO classification). (Methodology, http://www.whocc.no/atcddd/.) 2.3. Physiological measurements Heart Rate Variability (HRV) was measured from a 24 h electrocardiographic Holter system (Vista and HolterSoft, Novacor, Rueil-Malmason, France). HRV was assessed by analysing RR intervals according to the frequency of the signal represented by successive RR intervals. Frequency and time domain indices and mean heart rate were calculated as recommended. (1996) The ANS indices used in the analysis were the total frequency power (Ptot) and the standard deviation of normal to normal RR interval (SDNN). The components of the spectrum were also analysed: high frequency (HF), low frequency (LF), very low frequency (VLF) and the sympathovagal balance at night (LF/HF ratio). Spontaneous cardiac baroreflex activity was assessed at each examination. It was calculated using the sequence method (Parlow et al., 1995). A 15-min simultaneous recording of electrocardiogram (Marquette 5000), blood pressure (Finapress 2300, Ohmedas) and ventilation (Gould) was performed at rest. BRS (expressed in milliseconds per millimeter of Hg) was calculated as the mean of the slopes of all the sequences of at least three or more successive heart beats in which there were concordant increases or decreases in systolic blood pressure and RR interval. 2.4. Clinical covariates Gender, number of years of education, body mass index (BMI), fasting glycaemia and total cholesterol were collected. Level of physical activity was assessed with the Population Physical Activity Questionnaire, which was previsouly validated. We focused on the daily energy expenditure (DEE, kj/24 h) (Achour et al., 2011; Garet et al., 2004). Twenty-four-hour blood pressure was assessed by ambulatory holter recordings using auscultatory method (Diasys Integra, Novacor, Rueil-Malmaison, France). Casual blood pressure was also measured. Information regarding the use of antihypertensive treatment was collected: angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, diuretics, calcium channel blockers and other antihypertensive drugs. 2.5. Statistical analysis Cross-sectional analyses were performed using data collected at inclusion in the PROOF cohort study. The subjects’ characteristics were compared between individuals who completed the examination with likelihood data and those who were not included in the analyses. Percentages were compared using Pearson’s Chi square test. Means were compared using appropriated Student’s t-test, with hypothesis of equal or unequal variance according to the result of the Levene test. HRV indices and BRS were transformed into logarithm to correct the skewed distribution. The relationship between depression and HRV indices and BRS was studied by three different ways to identify subjects with depressive symptoms. First, the relationship between history of depression and HRV indices and BRS was studied. A multivariate analyse of variance (MANOVA) was built to compare the HRV indices’ and BRS means between groups; P value of the Fisher test as well as means7standard deviation (SD) were reported. Results were adjusted for potential confounding factors i.e., gender, education level, physical activity, anxiety symptom and current depression score. In addition, multiple stepwise linear regression models were
V. Dauphinot et al. / Journal of Affective Disorders 143 (2012) 153–159
performed to calculate the coefficients R2 of Cox-Snell that gave an estimation of the proportion of the variance explained by the model. Second, the relationship between the current depressive symptoms (QD2A score) and HRV and BRS indices was assessed, without taking into account history of depression. Same statistical models were used as previously. In a third analysis, current depressive symptoms and self-report of history of depression were both included in the same model. ‘‘Treated depressive’’ and ‘‘untreated depressive’’ groups were identified with the current depression score, history of depression and use of psychoactive drugs. Since interaction between the groups of interest and gender was not significant in each model, results were presented for both genders together. All P values were two-sided. The significance level was at 0.05. Data were analysed using Statistical Package for the Social Sciences version 15.0 for Windows (SPSS Inc., Chicago, Illinois, USA).
3. Results 3.1. Characteristics of the study population Among the 1011 PROOF study participants, 823 subjects were included in the analysis. These subjects were characterized by higher means of HRV and BRS indices in comparison to those who were not included (Table 1). No significant difference was observed between the groups for cardiovascular comorbidities. History of depression was reported by 228 subjects (27.8%). Current depressive symptoms were present among 67 subjects (8.1%) according to the QD2A score questionnaire, without taking into account the use of psychoactive drugs. Fifty nine subjects (7.2%) took antidepressant drugs. Benzodiazepine drugs were used by 109 subjects (13.2%) and 121 subjects (14.7%) used other psychoactive medication. 3.2. HRV and BRS according to the self-reported history of depression and use of psychoactive drugs (Table 2) Among the 819 analysed subjects, 228 reported a history of depression, of which 55 currently used psychoactive drugs. Study population with a history of depression was characterized by
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higher proportions of women and anxiety symptoms, higher means of QD2A depression score and lower education level. Crude means of LF, VLF, LF/HF ratio, SDNN, and RR were significantly lower among the subjects with history of depression, and even lower among those who used psychoactive drugs, according to the MANOVA model. After adjustment for gender and physical activity, the relationship between history of depression and LF/HF ratio remained significant (p ¼0.008). The associations with the others HRV indices and BRS had similar trend, without reaching the statistical significance. The stepwise linear regression model to explain LF/HF ratio included first the gender (po0.001; R2 ¼ 6.0%), second the physical activity (p¼0.01; R2 ¼6.7%), and third history of depression (p¼0.01; R2 ¼7.2%). The variables educational level, anxiety symptoms and current depression score did not contribute significantly to the relationship. 3.3. HRV indices and BRS according to the QD2A score and the use of psychoactive drugs (Table 3) Among the 823 subjects included in the analyses, 52 had current depressive symptoms without being treated, 44 were treated with psychoactive drugs and 15 had current depressive symptoms and used psychoactive drugs. Proportions of men were smaller in the groups with depressive symptoms or psychoactive treatment use. Current depression score and proportion of subjects with anxiety symptoms were higher and educational level lower among the subjects with current depressive symptoms in comparison to those who had no depressive symptoms. Crude mean of LF/HF ratio was lower among the subjects with current depressive symptoms in comparison to those without depressive symptoms nor psychoactive treatment. Crude means of VLF and RR were lower among the untreated depressive subjects and the treated non-depressive subjects in comparison to other groups. After adjustment for gender, and physical activity, the association between current depressive symptoms and LF/HF ratio remained significant (p¼ 0.01), and the association with BRS became significant (p ¼0.04). The stepwise linear regression model to explain LF/HF ratio included first the gender (po0.001; R2 ¼ 6.1%), second the current depressive status (p¼0.002; R2 ¼7.3%) and third physical activity (p¼0.007; R2 ¼8.2%).
Table 1 Comparison of characteristics of the Proof study population included or not in the analysis. Total n¼ 1011
Selected study population n¼ 823 (81.4%)
Excluded study population n¼ 188 (18.6%)
p value
Gender (Men/Women)
402/609
339/484
63/125
0.05
Mean 7 SD ln SDNN 24-h ln HF 24-h ln LF 24-h ln VLF 24-h ln Ptot 24-h ln LF/HF night ln BRS ln RR ABPM SBP ABPM DBP Casual SBP Casual DBP
4.857 0.3 4.597 0.9 5.287 0.7 6.297 0.6 8.117 0.6 0.907 0.7 1.797 0.5 6.737 0.1 119.01 7 14.0 76.017 7.9 143.287 18.3 87.79 7 10.1
4.86 7 0.3 4.63 7 0.9 5.32 7 0.7 6.33 7 0.6 8.14 7 0.6 0.907 0.7 1.81 7 0.5 6.73 7 0.1 118.777 13.7 76.007 7.8 143.287 18.2 87.84 7 10.1
4.82 70.2 4.53 70.9 5.15 70.7 6.13 70.6 8.01 70.6 0.83 70.7 1.70 70.5 6.71 70.1 120.16 715.2 76.05 78.2 143.3 719.0 87.59 710.2
0.10 0.17 o0.01 o0.001 0.01 0.22 0.01 0.01 0.23 0.95 0.98 0.76
25.31 7 3.8 5.647 1.2 6.057 1.0
25.38 7 3.7 5.65 7 1.2 6.037 1.0
24.98 73.8 5.60 71.2 6.16 71.1
BMI (kg/m2) Fasting glycaemia Total cholesterol
0.21 0.59 0.13
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Table 2 Comparison of characteristics and HRV indices according to the self-reported history of depression and use of psychoactive treatment.
Self-reported history of depression Gender (men)—n (%) Age—crude means7 SD Educational level—crude means 7SD DEE—crude means7 SD Anxiety symptoms—n (%) QD2A score—crude means7 SD HRV Indices—crude means7 SD ln HF ln LF ln VLF ln Ptot ln LF/HF (night) ln SDNN ln BRS ln RR
No
Untreated
Treated
Total
P value (univariate analyses)
n¼ 591
n¼ 173
n¼ 55
n¼ 819*
293 (49.58%) 65.64 7 0.83 11.25 7 2.84 10529.40 7 1919.01 178 (30.22%) 1.96 7 2.04
39 (22.54%) 65.65 70.76 10.69 73.09 100267 1891.02 101 (58.38%) 3.89 73.53
7 (12.73%) 65.54 7 0.94 10.19 72.22 9671.487 1603.15 37 (67.27%) 4.95 73.23
339 (41.39%) 65.61 7 0.82 10.71 72.88 0368.337 11911.75 316 (38.68%) 2.57 72.71
o 0.001 0.66 o 0.01 o 0.001 o 0.001 o 0.001
4.63 7 0.85 5.34 7 0.71 6.36 7 0.63 8.16 7 0.58 0.96 70.65 4.87 7 0.26 1.82 7 0.51 6.74 7 0.12
4.65 70.92 5.27 70.67 6.24 70.60 8.097 0.57 0.817 0.64 4.83 70.29 1.807 0.49 6.72 70.12
4.54 70.99 5.07 70.74 6.16 70.62 7.98 70.53 0.64 70.67 4.77 70.25 1.72 70.44 6.71 7 0.11
4.61 70.87 5.23 70.70 6.26 70.62 8.087 0.58 0.807 0.66 4.82 70.27 1.78 70.50 6.73 70.12
0.76 0.02 0.01 0.06 o 0.01 0.02 0.33 0.04
P value (multivariate analyses)
0.99 0.12 0.23 0.27 0.008 0.18 0.08 0.92
DEE: Daily energy expenditure, in kj/24 h. QD2A score: current depressive symptoms score. HRV: Heart rate variability. n
4 subjects have not reported a history of depression and were treated for depression (non included in the analysis).
Table 3 Comparison of characteristics and HRV according to the QD2A score of depressive symptoms and use of psychoactive treatment. Normal score and untreated
Untreated depressives
Normal score and treated
Treated depressives
Total
n ¼712
n¼ 52
n¼44
n¼15
n¼ 823
8 (15.38%) 65.62 7 0.89
5 (11.36%) 65.55 70.90
2 (13.33%) 65.507 1.02
339 (41.19%) 65.58 70.82
o 0.001 0.81
10.14 7 2.93
9.937 1.85
10.797 2.99
10.51 72.88
o 0.01
QD2A score of depression Gender (men)—n (%) 324 (45.51%) Age—crude 65.65 7 0.80 means7 SD 11.19 7 2.90 Educational level—crude means7 SD DEE—crude 10441.45 71912.30 means7 SD Anxiety 235 (33.05%) symptoms—n (%) QD2A score—crude 1.88 7 1.72 means7 SD HRV Indices—crude means7 SD ln HF 4.61 7 0.85 ln LF 5.33 7 0.69 ln VLF 6.34 7 0.62 ln Ptot 8.14 7 0.57 ln LF/HF (night) 0.95 7 0.65 ln SDNN 4.86 7 0.27 ln BRS 1.82 7 0.51 ln RR 6.74 7 0.12
P value (univariate analyses)
P value (multivariate analyses)
10091.64 7 2052.06 10113.857 1963.76 9286.287 1223.93 10382.06 7 1919.85 0.07 44 (86.27%)
26 (59.09%)
13 (86.67%)
318 (38.73%)
o 0.001
9.48 7 2.01
3.327 1.99
9.137 1.77
2.57 72.70
o 0.001
4.59 7 0.92 5.21 7 0.78 6.20 70.58 8.11 7 0.57 0.75 70.66 4.85 7 0.27 1.72 7 0.51 6.70 70.09
4.607 1.11 5.057 0.80 6.107 0.67 7.957 0.55 0.607 0.71 4.757 0.23 1.677 0.46 6.717 0.12
4.757 0.67 5.327 0.48 6.407 0.36 8.217 0.51 0.577 0.58 4.897 0.28 1.907 0.31 6.757 0.08
4.64 78.86 5.23 70.70 6.26 70.62 8.107 0.57 0.727 0.66 4.84 70.27 1.78 70.51 6.72 70.12
0.93 0.05 0.03 0.19 o 0.001 0.08 0.10 0.03
0.90 0.19 0.24 0.51 0.01 0.29 0.04 0.33
DEE: Daily energy expenditure, in kj/24 h. QD2A score: current depressive symptoms score. HRV: Heart rate variability.
3.4. HRV indices and BRS according to depression status, defined by the QD2A score, history of depression and use of psychoactive drugs (Table 4) Among the 819 subjects included in the analyses, 55 subjects were considered as the ‘‘treated depressive’’ group and 193 subjects as the ‘‘untreated depressive’’ group. Proportions of men and education level were lower in the depressive groups. Current depression score and proportion of subjects with anxiety symptoms were higher. Crude means of LF, VLF and LF/HF ratio were lower among the ‘‘untreated depressive’’ group, and even lower among the ‘‘treated depressive’’ one. After adjustment for gender, and
physical activity, the association remained significant for LF/HF ratio (p ¼0.004). As for the previous models, the stepwise linear regression model included first the gender (p o0.001; R2 ¼6.0%), second the depressive status (p ¼0.003; R2 ¼ 7.0%) and third physical activity (p ¼0.009; R2 ¼7.8%).
4. Discussion In this study, long-term HRV indices were reduced among 65 year-old subjects with current depressive symptoms and/or history of depression, independently of the use of psychoactive treatment.
V. Dauphinot et al. / Journal of Affective Disorders 143 (2012) 153–159
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Table 4 Comparison of HRV indices according to the depression characteristics: depressive status defined by both self-report history of depression and a depression QD2A score higher than the threshold 7, and use of psychoactive treatment.
Depressive status Gender (men)—n (%) Age—crude means7 SD Educational level—crude means7 SD DEE—crude means7 SD Anxiety symptoms—n (%) QD2A score—crude means7 SD HRV Indices—crude means7 SD ln HF ln LF ln VLF ln Ptot ln LF/HF (night) ln SDNN ln BRS ln RR
Normal and untreated
Untreated depressives
Treated depressives
Total
P Value (Univariate P value analyses) (multivariate analyses)
n ¼571
n ¼193
n¼55
n¼819*
290 (50.79%) 65.64 7 0.82 11.27 7 2.86 10552.83 71909.93 162 (28.42%) 1.96 7 1.62
42 (21.76%) 65.65 7 0.78 10.67 7 2.99 10011.04 7 1909.71 117 (60.94%) 3.89 7 3.69
7 (12.73%) 65.54 70.94 10.19 72.22 9671.487 1603.15 37 (67.27%) 4.95 73.17
339 (41.39%) 65.61 70.82 10.717 2.87 10368.337 1911.75 316 (38.68%) 3.707 2.72
o 0.001 0.67 o 0.01 o 0.001 o 0.001 o 0.001
4.61 7 0.83 5.34 7 0.71 6.37 7 0.63 8.15 7 0.58 0.98 7 0.65 4.87 7 0.26 1.82 7 0.51 6.74 7 0.12
4.64 7 0.91 5.26 7 0.68 6.24 7 0.59 8.10 7 0.55 0.80 70.66 4.84 7 0.28 1.80 7 0.50 6.72 7 0.12
4.57 70.98 5.087 0/74 6.17 70.64 8.007 0.55 0.617 0.68 4.79 70.27 1.71 70.43 6.71 70.11
4.617 0.86 5.237 0.70 6.267 0.62 8.097 0.57 0.907 0.66 4.837 0.27 1.787 0.50 6.737 0.12
0.85 0.02 o 0.01 0.13 o 0.001 0.06 0.34 0.07
0.99 0.10 0.14 0.31 0.004 0.27 0.09 0.85
DEE: Daily energy expenditure, in kj/24 h. QD2A score: current depressive symptoms score. HRV: Heart rate variability. n
4 subjects have not reported a history of depression and were however treated for depression (non included in the analysis).
This result is relevant with previous studies that highlighted lower short-term HRV indices among subjects with major depression, with and without cardiovascular disease (Agekink et al., 2002; Carney et al., 2005; Francis et al., 2009; Grippo and Johnson, 2002; Kamphuis et al., 2007; Kemp et al., 2010; Licht et al., 2008; Stein et al., 2000). While the analysis in the time-domain of HRV is well recognized to quantify normal and abnormal autonomic nervous system activity, measures of the same signal according to frequency domain analysis are discussed in their interpretation. Specifically, if the HF activity seems fairly associated with the level of parasympathetic tone, recent studies have shown that variations in LF during short term recordings should be interpreted as the cardiac response to activation or inhibition of baroreceptor function at the heart level (Goedhart et al., 2008; Goldstein et al., 2011). Thus, changes in the LF/HF ratio under controlled pharmacological (dynamic) conditions or during maneuvers of autonomic stimuli do not always reflect a change in the balance of sympathovagal balance. However, in our study we used data averaged over all 24 h or all of the night for the LF/HF ratio. The observed results convince us of a change (decrease) in cardiac autonomic activity when there is a masked or undiagnosed depression. This alteration is more marked on the total spectral power, LF and VLF patients undergoing treatment psychotropic. This reduction of variability cycles of low and very low frequencies could be associated with a decrease in baroreflex cardiac response to stimuli in these subjects. It has also been observed that a decrease of sympathetic activity, measured by other way than HRV, was proportional to the severity of the depression, which reinforces the link between ANS activity and depressive symptoms (Guinjoan et al., 1995; Williams et al., 1985). Correlatively, chronic stimulation of ANS activity, through vagal nerve stimulation, has been shown to improve symptoms of depression (Schlaepfer et al., 2008). Some previous studies have highlighted different results, with lower parasympathetic and higher sympathetic tone among subjects with major depression (Bar et al., 2004; Udupa et al., 2007) whereas others have found no significant association between subjects with major depression and HRV (Moser et al., 1998). In our study, self-reported history of depression and current depressive symptoms were used to indentify the subjects of
interest, whereas previous studies usually used the definition of major depression, defined by DSM III R, DSM IV criteria (Agekink et al., 2002; Bar et al., 2004; Licht et al., 2008; Rechlin et al., 1994; Udupa et al., 2007). Among the elderly without history of depression, newly depressive symptoms may be linked to a modification of life circumstances, like retirement (Alavinia and Burdorf, 2008). The significant association between self-reported history of depression and lower ANS activity may suggest a possible long-term effect of depressive symptoms during middle-age that may have adverse effects on later-life ANS activity. Other studies suggest that clinical diagnosis of major depression would not be required when studying the association between depressive symptoms and HRV (Grippo and Johnson, 2002). Mood states as well as affective disorders seem to impact the HRV (Rechlin et al., 1994). BRS showed a tendency to be lower among the subjects with depressive symptoms, which is congruent with a previous study (Broadley et al., 2005). The absence of association between the established parasympathetic indices i.e., HF and depressive symptoms in our study population could be explained by the age of the population which is older in comparison to previous study populations. There is a possible age-related attenuation of the clinical relevance of HRV indices since the ANS activity is known to decrease with age, in particular the parasympathetic tone (Stein et al., 2009). However the age of our study population was the same for all subjects, which avoids the possible bias of age. In our study, the use of psychoactive treatment seems to increase the dysfunction of ANS activity among subjects with depressive symptoms. Previous studies suggest that psychoactive treatment would be more associated to reduced ANS activity than depressive symptoms themselves (Bar et al., 2004; Licht et al., 2008). However, it is conceivable that subjects with depressive symptoms and using psychoactive treatment have a more severe stage of depression, it is then difficult to determine whether the use psychoactive treatment have a greater impact on ANS activity than depression symptoms themselves. It may be noted that in studies assessing electroconvulsive therapy (ECT) proposed in major or resistant to treatment depression, the confounding effects of psychoactive treatments on autonomic regulation can
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then not be discussed. This therapy (ECT) has been shown to improve HRV (Nahshoni et al., 2004, 2001). Thus the direct impact of ECT on the cardiac autonomic regulation confirms the important role of neural cortico-subcortical integration pathways on the central brainstem autonomic regulation. Anxiety symptoms did not contribute to change the association between depressive symptoms or history of depression and ANS indices in our study; this result is relevant with a previous study underlining that depression but not anxiety is associated with reduced ANS activity among patients after myocardial infarctus (Pitzalis et al., 2001). Our study presents several limitations. The study population included in the analyses had higher HRV and BRS indices than subjects that were not included, because of incomplete data in the neuropsychological evaluation or electrocardiographic recordings showing abnormal pattern that could fit with an exclusion criteria. This has to be considered as a selection bias of our population and should take into account in the interpretation of our results. It can be hypothesised that the excluded subjects have an unhealthy profile and that the prevalence of subjects with depressive symptoms, and/or history of depression was underestimated in our study. Nevertheless the association between depressive symptoms and ANS indices may not be affected since the ANS indices are found lower among the excluded subjects. Distinction between the different classes of psychoactive treatments was not made because the sample population size was small for each groups of interest. However a previous study has shown that the different classes of psychoactive treatment have different impact on the ANS activity; tricyclic antidepressants have been shown to reduce HRV whereas results are more variable for SSRIs (Kemp et al., 2010; van Zyl et al., 2008). Finally, our criteria to define depressive symptoms were not validated by a psychiatrist, what may conduct to a misclassification of subjects. On the whole, our results suggest that even minor current depressive symptoms can be linked to ANS lower performance. A possible long-term effect of depressive symptoms at middle-age may influence later-life ANS activity. This highlights the importance to take into account the depressive symptoms in the cardiovascular risk, even in the elderly more vulnerable than adults.
Role of funding source The Proof cohort study was supported by the French Ministry of Health (Programmes Hospitaliers de Recherche Clinique: PHRC National PROOF, 1998; PHRC National SYNAPSE, 2002; PHRC Regional Telamons, 2003). The study was also funded through a grant from Mutual Insurance Companies, AG2R and MPCL. A complementary funding came from the Association SYNAPSE (Michel Segura).ClinicalTrials.gov number, NCT 00759304.
Conflict of interest All authors declare that they have no conflicts of interest.
Acknowledgements We thank Mrs. Delphine Maudoux and Mrs. Judith Kerleroux, who helped to collect the data.
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Journal of Affective Disorders journal homepage: www.elsevier.com/locate/jad
Research report
Depressive symptoms and autonomic nervous system dysfunction in an elderly population-based study: The PROOF study Virginie Dauphinot a,b,n, Isabelle Rouch a,f, Michel P. Kossovsky c, Vincent Pichot d, Jean-Michel Dorey e, Pierre Krolak-Salmon a,b, Bernard Laurent a,f, Fre´de´ric Roche d, Jean-Claude Barthe´le´my d a
Research Memory Centre, hˆ opital des Charpennes, Lyon, France University Claude Bernard Lyon 1, Lyon, France c Department of Internal medicine, Rehabilitation and Geriatrics, University Hospitals of Geneva and University of Geneva, Geneva, Switzerland d Clinical and exercise physiology laboratory, University hospital, Saint-Etienne, France e Department of psychiatry, Hospital centre Le Vinatier, Bron, France f Neurology Department, EMI Inserm U342, University hospital, Saint-Etienne, France b
a r t i c l e i n f o
abstract
Article history: Received 27 November 2011 Received in revised form 16 May 2012 Accepted 16 May 2012 Available online 19 August 2012
Background: To assess the relationship between depressive symptoms, evaluated through self-reported history as well as current depressive symptoms, and impaired autonomic nervous system activity, evaluated by long-term heart rate variability and baroreflex sensitivity among elderly community residents, aged 65 years. Methods: Subjects from the Proof cohort Study were evaluated for depressive symptoms and self-reported history of depression at inclusion. Autonomic nervous system activity was assessed through 24-h heart rate variability and baroreflex sensitivity. Cross-sectional analyses were performed to study the relationship between the different status of depression and autonomic nervous system activity. Results: Among the 1011 Proof study participants, 823 subjects were included in the analyses. Current depressive symptoms were present among 67 subjects; history of depression was reported by 228 subjects. Psychoactive drugs were used by 59 subjects. Low frequency (p¼ 0.02), very low frequency (po0.01) and Low/High frequency ratio (po0.001) were lower among subjects with depressive symptoms and history of depression, independently of antidepressant treatment. The association remained significant for Low/High frequency ratio after adjustment for gender and physical activity (p¼ 0.004). Conclusion: Current depressive symptoms may be linked to autonomic nervous system lower performances. A possible long-term effect of depressive symptoms at middle-age may influence later-life autonomic nervous system activity. Our results highlight the importance of taking into account the depressive symptoms in the cardiovascular risk, even in the elderly. & 2012 Elsevier B.V. All rights reserved.
Keywords: Psychosocial Sympathetic nervous activity Aging
1. Introduction Depressive symptoms are known as a risk factor of cardiovascular morbidity and mortality (Lopez et al., 2006). Autonomic nervous system (ANS) dysfunction, evaluated through heart rate variability (HRV) and baroreflex sensitivity (BRS), is associated with depressive disorders in adult population, in cross-sectional studies (Broadley et al., 2005; Kemp et al., 2010; Licht et al., 2008). Depressive disorders are associated with a
n Corresponding author at: Virginie Dauphinot, hoˆ pital des Charpennes, 27 rue Gabriel Pe´ri, 69100 Villeurbanne, France. Tel: þ 33 472433114. E-mail address:
[email protected] (V. Dauphinot). 0165-0327/$ - see front matter & 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jad.2012.05.045
dysfunction of the hypothalamo-pituitary axis, inducing an increased secretion of cortisol, adrenalin and noradrenalin, eventually conducting to an increase of the sympathetic tone and a decrease of the parasympathetic tone of the ANS (Grippo and Johnson, 2002). This association may then contribute to the link between depression and cardiovascular and cerebrovascular mortality (Carney et al., 2005), since impairment of the ANS has been demonstrated to be highly predictive of such severe vascular clinical events (Tsuji et al., 1996). This association remains controversial since this statement has not been observed in studies supporting rather a decreased sympathetic tone among depressed subjects (Guinjoan et al., 1995; Williams et al., 1985). Also, the inconsistency between studies has highlighted the heterogenetity of the methods used to assess both ANS activity and depressive symptoms. Most of the previous studies assessed
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the relationship between major depressive disorders and shortterm HRV in adult subjects at different ages (Bar et al., 2004; Broadley et al., 2005; Licht et al., 2008). To our knowledge, no study has been carried out using long-term ANS measurements exclusively among elderly community residents of a same age, a population characterized by higher prevalence of depressive symptoms and cardiovascular comorbidities whereas the ANS activity decreases with age (Ranga R. Krishnan et al., 2002; Stein et al., 2009). In this study, we aimed at assessing whether self-reported history of depression and current depressive symptoms, were associated with impaired ANS activity, evaluated by long-term HRV recordings and BRS among a large elderly community population.
2. Methods 2.1. Study population and design The present study sample was selected from the PROOF study, a prospective observational cohort of 1011 age-matched subjects at baseline. The PROOF study was designed to assess the prognostic values of the ANS activity in the cardiovascular and cerebrovascular morbidity and mortality. The population was selected in 2001, from the electoral list of 65-year-old people living in the town of Saint-Etienne, France. Exclusion criteria of the PROOF study were previous cardiac disease (i.e.,: prior myocardial infarction, stroke, heart failure, atrial fibrillation, insulin-treated diabetes mellitus and cardiac pacemaker), a severe disease limiting life expectancy to 5 years or less, contraindication to brain MRI, living in an institution and intention to move during the next 2 years. The design of the PROOF study and description of the data has been previously published (Barthelemy et al., 2007; Dauphinot et al., 2009; Rouch et al., 2008). All subjects were assessed under standardised conditions and gave their informed written consent. In the present study, subjects with inconsistent or missing depression data were not included in the analysis. 2.2. Depressive symptoms Subjects were asked about history of depression: ‘Do you have a history of depression?’ In addition, current depressive symptoms were detected by the QD2A questionnaire, performed during a structured interview with a psychologist. The QD2A questionnaire is a self- evaluated inventory for depressive complaints, including 13 questions and assessing the severity of depressive symptoms (Pichot et al., 1984). This questionnaire is an abridged version and was initially developed using the Hopkins Symptoms check-list (Parloff et al., 1954), the Beck Depression Inventory (BDI) (Gallagher et al., 1982), the MMPI (Minnesota Multiphasic Personality Inventory) D scale (Gravitz, 1968; Hathaway and Briggs, 1957) and the Depressive symptom questionnaire of Zung (Zung et al., 1984). The threshold of 7 was previously defined to identify depressive subjects and was highly correlated to clinical diagnosis of depression (Guelfi, 1993). The anxiety disorders were assessed using the French version of Goldberg scale, which was associated with the psychiatric assessment (Goldberg et al., 1998). It consisted in a 9-item scale with scores ranging from 0 to 9. The subjects with a score higher than 4 were considered anxious (Goldberg et al., 1998). The use of benzodiazepine and other non depressive psychoactive medication was also collected. The current use of psychoactive medication for depressive symptoms was collected by subject’s report and was confirmed
by their physician’s prescription. Selective serotonin reuptake inhibitors (SSRI), tricyclic antidepressant (TCA), and other antidepressants were distinguished using the ATC (anatomical, therapeutically, chemical) code (WHO classification). (Methodology, http://www.whocc.no/atcddd/.) 2.3. Physiological measurements Heart Rate Variability (HRV) was measured from a 24 h electrocardiographic Holter system (Vista and HolterSoft, Novacor, Rueil-Malmason, France). HRV was assessed by analysing RR intervals according to the frequency of the signal represented by successive RR intervals. Frequency and time domain indices and mean heart rate were calculated as recommended. (1996) The ANS indices used in the analysis were the total frequency power (Ptot) and the standard deviation of normal to normal RR interval (SDNN). The components of the spectrum were also analysed: high frequency (HF), low frequency (LF), very low frequency (VLF) and the sympathovagal balance at night (LF/HF ratio). Spontaneous cardiac baroreflex activity was assessed at each examination. It was calculated using the sequence method (Parlow et al., 1995). A 15-min simultaneous recording of electrocardiogram (Marquette 5000), blood pressure (Finapress 2300, Ohmedas) and ventilation (Gould) was performed at rest. BRS (expressed in milliseconds per millimeter of Hg) was calculated as the mean of the slopes of all the sequences of at least three or more successive heart beats in which there were concordant increases or decreases in systolic blood pressure and RR interval. 2.4. Clinical covariates Gender, number of years of education, body mass index (BMI), fasting glycaemia and total cholesterol were collected. Level of physical activity was assessed with the Population Physical Activity Questionnaire, which was previsouly validated. We focused on the daily energy expenditure (DEE, kj/24 h) (Achour et al., 2011; Garet et al., 2004). Twenty-four-hour blood pressure was assessed by ambulatory holter recordings using auscultatory method (Diasys Integra, Novacor, Rueil-Malmaison, France). Casual blood pressure was also measured. Information regarding the use of antihypertensive treatment was collected: angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, diuretics, calcium channel blockers and other antihypertensive drugs. 2.5. Statistical analysis Cross-sectional analyses were performed using data collected at inclusion in the PROOF cohort study. The subjects’ characteristics were compared between individuals who completed the examination with likelihood data and those who were not included in the analyses. Percentages were compared using Pearson’s Chi square test. Means were compared using appropriated Student’s t-test, with hypothesis of equal or unequal variance according to the result of the Levene test. HRV indices and BRS were transformed into logarithm to correct the skewed distribution. The relationship between depression and HRV indices and BRS was studied by three different ways to identify subjects with depressive symptoms. First, the relationship between history of depression and HRV indices and BRS was studied. A multivariate analyse of variance (MANOVA) was built to compare the HRV indices’ and BRS means between groups; P value of the Fisher test as well as means7standard deviation (SD) were reported. Results were adjusted for potential confounding factors i.e., gender, education level, physical activity, anxiety symptom and current depression score. In addition, multiple stepwise linear regression models were
V. Dauphinot et al. / Journal of Affective Disorders 143 (2012) 153–159
performed to calculate the coefficients R2 of Cox-Snell that gave an estimation of the proportion of the variance explained by the model. Second, the relationship between the current depressive symptoms (QD2A score) and HRV and BRS indices was assessed, without taking into account history of depression. Same statistical models were used as previously. In a third analysis, current depressive symptoms and self-report of history of depression were both included in the same model. ‘‘Treated depressive’’ and ‘‘untreated depressive’’ groups were identified with the current depression score, history of depression and use of psychoactive drugs. Since interaction between the groups of interest and gender was not significant in each model, results were presented for both genders together. All P values were two-sided. The significance level was at 0.05. Data were analysed using Statistical Package for the Social Sciences version 15.0 for Windows (SPSS Inc., Chicago, Illinois, USA).
3. Results 3.1. Characteristics of the study population Among the 1011 PROOF study participants, 823 subjects were included in the analysis. These subjects were characterized by higher means of HRV and BRS indices in comparison to those who were not included (Table 1). No significant difference was observed between the groups for cardiovascular comorbidities. History of depression was reported by 228 subjects (27.8%). Current depressive symptoms were present among 67 subjects (8.1%) according to the QD2A score questionnaire, without taking into account the use of psychoactive drugs. Fifty nine subjects (7.2%) took antidepressant drugs. Benzodiazepine drugs were used by 109 subjects (13.2%) and 121 subjects (14.7%) used other psychoactive medication. 3.2. HRV and BRS according to the self-reported history of depression and use of psychoactive drugs (Table 2) Among the 819 analysed subjects, 228 reported a history of depression, of which 55 currently used psychoactive drugs. Study population with a history of depression was characterized by
155
higher proportions of women and anxiety symptoms, higher means of QD2A depression score and lower education level. Crude means of LF, VLF, LF/HF ratio, SDNN, and RR were significantly lower among the subjects with history of depression, and even lower among those who used psychoactive drugs, according to the MANOVA model. After adjustment for gender and physical activity, the relationship between history of depression and LF/HF ratio remained significant (p ¼0.008). The associations with the others HRV indices and BRS had similar trend, without reaching the statistical significance. The stepwise linear regression model to explain LF/HF ratio included first the gender (po0.001; R2 ¼ 6.0%), second the physical activity (p¼0.01; R2 ¼6.7%), and third history of depression (p¼0.01; R2 ¼7.2%). The variables educational level, anxiety symptoms and current depression score did not contribute significantly to the relationship. 3.3. HRV indices and BRS according to the QD2A score and the use of psychoactive drugs (Table 3) Among the 823 subjects included in the analyses, 52 had current depressive symptoms without being treated, 44 were treated with psychoactive drugs and 15 had current depressive symptoms and used psychoactive drugs. Proportions of men were smaller in the groups with depressive symptoms or psychoactive treatment use. Current depression score and proportion of subjects with anxiety symptoms were higher and educational level lower among the subjects with current depressive symptoms in comparison to those who had no depressive symptoms. Crude mean of LF/HF ratio was lower among the subjects with current depressive symptoms in comparison to those without depressive symptoms nor psychoactive treatment. Crude means of VLF and RR were lower among the untreated depressive subjects and the treated non-depressive subjects in comparison to other groups. After adjustment for gender, and physical activity, the association between current depressive symptoms and LF/HF ratio remained significant (p¼ 0.01), and the association with BRS became significant (p ¼0.04). The stepwise linear regression model to explain LF/HF ratio included first the gender (po0.001; R2 ¼ 6.1%), second the current depressive status (p¼0.002; R2 ¼7.3%) and third physical activity (p¼0.007; R2 ¼8.2%).
Table 1 Comparison of characteristics of the Proof study population included or not in the analysis. Total n¼ 1011
Selected study population n¼ 823 (81.4%)
Excluded study population n¼ 188 (18.6%)
p value
Gender (Men/Women)
402/609
339/484
63/125
0.05
Mean 7 SD ln SDNN 24-h ln HF 24-h ln LF 24-h ln VLF 24-h ln Ptot 24-h ln LF/HF night ln BRS ln RR ABPM SBP ABPM DBP Casual SBP Casual DBP
4.857 0.3 4.597 0.9 5.287 0.7 6.297 0.6 8.117 0.6 0.907 0.7 1.797 0.5 6.737 0.1 119.01 7 14.0 76.017 7.9 143.287 18.3 87.79 7 10.1
4.86 7 0.3 4.63 7 0.9 5.32 7 0.7 6.33 7 0.6 8.14 7 0.6 0.907 0.7 1.81 7 0.5 6.73 7 0.1 118.777 13.7 76.007 7.8 143.287 18.2 87.84 7 10.1
4.82 70.2 4.53 70.9 5.15 70.7 6.13 70.6 8.01 70.6 0.83 70.7 1.70 70.5 6.71 70.1 120.16 715.2 76.05 78.2 143.3 719.0 87.59 710.2
0.10 0.17 o0.01 o0.001 0.01 0.22 0.01 0.01 0.23 0.95 0.98 0.76
25.31 7 3.8 5.647 1.2 6.057 1.0
25.38 7 3.7 5.65 7 1.2 6.037 1.0
24.98 73.8 5.60 71.2 6.16 71.1
BMI (kg/m2) Fasting glycaemia Total cholesterol
0.21 0.59 0.13
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Table 2 Comparison of characteristics and HRV indices according to the self-reported history of depression and use of psychoactive treatment.
Self-reported history of depression Gender (men)—n (%) Age—crude means7 SD Educational level—crude means 7SD DEE—crude means7 SD Anxiety symptoms—n (%) QD2A score—crude means7 SD HRV Indices—crude means7 SD ln HF ln LF ln VLF ln Ptot ln LF/HF (night) ln SDNN ln BRS ln RR
No
Untreated
Treated
Total
P value (univariate analyses)
n¼ 591
n¼ 173
n¼ 55
n¼ 819*
293 (49.58%) 65.64 7 0.83 11.25 7 2.84 10529.40 7 1919.01 178 (30.22%) 1.96 7 2.04
39 (22.54%) 65.65 70.76 10.69 73.09 100267 1891.02 101 (58.38%) 3.89 73.53
7 (12.73%) 65.54 7 0.94 10.19 72.22 9671.487 1603.15 37 (67.27%) 4.95 73.23
339 (41.39%) 65.61 7 0.82 10.71 72.88 0368.337 11911.75 316 (38.68%) 2.57 72.71
o 0.001 0.66 o 0.01 o 0.001 o 0.001 o 0.001
4.63 7 0.85 5.34 7 0.71 6.36 7 0.63 8.16 7 0.58 0.96 70.65 4.87 7 0.26 1.82 7 0.51 6.74 7 0.12
4.65 70.92 5.27 70.67 6.24 70.60 8.097 0.57 0.817 0.64 4.83 70.29 1.807 0.49 6.72 70.12
4.54 70.99 5.07 70.74 6.16 70.62 7.98 70.53 0.64 70.67 4.77 70.25 1.72 70.44 6.71 7 0.11
4.61 70.87 5.23 70.70 6.26 70.62 8.087 0.58 0.807 0.66 4.82 70.27 1.78 70.50 6.73 70.12
0.76 0.02 0.01 0.06 o 0.01 0.02 0.33 0.04
P value (multivariate analyses)
0.99 0.12 0.23 0.27 0.008 0.18 0.08 0.92
DEE: Daily energy expenditure, in kj/24 h. QD2A score: current depressive symptoms score. HRV: Heart rate variability. n
4 subjects have not reported a history of depression and were treated for depression (non included in the analysis).
Table 3 Comparison of characteristics and HRV according to the QD2A score of depressive symptoms and use of psychoactive treatment. Normal score and untreated
Untreated depressives
Normal score and treated
Treated depressives
Total
n ¼712
n¼ 52
n¼44
n¼15
n¼ 823
8 (15.38%) 65.62 7 0.89
5 (11.36%) 65.55 70.90
2 (13.33%) 65.507 1.02
339 (41.19%) 65.58 70.82
o 0.001 0.81
10.14 7 2.93
9.937 1.85
10.797 2.99
10.51 72.88
o 0.01
QD2A score of depression Gender (men)—n (%) 324 (45.51%) Age—crude 65.65 7 0.80 means7 SD 11.19 7 2.90 Educational level—crude means7 SD DEE—crude 10441.45 71912.30 means7 SD Anxiety 235 (33.05%) symptoms—n (%) QD2A score—crude 1.88 7 1.72 means7 SD HRV Indices—crude means7 SD ln HF 4.61 7 0.85 ln LF 5.33 7 0.69 ln VLF 6.34 7 0.62 ln Ptot 8.14 7 0.57 ln LF/HF (night) 0.95 7 0.65 ln SDNN 4.86 7 0.27 ln BRS 1.82 7 0.51 ln RR 6.74 7 0.12
P value (univariate analyses)
P value (multivariate analyses)
10091.64 7 2052.06 10113.857 1963.76 9286.287 1223.93 10382.06 7 1919.85 0.07 44 (86.27%)
26 (59.09%)
13 (86.67%)
318 (38.73%)
o 0.001
9.48 7 2.01
3.327 1.99
9.137 1.77
2.57 72.70
o 0.001
4.59 7 0.92 5.21 7 0.78 6.20 70.58 8.11 7 0.57 0.75 70.66 4.85 7 0.27 1.72 7 0.51 6.70 70.09
4.607 1.11 5.057 0.80 6.107 0.67 7.957 0.55 0.607 0.71 4.757 0.23 1.677 0.46 6.717 0.12
4.757 0.67 5.327 0.48 6.407 0.36 8.217 0.51 0.577 0.58 4.897 0.28 1.907 0.31 6.757 0.08
4.64 78.86 5.23 70.70 6.26 70.62 8.107 0.57 0.727 0.66 4.84 70.27 1.78 70.51 6.72 70.12
0.93 0.05 0.03 0.19 o 0.001 0.08 0.10 0.03
0.90 0.19 0.24 0.51 0.01 0.29 0.04 0.33
DEE: Daily energy expenditure, in kj/24 h. QD2A score: current depressive symptoms score. HRV: Heart rate variability.
3.4. HRV indices and BRS according to depression status, defined by the QD2A score, history of depression and use of psychoactive drugs (Table 4) Among the 819 subjects included in the analyses, 55 subjects were considered as the ‘‘treated depressive’’ group and 193 subjects as the ‘‘untreated depressive’’ group. Proportions of men and education level were lower in the depressive groups. Current depression score and proportion of subjects with anxiety symptoms were higher. Crude means of LF, VLF and LF/HF ratio were lower among the ‘‘untreated depressive’’ group, and even lower among the ‘‘treated depressive’’ one. After adjustment for gender, and
physical activity, the association remained significant for LF/HF ratio (p ¼0.004). As for the previous models, the stepwise linear regression model included first the gender (p o0.001; R2 ¼6.0%), second the depressive status (p ¼0.003; R2 ¼ 7.0%) and third physical activity (p ¼0.009; R2 ¼7.8%).
4. Discussion In this study, long-term HRV indices were reduced among 65 year-old subjects with current depressive symptoms and/or history of depression, independently of the use of psychoactive treatment.
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157
Table 4 Comparison of HRV indices according to the depression characteristics: depressive status defined by both self-report history of depression and a depression QD2A score higher than the threshold 7, and use of psychoactive treatment.
Depressive status Gender (men)—n (%) Age—crude means7 SD Educational level—crude means7 SD DEE—crude means7 SD Anxiety symptoms—n (%) QD2A score—crude means7 SD HRV Indices—crude means7 SD ln HF ln LF ln VLF ln Ptot ln LF/HF (night) ln SDNN ln BRS ln RR
Normal and untreated
Untreated depressives
Treated depressives
Total
P Value (Univariate P value analyses) (multivariate analyses)
n ¼571
n ¼193
n¼55
n¼819*
290 (50.79%) 65.64 7 0.82 11.27 7 2.86 10552.83 71909.93 162 (28.42%) 1.96 7 1.62
42 (21.76%) 65.65 7 0.78 10.67 7 2.99 10011.04 7 1909.71 117 (60.94%) 3.89 7 3.69
7 (12.73%) 65.54 70.94 10.19 72.22 9671.487 1603.15 37 (67.27%) 4.95 73.17
339 (41.39%) 65.61 70.82 10.717 2.87 10368.337 1911.75 316 (38.68%) 3.707 2.72
o 0.001 0.67 o 0.01 o 0.001 o 0.001 o 0.001
4.61 7 0.83 5.34 7 0.71 6.37 7 0.63 8.15 7 0.58 0.98 7 0.65 4.87 7 0.26 1.82 7 0.51 6.74 7 0.12
4.64 7 0.91 5.26 7 0.68 6.24 7 0.59 8.10 7 0.55 0.80 70.66 4.84 7 0.28 1.80 7 0.50 6.72 7 0.12
4.57 70.98 5.087 0/74 6.17 70.64 8.007 0.55 0.617 0.68 4.79 70.27 1.71 70.43 6.71 70.11
4.617 0.86 5.237 0.70 6.267 0.62 8.097 0.57 0.907 0.66 4.837 0.27 1.787 0.50 6.737 0.12
0.85 0.02 o 0.01 0.13 o 0.001 0.06 0.34 0.07
0.99 0.10 0.14 0.31 0.004 0.27 0.09 0.85
DEE: Daily energy expenditure, in kj/24 h. QD2A score: current depressive symptoms score. HRV: Heart rate variability. n
4 subjects have not reported a history of depression and were however treated for depression (non included in the analysis).
This result is relevant with previous studies that highlighted lower short-term HRV indices among subjects with major depression, with and without cardiovascular disease (Agekink et al., 2002; Carney et al., 2005; Francis et al., 2009; Grippo and Johnson, 2002; Kamphuis et al., 2007; Kemp et al., 2010; Licht et al., 2008; Stein et al., 2000). While the analysis in the time-domain of HRV is well recognized to quantify normal and abnormal autonomic nervous system activity, measures of the same signal according to frequency domain analysis are discussed in their interpretation. Specifically, if the HF activity seems fairly associated with the level of parasympathetic tone, recent studies have shown that variations in LF during short term recordings should be interpreted as the cardiac response to activation or inhibition of baroreceptor function at the heart level (Goedhart et al., 2008; Goldstein et al., 2011). Thus, changes in the LF/HF ratio under controlled pharmacological (dynamic) conditions or during maneuvers of autonomic stimuli do not always reflect a change in the balance of sympathovagal balance. However, in our study we used data averaged over all 24 h or all of the night for the LF/HF ratio. The observed results convince us of a change (decrease) in cardiac autonomic activity when there is a masked or undiagnosed depression. This alteration is more marked on the total spectral power, LF and VLF patients undergoing treatment psychotropic. This reduction of variability cycles of low and very low frequencies could be associated with a decrease in baroreflex cardiac response to stimuli in these subjects. It has also been observed that a decrease of sympathetic activity, measured by other way than HRV, was proportional to the severity of the depression, which reinforces the link between ANS activity and depressive symptoms (Guinjoan et al., 1995; Williams et al., 1985). Correlatively, chronic stimulation of ANS activity, through vagal nerve stimulation, has been shown to improve symptoms of depression (Schlaepfer et al., 2008). Some previous studies have highlighted different results, with lower parasympathetic and higher sympathetic tone among subjects with major depression (Bar et al., 2004; Udupa et al., 2007) whereas others have found no significant association between subjects with major depression and HRV (Moser et al., 1998). In our study, self-reported history of depression and current depressive symptoms were used to indentify the subjects of
interest, whereas previous studies usually used the definition of major depression, defined by DSM III R, DSM IV criteria (Agekink et al., 2002; Bar et al., 2004; Licht et al., 2008; Rechlin et al., 1994; Udupa et al., 2007). Among the elderly without history of depression, newly depressive symptoms may be linked to a modification of life circumstances, like retirement (Alavinia and Burdorf, 2008). The significant association between self-reported history of depression and lower ANS activity may suggest a possible long-term effect of depressive symptoms during middle-age that may have adverse effects on later-life ANS activity. Other studies suggest that clinical diagnosis of major depression would not be required when studying the association between depressive symptoms and HRV (Grippo and Johnson, 2002). Mood states as well as affective disorders seem to impact the HRV (Rechlin et al., 1994). BRS showed a tendency to be lower among the subjects with depressive symptoms, which is congruent with a previous study (Broadley et al., 2005). The absence of association between the established parasympathetic indices i.e., HF and depressive symptoms in our study population could be explained by the age of the population which is older in comparison to previous study populations. There is a possible age-related attenuation of the clinical relevance of HRV indices since the ANS activity is known to decrease with age, in particular the parasympathetic tone (Stein et al., 2009). However the age of our study population was the same for all subjects, which avoids the possible bias of age. In our study, the use of psychoactive treatment seems to increase the dysfunction of ANS activity among subjects with depressive symptoms. Previous studies suggest that psychoactive treatment would be more associated to reduced ANS activity than depressive symptoms themselves (Bar et al., 2004; Licht et al., 2008). However, it is conceivable that subjects with depressive symptoms and using psychoactive treatment have a more severe stage of depression, it is then difficult to determine whether the use psychoactive treatment have a greater impact on ANS activity than depression symptoms themselves. It may be noted that in studies assessing electroconvulsive therapy (ECT) proposed in major or resistant to treatment depression, the confounding effects of psychoactive treatments on autonomic regulation can
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then not be discussed. This therapy (ECT) has been shown to improve HRV (Nahshoni et al., 2004, 2001). Thus the direct impact of ECT on the cardiac autonomic regulation confirms the important role of neural cortico-subcortical integration pathways on the central brainstem autonomic regulation. Anxiety symptoms did not contribute to change the association between depressive symptoms or history of depression and ANS indices in our study; this result is relevant with a previous study underlining that depression but not anxiety is associated with reduced ANS activity among patients after myocardial infarctus (Pitzalis et al., 2001). Our study presents several limitations. The study population included in the analyses had higher HRV and BRS indices than subjects that were not included, because of incomplete data in the neuropsychological evaluation or electrocardiographic recordings showing abnormal pattern that could fit with an exclusion criteria. This has to be considered as a selection bias of our population and should take into account in the interpretation of our results. It can be hypothesised that the excluded subjects have an unhealthy profile and that the prevalence of subjects with depressive symptoms, and/or history of depression was underestimated in our study. Nevertheless the association between depressive symptoms and ANS indices may not be affected since the ANS indices are found lower among the excluded subjects. Distinction between the different classes of psychoactive treatments was not made because the sample population size was small for each groups of interest. However a previous study has shown that the different classes of psychoactive treatment have different impact on the ANS activity; tricyclic antidepressants have been shown to reduce HRV whereas results are more variable for SSRIs (Kemp et al., 2010; van Zyl et al., 2008). Finally, our criteria to define depressive symptoms were not validated by a psychiatrist, what may conduct to a misclassification of subjects. On the whole, our results suggest that even minor current depressive symptoms can be linked to ANS lower performance. A possible long-term effect of depressive symptoms at middle-age may influence later-life ANS activity. This highlights the importance to take into account the depressive symptoms in the cardiovascular risk, even in the elderly more vulnerable than adults.
Role of funding source The Proof cohort study was supported by the French Ministry of Health (Programmes Hospitaliers de Recherche Clinique: PHRC National PROOF, 1998; PHRC National SYNAPSE, 2002; PHRC Regional Telamons, 2003). The study was also funded through a grant from Mutual Insurance Companies, AG2R and MPCL. A complementary funding came from the Association SYNAPSE (Michel Segura).ClinicalTrials.gov number, NCT 00759304.
Conflict of interest All authors declare that they have no conflicts of interest.
Acknowledgements We thank Mrs. Delphine Maudoux and Mrs. Judith Kerleroux, who helped to collect the data.
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