ORIGINAL ARTICLE
The Association Between Depressive Disorder
and Cardiac Autonomic Control in Adults
60 Years and Older
Carmilla M.M. Licht, PhD, Paul Naarding, MD, PhD, Brenda W.J.H. Penninx, PhD,
Roos C. van der Mast, MD, PhD, Eco J.C. de Geus, PhD, and Hannie Comijs, PhD
ABSTRACT
Background: Altered cardiac autonomic control has often been reported in depressed persons and might play an important
role in the increased risk for cardiovascular disease (CVD). A negative association between cardiac autonomic control and
depression might become specifically clinically relevant in persons 60 years or older as CVD risk increases with age.
Methods: This study included data of 321 persons with a depressive disorder and 115 controls participating in the
Netherlands Study of Depression in Older Persons (mean age = 70.3 years, 65.7% female). Respiratory sinus arrhythmia
(RSA), heart rate (HR), and preejection period (PEP) were measured and compared between depressed persons and controls.
In addition, the role of antidepressants and clinical characteristics (e.g., age of depression onset and comorbid anxiety)
was examined.
Results: Compared with controls, depressed persons had lower RSA (mean [standard error of the mean] = 23.5 [1.2] milliseconds versus 18.6 [0.7] milliseconds, p = .001, d = 0.373) and marginally higher HR (73.1 [1.1] beats/min versus 75.6
[0.6] beats/min, p = .065, d = 0.212), but comparable PEP (113.9 [2.1] milliseconds versus 112.0 [1.2] milliseconds, p = .45,
d = 0.087), fully adjusted. Antidepressants strongly attenuated the associations between depression and HR and RSA.
Antidepressant-naïve depressed persons had similar HR and RSA to controls, whereas users of antidepressants showed
significantly lower RSA. In addition, tricyclic antidepressant users had higher HR (p < .001, d = 0.768) and shorter PEP
(p = .014, d = 0.395) than did controls.
Conclusions: Depression was not associated with cardiac autonomic control, but antidepressants were in this sample. All
antidepressants were associated with low cardiac parasympathetic control and specifically tricyclic antidepressants with high
cardiac sympathetic control.
Key words: autonomic nervous system, major depressive disorder, heart rate (variability), elderly, preejection period,
antidepressants.
INTRODUCTION
effects of sympathetic and parasympathetic nerve activity
on target organs. To study the depression-CVD comorbidity, autonomic effects on the heart are an obvious target.
D
epression is a common mental disorder that affects
many people and hampers their daily functioning. In
addition, there is high comorbidity between depression
and somatic disorders, prominently including cardiovascular disease (CVD) (1,2). It has been hypothesized that altered functioning of the autonomic nervous system plays
an important role in this comorbidity (3–5). Autonomic
functioning is often operationalized by measuring the
ANOVA = analysis of variance, ATC = Anatomical Therapeutic
Chemical, BMI = body mass index, CAC = cardiac autonomic control, CIDI = Composite International Diagnostic Interview, CVD =
cardiovascular disease, ECG = electrocardiogram, HR = heart rate,
PEP = preejection period, RSA = respiratory sinus arrhythmia,
SSRI = selective serotonin reuptake inhibitor, TCA = tricyclic
antidepressant
Supplemental Content
From the GGZinGeest/Department of Psychiatry (Licht, Penninx, Comijs) and EMGO+ Institute (Licht, Penninx, de Geus, Comijs), VU University
Medical Center, Amsterdam, the Netherlands; Department of Old-Age Psychiatry (Naarding), GGNet, Apeldoorn/Zutphen, the Netherlands; Department
of Psychiatry (van der Mast), Leiden University Medical Center, Leiden, the Netherlands; and Department of Biological Psychology (de Geus), VU University, Amsterdam, the Netherlands.
Address correspondence and reprint requests to Carmilla M.M. Licht, PhD, Department of Psychiatry, VU University Medical Center, AJ Ernststraat
1187, 1081 HL, Amsterdam, the Netherlands. E-mail: [email protected]
Received for publication May 11, 2014; revision received November 18, 2014.
DOI: 10.1097/PSY.0000000000000165
Copyright © 2015 by the American Psychosomatic Society
Psychosomatic Medicine, V 77 • 279-291
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ORIGINAL ARTICLE
one study previously examined the effects of age of onset
on HRV. Although Vasudev et al. (26) reported lower lowfrequency HRV (generally considered as dominance of sympathetic control) in 42 older depressed patients compared
with controls, they found no significant difference in lowfrequency HRV between depressed patients with an early
age of onset and those with a late age of onset. Extension
of the analyses on age of onset with separate cardiac parasympathetic and sympathetic indices and a larger group of
depressed patients would be worthwhile. In addition, the
association of CAC with other clinical characteristics of
late-life depression such as severity and duration of the disorder has not been firmly studied to date.
In this study, we examined the association between
CAC and depressive disorders by comparing HR, respiratory sinus arrhythmia (RSA; a measure of HRV), and
PEP between depressed persons and controls 60 years
or older, taking antidepressant use and other clinical features such as severity, comorbid anxiety, and age of onset
into account.
Cardiac autonomic control (CAC) can be measured noninvasively by the preejection period (PEP; indicating sympathetic
control (6)), heart rate (HR; combined sympathetic and parasympathetic control (7)), and HR variability (HRV; mainly
parasympathetic control (8)). A combination of shortened
PEP, high HR, and low HRV reflects a shift from cardiac
parasympathetic to sympathetic control, and this is known
to constitute a risk factor for CVD (9–11) and cardiovascular
precursors such as diabetes and the metabolic syndrome
(12,13). These expressions of altered CAC are also associated with depression (14–16). However, recent research in
an adult cohort indicated that the relationship between
depression and CAC may be driven by the use of antidepressants rather than by the depression itself: antidepressantnaïve depressed patients did not display altered CAC
compared with controls, whereas users of different antidepressants had higher HR, lower HRV, and shorter PEP compared with healthy controls (17–19). Several studies support
the HRV-lowering effects of antidepressants, although findings are not always consistent in magnitude and direction for
all types of antidepressants (14,20,21).
Because the older population is already at high risk for
developing CVD and display age-related decreases in cardiac parasympathetic control (22–24), examining the relationship between CAC and depression in this group seems
to be of clinical interest. Although several studies indeed
suggested that altered CAC is commonly seen in depressed
older people (25,26), other studies found no association
between several measures of HRV and depression (27,28)
or depressive symptom profiles (29), indicating that results
are inconsistent. In addition, most studies were limited by
small sample sizes, samples that consisted only of persons
who already had CVD, and few studies took the use of
antidepressant into account. It is therefore still not clear
whether altered CAC is associated with depressive disorder
in a general older population.
A review that summarized research on depression in
older persons suggested that late-life depression is related
to specific clinical and (neuro)biological features of depression which are different from features modeled for younger
depressive patients (30). The authors indicated that a distinctive profile is present for late-onset and early-onset depression. For instance, cognitive dysfunction, white matter
hyperintensities, and other vascular problems are specifically reported in late-onset depression and less in earlyonset depression (30,31). This is in line with the vascular
depression hypothesis of Alexopoulos et al. (32), which
suggests that (cerebro)vascular disease may predispose, initiate, or perpetuate symptoms in at least some of the participants with late-life depression. Because cerebrovascular
problems are closely linked to more generalized vascular diseases, electrocardiographical changes, and CAC (33–35), it
is also worthwhile investigating the association between
age of depression onset and CAC. To our knowledge, only
Psychosomatic Medicine, V 77 • 279-291
METHODS
Participants
Participants in the present study were derived from the Netherlands
Study of Depression in Older persons (NESDO). NESDO is a prospective cohort study conducted among 510 older participants
(age ≥ 60 years) designed to examine (predictors of ) the longterm course and consequences of depression in older persons.
The rationale, methods, and recruitment strategy have been described in detail elsewhere (36), but are briefly summarized here.
The NESDO cohort included 378 depressed (major depressive
disorder [MDD], dysthymia, or minor depression according to
DSM-IV criteria) (37) and 132 nondepressed adults aged 60
through 93 years. Recruitment of depressed older adults took place
in five regions in the Netherlands from both mental health care institutes and general practitioners. Persons with a primary diagnosis
of dementia, a Mini Mental State Examination score lower than 18
(of 30 points), and insufficient command of the Dutch language
were excluded. Nondepressed control persons were recruited from
general practitioners. Inclusion criteria for controls were as follows: no lifetime diagnosis of depression, dementia, or other serious psychiatric disorders and good command of the Dutch
language. All interviews were audio-taped to monitor the quality of the data. Data collection of the first measurement started
in 2007 and was finished in September 2010. The study protocol was approved by the ethical review board of the VU University Medical Center and, subsequently, by the local review
boards of each participating center. After providing information
about the study, written informed consent from each participant
was obtained.
Measurements
Baseline assessment included a complete Composite International
Diagnostic Interview (CIDI 2.1 lifetime version), together with
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Depressive Disorder and CAC in Adults
adrenoceptor status and circulating catecholamines. In contrast to
cardiac norepinephrine spillover (45) or direct recording of the
activity of sympathetic nerves (45,46), PEP is a measure that can
be obtained in large samples of patients and controls.
Both time and frequency domain measures of HRV are used in
research on autonomic control and depression. Previous research
from our group (and repeated by others) has indicated that the correlations between high-frequency HRV (frequency domain) and
RSA (time domain) are very high (approximately 0.9) (47), and
that the measures can be used interchangeably. A clear advantage
of the peak-valley method on ECG and impedance cardiogram signals over Fourier decomposition of the ECG is that it additionally
generates the respiration rate (RR; which was used as a covariate).
RSA is a reliable index of cardiac parasympathetic control as
shown by experimental research indicating that RSA is generally
not altered by sympathectomy (48) and β-adrenergic blockade
(49), but is attenuated by 99% after vagal blockade with atropine
(8) or scopoloamine methyl nitrate (50). RSA was obtained by
combining the IBI time series with the filtered (0.1–0.4 Hz) dZ
signal, which corresponds to the respiration signal. RSA was obtained by subtracting the shortest IBI during HR acceleration in
the inspirational phase from the longest IBI during deceleration
in the expirational phase for all breaths, as described in detail
elsewhere (39).
Although automated scoring of IBI, RSA, and PEP removes
most artifacts and noise, the signals were checked by visual inspection to make sure no arrhythmias—which might be more frequently present in older and depressed adults (51,52)—were
included. Preliminary mixed-model analyses showed that differences in HR, RSA, PEP, and RR between depressed persons and
controls were similar across all separate assessment conditions
(overall test statistics were as follows: F = 0.376 [p = .997], F =
1.086 [p = .35], F = 0.384 [p = .996], and F = 0.989 [p = .48],
respectively). We therefore decided to average all data over the total duration of the assessment (approximately 116 minutes) to create a single resting PEP, RSA, HR, and RR.
other interviews and questionnaires. The CIDI determined the
presence of MDD, minor depression, and dysthymia diagnoses
in the past 12 months. The CIDI establishes diagnoses according
to the DSM-IV criteria (37) and has shown high interrater and testretest reliability and high validity for depressive disorders (38).
We distinguished two groups: healthy controls without a history of depressive or anxiety disorders not using antidepressant
medication and depressed participants with dysthymia or MDD diagnosis in the past 6 months. After exclusion of 60 participants
with missing physiological data due to equipment failure during
assessment or poor data quality, 13 participants with a minor
depression only, and exclusion of 1 control participant with an
anxiety diagnosis, the depressed group consisted of 321 participants and the control group of 115 participants.
Physiological Measurement
Physiological measurement was performed with the “Vrije
Universiteit Ambulatory Monitoring System” recording the electrocardiogram (ECG) and changes in thorax impedance (dZ) from
six electrodes placed on the chest and back of the participants
(39,40). NESDO participants wore the Vrije Universiteit Ambulatory Monitoring System device during a large part of the NESDO
baseline assessment, while participating in different assessment
parts (medical examination, interview, and cognitive tasks). The
start of the various assessment parts was marked with an event
marker to divide the total recording into fixed periods (e.g., resting
Phase 1, break, interview Part 1, Stroop task, Mini Mental State
Exam, Digit span, 10-word test, interview Part 2). Movement registration through vertical accelerometry was used to excise periods
where participants were nonstationary. Removal of breaks and
nonstationary parts (approximately 20 minutes) left an average
(standard deviation [SD]) registration of 116.1 (37.0) minutes.
This final registration included a supine rest condition (with three
blood pressure measurements, 8.9 [2.7] minutes) and three rest
conditions in which the participants were sitting or standing
upright: Rest 1 (sitting, 9.8 [2.3] minutes), Rest 2 (sitting, 1.8
[0.5] minutes), and Rest 3 (standing, 1.8 [0.5] minutes). Physical
strength was measured using a grip strength test and a walking task
(active, 2.3 [1.2] minutes). In addition, several interview parts
were administered: basic interview (demographics, sitting 48.2
[24.4] minutes), medical interview (medical history, health care
use, sitting 24.1 [11.9] minutes), and trauma interview (childhood
trauma and life events, sitting 10.8 [6.7] minutes), followed by a
number of cognitive tasks (e.g., Stroop, sitting 17.2 [5.7] minutes).
The interbeat interval (IBI) time series was extracted from the
ECG signal to obtain HR, an indicator of combined cardiac sympathetic and parasympathetic control. We used noninvasive thoracic impedance cardiography to derive the PEP as the time
interval between the onset of ventricular depolarization and the
opening of the semilunar valves (41), as was done before (40).
Changes in PEP are a reliable index of changes in β-adrenergic
inotropic drive to the left ventricle as shown in laboratory studies
manipulating β-adrenergic tone by epinephrine infusion (6,42),
amyl nitrite inhalation (43), or adrenoceptor blockade (6,44).
Throughout the text, we therefore refer to PEP as a measure of cardiac sympathetic control, rather than cardiac sympathetic activity
because the sympathetic effects on the left ventricle are determined
not just by changes in cardiac norepinephrine release but also by
Psychosomatic Medicine, V 77 • 279-291
Clinical Characteristics
Several potentially relevant clinical characteristics were determined. Frequent use (daily or >50% of the time) of antidepressant
medication was assessed by copying the names of medicines from
the containers brought in by the participants. Medication was classified using the World Health Organization Anatomical Therapeutic Chemical (ATC) classification (53). We distinguished selective
serotonin reuptake inhibitors (SSRIs, ATC code N06AB), tricyclic
antidepressants (TCAs, ATC code N06AA), and other antidepressants (including monoamine oxidase inhibitors, nonselective
N06AF, and antidepressants classified as N06AX). A derived
daily dose (DDD) was calculated for all antidepressants by dividing the participant's mean daily dose used by the defined daily
dose recommended by the World Health Organization (53). In
addition, the duration of antidepressant use was determined and
expressed in months of use.
The severity of depression was measured among all participants
using the 30-item Inventory of Depressive Symptoms (IDS) selfreport version (54).
To account for antidepressant use and severity of depression,
we first distinguished depressed participants using and not using
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ORIGINAL ARTICLE
were experienced. A categorical variable was computed based on
tertiles: an early age-of-onset group (onset at age ≤40 years), an intermediate age-of-onset group (onset at age >40 and <60 years),
and a late age-of-onset group (age of onset at >60 years). The presence of comorbid anxiety was determined using the CIDI and confirmed when a 6-month diagnosis of panic disorder, social phobia,
agoraphobia, or generalized anxiety disorder was present in addition to the depressive disorder. The number of depressive episodes
experienced was questioned in the CIDI. This count measure was
dichotomized in single or recurrent episodes.
different types of antidepressants. Second, we wanted to further
divide the depressed participants not using an antidepressant based
on severity. Because the users of antidepressants might have been
more severely depressed before starting antidepressant use, and
their severity might have significantly decreased since then, severity of depression might be a major confounding factor when comparing antidepressant-naïve and antidepressant-using depressed
participants. To advance this issue, we used information from
meta-analyses and reviews summarizing clinical trials and longitudinal observational studies on the effects of antidepressants on
depressive symptoms scores. On average, antidepressants achieve
a reduction in symptom score of 45% (55–59). Based on this average reduction, an IDS score for the antidepressant users was calculated that was more likely to represent their severity before they
started using this antidepressant (by dividing their current IDS
score by 0.55). We subsequently allocated the antidepressantnaïve depressed participants to two groups based on their IDS
score. The cutoff point was chosen such that the most severe group
matched the mean IDS score of the depressed participants before
they started the use of an antidepressant. In this way, a group variable with six categories was constructed: the control group, a
depressed group not taking antidepressants with an IDS < 32
(n = 51), a depressed group not taking antidepressants with an
IDS ≥ 32 (n = 37), a depressed group taking TCAs (n = 73), a
depressed group taking SSRIs (n = 77), and a depressed group taking other antidepressants (n = 83).
The CIDI provided the age of depression onset, which was
defined as the first age at which significant depressive symptoms
Covariates
Several studies have suggested that research investigating RSA
should take RR into account as a confounder (39,60). We therefore
adjusted all RSA analyses for RR. Sociodemographic characteristics included age, sex, and education in years. In addition, various
health indicators were included as covariates: body mass index
(BMI) was determined as measured weight in kilograms divided
by the square of the measured height in meters and included as a
continuous variable. Physical activity was measured using the International Physical Activity Questionnaire (61) and expressed in
MET-minutes per week (the multiple of the resting metabolic rate
of an activity times the minutes this activity was performed).
Smoking status was defined as nonsmoker, former smoker, and
current smoker. Alcohol use was determined as number of alcohol
consumptions a day. Self-reports were used to ascertain the presence of heart disease (including coronary disease, cardiac arrhythmia, angina pectoris, heart failure, and myocardial infarction) and
TABLE 1. Sample Characteristics
Characteristics
Demographics
Age, M (SD), y
Sex, % female
Education, M (SD), y
Health and life-style factors
BMI, M (SD), kg/m2
Physical activity, M (SD), 1000 MET-min/wk
Smoking status, %
Nonsmoker
Former smoker
Current smoker
Alcohol use, M (SD), no. of alcohol
consumptions/d
Chronic diseases, M (SD), no.
Cardiovascular disease, % yes
Medication use
β-Blockers, % yes
Other cardiovascular medication, % yes
Respiration rate, M (SD), breaths/min
Control (n = 115)
Depressive Disorder (n = 321)
pa
69.6 (6.9)
63.5
12.4 (3.4)
70.5 (7.3)
66.4
10.3 (3.4)
.28
.57
<.001
27.0 (4.1)
3.6 (2.8)
26.2 (4.3)
2.3 (2.3)
.074
<.001
33.0
58.3
8.7
1.03 (1.0)
29.0
43.6
27.4
0.54 (0.9)
<.001
1.48 (1.1)
14.8
2.10 (1.5)
23.4
<.001
.062
20.0
37.4
16.5 (1.2)
26.5
31.8
16.7 (1.4)
.21
.52
.23
<.001
M = mean; SD = standard deviation; BMI = body mass index; MET = multiple of the resting metabolic rate.
a
Comparison using analyses of variance (continuous variables) and χ2 test (categorical variables).
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Depressive Disorder and CAC in Adults
TABLE 2. Heart Rate, RSA, and PEP Compared Between Healthy Control and Depressed Participants
Characteristics
Heart rate
Heart rate, M (SD), beats/min
Heart ratea, M (SE), beats/min
Heart rateb, M (SE), beats/min
RSA
RSA, mean (SD/SE), ms
RSAa, M (SE), ms
RSAb, M (SE), ms
PEP
PEP, M (SD), ms
PEPa, M (SE), ms
PEPb, M (SE), ms
Control Versus Current Depression
Control
(n = 115)
Current Depression
(n = 321)
F
p*
Cohen d
73.7 (11.8)
73.3 (1.1)
73.1 (1.1)
75.4 (11.8)
75.6 (0.7)
75.6 (0.6)
1.685
3.051
3.417
.20
.081
.065
0.141
0.193
0.212
23.6 (11.9)
23.4 (1.2)
23.5 (1.2)
18.6 (12.5)
18.7 (0.7)
18.6 (0.7)
14.029
11.627
10.607
<.001
.001
.001
0.412
0.377
0.373
111.5 (19.6)
111.7 (2.0)
113.9 (2.1)
112.8 (21.4)
112.7 (1.2)
112.0 (1.2)
0.326
0.197
0.571
.57
.66
.45
0.064
0.049
0.087
RSA = respiratory sinus arrhythmia; PEP = preejection period; M = mean; SD = standard deviation; SE = standard error.
* Based on F statistics for contrast comparison with 1 degree of freedom (error df = 434).
a
Adjusted age, sex, and education (RSA additionally for respiration rate; error df = 431 and for RSA error df = 430).
Additionally adjusted for body mass index, physical activity, smoking, alcohol use, cardiovascular disease, chronic disease, use of β-blockers, and use of
other heart medication (error df = 423 and for RSA error df = 422).
b
episodes using fully adjusted ANOVAs. Analyses were repeated
separately for the antidepressant-naïve depressed participants.
Finally, we performed partial correlation between CAC and the
duration of TCA, SSRI, and other antidepressant use and the DDD
of these antidepressants. Correlations were adjusted for age and
sex (RSA additionally for RR).
Sensitivity analyses were performed excluding alternately
CVD patients and depressed participants without a diagnosis in
the month before the baseline assessment.
a disease count of other chronic conditions (epilepsy, diabetes,
osteoarthritis, stroke, cancer, chronic lung disease, thyroid disease,
liver disease, chronic fatigue syndrome, intestinal disorders, and
ulcer [stomach or intestinal]). Furthermore, it was determined
whether participants were using heart medication. A dichotomous
variable was computed, scoring “yes” if participants frequently
(daily or >50% of the time) used a β-blocker (ATC codes: C07
[β-blocking agents]) or other heart medication (ATC codes: C01
[cardiac therapy], C02 [antihypertensives], C03 [diuretics], C04
[peripheral vasodilators], C05 [vasoprotectives], C08 [calcium
channel blockers], C09 [renin and angiotensin agents], and C10
[lipid modifying agents]).
RESULTS
The mean (SD) age of the study sample (n = 436) was 70.3
(7.3) years, 65.7% was female, and 65.2% had less than
12 years of education. Table 1 shows the demographic,
life-style, and health characteristics for healthy controls
and depressed participants. Compared with the nondepressed persons, depressed persons had less education, a
slightly lower BMI, performed less physical activity, were
more likely to smoke but less likely to drink, had more
chronic diseases, and more often had CVD.
Table 2 presents unadjusted and adjusted results of the
mean HR, RSA, and PEP for the controls and depressed
persons. The depressed group had a borderline higher HR
than did the control group (in the fully adjusted analysis
2.5 beats/min higher, p = .07) and no significantly different
PEP (in the fully adjusted analysis, p = .45). The depression
groups did significantly differ from the control group in
mean RSA (in adjusted analysis 4.9 milliseconds lower
RSA, p = .001). The effect sizes for lower RSA and higher
Statistical Analyses
Data were analyzed using SPSS 21.0. Characteristics of the depression and control groups were compared using t tests and χ2
tests. Analyses of variance (ANOVAs) were used to compare
HR, RSA, and PEP between the depression group and controls.
These analyses were repeated with consideration of covariates. Effect sizes were calculated with Cohen d (1988) defined as the difference in the means between two groups, divided by the pooled
SD of these groups.
We subsequently compared the antidepressant and severity
groups with the controls on cardiac autonomic measures in unadjusted and fully adjusted ANOVAs. These analyses were repeated
within the rest and other separate assessment conditions of the interview. Furthermore, the impact of different clinical characteristics was evaluated. CAC was compared between depressed
persons with and without comorbid anxiety disorders; between depressed participants with an early, intermediate, and late age of onset; and between depressed participants with single or recurrent
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ORIGINAL ARTICLE
TABLE 3. Clinical Characteristics of the Sample by Antidepressant Use and Severity Group
Depressive Disorder
Antidepressant Naïve
Characteristics
Demographics
Age, M (SD), y
Sex, % female
Education, M (SD), y
Health and life-style factors
BMI, M (SD), kg/m2
Physical activity, M (SD), 1000 MET-min/wk
Smoking status, %
Nonsmoker
Former smoker
Current smoker
Alcohol use, M (SD), no. of alcohol
consumptions/d
Chronic diseases, M (SD), no.
Cardiovascular disease, % yes
Medication use
β-Blockers, % yes
Other cardiovascular medication, % yes
Tricyclic antidepressants, % yes
Selective serotonin reuptake inhibitors, % yes
Other antidepressants, % yes
Clinical characteristics
Dysthymia, % yes
% with a 1-mo recency of dysthymia
MDD, % yes
% with a 1-mo recency of MDD
IDS score, M (SD)
Age of onset, M (SD), y
Early age of onset (<40 y), % yes
Middle age of onset (40–59 y), % yes
Late age of onset (≥60 y), % yes
No. episodes, M (SD)
1 episode, % yes
Recurrent episodes, % yes
Comorbid anxiety, % yes
Generalized anxiety disorder, % yes
Panic disorder (with or without agoraphobia), %
yes
Social phobia, % yes
Respiration rate, M (SD), breaths/min
Antidepressant Users
On Other
Antidepressant
(n = 77)
pa
69.7 (6.5) 71.4 (7.4)
71.2
60.2
9.9 (3.4) 10.8 (3.6)
69.7 (6.9)
71.4
9.8 (3.0)
.23
.22
<.001
27.1 (4.5) 25.9 (3.9)
1.5 (1.5) 2.6 (2.8)
25.9 (4.4)
2.3 (1.8)
.31
.005
31.5
45.2
23.3
0.35 (0.6)
21.7
49.4
28.9
0.59 (0.9)
33.8
40.3
26.0
0.52 (0.9)
.60
2.21 (1.4) 2.58 (1.7) 1.68 (1.3) 2.34 (1.6)
24.6
19.4
15.1
24.1
1.96 (1.4)
10.4
.016
.13
IDS < 32
(n = 51)
IDS ≥ 32
(n = 37)
71.9 (7.9)
57.9
10.9 (3.8)
69.3 (8.6)
74.2
10.4 (3.5)
26.4 (4.5)
2.9 (2.2)
25.5 (4.5)
2.5 (2.7)
24.6
38.7
43.9
32.3
31.6
29.0
0.76 (1.2) 0.53 (1.0)
35.1
21.0
—
—
—
35.5
19.3
—
—
—
On TCA
(n = 73)
23.3
38.3
100.0
4.3
8.2
On SSRI
(n = 83)
27.7
33.7
0.0
100.0
0.0
22.8b
45.2b
26.0b
92.3
100.0
78.9
96.5b
100.0b
100.0b
67.3
87.1
68.5
21.0 (6.7) 46.7 (8.8) 29.0 (14.6)
45.7 (23.0) 43.0 (23.2) 45.6 (21.7)
50.0
37.5
33.3
18.8
18.8
38.1
31.2
43.8
28.6
10.2 (22.6) 11.6 (25.0) 9.9 (22.5)
35.1
45.2
27.4
64.9
54.8
72.6
21.1
38.7
43.8
5.3
16.1
9.6
12.3
32.3
24.7
5.3
16.6 (1.4)
18.2
36.3
0.0
10.8
100.0
.14
.16
.52
<.001
<.001
<.001
25.3b
29.9b
.22
95.2
100.0
.075
97.6b
97.4b
.53
79.0
86.7
.025
29.7 (12.0) 33.7 (11.4) <.001
52.4 (21.9) 46.1 (20.7)
.16
20.8
27.6
.59
41.7
37.9
37.5
34.5
9.5 (20.5)
5.4 (9.1)
.50
34.9
28.6
.40
65.1
71.4
39.8
44.2
.054
8.4
10.4
.56
21.7
31.2
.10
19.4
26.0
25.3
16.7 (1.3) 17.0 (1.5) 16.8 (1.4)
15.6
16.3 (1.2)
.017
.039
IDS = Inventory of Depressive Symptoms; TCA = tricyclic antidepressant; SSRI = selective serotonin reuptake inhibitor; M = mean; SD = standard
deviation; BMI = body mass index; MET = multiple of the resting metabolic rate; MDD = major depressive disorder.
a
Comparison using analyses of variance (continuous variables) and χ2 test (categorical variables).
b
Percentages add up to more than 100% because of multiple diagnoses within 12 months or comorbidity between disorders.
Psychosomatic Medicine, V 77 • 279-291
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April 2015
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Depressive Disorder and CAC in Adults
Additional analyses were performed to investigate the role
of clinical depressive characteristics. Within the depressed
persons, the association of age of onset, comorbid anxiety,
and number of experienced depressive episodes with CAC
was investigated (graphs can be found in Supplement Digital Content 2, http://links.lww.com/PSYMED/A196). Comparison of HR, RSA, and PEP between depressed persons
with early, middle, or late age of onset revealed no differences (p = .78, p = .74, and p = .62, respectively). In addition, HR, RSA, and PEP were similar for depressed persons
with and without comorbid anxiety (p = .59, p = .46, and
p = .90, respectively). Finally, the comparison of single episode versus multiple episodes also revealed no differences
in HR, RSA, or PEP (p = .35, p = .58, and p = .59, respectively). The analyses with antidepressant-naïve participants
only yielded similar findings.
Table 5 shows the partial correlations between CAC and
the duration and DDD of antidepressant use. Correlations
were adjusted for age and sex. The duration and DDD of
TCA use correlated negatively with RSA and PEP, indicating that a longer duration of use and a higher DDD associated with lower values of RSA and shorter PEP. Although
the other correlations correspond with the findings presented in Table 4 in terms of direction, they do not exceed
borderline significance.
Sensitivity analyses showed that the exclusion of CVD
patients did not alter any of the findings. In addition, excluding all depressed participants who were not depressed
in the month before the baseline interview from the analyses also resulted in similar findings.
HR in the depression group compared with the controls
were moderate: d = 0.373 and d = 0.212, respectively. Covariates that associated strongest with HR were education,
physical activity, CVD, and the use of β-blocking agents.
Covariates that associated strongest with RSA were RR and
β-blocking agents. Covariates that associated strongest with
PEP were BMI, β-blocking agents, alcohol use, and CVD.
Table 3 describes all characteristics for the groups
divided according to antidepressant use and severity. Compared with the depressed persons not taking antidepressants,
antidepressant users had less education, performed less physical activity, had fewer chronic diseases, and more often had
a comorbid anxiety disorder (mainly social phobia). Figure 1
represents the unadjusted results of ANOVAs on these six
groups and HR, RSA, and PEP. The overall group effect
for HR was F = 10.86, p < .001. Post hoc Dunnett test revealed that only the depressive TCA users differed significantly in HR from the controls (p < .001). Repetition of these
analyses comparing the antidepressant groups with the depressed participants with an IDS ≥ 32 also showed a difference between TCA users and these depressed participants
(p < .001). The overall effect for RSA was F = 7.80, p < .001.
Post hoc Dunnett test indicated that the depressive TCA
(p < .001) and other antidepressant (p = .017) users differed
significantly in RSA from the controls. SSRI users have
borderline lower RSA (p = .101). The TCA users also had
a significantly lower RSA than the depressed participants
with IDS ≥ 32 (p < .001). The overall test for the PEP
was also significant (F = 3.31, p = .006). Post hoc Dunnett
test revealed that the depressive SSRI users have borderline
longer PEP (p = .078) compared with the controls. The depressed participants with an IDS ≥ 32 had a significantly
longer PEP compared with the TCA users (p = .002).
Table 4 presents the results of the fully adjusted analysis
of covariance comparing CAC between these groups. The
differences in RSA between controls and depressed participants seen in Table 2 seemed to be entirely driven by the
use of antidepressants. Depressed participants not using antidepressants had comparable RSA values with those of
controls. Depression severity was not associated with
CAC. In contrast, however, RSA differed significantly between controls and depressed participants on TCAs (p <
.001, effect size d = 0.768), SSRIs (p = .031, effect size
d = 0.333), and other antidepressants (p = .013, effect size
d = 0.376). The subdivision based on medication use additionally revealed an association between TCA use and
higher HR (p < .001, effect size d = 0.921) and shorter PEP
(p = .014, effect size d = 0.395). Supplemental Digital Content 1 (http://links.lww.com/PSYMED/A195) shows the
results of these analyses for rest conditions only. Findings
are very similar, and significant associations are even
more pronounced. Highly comparable results were also obtained from analyses within all other separate assessment
conditions.
Psychosomatic Medicine, V 77 • 279-291
DISCUSSION
This study among older people showed that—when compared with healthy controls—depressed persons have significantly lower HRV in the respiratory frequency range.
This is considered to reflect lower cardiac parasympathetic
control (62,63). Comparing the users of different antidepressants and antidepressant-naïve depressed persons with
healthy controls revealed that depressed persons not using
antidepressants do not have altered RSA, HR, or PEP compared with healthy controls, irrespective of their severity
scores. In contrast, depressed persons using TCAs had decreased RSA, increased HR, and shortened PEP (medium
to large effect sizes). The use of SSRIs and other antidepressants was also associated with decreased RSA with moderate effect sizes. Our findings are in agreement with a
previous meta-analysis on much smaller-scale studies in
adults (16) and also with smaller-scale studies in older persons (25,64–66) that also reported altered autonomic control in depressed older persons. However, these previous
studies did not consider the effects of antidepressants,
whereas we did.
We see many similarities when we compare the results
of the present study among older people with the results
285
April 2015
Copyright © 2015 by the American Psychosomatic Society. Unauthorized reproduction of this article is prohibited.
ORIGINAL ARTICLE
FIGURE 1. Association between heart rate, RSA, and PEP and groups divided on depression and antidepressant status. Based on
unadjusted univariable ANOVA results. Error bars depict the SD in cardiac autonomic measure of the specific group (from the upper
mark to the lower mark is 1 SD). RSA = respiratory sinus arrhythmia; PEP = preejection period; ANOVA = analysis of variance; SD =
standard deviation; bpm = beats/min; IDS = Inventory of Depressive Symptoms; TCA = tricyclic antidepressant; AD = antidepressant;
SSRI = selective serotonin reuptake inhibitor.
we previously obtained in a young to middle-aged adult cohort (17,18). In the latter study, the presence of a depressive
disorder itself was also not associated with altered CAC but
the use of different antidepressants was. However, in these
Psychosomatic Medicine, V 77 • 279-291
younger adults, we found lower HR and longer PEP in
SSRI users but an association between the use of other antidepressants and shorter PEP and high HR (19), which is
not in line with the present findings in an older population.
286
April 2015
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Psychosomatic Medicine, V 77 • 279-291
287
73.1 (1.1)
74.1 (1.4)
72.7 (1.9)
83.4 (1.3)
75.0 (1.2)
71.3 (1.2)
115
51
37
73
83
77
M (SE)
5.896
1.117
−1.069
REFb
0.378
−0.446
tb
<.001
.24
.29
REFb
.59
.87
pb
0.921
0.173
0.161
REFb
0.087
0.034
Cohen db
13.6 (1.5)
18.8 (1.4)
19.3 (1.4)
23.6 (1.2)
21.5 (1.6)
22.8 (2.2)
M (SE)
REFb
.33
.77
<.001
.013
.031
−5.020
−2.484
−2.213
pb
REFb
−1.186
−0.872
tb
RSA, msa
0.768
0.376
0.333
REFb
0.158
0.060
Cohen db
105.3 (2.5)
111.7 (2.3)
116.1 (2.3)
113.8 (2.1)
111.9 (2.7)
115.7 (3.7)
M (SE)
−2.523
−0.637
0.737
REFb
−0.704
0.514
tb
.014
.50
.46
REFb
.40
.45
pb
b
a
Statistics are based on the results of univariable-adjusted analyses of variance and comparison with the control group.
Adjusted for age, sex, education, chronic diseases, cardiovascular diseases, use of β-blockers, use of other heart medication, physical activity, body mass index, smoking, and alcohol use.
0.395
0.099
0.111
REFb
0.089
0.092
Cohen db
Preejection Period, msa
RSA = respiratory sinus arrhythmia; PEP = preejection period; M = mean; SE = standard error; REF = reference group; IDS = Inventory of Depressive Symptoms; TCA = tricyclic antidepressant;
AD = antidepressant; SSRI = selective serotonin reuptake inhibitor.
Participants not using antidepressants
Control
Depressive disorder with IDS < 32
Depressive disorder with IDS ≥ 32
Participants using antidepressants
Depressive on TCA
Depressive on other AD
Depressive on SSRI
n
Heart Rate, beat/mina
Autonomic Measures
TABLE 4. Heart Rate, RSA, and PEP, Grouped by Depression and Antidepressant Statusa
Depressive Disorder and CAC in Adults
April 2015
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ORIGINAL ARTICLE
TABLE 5. Correlation Between DDD and Duration of Use, and Heart Rate, RSA, and PEP Among Depressed
Participants Using Psychoactive Medication
Correlation DDD
and RSAb,c
Correlation DDD
and Heart Rateb
Psychoactive
Medication
TCA users
SSRI users
Other antidepressant
users
Psychoactive
Medication
TCA users
SSRI users
Other antidepressant
users
n DDD,a M (SD)
73
77
83
1.07 (0.69)
1.37 (0.70)
1.11 (0.91)
n
Duration of
Use,
M (SD), mo
73
77
83
34.5 (78.0)
32.6 (55.8)
25.9 (75.9)
Correlation
Coefficient
p
Correlation
Coefficient
0.196
−0.028
0.046
.091
.80
.67
−0.321
−0.045
−0.050
Correlation Duration
and Heart Rateb
Correlation DDD
and PEPb
p
.007
.68
.65
Correlation Duration
and RSAb,c
Correlation
Coefficient
p
−0.293
0.145
−0.184
.014
.18
.093
Correlation Duration
and PEPb
Correlation
Coefficient
p
Correlation
Coefficient
p
Correlation
Coefficient
p
0.134
0.134
−0.014
.29
.26
.90
−0.502
0.010
0.005
<.001
.93
.96
−0.231
0.199
−0.029
.067
.089
.80
DDD = derived daily dose; RSA = respiratory sinus arrhythmia; PEP = preejection period; M = mean; SD = standard deviation; TCA = tricyclic
antidepressant; SSRI = selective serotonin reuptake inhibitor.
a
DDD is expressed as the daily dose used by the participants divided by the defined daily dose assigned by the World Health Organization. The defined daily
dose is the assumed average maintenance dose per day for a drug used for its main indication in adults. Analyses for specific psychoactive medications were
performed when at least 20 participants were using that particular medication.
b
Adjusted for sex and age.
c
Additionally adjusted for respiration rate.
these could be reflected in altered peripheral autonomic
regulation. The latter chain of events is not supported by
our study. Although we do not rule out that part of the depression in these older participants was caused by cerebrovascular problems, these were not reflected in altered CAC.
In addition, none of the clinical characteristics of
depression taken into account in the present study were significantly associated with any of the autonomic measures.
This argues against the idea that altered CAC could have
been limited to a specific subgroup of (antidepressant-naïve)
depressed older persons.
The strengths of our study are the large sample of control and depressed older persons, both medicated and nonmedicated. In addition, multiple cardiac autonomic measures
were available, providing us with reliable indices of parasympathetic and sympathetic control. Finally, the inclusion of different clinical characteristics such as depression severity and
age of onset distinguishes our study from previous ones.
Some limitations also have to be acknowledged. The crosssectional design makes it impossible to directly attribute
the results to the effects of antidepressants. However, extensive analyses of several clinical characteristics make it less
likely that the actual cause of our findings lies in differences
between antidepressant users and nonusers in these variables.
In addition, the finding that a longer duration of TCA use
Although proportionally fewer SSRI users and users of antidepressant other than TCAs were present in this older population compared with the adult cohort, the groups were
large enough to detect significant associations. An explanation might be that HR is already higher and PEP shorter in
older persons and that the more subtle effects of SSRIs and
other antidepressants on cardiac sympathetic control are
more difficult to detect.
Among other studies on CAC and depression in younger
adults, there were some studies that did address antidepressant medication and that reported an association between
CAC and depressive disorders (14,16). It was suggested
in previous discussions that differences in results might be
due to the inclusion of CVD patients in our sample
(20,67). Although there is a considerable percentage of
CVD patients in our older sample (on average, 17.5%), no
significant difference in percentage of CVD patients between depressed participants not using antidepressants
and those who use antidepressants was found. In addition,
the results of analyses adjusted for the presence of CVD
were similar to the results of unadjusted analyses. Moreover, sensitivity analyses excluding all CVD patients also
produced similar results.
According to the vascular depression hypothesis, depression may be caused by cerebrovascular problems and
Psychosomatic Medicine, V 77 • 279-291
288
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Depressive Disorder and CAC in Adults
grant from NARSAD The Brain and Behaviour Research
Fund (Grant ID 41080) awarded to Dr. Hannie Comijs
and an EMGO+ fellowship to Dr. Licht. The authors report
no conflicts of interest.
and a higher DDD of TCA associates with decreased cardiac
parasympathetic control and increased sympathetic control
supports the hypothesis that the found effects can actually
be attributed to TCA use. Moreover, the longitudinal results
of our adult cohort do imply that the associations found have
a causal basis (18,19). In addition, we cannot completely exclude the possibility that depressed persons using antidepressants differed in one or more aspects (different from the ones
we tested) from the depressed participants not using antidepressants. However, the most likely characteristics including
differences in depression symptom severity, age of depression onset, recency of the diagnosis, and number of episodes
did not seem to explain the findings.
In sum, our findings demonstrate that depressed older
persons not using antidepressants do not show altered CAC
compared with controls, whereas depressed older persons
using antidepressants do. It has been widely established that
a shift from cardiac parasympathetic to sympathetic control is a risk factor for cardiovascular morbidity and mortality (9–11,68). In previous work among younger adults,
we showed that such a shift also predicts future development
of the metabolic syndrome and metabolic dysregulations
(13,69). In addition, we found that the use of antidepressants
was also associated with increased blood pressure and hypertension, partially mediated by altered CAC (13,70). These
previous results suggest that the present findings among
older people could be of significant clinical importance and
deserve attention and evaluation in clinical practice. The
question whether the observed reduction in cardiac parasympathetic control in users of antidepressants actually increases
the risk for CVD remains to be answered. The detrimental
effects of antidepressants on CAC need to be weighed against
their beneficial effects on depression, which themselves could
reduce the risk for future heart disease. An article by Rahman
et al. (71) suggests that the balance is in favor of antidepressants. They noted a contribution of both major depression
and antidepressant use to CVD risk, but the antidepressantnaïve depressive persons had the highest risk. Unfortunately,
the aggregated result of the research investigating the risk for
CVD by antidepressant use yields no consistent answers,
with some studies finding a protective effect, others finding
an increased risk, and some finding no relationship (72–77).
Type of antidepressant, type of cardiac event, and sample
characteristics may explain some of the inconsistencies.
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