Effects of Antidepressants, but not Psychopathology, on Cardiac Sympathetic Control: A Longitudinal Study.

Abstract

Increased sympathetic activity has been hypothesized to have a role in the elevated somatic disease risk in persons with depressive or anxiety disorders. However, it remains unclear whether increased sympathetic activity reflects a direct effect of anxiety or depression or an indirect effect of antidepressant medication. The aim of this study was to test longitudinally whether cardiac sympathetic control, measured by pre-ejection period (PEP), was increased by depression/anxiety status and by antidepressant use. Cross-sectional and longitudinal data were from a depression and anxiety cohort: the Netherlands Study of Depression and Anxiety (NESDA). Baseline data of 2838 NESDA subjects (mean age 41.7 years, 66.7% female) and 2-year follow-up data of 2226 subjects were available for analyses. Included were subjects with and without depressive/anxiety disorders, using or not using different antidepressants at baseline or follow-up. The PEP was measured non-invasively by 1.5 h of ambulatory impedance cardiography. Cross-sectional analyses compared PEP across psychopathology and antidepressant groups. Longitudinal analyses compared 2-year changes in PEP in relation to changes in psychopathology and antidepressant use. Cross-sectional analyses showed that antidepressant-naïve depressive/anxious subjects had comparable PEP as controls, whereas subjects using tricyclic (TCA) or combined serotonergic/noradrenergic antidepressants (SNRI) had significantly shorter PEP compared with controls. In contrast, subjects using selective serotonin re-uptake inhibitors (SSRIs) had longer PEP than controls. Longitudinal results confirmed these findings: compared with 2-year change in PEP in continuous non-users (+2 ms), subjects who started TCA or SNRI treatment showed significantly shortened PEP (-11 ms, p=0.005 and p<0.001), whereas subjects who started SSRI treatment showed significant prolongation of PEP (+9 ms, p=0.002). Reversed findings were observed among those who stopped antidepressant use. These findings suggest that depressive and anxiety disorders are not associated with increased cardiac sympathetic control. However, results pose that TCA and SNRI use increases sympathetic control, whereas SSRI use decreases sympathetic control.

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Effects of Antidepressants, but not Psychopathology,
on Cardiac Sympathetic Control: A Longitudinal Study
Carmilla MM Licht*,1, Brenda WJH Penninx1,2,3and Eco JC de Geus4
1Department of Psychiatry/EMGO Institute for Health and Care Research, VU University Medical Center, Amsterdam, The Netherlands;
2Department of Psychiatry, Leiden University Medical Center, Leiden, The Netherlands;3Department of Psychiatry, Groningen University Medical
Center, Groningen, The Netherlands;4Department of Biological Psychology, VU University, Amsterdam, The Netherlands
Increased sympathetic activity has been hypothesized to have a role in the elevated somatic disease risk in persons with depressive or
anxiety disorders. However, it remains unclear whether increased sympathetic activity reflects a direct effect of anxiety or depression or
an indirect effect of antidepressant medication. The aim of this study was to test longitudinally whether cardiac sympathetic control,
measured by pre-ejection period (PEP), was increased by depression/anxiety status and by antidepressant use. Cross-sectional and
longitudinal data were from a depression and anxiety cohort: the Netherlands Study of Depression and Anxiety (NESDA). Baseline data
of 2838 NESDA subjects (mean age 41.7 years, 66.7% female) and 2-year follow-up data of 2226 subjects were available for analyses.
Included were subjects with and without depressive/anxiety disorders, using or not using different antidepressants at baseline or follow-
up. The PEP was measured non-invasively by 1.5h of ambulatory impedance cardiography. Cross-sectional analyses compared PEP
across psychopathology and antidepressant groups. Longitudinal analyses compared 2-year changes in PEP in relation to changes in
psychopathology and antidepressant use. Cross-sectional analyses showed that antidepressant-naı ¨ve depressive/anxious subjects had
comparable PEP as controls, whereas subjects using tricyclic (TCA) or combined serotonergic/noradrenergic antidepressants (SNRI) had
significantly shorter PEP compared with controls. In contrast, subjects using selective serotonin re-uptake inhibitors (SSRIs) had longer
PEP than controls. Longitudinal results confirmed these findings: compared with 2-year change in PEP in continuous non-users (+2ms),
subjects who started TCA or SNRI treatment showed significantly shortened PEP (?11ms, p¼0.005 and po0.001), whereas subjects
who started SSRI treatment showed significant prolongation of PEP (+9ms, p¼0.002). Reversed findings were observed among those
who stopped antidepressant use. These findings suggest that depressive and anxiety disorders are not associated with increased cardiac
sympathetic control. However, results pose that TCA and SNRI use increases sympathetic control, whereas SSRI use decreases
sympathetic control.
Neuropsychopharmacology (2012) 37, 2487–2495; doi:10.1038/npp.2012.107; published online 4 July 2012
Keywords: sympathetic nervous system; major depressive disorder; pre-ejection period; antidepressants; anxiety disorder
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INTRODUCTION
Increased activity of the sympathetic nervous system (SNS)
may have an important role in the increased risk for
cardiovascular and metabolic disease in patients with
depressive and anxiety disorders (Glassman, 2008; Penninx
et al, 2001; Eaker et al, 2005; Nicholson et al, 2006; Esler et al,
2006; Flaa et al, 2008a,b; Masuo et al, 2005, 2010). Various
studies reported increased sympathetic activity in depressed
and anxious subjects compared with healthy controls, mea-
sured by different indices like spillover of norepinephrine
(NE) and epinephrine (EPI), skin conductance responses, QT
interval variability (QTvi), or the pre-ejection period (PEP)
(Light et al, 1998; Esler et al, 1982; Guinjoan et al, 1995; Gold
et al, 2005; Koschke et al, 2009; Barton et al, 2007). However,
other studies reported no association between psychopathol-
ogy and SNS activity or reported decreased SNS activity in
subjects with depressive or anxiety disorders (Wilkinson
et al, 1998; Esler et al, 2004; Roth et al, 2008; Ahrens et al,
2008), so findings remain inconclusive. A first major source
of confounding in studies comparing SNS activity between
depressed/anxious subjects and controls might be the
different SNS indices used, with some measuring true NE
release whereas others measure organ responsivity, which
may also be influence by changes in clearance, re-uptake, or
adrenoceptor sensitivity. A second major source of con-
founding might be the high prevalence of antidepressants in
the patient groups.
The potential for confounding of autonomic effects by
antidepressants was clearly demonstrated in our own recent
Received 19 January 2012; revised 16 May 2012; accepted 31 May
2012
*Correspondence: Dr CMM Licht, Department of Psychiatry/EMGO
Institute for Health and Care Research, VU University Medical Center,
AJ Ernststraat 1187, Amsterdam 1081 HL, The Netherlands,
Tel: +31 (0)20 788 4664, Fax: +31 (0)20 788 5664,
E-mail: C.Licht@vumc.nl or C.Licht@ggzingeest.nl
Neuropsychopharmacology (2012) 37, 2487–2495
& 2012 American College of Neuropsychopharmacology.All rights reserved 0893-133X/12
www.neuropsychopharmacology.org

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research on the association between major depressive
disorder (MDD) and anxiety disorders and cardiac vagal
activity and blood pressure (Licht et al, 2008, 2009b,c),
where we found that especially the use of tricyclic
antidepressants (TCAs) and serotonergic and noradrenergic
reuptake inhibitors (SNRIs) were associated with decreased
vagal activity and increased blood pressure. We confirmed
these findings with longitudinal evidence indicating that
starting the intake of TCAs and SNRIs caused a decrease in
vagal activity paired to an increase in heart rate (HR) (Licht
et al, 2010). These findings suggest that TCAs and SNRIs
increase sympathetic control of the heart. Remarkably,
starting selective serotonin re-uptake inhibitor (SSRI) use
was found to cause a decrease in HR in spite of lowered
vagal activity (Licht et al, 2010), which suggests that SSRI
use leads to a decrease in cardiac sympathetic control.
Similar results were found by other research groups:
Roth et al (1988) and Koschke et al (2009) reported
increases in HR after administration of imipramine (a TCA)
and venlafaxine and duloxetine (SNRIs). Shores et al (2001)
and Barton et al (2007) found decreases in plasma NE, after
SSRI use. These patterns of findings suggest differential
effects of different antidepressants (Dawood et al, 2009;
Licht et al, 2009a; Koschke et al, 2009).
Here, we examine the (longitudinal) association between
cardiac sympathetic activity and depression and/or anxiety
disorder, taking effects of different antidepressants into
account. To measure cardiac sympathetic activity, we use
non-invasive thoracic impedance cardiography to derive
the PEP as the time interval between the onset of
ventricular depolarization and the opening of the semilunar
valves (Sherwood et al, 1990). Changes in PEP reliably
index changes in b-adrenergic inotropic drive to the left
ventricle as shown in laboratory studies manipulating
b-adrenergic tone by EPI infusion (Mezzacappa et al,
1999; Schachinger et al, 2001; Svedenhag et al, 1986), amyl
nitrite inhalation (Nelesen et al, 1999), adrenoceptor
blockade (Harris et al, 1967; Schachinger et al, 2001;
Winzer et al, 1999; Cacioppo et al, 1994), exercise
(Krzeminski et al, 2000; Miyamoto et al, 1983; Smith
et al, 1989), or emotional stress (Berntson et al, 1994;
Newlin and Levenson, 1979; Sherwood et al, 1986). PEP is
an indirect measure of cardiac sympathetic activity as the
sympathetic effects on the left ventricle are not just
determined by changes in cardiac NE release but also by
adrenoceptorstatus and
Throughout the text, we therefore refer to PEP as a
measure of cardiac sympathetic control, rather than
activity. In contrast to cardiac NE spillover (Barton et al,
2007; Esler et al, 1982, 2004), PEP is a measure that can be
obtained in large samples of patients and controls.
We measured PEP in subjects with and without
depressive and/or anxiety disorders, using or not using an
antidepressant, at the baseline assessment and 2-year
follow-up of a large cohort study. We expect shorter PEP
(reflecting increased cardiac sympathetic activity) in sub-
jects with anxiety and/or depression, signalling higher
cardiac sympathetic control, which normalizes when
patients remit at follow-up. In addition, in view of our
previous results, we expect to find a shorter PEP in subjects
taking TCAs and SNRIs, but a longer PEP in SSRI users.
To determine causality more closely, we will test whether
circulating catecholamines.
changes in psychopathology/antidepressant status from
baseline to follow-up are reflected in parallel changes in
cardiac sympathetic control.
SUBJECTS AND METHODS
Subjects
Subjects participating in this study came from the Nether-
lands Study of Depression and Anxiety (NESDA), an
ongoing longitudinal cohort study conducted among 2981
subjects (18–65 years, 95.2% of North European ancestry) to
examine the long-term course of depression and anxiety
disorders. The rationale, methods, and recruitment strategy
have been described elsewhere (Penninx et al, 2008). The
NESDA sample consists of persons without depression and
anxiety disorders and persons with a (remitted or current)
diagnosis of depressive or anxiety disorder. In order to
represent various settings and stages of psychopathology,
depressed or anxious subjects were recruited at three
different locations in the Netherlands in different settings:
general community, through a screening procedure in
primary care, and via mental health-care organizations.
The baseline assessment lasted on average 4h and included
assessment of demographic and health and lifestyle
characteristics, a standardized diagnostic psychiatric inter-
view and a medical assessment. The presence of a
depressive (MDD or dysthymia) and/or anxiety disorder
(social phobia, generalized anxiety disorder, panic disorder
with or without agoraphobia, and agoraphobia only) was
ascertained using the lifetime version of the CIDI psychia-
tric interview (WHO version 2.1). The CIDI establishes
diagnoses according to the DSM-IV criteria (American
Psychiatric Association, 2001) and has shown high inter-
rater and test–retest reliability and high validity for depres-
sive and anxiety disorders (Wittchen, 1994). In addition, the
severity of anxiety was measured among all subjects using
the Beck Anxiety Inventory (BAI; Steer et al, 1995) and
the severity of depression with the 30-item Inventory of
Depressive Symptoms self-report version (Rush et al, 1996).
The research protocol was approved by the ethical
committee of participating universities and all respondents
provided written informed consent.
Two years after baseline assessment, a face-to-face follow-
up assessment was conducted with a response of 87.1%
(2596 of the 2981 respondents participated). Non-respon-
ders were younger, more often of non-North European
ancestry, less educated, and more often had MDD (Lamers
et al, 2012).
Patterns of (Change in) Psychopathology and
Antidepressant Use
First, for cross-sectional analyses, the sample was divided
into groups based on psychiatric status and the use of
antidepressants. The use of different antidepressants at
baseline and at follow-up was determined based on drug
container inspection of all drugs used in the month before
assessment and classified according to the Anatomical
Therapeutic Chemical (ATC) classification (World Health
Organization Collaborating Centre for Drug Statistics
Methodology, 2010). Use of antidepressants was considered
present when taken for at least 1 month and 50% of the
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time, and included TCAs (ATC-code N06AA), noradrener-
gic and serotonergic working antidepressants (SNRIs, ATC-
code N06AF/N06AX) and SSRIs (ATC-code N06AB). In this
way, a seven-group variable was created for cross-sectional
analyses for baseline as well as with 2-year follow-up. The
first five groups comprises antidepressant-naı ¨ve indivi-
duals: a control group without lifetime diagnoses, a group
with a lifetime but no current depressive and/or anxiety
disorder (46 month ago), a group with a current (6-month
recency) anxiety disorder, a current depressive group, and a
group with current comorbid depressive and anxiety
disorders. The final three groups comprises those taking a
TCA, SNRI, or SSRI. At baseline, 143 subjects had missing
physiological data, at follow-up 370 (60 subjects at both
time points). Therefore, at baseline and at the 2-year follow-
up 2838 and 2226 persons, respectively, fulfilled one of the
group criteria.
Second, patterns of change in depressive and anxiety
disorder status were defined to examine 2-year changes in
sympathetic control in these groups. To investigate the pure
effects of incidence or remission of depressive or anxiety
disorders, persistence, remission, or new onset of depres-
sive and anxiety disorders were determined categorizing
antidepressant-naı ¨ve subjects into four disorder groups:
(a) persistent controls, no (lifetime) diagnoses at baseline
and follow-up, (b) persistent patients, a current depressive
and/or anxiety diagnoses at baseline and follow-up,
(c) remitted patients, subjects with a current diagnosis at
baseline and no current diagnosis at follow-up, and (d) new
patients, no diagnosis at baseline and current diagnosis at
follow-up.
Patterns of change in antidepressant use were determined
by categorizing subjects based on antidepressant status over
2 years as: (1) persistent non-users, consisting of subjects
who did not use any antidepressant at baseline and
follow-up, (2) persistent users, defined as use of a specific
antidepressant at both baseline and follow-up, (3) new users
of an antidepressant, which was defined as no use at
baseline and the use of an antidepressant at follow-up,
(4) subjects that stopped using antidepressants, defined as
using an antidepressant at baseline and none at follow-up,
and (5) subjects that switched from using one type of
antidepressant at baseline to another type of antidepressant
at follow-up (SSRI-SNRI, SNRI-SSRI, and so on).
Measurements
Pre-ejection period. During the baseline as well as 2-year
follow-up visit to the research centers, NESDA subjects were
wearing the Vrije Universiteit Ambulatory Monitoring
System (VU-AMS). The VU-AMS is a light-weight device
that unobtrusively records the electrocardiogram (ECG)
and changes in thorax impedance (dZ) from six surface
electrodes placed at the chest and back of the subjects (de
Geus et al, 1995; Willemsen et al, 1996). From the ECG, the
R-wave times were extracted from which, after visual
inspection of the inter-beat-interval time series, HR was
computed. The PEP was extracted from the dZ/dt (ICG)
signal that was ensemble averaged across 1-min periods
time-locked to the R waves in the ECG. Three time points
can be scored in ICG ensemble averages: the upstroke or B
point, the dZ/dt(min) point, and the incisura or X point.
The PEP is defined as the interval from the upstroke of the
ICG (B point), which is the onset of the left ventricular
electrical activity to the dZ/dt(min) point that indicates the
beginning of blood ejection through the aortic valve.
Postural changes can cause changes in PEP that are
partially independent of changes in sympathetic control
(Houtveen et al, 2005). To avoid confounding of PEP by
posture, three periods were identified in the total recording
period in which subjects did not change posture and were
quietly sitting for a prolonged period. Movement registra-
tion through vertical accelerometry was used to excise
fragments of the recording where subjects were physically
active (eg, bathroom visit). There were three assessment
parts in which subjects did not change posture and were
sitting for a prolonged period at both baseline and follow-
up: interview session 1 (sitting, baseline: 38.2±12.7min,
follow-up: 46.0±25.9min), interview session 2 (sitting,
baseline: 35.6±12.7min, follow-up: 32.5±12.0min), and
a non-stressful computer task (sitting, baseline: 16.2±
4.0min, follow-up: 15.2±3.4min). These three assessment
parts were used in the final analyses. A single large-scale
ensemble average was then created for the three interview
parts and the relevant time point (B point) were scored in
each of these large-scale ensembles by a single rater (CL).
Ensembled ICGs that showed irregularities or had ambig-
uous B point were not considered valid and were rejected
and removed from further processing during visual
inspection (Eckberg, 2003; Grossman et al, 1990). A second
independent rater (EdG) re-scored 600 randomly chosen
subjects from baseline and follow-up yielding an inter-rater
reliability for PEP scoring of 0.84.
Exploratory mixed model analyses revealed that differ-
ences across antidepressants and psychopathology groups
were very comparable in the three different interview
conditions, at baseline as well as at follow-up. Therefore,
data during the computer task and interview parts were
collapsed to create one single PEP value per subject, for the
baseline (averaged over 90.2±23min time) and 2-year
follow-up assessment (averaged over 93.6±36min time).
Covariates. Sociodemographics included age, sex, and
education in years. In addition, various health indicators
(at both time points) were considered as covariates because
these have been linked with depressive/anxiety disorder and
SNS activity. Body mass index (BMI) was determined as
measured weight in kilograms divided by the square of the
measured height in meters. Physical activity was measured
using the International Physical Activity Questionnaire
(Booth, 2000) and expressed in MET-minutes per week
(the multiple of one’s resting metabolic rate times minutes
of physical activity per week). Smoking status was defined
as number of smokes a day. Similarly, alcohol use was
defined as number of alcoholic consumptions a day. Self-
reports of the presence of heart disease were used for
ascertainment of cardiovascular diseases (CVDs; including
coronary disease, cardiac arrhythmia, angina, heart failure,
and myocardial infarction), only when confirmed with the
use of specific medication. Dichotomous variables for the
use of medication were computed, scoring ‘yes’ if subjects
frequently (daily or 450% of the time) used a medication.
For the confirmation of CVD, cardiac medication (starting
with ATC-code C01DA, and C08) was used. Self-reports
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were used for ascertainment of the presence of other
chronicconditions (epilepsy,
stroke, cancer, chronic lung disease, thyroid disease, liver
disease, chronic fatigue syndrome, intestinal disorders, and
ulcer). Furthermore, it was determined whether subjects
were using b-blocking agents (ATC code C07) or other
cardiac medication (ATC-codes C01 (minus C01DA), C02,
C03, C04, C05, and C09).
Independent of cardiac sympathetic drive, the PEP can be
prolonged by increases in afterload or decreases in preload.
No non-invasive measures of between-subject differences in
preload that can be applied in large samples are currently
available (Norton, 2001). To account for between-subject
differences in afterload, mean arterial blood pressure (MAP)
was used as a proxy for mean aortic pressure. Systolic (SBP)
and diastolic blood pressure (DBP) were recorded in a
supine position by two repeated measurements using the
OMRON M4 IntelliSense (HEM-752A, Omron Healthcare,
Bannockburn, IL). MAP was calculated by (SBP+2?DBP)/
3. In a separate adjustment step, we checked whether results
were further influenced by taking individual differences in
HR (extracted from the ECG inter-beat-interval time series)
and MAP into account (Weissler et al, 1968; Wolf et al,
1978). Finally, in order to examine whether severity of
symptomatology further impacted on found associations,
analyses were additionally corrected for depression and
anxiety severity using the IDS and BAI scores (Rush et al,
1996; Steer et al, 1995).
diabetes,osteoarthritis,
Statistical Analyses
Data was analyzed using SPSS 18.0. Characteristics at
baseline and follow-up assessment were compared using
unpaired t-tests and w2statistics. Cross-sectional analyses of
variance at both time points were conducted to compare
PEP across the controls, the unmedicated depressed and/or
anxious subjects, and the depressed and/or anxious subjects
using different antidepressants (eight groups). These
analyses were repeated with consideration of covariates.
Subsequently, effect sizes were calculated with Cohen’s d
(1988) defined as the difference in the mean PEP between
groups, divided by the pooled standard deviation of these
groups. For longitudinal analyses, adjusted linear mixed
model analyses were conducted for the 2-year change in
PEP across psychopathology (persistent control or new,
remitted or persistent diagnosis) and antidepressant groups
(continued (non)use, new or stopped use of antidepres-
sants). Since covariates can change within persons over a
period of 2 years and these changes might influence PEP, we
took possible changes in covariates into account when
analyzing the longitudinal data by using linear mixed model
analyses with time varying covariates.
RESULTS
Table 1 shows and compares the main characteristics of the
samples at baseline (n¼2838) and follow-up (n¼2226).
Compared with the baseline sample, subjects were more
physically active, had a higher BMI, smoked less often, and
used more cardiac medication (other than b-blockers) at
follow-up. At follow-up, subjects had less current but more
remitted depression or anxiety diagnoses and fewer subjects
used a SSRI. HR was slightly higher and MAP slightly lower
in the follow-up sample. PEP did not significantly differ
between the baseline and follow-up sample.
Table 2 shows the results of ANCOVA analyses conducted
for both time points. The PEP of the psychopathology and
antidepressant groups was compared with the PEP of the
control group, first uncorrected and then corrected for
age, sex, education, lifestyle, and health factors. In both
unadjusted (data not shown) and adjusted analyses (see
Table 2), no differences in PEP were found between the
unmedicated patient groups and the controls. However,
consistently across time points, PEP was significantly
shorter in TCA and SNRI users (p-valuesp0.001 and
d-values 0.296–1.248) and significantly longer in SSRI users
(p-valueso0.001 and d-values 0.444–0.410 for baseline and
follow-up, respectively). Although HR and MAP also
differed between groups, additional adjustment for HR
and MAP did not further influence the results for the
comparison between (un)medicated patients and controls.
In spite of the potential effects of these agents on PEP,
repetition of all analyses excluding users of b-blocking
agents yielded similar results. Table 2 indicates substantial
differences in IDS and BAI scores between controls and
(un)medicated patients, therefore additional analyses were
performed investigating the effects of severity. When PEP
was compared between controls and unmedicated patients
with (at least) similar IDS and BAI scores as medicated
patients, still no differences were found. This finding was
confirmed by the absence of significant correlations
between the pre-ejection with the IDS and BAI score
(r¼0.033, p¼0.13 and r¼0.028, p¼0.20, respectively).
Additional analyses were performed to compare PEPs
between different anxiety disorders, but no differences were
found.
Longitudinal fully adjusted mixed model analysis on the
four different psychiatric groups (not using antidepres-
sants) showed that persons who developed a new diagnosis,
persons with a persistent diagnosis, or persons who
remitted from a current diagnosis did not differ in 2-year
change in PEP compared with persistent healthy controls
(group?time F¼1.192, df¼3, p¼0.31). This analysis
further confirms the lack of association between the
presence of (antidepressant-naı ¨ve) depressive or anxiety
disorders with PEP.
Figure 1 shows the results of the fully adjusted linear
mixed model analysis on 2-year change in PEP across the 12
different antidepressant groups. The overall group?time
interaction was significant (F¼16.470, df¼11, po0.001),
indicating that changes in PEP over time were significantly
different across antidepressant groups, taking into account
all covariates. The 2-year change in PEP among persistent
non-users was only minor: 1.9ms (1.6%). Subjects who
started using a TCA or SNRI, showed a prominent shorten-
ing in PEP: new TCA users had a 2-year PEP shortening of
9.8% (compared with persistent non-users: p¼0.005, effect
size d¼0.783) and new SNRI users of 9.1% (po0.001,
d¼0.766). Subjects switching from an SSRI to an SNRI led
to a shortening in PEP (?19.5%, po0.001, d¼1.882), and a
further shortening in the PEP was observed in continuous
users of TCAs at baseline and follow-up (?9.4%, po0.001,
d¼0.560). Consistent with these observations, subjects that
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stopped taking a TCA or SNRI showed a lengthening in PEP
over time (15.6%, p¼0.006, d¼1.056 and 6.8%, p¼0.02,
d¼0.596, respectively). In contrast to the PEP shortening
effect of TCA and SNRIs, new SSRI users had a 7.3% longer
PEP at the 2-year follow-up (po0.001, d¼0.542). Consis-
tent with this, the PEP of SSRI users that stopped taking
medication had significantly shortened (?9.9%, po0.001,
d¼0.979).
Adding the IDS and BAI scores of both time points as
covariates did not change any of the above-mentioned
results indicating that observed medication effects were
independent of potential differences in severity of depres-
sive and anxiety symptoms.
DISCUSSION
This large-scale cohort study showed that cardiac sympa-
thetic control, as measured by the PEP, is increased in
subjects using TCAs or SNRIs. Users of SSRIs had a
Table 1 Sample Characteristics
Baseline (N¼2838)2-year FU (N¼2226)
D
pa
Sociodemographics
Age, years (SD)41.7 (13.1) 44.2 (13.2)2.5
o0.001
0.81Female % (N) 66.7 (1892) 66.4 (1477)–0.3
Education, years (SD) 2.2 (3.3)12.5 (3.3) 0.3 0.001
Health factors
Physical activity, 1000 MET min/week (SD)3.7 (3.0) 4.1 (3.3) 0.4
o0.001
0.03
o0.001
0.04
Body mass index (SD) 25.5 (5.0) 25.8 (4.9)0.3
Smoking, number/day (SD) 5.0 (8.7)4.2 (7.8) –0.8
Non-smoker, % (n) 28.3 (802) 30.9 (688) 2.6
Former smoker, % (n) 33.3 (944)34.7 (773) 1.3 0.28
Current smoker, % (n) 38.5 (1092) 34.4 (765)–4.10.003
Alcohol use, drinks/day (SD) 1.00 (1.4)0.98 (1.4)0.02 0.62
Non-drinker, % (n) 17.4 (495)16.8 (373) –0.60.52
Mild/moderate drinker, % (n) 71.2 (2020)72.7 (1619)1.5 0.23
Heavy drinker, % (n)
Use b-blockers, % (n)
Use other heart medication, % (n)
11.4 (323) 10.5 (234)–0.9 0.34
7.8 (220) 8.4 (188) 0.6 0.37
10.7 (304) 13.3 (296) 2.60.005
Cardiovascular disease, % (n)7.4 (209) 8.5 (189)1.1 0.14
Number of chronic diseases, mean (SD) 0.92 (1.1)0.94 (1.1)0.02 0.52
Mean arterial pressure, mmHg (SD)98.7 (12.4) 96.5 (11.8)–2.2
o0.001
0.01 Heart rate, b.p.m. (SD)72.0 (9.6) 72.7 (9.7)0.7
Psychopathological factors
Control, % (n) 21.9 (621) 20.7 (460)–0.50.63
Remitted diagnosis, % (n) 20.9 (593) 41.3 (920)21.0
o0.001
Current diagnosis, % (n) 57.2 (1624)
Within current diagnosis
Current anxiety, % (n) 32.0 (520)35.0 (296) 3.00.14
Current dysthymia, % (n)0.7 (11)1.4 (12)0.70.08
Current major depressive disorder, % (n) 22.6 (367) 25.4 (215)2.80.12
Current comorbid diagnosis, % (n) 44.7 (726)38.2 (323)–6.5 0.002
TCA use, % (n) 2.6 (75)2.8 (63)0.20.66
SNRI use, % (n) 5.7 (162)5.7 (126)0.0 0.95
SSRI use, % (n) 17.1 (484)13.7 (305)–3.4 0.001
Cardiac autonomic control
Pre-ejection period, ms (SD)119.3 (18.3)119.4 (17.5) 0.1 0.84
Abbreviations: FU, follow-up; MET, multiple of the resting metabolic rate.
aComparison of baseline and FU values using t-test (continuous variables) and w2-square statistics (dichotomous/categorical variable).
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significantly longer PEP compared with non-medicated sub-
jects, indicative of decreased cardiac sympathetic control.
The presence of depressive or (different) anxiety disorders
itself was not related to cardiac sympathetic control, nor
was severity of the disorder. Results were confirmed and
consistent in cross-sectional and longitudinal analyses.
Our findings are in agreement with our previous findings
on HR and blood pressure. Similar HR and MAP was found
in the unmedicated patients compared with healthy controls.
TCA and SNRI users showed increased values of HR and
MAP, whereas the SSRI users had a similar or lower HR and
MAP. Of the two previous studies comparing PEP between
depressed and healthy controls, one also failed to find
systematic evidence for PEP differences between depressive
and healthy persons, whereas the other found a significant
decreased PEP in depressed compared with healthy controls
(Bruno et al, 1983; Light et al, 1998). A reason for the
different results could be the difference in sample size and
composition. Our study sample had a much larger sample
size than previous studies and, through the recruitment
strategy in both general practice as well as specialized
Table 2 The AdjustedaPEP (ms) per Psychiatric and Medication Group, Cross-Sectional for Baseline and Follow-Up
N IDSBAI MAP HR Mean PEP (SE)a
p Effect size
Baseline
Not using antidepressants
Control597 8.13.998.7 (12.6)72.0 (8.8) 120.3 (0.7)Refb
Refb
Remitted anxiety or depressive 50113.4 6.698.1 (12.0) 71.3 (9.9)119.2 (0.8)0.29 0.063
Current anxiety disorder 35821.6 14.3 98.6 (13.1)71.7 (9.4) 119.3 (0.9)0.350.063
Current depressive disorder 279 25.711.6 97.9 (11.4) 71.9 (9.1)119.9 (1.0)0.720.026
Current anxiety and depressive disorder 40233.1 20.0 98.2 (12.8)71.7 (9.5)120.7 (0.8) 0.720.023
Using antidepressants
TCA user7530.2 19.3105.8 (13.2) 81.1 (11.6) 109.4 (2.0)
o0.001
0.001
o0.001
0.639
SNRI user 160 32.317.8100.9 (11.5)73.7 (9.3)115.3 (1.3) 0.296
SSRI user466 30.1 17.898.6 (12.0)70.8 (9.6) 127.9 (0.8)0.444
2838
2-Year follow-up
Not using antidepressants
Control 4566.2 3.1 97.1 (12.4)73.0 (9.2) 120.6 (0.8)Refb
Refb
Remitted anxiety or depressive 734 12.16.2 95.6 (11.6)72.5 (9.5)118.8 (0.6)0.230.104
Current anxiety disorder 21919.0 12.396.0 (11.6)71.5 (10.7) 120.8 (1.1)0.82 0.012
Current depressive disorder 14721.6 10.796.5 (12.6) 71.1 (7.5) 120.6 (1.3)0.940.001
Current anxiety and depressive disorder18630.718.2 96.3 (11.0)71.5 (9.8) 120.6 (1.2)0.89 0.006
Using antidepressants
TCA user6322.4 13.1102.5 (11.0)82.4 (10.7) 99.9 (2.1)
o0.001
o0.001
o0.001
1.248
SNRI user12423.712.9100.2 (11.8) 76.9 (11.1)108.3 (1.5)0.746
SSRI user29721.111.8 95.6 (11.1)71.0 (9.0) 127.3 (0.9) 0.410
2226
Abbreviations: AD, antidepressant; BAI, Beck anxiety inventory; IDS, inventory of depressive symptoms; PEP, pre-ejection period; SNRI, serotonergic and
noradrenergic working antidepressant; SSRI, selective serotonin re-uptake inhibitor; TCA, tricyclic antidepressant.
aAnalyses were adjusted for age, sex and education, BMI, physical activity, smoking, alcohol use, use of b-blocking agents, use of other heart medication, chronic disease,
and CVD.
bControl is the reference group. All p-values and effect sizes are for comparison of the group in that specific line and control subjects.
-30
-25
-20
-15
-10
-5
0
5
10
15
20
? PEP, ms
<0.001
0.005
0.006
0.002
<0.001
0.02
0.21
0.33
<0.001
<0.001
0.25
SSRI
SSRISSRISSRI
SSRI
192
SNRI
25
no
no
12173
SNRISNRI SNRI
SNRI SNRI SNRI no
no
2334 1068
TCA
TCA
TCA
TCA
10 11
no
no
40
AD baseline: no
AD follow-up: no
N: 1500
Figure 1
baseline to 2-year follow-up for different antidepressant groups. *Adjusted
for age, sex and education, BMI, physical activity, smoking, alcohol use, use
of b-blocking agents, use of other heart medication, chronic disease, and
CVD. The p-values are for changes in PEP in the indicated groups in
comparison with the 1500 persistent non-users (‘no–no’).
Mean adjusted* change in pre-ejection period (ms) from
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mental health-care practice, reflects the general population
of depressed and anxiety patients. Several reports using
different SNS indices also found increased sympathetic
activity in depressed or anxious subjects (Esler et al, 1982;
Gold et al, 2005; Guinjoan et al, 1995; Light et al, 1998;
Koschke et al, 2009). These previous reports focused on
general sympathetic activity, whereas we measured sympa-
thetic control more narrowly by its effects on cardiac
contractility. Guinjoan et al (1995) described a higher
sympathetic skin response in 18 melancholically depressed
patients compared with 18 healthy controls. Gold et al
(2005), reported higher plasma NE levels in 10 subjects with
severe melancholic depression than in 12 healthy controls.
Light et al (1998) also found higher plasma NE levels
in high-symptom group compared with a low-symptom
group. Higher plasma catecholamine levels could reflect
either an increase in catecholamine production or a
decrease in the clearance of catecholamines between
patients and controls. To resolve this, radiotracer techni-
ques can be used. Esler et al (1982) detected greater SNS
activity by whole body NE spillover in 11 depressed
outpatients compared with 17 healthy controls, arguing in
favor of a true increase in sympathetic activity in the nerves
in depressed patients. This was partly replicated by later
spillover studies that only detected high sympathetic
nervous activity, including in the sympathetic outflow to
the heart, in the subset of MDD patients comorbid for panic
disorder (Barton et al, 2007). It is important to note that
an increase in cardiac sympathetic nerve activity is not
incompatible with the absence of effects on cardiac
contractility as reported here. Chronic exposure to high
levels of NE may have led to a downregulation of cardiac
b-receptors in the depressed or anxious patients. A similar
state of events is seen in patients with left heart failure,
where the ejection fraction, another measure of contrac-
tility, is strongly reduced in the presence of increased
sympathetic drive (Eisenhofer et al, 1996; Esler et al, 1982).
Studies that measure the cardiac adrenoceptor status of
depressive and anxiety patients are needed to test this.
Our results suggest a potential lowering effect of SSRIs on
cardiac sympathetic control, whereas TCAs and SNRIs seem
to increase cardiac sympathetic control. Differential effects
of SNRI and SSRI were also seen by Koschke et al (2009)
and findings are consistent with most previous studies on
the effects of these drugs (Howell et al, 2007; Barton et al,
2007; Shores et al, 2001; Roth et al, 1988; Veith et al, 1983;
Vincent et al, 2004; Dawood et al, 2009; Licht et al, 2009a;
Koschke et al, 2009). TCAs and SNRIs both work through
inhibition of NE in the synaptic cleft or by blocking its
clearance. Veith et al (1994) showed that, using plasma NE
kinetic measurements, desipramine acutely (2 days) sup-
pressed plasma NE appearance (suggesting suppression of
total body SNS activity) followed by a return to baseline
levels after 4 weeks. The elevation of plasma NE at that time
point was due to decreased clearance and this is likely to be
a major reason why other studies of TCA effects have shown
elevation of circulating NE.
Increased circulating NE levels likely also increase NE
concentration in the sinoatrial node (Shimizu et al, 2010)
and the left ventricle, thereby directly affecting contractility
and HR. In contrast, SSRIs do not exert an effect on
circulating NE but instead reduce the firing rate in the
noradrenergic locus coeruleus (Grant and Weiss, 2001),
which is part of the brainstem circuitry generating cardiac
sympathetic activity (Elam et al, 1984, 1986; Svensson,
1987). Furthermore, serotonergic inhibitory receptors are
present in ventral medulla (Helke et al, 1997), which is part
of the same regulatory circuitry of sympathetic activity
(Nalivaiko, 2006). The significant differences between the
effects of these classes of medication on cardiac sympathetic
effects in our study appear to have a plausible biological
basis.
A study limitation has to be mentioned. Activity of the
cardiac sympathetic nerves was derived indirectly by a
measure of contractility, namely the time it takes to build up
enough force in the left ventricle after the start of electrical
activity to open the aortic valves. Although this time is
strongly dependent on noradrenergic effects on the
ventricle, it is also sensitive to pre- and afterload. Effects
of between-subject differences in pre- and afterload may be
incompletely captured by the covariates MAP and HR. This
limitation is balanced by strong points: this is the first
longitudinal study with a large enough sample to separate
antidepressant effects from those of the psychiatric condi-
tion per se, by including healthy controls and subjects with
depressive and/or anxiety disorders not using antidepres-
sants as well as subjects using different types of anti-
depressants. Previous studies were much smaller, simply
excluded antidepressant users (Koschke et al, 2009; Light
et al, 1998) or applied antidepressant washout periods
before testing that may have been too short (10 day–2
weeks) (Esler et al, 1982; Guinjoan et al, 1995).
We conclude that SNRIs and TCAs, but not SSRIs exert
detrimental effects on cardiac sympathetic control over
time. These results converge with several studies reporting
increased occurrence of hypertension, metabolic syndrome,
and adverse cardiovascular events in patients using TCAs
and SNRIs (Cohen et al, 2000; Tata et al, 2005; Degner et al,
2004; Licht et al, 2009b; Koschke et al, 2009; van Reedt
Dortland et al, 2010). Also in earlier NESDA papers, we
confirmed that TCAs and SNRIs did, but SSRIs did not,
negatively impact on the occurrence of hypertension and
metabolic syndrome (Licht et al, 2009b; van Reedt Dortland
et al, 2010). The detrimental effects of TCAs and SNRIs
on cardiac sympathetic regulation are alarming in view of
the well-established relation between depression/anxiety
and CVD. This may have consequences for the optimal
pharmacological treatment of depressive and anxiety
disorders, especially in patients already at increased risk
for CVD. For these patients, SSRIs may be the drug of first
choice because they do not yield the adverse increasing
effect on cardiac sympathetic regulation that was observed
for TCAs and SNRIs.
ACKNOWLEDGEMENTS
The infrastructure for the NESDA study (http://www.
nesda.nl) is funded through the Geestkracht program of
the Netherlands Organization for Health Research and
Development (Zon-Mw, grant number 10-000-1002) and is
supported by participating universities and mental health-
care organizations (VU University Medical Center, GGZ
inGeest, Arkin, Leiden University Medical Center, GGZ
Antidepressants and cardiac sympathetic control
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Rivierduinen, University Medical Center Groningen, Lentis,
GGZ Friesland, GGZ Drenthe, Scientific Institute for Quality
of Healthcare (IQ healthcare), Netherlands Institute for
Health Services Research (NIVEL) and Netherlands Insti-
tute of Mental Health and Addiction (Trimbos). Data
analyses were supported by NWO grant (Vidi, 917.66.320)
to Dr Penninx and an EMGO fellowship to Dr Licht.
DISCLOSURE
The authors declare no conflict of interest.
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CMM Licht et al
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