International Journal of Psychophysiology 89 (2013) 288–296

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International Journal of Psychophysiology

journal homepage: www.elsevier.com/locate/ijpsycho

Review

The relationship between mental and physical health: Insights from the
study of heart rate variability
Andrew H. Kemp a,b,c,⁎, Daniel S. Quintana a,d
a
SCAN Research & Teaching Unit, School of Psychology, University of Sydney, Australia
b
Discipline of Psychiatry, University of Sydney, Australia
c
Hospital Universitário, University of São Paulo, São Paulo, Brazil
d
Brain and Mind Research Institute, University of Sydney, Australia

a r t i c l e i n f o a b s t r a c t

Article history: Here we review our recent body of work on the impact of mood and comorbid anxiety disorders, alcohol
Received 29 January 2013 dependence, and their treatments on heart rate variability (HRV), a psychophysiological marker of mental
Received in revised form 6 June 2013 and physical wellbeing. We have shown that otherwise healthy, unmedicated patients with these disorders
Accepted 13 June 2013
display reduced resting-state HRV, and that pharmacological treatments do not ameliorate these reductions.
Available online 22 June 2013
Other studies highlight that tricyclic medications and the serotonin and noradrenaline reuptake inhibitors
Keywords:
in particular may have adverse cardiovascular consequences. Reduced HRV has important functional signifi-
Heart rate variability cance for motivation to engage social situations, social approach behaviours, self-regulation and psychologi-
Cardiovascular disease cal flexibility in the face of stressors. Over the longer-term, reduced HRV leads to immune dysfunction and
Mortality inflammation, cardiovascular disease and mortality, attributable to the downstream effects of a poorly func-
Depression tioning cholinergic anti-inflammatory reflex. We place our research in the context of the broader literature
Anxiety base and propose a working model for the effects of mood disorders, comorbid conditions, and their treat-
Alcohol dependence ments to help guide future research activities. Further research is urgently needed on the long-term effects
Psychological treatment
of autonomic dysregulation in otherwise healthy psychiatric patients, and appropriate interventions to halt
Pharmacological treatment
the progression of a host of conditions associated with morbidity and mortality.
Cardiovascular risk reduction
© 2013 Elsevier B.V. All rights reserved.

1. Introduction routine screening of depression in patients with coronary heart dis-

ease (CHD) (Lichtman et al., 2008), a leading cause of CVD mortality.
While depression increases risk for the development of CVD approx-
imately 1.5-fold, patients with CVD and depression have a two- to
“A sad soul can kill you quicker, far quicker than a germ” (John Steinbeck,
three-fold increased risk of future cardiac events compared to cardiac
Travels with Charley: In Search of America, 1962)
patients without depression (Rudisch and Nemeroff, 2003). More re-
cent research is consistent with this earlier data, and clinically diag-
Unipolar depressive disorders and cardiovascular disease (CVD)
nosed major depressive disorder is the most important risk factor
(including heart disease and stroke) are already leading burdens of
(Van Der Kooy et al., 2007).
disease and this burden is projected to worsen up to 2030 (Mathers
A meta-analysis (Pan et al., 2011) on more than 300,000 partici-
and Loncar, 2006). The global cost of mental health is estimated to
pants followed-up over a period ranging from 2 to 29 years reported
cost US$6 trillion by 2030, increasing from US$2.5 trillion in 2010,
a pooled adjusted hazard ratio of 1.45 for depression and stroke. The
while CVD is estimated to cost US$1.04 trillion by 2030 (rising from
authors estimated that 3.9% (n = 273,000) of stroke cases in the
US$863 billion in 2010) (Bloom et al., 2011). Critically, there is in-
United States could be attributable to depression. Another recent
creasing recognition that these disorders are related: depression is in-
study (Russ et al., 2012) reported a dose–response association be-
dependently associated with morbidity and mortality, and is common
tween psychological distress across the full range of severity and an
among patients with CVD (Carney and Freedland, 2009; Lichtman
increased risk of mortality from a number of causes including CVD,
et al., 2008). Increasing recognition of the relationship between de-
cancer and external causes over 8 years. This study was conducted
pression and CVD led the American Heart Association to recommend
on more than 65,000 people from the general population free of
CVD and cancer at study baseline. The researchers measured psycho-
⁎ Corresponding author at: Hospital Universitário, University of São Paulo, São Paulo,
logical distress using the General Health Questionnaire (GHQ-12), a
Brazil. Tel.: +55 11 98772 2602. valid screening tool for anxiety and depression as diagnosed by the
E-mail address: andrew.kemp@sydney.edu.au (A.H. Kemp). Diagnostic and Statistical Manual of Mental Disorders (Schmitz et al.,

0167-8760/$ – see front matter © 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.ijpsycho.2013.06.018
 A.H. Kemp, D.S. Quintana / International Journal of Psychophysiology 89 (2013) 288–296
1999). Age and sex adjusted hazard ratios were 1.20 for subclinically
symptomatic, 1.43 for symptomatic and 1.94 for highly symptomatic
participants. It is worth noting that comorbid anxiety disorders are
present in more than 60% of cases of MDD (Kessler et al., 2005),
highlighting a need to distinguish between the impact of depression
versus anxiety on future adverse events. Interestingly, evidence indi-
cates that patients with such comorbidity display an almost threefold
increase in the prevalence of CVD, while no such associations were ob-
served for depressive disorders without comorbidity (Vogelzangs et al.,
2010). A study on 4256 participants (Phillips et al., 2009) revealed that
the comorbidity of MDD and GAD is strongly associated with all-cause
mortality (hazard ratio = 2.29) and CVD (hazard ratio = 2.68) even
after accounting for a host of confounding variables. Another body of
evidence indicates that alcohol dependence – a disorder associated
with a variety of psychological problems including depression and
anxiety – also leads to CVD and mortality (Rehm et al., 2009). In fact,
age- and gender-adjusted risk of death has been estimated at 2.3 to
2.6-fold among patients with depressive, anxiety or alcohol use disor-
ders (Markkula et al., 2012). When controlling for psychiatric comor-
bidity, these associations decreased (HR = 1.56–2.34) although these
remained significant for depressive (HR = 1.97) and alcohol use disor-
ders (including misuse and dependence) (HR = 1.72).
Mood and anxiety disorders are associated with a variety of behav-
ioural issues including smoking (Jane-Llopis and Matytsina, 2006),
problems with alcohol (Jane-Llopis and Matytsina, 2006) and physical
inactivity (Goodwin, 2003), and these all increase risk for CVD and
mortality. However, these behavioural aspects do not fully account
for the strong relationship between mental and physical illness.
While a variety of biological factors – including the hypothalamic–
pituitary–adrenal (HPA) axis and inflammatory processes – contribute
to this relationship, one specific mechanism thought to underlie a sub-
stantial part of risk for increased mortality is autonomic dysregulation
(Nemeroff and Goldschmidt-Clermont, 2012; Thayer et al., 2010b),
indexed by reductions in heart rate variability (HRV). Here we review
the link between depression, cardiovascular disease and mortality,
discuss the relationship between HRV, mental, and physical wellbeing,
highlight recent studies from our laboratory on physically healthy,
psychiatric patients and treatments for these disorders, and propose a
model to guide future research activities.
Several points regarding our review should be noted. First, for
brevity, we focus on mood disorders and common comorbid condi-
tions. It is important to note that reduced heart rate variability has
been reported in a variety of psychiatric disorders including schizo-
phrenia (Berger et al., 2010), bipolar disorder (Henry et al., 2010;
Lee et al., 2012), attention deficit hyperactivity disorder (Buchhorn
et al., 2012) and conduct disorder (Beauchaine et al., 2007). This
data highlight the adverse effects of a wide range of disorders on the
autonomic nervous system, a finding that may be related to emotion
dysregulation, a core feature of all of these conditions. Second, while
studies have generally reported reduced HRV in many psychiatric dis-
orders, contradictory findings have also been published. These contra-
dictory findings highlight the importance of taking into consideration
potential confounding variables including the effects of medication
and a history of CVD. With respects to our own work, contradictory
findings in the literature led us to conduct meta-analyses on major
depressive disorder (Kemp et al., 2010) and alcohol dependence
(Quintana et al., 2013b), the results of which are discussed below.
Third, our review draws heavily on models (Pavlov and Tracey, 2012;
Thayer and Brosschot, 2005; Thayer and Lane, 2007; Thayer et al.,
2010b; Tracey, 2002, 2007) that propose a link between HRV and
longer-term changes in health and wellbeing. These models also high-
light that changes in HRV may be a particularly sensitive early marker
for CVD. However, we note that these models are not without contro-
versy (Kluttig et al., 2010; Thayer et al., 2010a), indicating a need for
large longitudinal, epidemiological studies to further explore the pro-
posed importance of HRV changes in the context of more established
289
risk markers including age, smoking, cholesterol, hypertension, diabe-
tes and obesity. Fourth, we focus specifically on the relationship be-
tween decreased HRV, psychiatric illness, adverse downstream effects
and CVD. Chronic decreases in HRV will lead to immune dysfunction
and inflammation, and subsequently, a wide variety of conditions and
diseases including diabetes, obesity, osteoporosis, arthritis, Alzheimer's
disease, periodontal disease, cancer, frailty and disability (Katon et al.,
2011; Kissane et al., 2011; Thayer et al., 2010b).
2. Heart rate variability (HRV): a psychophysiological phenomenon
with broad implications
HRV is a measure of beat-to-beat temporal changes in heart rate
and these changes, rather than being random noise, reflect the output
of the central autonomic network. This inhibitory cortico-subcortical
neural circuit – comprising the prefrontal cortex, cingulate cortex,
insula, amygdala, and brainstem regions – is responsible for the con-
trol of visceral response to stimuli (Thayer et al., 2009; Thayer and
Lane, 2000, 2009). HRV is mediated through preganglionic sympathet-
ic and parasympathetic neurons innervating the heart via the stellate
ganglia and the vagus nerve, respectively (Thayer et al., 2009). The
parasympathetic nervous system (PNS) is mediated by acetylcholine,
which inhibits cardiac muscle and slows heart rate, while the sympa-
thetic nervous system (SNS) is medicated by norepinephrine, which
excites cardiac muscle and speeds heart rate. HRV is dominated by
parasympathetic (vagal) influence, which has a very short latency of
response; its peak effects are observed within 1/2 s and returns to
baseline within 1 s. By contrast, the sympathetic influence on the
heart is too slow to produce beat-to-beat changes, with peak effects
occurring after approximately 4 s and returning to baseline after 20 s
(Appelhans and Luecken, 2006). Heart rate varies with respiration; it
increases on inspiration and decreases on expiration, a phenomenon
known as respiratory sinus arrhythmia (RSA) (Yasuma, 2004). Research
now shows that this well-known physiological phenomenon is associ-
ated with emotion and mood, and these associations may have impor-
tant implications for mental and physical wellbeing. This research will
be discussed further below.
HRV may be considered a marker of one's capacity for self-
regulation, social engagement and psychological flexibility. A recent
study (Geisler et al., 2013) reported that young adults with higher
resting state HRV display more adaptive self-regulation and more
social engagement than those with lower resting state HRV. More
specifically, individuals with higher HRV reported using more engage-
ment strategies when coping with distress and less disengagement
when regulating negative emotions. They were more inclined to seek
social support to deal with distress and sadness. Consistent with the
idea that HRV is associated with self-regulation, we (Quintana et al.,
2013) have shown that resting-state HRV predicts alcohol cravings as
measured by the obsessive compulsive drinking scale, in alcohol
dependent outpatients, such that decreases in HRV are associated
with increases in cravings. With respects to a role for HRV in social
engagement, we reported (Kemp et al., 2012b) that oxytocin – a mam-
malian neuropeptide that plays a central regulatory role in human
social behaviour and social cognition – increases resting state HRV.
We interpreted these findings as reflecting increased participant's
capacity for social approach-related motivation and capacity for social
engagement. On the basis of this research and the work of others we
have proposed a role for the parasympathetic nervous system in the
effects of oxytocin social behaviour (Quintana et al., 2013a). According
to polyvagal theory (Porges, 1995, 1997, 1998, 2001, 2003a,b, 2007,
2009, 2011) HRV is associated with the experience and expression
of social and emotional behaviour. This theory distinguishes between
the myelinated and unmyelinated vagus nerves (hence ‘polyvagal’),
such that the myelinated vagus underpins changes in HRV and
approach-related behaviours including social engagement, while
the phylogenetically older unmyelinated vagus – in combination
290 A.H. Kemp, D.S. Quintana / International Journal of Psychophysiology 89 (2013) 288–296
with the SNS – supports the organism during dangerous or life-
threatening events. This theory is a phylogenetically ordered hierar-
chical model that draws on the Jacksonian principle of dissolution in
which higher neural circuits inhibit lower circuits, but when higher
circuitry is rendered functionless, the lower rise in activity (Porges,
2009). This process is a potential mechanism for the expression
and disruption of positive social behaviours. According to the theory,
social engagement can only occur when the environment is per-
ceived as safe and the defensive circuits are inhibited. If these circuits
are not inhibited when they should be, then the ability to detect and
express positive social cues is compromised.
We have also demonstrated a relationship between HRV and so-
cial cognition in healthy volunteers (Quintana et al., 2012), reporting
that increased resting-state HRV is associated with better subsequent
emotion recognition, an important facet of social communication. This
study suggests that emotion recognition may be impaired when HRV
is low. Supporting this interpretation, an earlier study on children
with autism spectrum disorders – associated with marked impair-
ment in social interactions – reported reduced respiratory sinus
arrhythmia (RSA) and a positive relationship between RSA and faster
emotion recognition (Bal et al., 2010). Together these studies indicate
that individuals with decreased parasympathetic nervous system
function – as indicated by reduced HRV – are unable to suppress sym-
pathetic nervous system function, leading to a mobilised behavioural
state and negative affect which adversely impacts on social engage-
ment. The link between HRV and social cognition is supported by
recent studies that have examined the relationship between cerebral
blood flow and HRV, summarised in a recent meta-analysis (Thayer
et al., 2012), which concluded that HRV may index a central autonom-
ic network that directly regulates the heart and guides flexible control
over behaviour.
This central autonomic network plays a major role in the inhibi-
tion of medullary cardioacceleratory circuits; controlling psychophys-
iological resources during emotion; goal-directed behaviour and
flexibility to environmental change (Thayer et al., 2009; Thayer and
Lane, 2000, 2009). A recent study (Di Simplicio et al., 2012) measured
HRV during an emotion regulation task which required participants
to either passively view negative images versus down-regulating the
affect elicited by the images. This study demonstrated that individuals
with low neuroticism displayed higher HRV during down-regulation
relative to passive viewing, while those with high neuroticism dis-
played decreased HRV. These findings were interpreted as signalling a
distinct impairment in cognitive inhibitory responses over negative af-
fect. These findings are consistent with those of other studies reporting
that persons with high HRV display better performance on tasks involv-
ing executive function (Hansen et al., 2003), and more differentiated
emotion-modulated startle effects, suggesting a more flexible response
to situational demands (Ruiz-Padial et al., 2003). Increased HRV is also
associated with various indices of psychological wellbeing including
cheerfulness and calmness (Geisler et al., 2010), trait positive emo-
tionality (Oveis et al., 2009), motivation for social engagement (Kemp
et al., 2012b; Porges, 2011), resilience and wellbeing (Kashdan and
Rottenberg, 2010). By contrast, reduced HRV – reflecting a hypoactive
parasympathetic (vagal) system – is associated with cognitive and
affective dysregulation (Kashdan and Rottenberg, 2010; Thayer et al.,
2009), and psychological inflexibility (Kashdan and Rottenberg, 2010),
major psychological risk factors for psychopathology.
HRV may also be considered a somatic marker that contributes
to emotional experience and initiates subsequent emotion regulation
strategies. While visceral information is conveyed to the CNS through
many channels, vagal afferent feedback to the nucleus of solitary tract
(NST) (and cortex) plays an important role (Porges, 1995, 1997, 1998,
2001, 2003a,b, 2007, 2009, 2011). The process by which visceral affer-
ent feedback may impact on subsequent behavioural patterns has
been labelled ‘neuroception’ (Porges, 2009), a risk-evaluation pro-
cess involving the continuous non-conscious processing of sensory
information from the environment and the viscera. According to
polyvagal theory (Porges, 2011), perception of threat is associated
with increases in amygdala activity and vagal withdrawal (decreased
HRV), triggering fight or flight responses and negative social interac-
tions with the environment (social withdrawal). Information relating
to the status of the viscera and internal milieu is then fed back to the nu-
cleus of solitary tract, and the cortex, allowing for subsequent regulation
of the emotion response. By contrast, cortical inhibition of the amygdala
and increases in vagal tone allow for socially engaging facial expressions
to be elicited, leading to positive interactions with the environment
(social engagement). Again, the nucleus of the solitary tract receives
vagal afferent feedback from the viscera and internal milieu allowing
for ongoing neuroception.
The neurovisceral integration model (Thayer et al., 2009; Thayer
and Lane, 2000, 2009) further highlights an important inhibitory
role for vagal activity (indexed by HRV) in the regulation of a variety
of allostatic systems including inflammatory processes, glucose reg-
ulation and hypothalamic–pituitary–adrenal (HPA) function (Thayer
and Sternberg, 2006) (see also Pavlov and Tracey, 2012; Tracey,
2002, 2007). According to this model, reduced HRV leads to an ex-
cess of proinflammatory cytokines, impaired fasting glucose levels
and HPA-axis dysregulation; all conditions associated with increased
allostasis and poor health. Eventually, if not addressed, these conditions
will lead to premature ageing, cardiovascular disease and mortality
(Thayer et al., 2010b). The long-term sequelae of impaired autonomic
nervous system function – indicated by reduced HRV – will therefore
contribute to cardiovascular, lipid and endocrine abnormalities and in-
crease risk for developing important components of the metabolic syn-
drome (i.e., hypertension, diabetes, and obesity) (Koskinen et al., 2009;
Licht et al., 2013; Soares-Miranda et al., 2012; Windham et al., 2012).
The process by which vagal activity regulates these allostatic systems
may relate to the actions of the vagus nerve labelled as the ‘inflammatory
reflex’ (Tracey, 2002, 2007): the afferent (sensory) vagus nerve is
responsible for detecting cytokines and pathogen-derived products,
while the efferent (motor) vagus nerve is responsible for their regulation
and control. The ANS is well suited to play a key regulatory role in inflam-
matory signalling given its precise, rapid and lightning-fast responsivity;
in this way acute inflammation is contained and spread of inflammation
to the bloodstream prevented. The principle parasympathetic neuro-
transmitter, acetylcholine, effectively inhibits macrophage activation
and synthesis of tumour-necrosis factor (TNF) via the alpha-7 nicotinic
acetylcholine receptor sub-unit expressed on monocytes, macrophages
and other cytokine producing cells (Huston and Tracey, 2011; Wang
et al., 2003). This inhibitory action of the efferent vagus nerve has
been interpreted (Thayer, 2009) as an early intervention to short-
circuit the subsequent inflammatory cascade and over the longer-
term, inflammatory-mediated disease. Neural anti-inflammatory mech-
anisms may also inhibit release of other cytokines in inflammatory
cascade including interleukin-1 and high mobility group B1 (Tracey,
2002). Large longitudinal epidemiological studies are now required to
further examine the prognostic utility of early changes in HRV.
2.1. Physically healthy patients with mood and anxiety disorders, and
alcohol dependence display reductions in HRV
When we started investigating this issue, the majority of studies
on HRV in depressed samples had been conducted on patients with
a prior history of CVD (see Carney and Freedland, 2009; Taylor,
2010 for a review). These studies had made significant progress in
understanding the relationships between depressed mood physiology
and mortality. Yet, it had remained unclear whether HRV was also
decreased in physically healthy patients with depression, as factors
concomitant with CVD could be contributing to decreases in vari-
ability. If HRV was to be decreased in physical healthy samples of de-
pressed patients, then this would have important implications for our
understanding and treatment of this disorder, particularly in young
 A.H. Kemp, D.S. Quintana / International Journal of Psychophysiology 89 (2013) 288–296
adults. When we examined the literature in regards to this question,
the research was characterised by generally small samples and in-
consistent findings leading us to conduct and publish our meta-
analysis on the impact of major depressive disorder (MDD) on HRV
(Kemp et al., 2010). Our findings indicated that otherwise healthy,
unmedicated patients with major depressive disorder (MDD) (n =
673) display reduced heart-rate variability (HRV) relative to controls
(n = 407) (Kemp et al., 2010), indicating compromised cardio-
vascular function even in those patients without a prior history of
CVD. We also observed that these reductions in HRV were associated
with increasing depression severity. We concluded that depression
is associated with reductions in HRV and that these reductions are
most apparent with nonlinear measures (Hedges' g = − 1.955).
We also noted that antidepressant medications might not have
HRV-mediated cardioprotective effects and highlighted that patients
even in remission from depression may still be at risk of future ill
health.
While our meta-analysis was based on a relatively large sample
size (patient n = 673), an earlier study (Licht et al., 2008) on 1075
MDD patients concluded that although depression is associated with
reduced HRV, these reductions were driven by antidepressant medi-
cation. This proposal has led to significant debate and discussion
(Kemp, 2011, 2012; Kemp et al., 2011a,b; Licht et al., 2011a,b).
Regardless, the findings reported by Licht et al. (2008) raised two
important issues. Firstly, medication status may be a moderating var-
iable of observed effects, highlighting the importance of excluding
medicated patients when seeking to determine the impact of a disor-
der on HRV (as we did in our meta-analysis). Secondly, it highlighted
the need for further study on the impact of psychotropic medication
on HRV and major endpoints such as CVD and mortality.
Recently, we extended on our meta-analytic findings (Kemp et al.,
2010), confirming the finding of reduced HRV in an independent and
otherwise healthy, unmedicated MDD patient sample (Kemp et al.,
2012a). Our new study also indicated that MDD patients with comor-
bid GAD (n = 24) in particular, display the greatest reductions in
HRV relative to MDD patients without comorbidity as well as those
with comorbid panic and posttraumatic stress disorder. We concluded
that MDD patients with comorbid GAD would benefit from compre-
hensive cardiovascular risk reduction strategies. We have recently
confirmed these findings using meta-analysis on anxiety disorders
(Chalmers et al., in preparation), observing that patients with GAD
display the largest reductions in HRV relative to controls. We have
suggested (Kemp et al., 2012a) that GAD, a disorder characterised by
worry and hypervigilance, may have difficulty disengaging from
threat detection, which may lead to a chronic withdrawal of parasym-
pathetic nervous system activity, over-activation of sympathetic ner-
vous system activity and long-term reductions in HRV, subsequently
increasing the risk for CVD and sudden cardiac death.
More recently, we have reported evidence indicating that alcohol
dependent patients (Quintana et al., 2013b) (n = 177) relative to
healthy, non-dependent controls (n = 216) display reductions in
HRV, and that these findings are not due to cardiovascular disease
or comorbid psychiatric illness. This finding was associated with a
medium effect size (Hedges' g = −0.6), which is slightly smaller
than the effects we observed in patients with MDD and comorbid
anxiety disorder (Cohen's d = −0.8) (Kemp et al., 2012a). While an
earlier study reported that heavy alcohol use (n = 337), rather than
alcohol dependence (n = 208) is associated with dysregulation of the
autonomic nervous system (Boschloo et al., 2011), inclusion of this
study in our meta-analysis did not change our overall conclusions
(Quintana et al., 2013b), although it did reduce the effect size (Hedges'
g = 0.29). In summary, we have observed robust reductions in HRV
in patients with mood (Kemp et al., 2010) and anxiety (Kemp et al.,
2012a) disorders, and alcohol dependence (Quintana et al., 2013b)
who do not have CVD. It remains unclear however, to what extent
these HRV reductions in patients without CVD actually predict future
291
adverse events such as CVD and mortality. Future research is needed
to examine this particular issue.
2.2. Treatments for mood and anxiety disorders, and heart rate variability
If HRV is reduced in otherwise healthy patients with depression
and comorbid conditions, then an important question is whether
treatments for these disorders are able to ameliorate these decreases.
Antidepressant medications have surpassed antihypertensive agents
to become the most commonly prescribed medications in medical
practice (Cherry et al., 2007; Middleton et al., 2007). While the ad-
verse effects of tricyclic (TCA) antidepressants are well described,
the second-generation antidepressants including the selective seroto-
nin reuptake inhibitors (SSRIs) in particular, are generally considered
to have a much safer pharmacological profile. In our meta-analysis
(Kemp et al., 2010), we explored the question as to whether antide-
pressant medications ameliorate the reductions in HRV associated
with depression. Although tricyclic medication was found to further
decrease HRV – a finding associated with a large effect size – we
found no evidence for the SSRIs or other antidepressant medications
including mirtazapine, and nefazodone to increase (or decrease)
HRV, even when patients responded to treatment. The impact of the
tricyclic antidepressants on HRV has been well reported and our
results highlight the robustness of this finding. Decreases in HRV pre-
dict future CVD (discussed further below), raising the question as to
whether these older medications increase risk for CVD. A prospective
cohort study of 14,784 adults provided such a confirmation (Hamer
et al., 2010). TCA antidepressants were reported to raise the risk of
developing cardiovascular disease by 35% over 8 years but not all-
cause mortality risk. The SSRIs were not associated with CVD or all-
cause mortality in this study.
While our meta-analysis provided evidence for the benign effects
of the SSRIs, a 2-year longitudinal study (Licht et al., 2010) reported
that all classes of antidepressants including the TCAs, the selective
serotonin and noradrenaline reuptake inhibitors and the SSRIs, were
associated with adverse cardiovascular effects as indicated by reduc-
tions in heart rate variability (HRV). Patients in the 2-year longitudinal
study who discontinued antidepressants experienced the opposite
effect; HRV returned to levels observed among patients not on antide-
pressants. Although there were a number of methodological issues
with this study that may have contributed to the reported findings
(Licht et al., 2010) – we have commented on these previously (Kemp,
2011; Kemp et al., 2011b) – it highlighted the sensitivity of HRV mea-
sures to different classes of antidepressants and the need for the impact
of antidepressants to be examined over much longer time scales (years)
than a typical clinical trial (8–12 weeks).
In addition to the adverse HRV findings on the SSRIs, other studies
highlight the need for an urgent re-examination of the longer-term
impact of the second-generation antidepressants. For instance, the
significantly lowered risk of death in patients with depression and
coronary heart disease treated for SSRIs (Pizzi et al., 2011), is no longer
observed when studies with methodological problems are removed
from meta-analysis. Another study (Whang et al., 2009) on 63,469
women aged 30 to 55 years without baseline coronary heart disease
(CHD) found that while depressive symptoms were associated with
fatal CHD, antidepressant use (61% of participants were using an SSRI)
was specifically associated with a 3.34 increased risk for sudden cardiac
death even after controlling for a variety of confounds including age,
smoking status, alcohol intake, physical activity, body mass index and
coronary risk factors. Intriguingly, depression no longer conferred an el-
evated risk after these variables were accounted for. Finally, the US Food
and Drug Administration recently advised that the SSRI, citalopram,
should no longer be used at doses N40 mg/day, due to prolongation
of the QT interval of the electrocardiogram (2011), which might be
fatal. In this regard, studies have determined that prolonged QT interval
292 A.H. Kemp, D.S. Quintana / International Journal of Psychophysiology 89 (2013) 288–296
might increase risk of mortality by as much as 35% to 71% (Zhang et al.,
2011).
It is interesting to note here that the effects of cognitive behav-
ioural therapy (CBT) appears to have differential effects on HRV as
compared to antidepressant medications. In a study of 30 depressed
patients with stable CHD (Carney et al., 2000), average heart rate
and daytime HRV significantly improved after 16 sessions of CBT,
although this finding was only observed in the 12 severely depressed
individuals relative to the mildly depressed and control patients. In
another study of 54 patients with panic disorder (Garakani et al.,
2009), only those administered CBT displayed decreases in heart
rate and increases in HRV, while those receiving CBT with sertraline
(an SSRI) did not display any change despite significant clinical im-
provement. These SSRI findings are consistent with those from our
own meta-analysis on depression (Kemp et al., 2010), which indicated
that antidepressant medication did not increase (or decrease) HRV in
MDD patients. Other non-pharmacological interventions including
electroconvulsive therapy (Nahshoni et al., 2001, 2004), repetitive
transcranial magnetic stimulation (Udupa et al., 2007) and biofeed-
back (Karavidas et al., 2007) also appear to increase HRV in MDD
patients. In addition, we recently showed slow breathing and HRV
biofeedback with a focus on prolongation of the outbreath enhanced
HRV and decreased self-reported anxiety in anxious musicians during
stressful performance (Wells et al., 2012). Together, these studies
provide intriguing evidence of the capacity to increase HRV through
non-pharmacological means; this is an important consideration for
clinicians treating patients with already compromised parasympa-
thetic function.
In their review of the literature, Thayer et al. (2010b) describe
a variety of modifiable CVD risk factors including hypertension,
diabetes, cholesterol, psychosocial and lifestyle-related risk factors
highlighting the opportunity to minimise the long-term deleterious
effects of psychiatric illness. Initiatives such as 10,000 steps a day
in combination with objective monitoring of physical activity with
pedometers provide a pragmatic means to measure and track habitual
levels of activity (Tudor-Locke et al., 2011). Interestingly, exercise
increases HRV and reduces levels of TNF and other cytokines, suggesting
that the beneficial effects of exercise may, in part, be attributable to the
cholinergic anti-inflammatory pathway. Indeed, exercise and other car-
diovascular risk reduction strategies including physical exercise, medi-
tation, smoking cessation, and dietary changes have been shown to
have beneficial effects on HRV (Minami et al., 1999; Park et al., 2009;
Rennie et al., 2003; Tang et al., 2009). Critically, research findings now
highlight an association between positive psychological wellbeing – a
psychological state associated with increased HRV – and cardiovascular
health (Boehm and Kubzansky, 2012; Dubois et al., 2012); attributes
such as mindfulness, optimism and gratitude appear to be particularly
pertinent. Future studies are needed to further examine the effects of
antidepressant medications versus psychological treatments of mood
and anxiety disorders on HRV and additional endpoints including the
development of CVD and mortality.
3. Reduced HRV is associated with future adverse health outcomes
While HRV clearly has important functional significance for men-
tal health, over the longer-term, reductions in HRV precede the pres-
ence of a variety of CVD risk factors such as hypertension. HRV is also
an early marker of CVD and is predictive of mortality (see Thayer
et al., 2010b for a review). An early prospective study on 1338 normo-
tensive participants recruited as part of the Atherosclerosis Risk in
Communities (ARIC) study (Liao et al., 1996), reported an inverse
association between baseline HRV and risk of incident hypertension
within a 3-year follow-up period. Adjusted incident odds ratios ranged
from 1.00, 1.46, 1.50 and 2.44 for the highest to the lowest quartiles
of HRV respectively. A more recent publication from the same study
(Schroeder et al., 2003) reported that reduced HRV predicted greater
risk of incident hypertension in 7099 individuals without hypertension
at baseline over 9 years of follow-up. Hazard ratios for the lowest com-
pared to the highest quartile ranged between 1.24 and 1.44 providing
further support for the proposal that the autonomic nervous system is
involved in the development of hypertension.
Another ARIC study (Dekker et al., 2000) determined HRV from a
2-minute rhythm ECG strip in a random sample of 900 participants
(aged 45 to 65) without prevalent coronary heart disease at baseline.
Participants with low HRV had an adverse cardiovascular risk profile
and an elevated risk of incident CHD and death. The authors reported
that middle-aged men and women with high heart rate and especially
low HRV was associated with a two-fold increased risk of mortality
in individuals without a history of CVD. A more recent study on
85 healthy and unmedicated adults with a mean age of 58 years
reported that persons with a one standard deviation increase in HRV –
determined from a 20-minute ECG resting-state recording – had a 52–
59% reduction in their 10-year risk of developing coronary heart disease
(CHD) (Yoo et al., 2011). This study also reported an inverse correlation
between HRV and the Framingham risk score, a global risk assessment of
CHD focusing on patient age, smoking activity, low density lipoprotein
cholesterol, high density lipoprotein cholesterol, blood pressure and pres-
ence of diabetes, although this finding was only observed in men.
An early study (Tsuji et al., 1994) on the relationship between re-
duced HRV and all-cause mortality reported that HRV was associated
with mortality even after adjusting for relevant risk factors. These
findings were based on an elderly cohort of 736 participants from
the Framingham Heart Study with a mean age of 72 years. One stan-
dard deviation decrement in HRV was associated with a 1.70 times
greater hazard for all-cause mortality during 4-years of follow-up.
Two years later, the same authors (Tsuji et al., 1996) reported find-
ings on 2501 participants from the Framingham Heart study (mean
age of 53 years) who were initially free of clinically apparent coro-
nary heart disease or congestive heart failure. As with their earlier
study, the authors concluded that estimation of HRV from 2 h of ambu-
latory monitoring offered prognostic information beyond that provided
by traditional CVD risk factors including age, sex, smoking, diabetes and
left ventricular hypertrophy. One standard deviation decrement in HRV
was associated with a hazard ratio of 1.47 for new cardiac events
3.5 years later.
Another body of work has examined the ability to predict mortality
in patients with stable CHD and in those with a recent acute coronary
event, with findings indicating that HRV accounts for a substantial
part of the risk associated with depression in CHD (see Carney and
Freedland, 2009 for a review). In the Multicenter Post-Infarction
Program (MPIP), 715 patients underwent a 24-hour continuous ECG
recording 2 weeks after myocardial infarction and were then followed-
up over a period of 4 years (Bigger et al., 1992). The authors reported
that even after controlling for 5 previously established post-infarction
risk predictors including age, New York Heart Association functional
class, pulmonary rales in the coronary care unit phase of the infarction,
left ventricular ejection fraction and frequency of ventricular arrhyth-
mias, HRV was able to identify participants with a 2.5 year mortality
risk of ~50%. In a later study published by the same authors, 331
un-medicated participants recruited in the Cardiac Arrhythmia Pilot
Study underwent a 24-h electrocardiographic (ECG) recording 1 year
after infarction and were then followed-up over an interval time up to
3 years after enrolment (Bigger et al., 1993). HRV demonstrated a strong
association with mortality with relative risks ranging from 2.5 to 5.6, and
these findings were independent of other well known post-infarction
risk predictors including heart failure, left ventricular ejection fraction
and ventricular arrhythmias. A more recent study (Carney et al., 2005)
on 311 depressed patients with a recent acute myocardial infarction
recruited for the Enhancing Recovery in Coronary Heart Disease
(ENRICHD) study, reported that depressed patients remained at a higher
risk for all-cause mortality over a 30-month follow-up period (hazard
ratio: 2.8) after adjusting for potential confounders. The authors also
 A.H. Kemp, D.S. Quintana / International Journal of Psychophysiology 89 (2013) 288–296 293

reported that reduced HRV accounted for one-quarter of the mortality

risk for depression.

3.1. A working model for the adverse effects of depression, comorbid

conditions and treatment on HRV

A model (Fig. 1) for the adverse effects of mood and anxiety dis-
orders, alcohol dependence as well as their treatments is presented
to guide future research activities. It is hypothesised that the adverse
effects (i.e. cardiovascular disease and mortality) of these disorders
and treatment with antidepressants – particularly the tricyclic anti-
depressants and serotonin and noradrenaline reuptake inhibitors
(SNRIs) – are a consequence of chronic autonomic dysregulation
(Thayer et al., 2010b), and impairment in the cholinergic inflammatory
reflex (Pavlov and Tracey, 2012; Tracey, 2002, 2007) as operationalized
by reductions in HRV. This proposal is based on a number of lines of
research: 1) HRV is reduced in otherwise healthy, unmedicated patients
with mood (Kemp et al., 2010), and anxiety disorders (Friedman, 2007;
Kemp et al., 2012a), and alcohol dependence (Quintana et al., 2013b), 2)
associations between HRV and the metabolic syndrome (Licht et al.,
2013; Soares-Miranda et al., 2012), with evidence indicating that auto-
nomic dysregulation predicts an increase in metabolic abnormalities
over time (Licht et al., 2013), 3) reduced vagal activity (reduced HRV)
leads to a variety of conditions associated with increased allostasis
and poor health (Thayer and Sternberg, 2006), attributable to the cho-
linergic anti-inflammatory pathway (Pavlov and Tracey, 2012; Tracey,
2002, 2007), 4) associations between mood disorders and physical ill-
ness such as diabetes (Katon et al., 2011), CVD (Glassman et al., 2010)
and cancer (Kissane et al., 2011), 5) longitudinal evidence (Licht et al.,
2010) indicating that all classes of antidepressants decrease HRV and
that HRV increases following their cessation, 6) evidence indicating
that the adverse cardiovascular effects are greatest for the TCAs,
followed by SNRIs and SSRIs (Licht et al., 2010; Licht et al., 2012), further
supported in recent cross-sectional analysis of baseline characteristics
(Kemp & colleagues, unpublished observations) of the Brazilian Longi-
tudinal Study of Adult Health (ELSA-BRASIL) (Aquino et al., 2012)
(there is less consensus on the adverse effects of the SSRIs) (Kemp
et al., 2011b), and 7) epidemiological evidence linking psychological
distress (Russ et al., 2012), mood and anxiety disorders (Phillips et al.,
2009) and their pharmacological treatments (Whang et al., 2009)
to CVD and mortality. The model draws heavily on the evidence indicat-
ing that changes in HRV and chronic autonomic dysregulation may
be the final common pathway for a host of conditions and diseases,
including cardiovascular disease and mortality (Thayer et al., 2010b),
which may be attributable to impairment in the cholinergic anti-
inflammatory pathway (Pavlov and Tracey, 2012; Tracey, 2002, 2007). Fig. 1. Model summary for the link between mood disorders, comorbid conditions,
It highlights that change in HRV will be observed prior to changes in cardiovascular disease and mortality. Mood and anxiety disorders, and alcohol depen-
inflammatory markers and oxidative stress; while a typical, diffusible dence are associated with reduced HRV. Antidepressant medications – particularly
tricyclic medications and the serotonin and noradrenaline reuptake inhibitors – are
inflammatory response may take hours to days to develop, neural sig-
also associated with reduced HRV, while non-pharmacological therapies are associated
nalling contributing to changes in HRV occur within milliseconds with increased HRV. Response to treatment and cardiovascular risk reduction strategies
(Tracey, 2002). The established link (Dantzer et al., 2008) between such as physical exercise, meditation, smoking cessation and dietary changes may in-
inflammation, sickness and depression is acknowledged, indicated by crease HRV partly ameliorating adverse downstream effects. Current debate in the liter-
a bi-directional arrow connecting mood disorders and comorbid condi- ature has focused on whether the disorder or medications are driving the adverse
effects reported in the literature highlighting the need for further study. Fewer studies
tions with downstream risk markers associated with inflammatory pro- have focused on the impact of non-pharmacological therapies – relative to medication –
cesses. The model also highlights the possibility that the adverse effects on HRV. HRV is argued to precede downstream risk markers such as tumour-necrosis
of chronically administered antidepressants – particularly the TCAs and factor on the basis of evidence highlighting an important regulatory role of the vagus
the SNRIs – are associated with downstream increases in inflammatory nerve in inflammatory processes. A poorly functioning cholinergic inflammatory reflex
(indexed by reduced HRV) will lead to downstream risk markers, and morbidity and
markers including interleukin-6 and C-reactive protein. Indeed, there
mortality from a host of conditions including cardiovascular disease.
is already some evidence that this is the case (Hamer et al., 2011). It is
also noted that the alleviation of disorder symptoms may, in part, ame-
liorate the adverse cardiovascular effects of antidepressants (i.e. depres- 4. Conclusions
sion severity is negatively correlated with HRV; Kemp et al., 2010).
Non-pharmacological treatments including cognitive and behavioural Cross-disciplinary findings from clinical epidemiology, to psycho-
therapies and cardiovascular risk reduction strategies are associated physiology, neuroimaging and molecular neuroscience support a key
with increased HRV – indicated by dashed lines and borders (Fig. 1) – role for HRV in mental and physical wellbeing. While further research
and reduced disorder severity. is needed on the implications of reduced HRV in otherwise healthy,
294 A.H. Kemp, D.S. Quintana / International Journal of Psychophysiology 89 (2013) 288–296
psychiatric populations, the available evidence suggests that chronic
reductions in HRV are closely linked to impairments in the cholinergic
anti-inflammatory reflex and downstream changes in allostatic sys-
tems that increase risk for CVD and mortality. By contrast, interven-
tions leading to increased HRV and the alleviation of psychiatric
symptoms, appear to lower the risk of future morbidity and mortality.
We suggest here that otherwise healthy patients with psychiatric
illness should consider cardiovascular risk reduction strategies in-
cluding physical exercise, meditation, smoking cessation, and dietary
changes – all of which are known to increase HRV – especially when
treated with antidepressant medication. In conclusion, HRV provides
an easily accessible and meaningful measure of future health and
wellbeing.
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