Current Heart Failure Reports

https://doi.org/10.1007/s11897-018-0414-8

COMORBIDITIES OF HEART FAILURE (C ANGERMANN, SECTION EDITOR)

Depression, Anxiety, and Cognitive Impairment

Comorbid Mental Health Disorders in Heart Failure

Christiane E. Angermann 1 & Georg Ertl 1

# Springer Science+Business Media, LLC, part of Springer Nature 2018

Abstract
Purpose of Review Depression, anxiety, and cognitive impairment constitute established risk markers for incident cardiovascular
disease (CVD) and are associated with impaired life expectancy and quality of life and high hospitalization rates and healthcare
expenditure. This review summarizes current knowledge about mental health disorders in patients with CVD and heart failure (HF).
Recent Findings Emerging evidence suggests various shared pathophysiological mechanisms between psychological comorbid-
ities and CVD (e.g., systemic inflammation and autonomic dysfunction). Bi-directional interactions involving the central nervous
and cardiovascular systems may help explain the rising prevalence of comorbid mood disorders with increasing CVD severity
and support the concept of alternative pathophysiological mechanisms in the presence of severe somatic illness, making symp-
toms less responsive or unresponsive to psychotropic pharmacotherapy.
Summary Considering high prevalence and negative impact of psychological comorbidities in CVD and HF, routine care should
integrate screening for these conditions. Multidisciplinary treatment approaches with active patient participation in disease
management were shown to improve outcomes. However, better understanding of factors mediating the adverse prognostic
effects of mood disorders is needed. This might enable more targeted treatment and possibly also facilitate better understanding of
the pathophysiological mechanisms driving CVD.

Keywords Heart failure . Depression . Anxiety . Cognitive dysfunction . Morbidity . Mortality

Introduction [1–4], and a substantial proportion of HF patients had

Heart failure (HF) constitutes a major cause of morbidity and
mortality and affects an increasing number of patients given
greater longevity and improved treatment options for acute
cardiovascular diseases (CVD) in industrialized countries. In
previous reports, including meta-analyses, the prevalence of
depressive symptoms and/or anxiety disorders was several
times higher in HF patients than in the general population
This article is part of the Topical Collection on Comorbidities of Heart
Failure
* Christiane E. Angermann
Angermann_C@ukw.de
1
Department of Internal Medicine I and Comprehensive Heart Failure
Center, University and University Hospital of Würzburg, Am
Schwarzenberg 15, 97078 Würzburg, Germany
coexisting cognitive problems [5•].
Comorbid mood disorders are associated with increased
morbidity, mortality, and costs in HF [6–18], but often remain
underdiagnosed and undertreated [8, 15, 19]. Given the over-
lap between cardiac and psychological symptoms, accurately
diagnosing mood disorders in HF patients can be challenging.
To date, evidence is lacking that antidepressant pharmacother-
apy improves symptoms or hard clinical endpoints in HF pa-
tients, and HF guidelines provide no specific treatment rec-
ommendations [20]. Enhanced physician awareness of the
high prevalence rates and serious consequences of mood dis-
orders and their complex pathophysiological interrelations
with the HF syndrome [5•, 8] might raise general awareness
of these important comorbidities and eventually lead to novel
standards and targets for treatment.
This review article provides a practical guide to the recog-
nition of mood disorders in routine patient care. It also sum-
marizes current knowledge about symptoms, epidemiology,
physiologic and behavioral disease mechanisms, and impact
on clinical outcomes and discusses possible implications for

the treatment of patients with CVD (including HF) and psy-
chological comorbidities.
Symptoms and Epidemiology
Depression can be easily overlooked in the routine care of HF
patients because symptoms of the two conditions overlap and
can, therefore, be misinterpreted by physicians and also by the
patients themselves [8, 21]. For example, fatigue, difficulty
concentrating, listlessness, and sleep disorders can be associ-
ated with both HF and depression. Only few gender differ-
ences were found in a recent study comparing single-item
scores in the 9-item Patient Health Questionnaire (PHQ-9)
[22] and disease severity, somatic symptoms, and physical
characteristics between men and women with symptomatic
HF, with or without depression [21].
The rate of depression increases in parallel with increasing
HF severity [3, 23]. Depression has been reported to occur in
10% of clinically asymptomatic outpatients, but prevalence
rates rise to 40–70% in hospitalized HF patients with New
York Heart Association (NYHA) class III–IV symptoms
[2–4, 23]. Similar to the general population, depression is
more common in women and younger individuals with HF
[3, 12, 13, 21] and has an adverse impact on health-related
quality of life irrespective of sex [21]. At least a quarter of HF
patients exhibit symptoms of both anxiety and depression
[24]. According to the literature, severe anxiety is also asso-
ciated with the rate of incident CVD [25, 26], and with in-
creased mortality risk in HF patients, independent of
coexisting depression, particularly when cardiac output is
markedly reduced [27].
Several studies have demonstrated a close interrelation be-
tween the intensity of cardiac and depressive symptoms and
anxiety disorders [4, 28]. Independent of objective measures
such as cardiac output or blood levels of HF biomarkers, HF
patients with depression or anxiety more often experience
more severe dyspnea and impaired quality of life. Intensified
perception of symptoms may result from misjudgment or
overestimation, but also from psychological strain or genetic
disposition [29]. It has also been shown that patients with both
anxiety and depression are at greater risk of CVD events than
those with either condition alone [30, 31].
Memory disorders (cognitive dysfunction) are also more
common in CVD than in the general population. Cognitive
dysfunction limits patients’ ability to cope with HF self-
management (e.g., underestimate or misinterpret signs of
worsening disease), meaning that recognition of this comor-
bidity is of clinical relevance. Furthermore, patients with cog-
nitive dysfunction may be unable to cope with more complex
treatment plans. Reports on the frequency of cognitive dys-
function in HF vary between 25 and 75% [32, 33]. A meta-
analysis of data from more than 8000 patients suggested
Curr Heart Fail Rep
greater cognitive decline in HF patients compared with non-
HF patients over the longer term [5•].
It is clinically relevant to discriminate between mild cogni-
tive impairment (MCI) and dementia. In more advanced
stages, cognitive dysfunction may be associated with the loss
of cerebral gray matter [34]. Other mechanisms contributing
to cognitive impairment (e.g., chronic or intermittent cerebral
hypoperfusion and/or microemboli) are reviewed in more de-
tail elsewhere [35••]. Interestingly, a recent study demonstrat-
ed that HF patients exhibit cognitive deficits particularly in the
attention and memory domains, and found that medial tempo-
ral lobe atrophy rather than white matter lesion load was re-
lated to cognitive impairment [36]. In the early stages, patients
may be able to compensate for cognitive deficits so that these
are not readily recognized during regular communication with
medical staff. Poor adherence to treatment recommendations
may be the first indicator of cognitive dysfunction.
Discrepancies between subjective symptoms and objective
findings should always alert caregivers to consider the possi-
bility of psychiatric comorbidities. Standardized and validated
screening tools, which are easy to apply (often by the patients
themselves), are helpful to identify such conditions, better
understand symptoms, and lead to more targeted management
and therapeutic interventions.
Pathophysiology
The complex interrelations between somatic and affective dis-
orders and possible mediators of the increased cardiovascular
risk seen in patients with comorbid mental health problems are
not completely understood. Twin data indicate, for example,
that genetically determined pathophysiological mechanisms
may play a role in the development of both coronary disease
and depression [37]. Interestingly, our investigations demon-
strated that a functional sequence variant of the neuropeptide
S receptor-1 gene may modulate clinical outcomes and
healthcare utilization in patients with systolic HF undergoing
telephone-based disease management. Consistent with the
previous observation of an association between the T-allele
[29] and higher anxiety sensitivity index scores in response
to bodily symptoms [38], we found that homozygous carriers
of the gain-of-function T-allele were rehospitalized following
cardiac decompensation for systolic HF significantly more
often than those with the AT or AA genotype [29]. This gene
× treatment interaction was not observed in patients receiving
usual care, and we therefore assumed that TT genotype car-
riers exaggerated self-assessed somatic symptoms during tele-
phone contacts. This could have led nurses and physicians to
more often recommend closer assessment of problems they
perceived as potentially dangerous when reported by patients
with increased anxiety and a tendency to over-interpret phys-
ical symptoms. In summary, this proof-of-principle study
Curr Heart Fail Rep
suggested the possibility of psychogenetic determinants of
clinical outcomes and healthcare utilization in HF patients
that, in the case of the neuropeptide S receptor-1 gene, was
modulated by the type of care.
Figure 1 provides a simplified schematic of possible bi-
directional interactions between social, mental, and physical
factors that may impact the development and progression of
CVD, but at the same time lead to depressive symptoms, anx-
iety, and cognitive impairment. Negative emotions could have
adverse effects on neurohormonal regulatory circuits in a sim-
ilar way to external stress. Dysregulation of autonomic ner-
vous control leads to increased sympathetic tone and higher
circulating levels of stress hormones, including cortisol and
proinflammatory cytokines, thus increasing the risk for car-
diovascular events [16–19]. Autonomic dysregulation and
systemic inflammation may also induce a procoagulant state
by potentiating platelet activation, altering the coagulation
cascade, and inducing endothelial dysfunction, all of which
contribute to the development and progression of atheroscle-
rosis [39–42]. Other relevant pathogenic mechanisms include
abnormal lipid metabolism and insulin resistance. Thus, there
are complex interrelations between depressive symptoms, in-
creased anxiety levels, and the multiple somatic features of
cardiovascular diseases that may accelerate disease
progression.
Fig. 1 Interrelations and pathophysiological mechanisms with possible bi-
directional impact that may contribute to the development of depressive
symptoms and other negative emotional states in cardiovascular disease and/
The pathogenesis of cognitive impairment following cere-
bral morphological damage and functional impairment is also
likely to be multifactorial. Trigger mechanisms include dimin-
ished perfusion of the brain and dysfunction of the blood-
brain barrier due to reduced oxygen supply as a consequence
of low cardiac output or embolic events [43]. The complex
sequelae of diminished oxygen supply include altered cerebral
metabolism, a proinflammatory state, augmented oxidative
stress, and neuronal dysfunction [35••]. Frequent HF comor-
bidities and complications, such as diabetes, anemia, arterio-
sclerosis, atrial fibrillation, renal dysfunction, electrolyte im-
balance, coagulopathies, ischemic cerebral events, and malnu-
trition, as well as drug-induced side effects could also play a
role [35••, 44]. Moreover, depression and anxiety tend to aug-
ment cognitive dysfunction. Loss of retentiveness, diminished
ability to concentrate, and memory decline further reduce log-
ical and emotional functions.
All of the described biological pathophysiological mecha-
nisms occur in addition to behavioral factors that are also
modulated by depression, anxiety, and cognitive impairment.
Patients with mental health problems tend to not take their
medicine regularly and often show inadequate adherence to
non-pharmacological treatment recommendations regarding
lifestyle issues such as nicotine abstinence, healthy nutrition,
or, in particular, physical activity [45]. In addition to
or that may increase the likelihood of mental health disorders in chronic somatic
cardiovascular diseases such as heart failure. AHP, adrenal-hypothalamic-
pituitary axis; SNS, sympathetic nervous system
 Curr Heart Fail Rep

psychosocial components, demographic and genetic factors,
and personal life circumstances multiply the manifold losses
that patients may experience as a consequence of the somatic
disease (e.g., a decline of health, functional capacity, indepen-
dence, and sexual activity, and loss of employment or finan-
cial security), which all together might also contribute to
explaining the interrelation between HF and mood disorders.
Depression, anxiety, and cognitive impairment may share
several principal somatic risks and disease mechanisms.
However, since the significance of each contributing factor
and personal resilience may vary considerably between indi-
viduals, the pathogenesis, disease profile, and clinical pheno-
type of psychological comorbidities may be heterogeneous,
and therefore treatment requirements may differ between in-
dividuals and also depend on whether affected patients are
physically healthy or have a chronic somatic illness. Why
depression, anxiety, and cognitive impairment are invariably
associated with a significantly increased mortality risk und
more frequent hospital admissions in affected patients with
CVD and to what extent psychological comorbidities are true
mediators or only markers of increased risk in cardiac patients
requires further investigation [46].
Diagnosis
Depression is defined based on subjective symptoms [47, 48];
there is no biological test for diagnosis verification. Severity is
an important characteristic of major depression and also an
“episode specifier” in the 5th revised edition of the
Diagnostic and Statistical Manual of Mental Disorders
(DSM-V), where depressive episodes are classified as “mild,”
“moderate,” or “severe” [48]. These severity subtypes rely on
three different criteria: the number of symptoms present,
symptom severity, and the degree of functional disability
resulting from the symptoms. Criteria have been proposed to
estimate depression severity (Table 1) [48]: mild, > 1 major
symptom plus 1–2 additional symptoms or 5–6 symptoms of
mild severity and functional impairment; moderate, > 1 major
symptom plus 2–3 additional symptoms, or 7–8 symptoms
with moderate functional impairment; severe, all 3 major
symptoms plus > 3 additional symptoms, or fewer symptoms
but any of the following: severe functional impairment, psy-
chotic symptoms, recent suicide attempt, or specific suicide
plan or clear intent. Several validated questionnaires allow for
standardized depression screening according to the DSM
criteria.
For example, the self-administered 9-item Patient Health
Questionnaire (PHQ-9) is often used in HF patients. The
PHQ-9 is validated in different languages and freely accessi-
ble online (http://www.phqscreeners.com) [22]. Patients are
asked how often nine of the most important symptoms have
been present in the past 2 weeks. Possible answers are “not at
all,” “several days,” “more than half the days,” and “nearly
every day.” Each item of the PHQ-9 yields a score of 0–3
resulting in an overall sum-score from 0 to 27, with higher
values indicating more severe depression. Usual cutoff points
are as follows: 0–5, normal; 6–10, mild depression; 11–15,
moderate depression; 16–20, moderately severe depression;
> 20, severe depression. Compared with a Structured
Clinical Interview and using DSM diagnostic criteria [48], a
sum-score of > 9 had a sensitivity (specificity) of 88% (88%)
for the diagnosis of major depressive disorder (likelihood ratio
7.1). Corresponding values for a sum-score > 11 were 83%
(92%), likelihood ratio 10.2 [49]. The abbreviated version of
the questionnaire, the PHQ-2, depicts the most important
symptoms (loss of interest or pleasure, melancholia, depres-
sion, and hopelessness) [50]. In patients with HF, the PHQ-2
appears similar to the PHQ-9 for risk assessment of depression
[51], and the American Heart Association recommends its use
as a screening tool in patients with CVD [52]. Patients scoring
2 or more points in the PHQ-2 should undergo an extended
d i a g n os t i c w or k - u p [4 8 ] . Yea r l y f o l l o w - up s a r e
recommended.
The 7-item Questionnaire on Generalized Anxiety
Disorder (GAD-7) [53] or its abbreviated version the GAD-

Table 1 Symptoms required to

be present for the diagnosis of
a depressive episode according
to the Diagnostic and Statistical
Manual of Mental Disorders
[47, 48]
Major symptoms
- Depressed mood
- Loss of interest and/or pleasure in activities
that are normally pleasurable
- Loss of energy or increased fatigability
Additional symptoms
- Loss of confidence and self-esteem
- Unreasonable feelings of self-reproach or excessive and
inappropriate guilt
- Recurrent thoughts of death or suicide, or any suicidal behavior
- Complaints or evidence of diminished ability to think or
concentrate, such as indecisiveness or vacillation
- Change in psychomotor activity, with agitation or retardation
(either subjective or objective)
- Sleep disturbance of any type
- Change in appetite (decrease or increase) with corresponding
weight change
Curr Heart Fail Rep
2 [54] is suitable for the diagnosis of anxiety and is also freely
available online (http://www.phqscreeners.com). The GAD
has a similar structure as the PHQ and includes the most
relevant diagnostic criteria for generalized anxiety disorders.
Each item of the GAD-7 yields a score of 0–3 resulting in an
overall sum-score from 0 to 21, with higher values indicating
more severe anxiety. Usual cutoff points are as follows: 0–5,
normal; 6–10, mild anxiety; 11–15, moderate anxiety; > 15,
severe anxiety. Using a threshold score of 10, the GAD-7 has a
sensitivity of 89% and a specificity of 82% for diagnosing
generalized anxiety disorders. GAD sum-scores of ≥ 10 re-
quire further diagnostic evaluation [53]. The items of the ab-
breviated version GAD-2 include the most important diagnos-
tic criteria (anxiety and worries concerning particular events
and actions, difficulty in controlling these worries). Sum-
scores of 3 points or higher support the diagnosis of an anx-
iety disorder.
Cognitive impairment can be diagnosed using neurophys-
iological tests. For example, the Mini-Mental State
Examination (MMSE) examines 11 domains of orientation
with regard to short-term memory, attentiveness, and visual
spatial perception using a 30-point scale [55]. The Montreal
Cognition Assessment has a better sensitivity especially when
assessing mild cognitive impairment [56, 57]. Expertise is
required to administer these diagnostic tools in a standardized
fashion. Serial examinations are recommended.
Prognostic Significance
A recent meta-analysis including more than 200 articles from
29 countries showed that people with mental disorders had a
greater than twofold increase in mortality risk versus the com-
parison population [58••], suggesting that psychological co-
morbidities have major global disease burden implications in
general. After myocardial infarction, depression was found to
be independently associated with an increased risk of all-cause
mortality [59] and the presence of depression predicted devel-
opment of CVD in primarily healthy individuals [60].
Depression is also a significant predictor of poor survival
and higher hospitalization rates in patients with HF [3, 4,
10–13, 16, 61, 62]. Even mild depressive symptoms worsen
the prognosis and increase healthcare costs [3, 10]. Thus, bi-
directional pathophysiological interrelations rather than mere
coincidence of depression and CVD are likely. Analyses from
the Interdisciplinary Network Heart Failure (INH) program
demonstrated a proportional relationship between the severity
of depressive symptoms measured by the PHQ-9 and the risk
of mortality and rehospitalization [13, 51]. In a recent INH
analysis, which compared clinical outcomes between men and
women discharged from hospital after cardiac decompensa-
tion for systolic HF, depressive symptoms predicted worse
survival in both sexes [21]. However, mortality risk was
comparable, although females had more severe HF, lower
health-related quality of life (HRQOL), and more depressive
symptoms than males. In addition, higher PHQ-9 sum-scores
predicted higher rehospitalization rates, but only in men [21].
A relationship between depressive symptoms and more fre-
quent cardiac decompensations and visits to the emergency
room has been repeatedly reported, and confirmed by meta-
analysis [3, 10].
Associations between anxiety and health outcomes in pa-
tients with HF are less clear. Evidence is limited, but two
recent meta-analyses suggest that anxiety alone may not exert
strong prognostic effects [8, 63]. On the other hand, anxiety
predicted premature all-cause and cardiovascular death in a
10-year follow-up of more than 5000 healthy middle-aged
Dutch women even after adjustment for standard risk factors
and depression [64]. Furthermore, two additional studies, with
follow-up of 37 and > 11 years, respectively, demonstrated
that anxiety correlated with a higher risk of coronary disease,
myocardial infarction, and cardiovascular death, suggesting
adverse long-term effects [25, 65]. When anxiety and depres-
sion coexist, the risk of adverse clinical outcomes appears to
increase in a cumulative fashion [6, 27, 31]. Poor treatment
adherence due to psychological disorders has a negative effect
on disease progression and prognosis, and cognitive dysfunc-
tion is also likely to play a major causal role [66].
Therapy
Given high prevalence rates and abundant evidence from the
literature demonstrating the adverse effects of psychological
disorders on clinical outcomes and HRQOL, therapeutic in-
terventions that do not aggravate patients’ cardiovascular
problems while improving mental health and prognosis are
urgently needed. Currently, HF guidelines do not provide spe-
cific recommendations about the treatment of psychological
comorbidities [20]. Various antidepressants are known to have
unfavorable side effects and should therefore only be pre-
scribed in patients with CVD after careful consideration of
the benefits and risks, including possible drug-drug interac-
tions [67•]. For example, the use of tricyclic antidepressants
was found associated with an increased risk of myocardial
infarction [68], and significant conduction delays, pro-
arrhythmic effects, and orthostatic hypotension have been re-
ported [67•].
Selective serotonin reuptake inhibitors (SSRIs) are the an-
tidepressant agents of choice in cardiovascular patients due to
a relatively favorable safety profile [67•]. However, there are
also contraindications with these agents, including co-
medication with substances prolonging the QT interval (e.g.,
amiodarone or several beta-blockers). Interestingly, a recent
animal study showed that treatment with citalopram in the
acute phase after experimental myocardial infarction

significantly increased mortality in mice by disturbing early
healing while this effect was not observed when treatment was
started 7 days after coronary ligation [69]. The data suggested
an interference of this SSRI with myocardial recovery and
remodeling. Similar findings have not yet been reported in
prospective studies in humans. In addition to antidepressant
pharmacotherapy, psychotherapy, exercise training, disease
management, and other multimodal strategies have been tried
to improve comorbid mental conditions. Two recent review
articles provide a more detailed overview of current knowl-
edge about possible pharmacological and non-
pharmacological interventions in patients with CVD and with
HF specifically [67•, 70].
Safety and Efficacy of Antidepressant
Pharmacotherapy
Evidence from studies evaluating antidepressant interventions
is inconsistent. While pharmacologically treated depression
was shown to be associated with an increased mortality risk
in a large clinical cohort [71], other authors observed that the
association between use of antidepressants and increased mor-
tality no longer existed after controlling for depression and
other confounders [72]. Table 2 provides an overview of se-
lected treatment trials and meta-analyses that evaluated differ-
ent treatment modalities in patients with depressive symptoms
and CVD (including HF) [73].
SSRIs have been shown to improve depression in patients
with acute coronary syndrome (ACS), including myocardial
infarction and unstable angina [74–76, 78, 79••].
Disappointingly, effects on clinical endpoints were often neu-
tral. For example, in the Myocardial Infarction and
Intervention Trial (MIND-IT), no difference in cardiac out-
comes was found between patients receiving mirtazapin
followed by citalopram compared with those receiving place-
bo [77], and neither cardiac function nor event rates were
improved by the study interventions in the Sertraline
Antidepressant Heart Attack Randomized Trial (SADHART)
[74] and the Enhancing Recovery in Coronary Artery Disease
Patients (ENRICHD) study [75], which evaluated cognitive
behavioral therapy (CBT) with or without an antidepressant.
Interestingly, a post hoc analysis from the ENRICHD trial
suggested that the risk of death or recurrent myocardial infarc-
tion at 29 months was lower in patients who had taken the
SSRI compared with those who did not take antidepressant
medication [86]. Long-term follow-up from SADHART indi-
cated that 6.7 years after randomization, mortality differed by
depression remission status at the end of the treatment phase,
but not by initial treatment allocation [87]. Only recently, Kim
and coworkers demonstrated that 24-week treatment with
escitalopram compared with placebo was after a recent ACS
event not only superior in reducing depressive symptoms at
24 weeks [78], but was also associated with a lower risk of
Curr Heart Fail Rep
major adverse cardiac events after a median follow-up of
8.1 years [79••]. As the authors noted, the severity of both
depressive symptoms and CVD was lower in their study par-
ticipants than in previous trials in patients with ACS. In line
with these findings, improvement in depressive symptoms
after myocardial infarction was associated with lower cardiac
mortality in patients with mild, but not in those with more
severe depression in an earlier observational study [59]. In a
post-stroke depression cohort, 12-week antidepressant treat-
ment after the event reduced mortality risk over the subse-
quent 9 years [88]. Taken together, these data support the
concept that, with or without a psychotropic intervention, de-
pression remission per se may impact favorably on long-term
survival in patients with CVD, and that is more likely to occur
with antidepressant pharmacotherapy if cardiac disease and/or
depressive symptoms are less severe.
To date, the use of antidepressants has not been shown to
improve either mood or prognosis in depressed patients with
symptomatic HF. Two randomized controlled trials have eval-
uated the SSRIs sertraline and escitalopram in patients with
symptomatic HF. The 12-week Sertraline Against Depression
and Heart Disease in Chronic Heart Failure (SADHART-
CHF) study and the 24-month Morbidity, Mortality and
Mood in Depressed Heart Failure Patients (MOOD-HF)
study showed no beneficial effects of SSRI antidepressant
therapy [80, 81••]. However, study participation involving
HF disease management with optimization of pharmacother-
apy, monitoring, and patient empowerment for all participants
in MOOD-HF was associated with significant improvement
of depressive symptoms and low overall mortality in both
study arms. Exploratory analyses from MOOD-HF suggested
that escitalopram may have unfavorable effects on cardiac
function, HRQOL, and clinical outcomes, especially in elder-
ly patients with more compromised cardiac function and more
severe depressive symptoms [81••]. In line with the observa-
tions after ACS including myocardial infarction [79••], post
hoc SADHART-CHF subgroup analysis demonstrated im-
proved cardiovascular outcomes 5 years after randomization
in HF patients with depression remission versus the non-
remission group [16]. Furthermore, in the MOOD-HF study,
the only subgroup to show a significant drug-placebo differ-
ence indicating antidepressant efficacy of escitalopram was
patients with relatively mild depression [89].
Another secondary analysis from the SADHART-CHF
trial investigated the prognostic value of omega-3 polyun-
saturated fatty acids in patients with HF and major depres-
sion and showed that low levels were a significant predic-
tor of reduced survival [90]. Meta-analysis findings sug-
gest that omega-3 fatty acid supplementation might be
beneficial for depressed HF patients [91]. In addition, the
large Gruppo Italiano per lo Studio della Sopravvivenza
nella Insufficienza Cardiaca-Heart Failure (GISSI-HF) trial
demonstrated that omega-3 fatty acid supplementation
Curr Heart Fail Rep

Table 2 Selected randomized controlled trials on various treatment approaches in patients with cardiovascular diseases including heart failure and
depression and/or anxiety (modified from [73])

Trials and meta- Study population RCT groups Outcome

analyses (treatment period)

Antidepressant pharmacotherapy
SADHART [74] n = 369 Sertraline vs. placebo - Safety of the SSRI sertraline
post-ACS (24 weeks) - Antidepressant efficacy
(57 y, 71% m) - No effect on cardiac function
- No improvement of mortality
ENRICHD [75] n = 2481 CBT ± SSRI vs. UC - Antidepressant efficacy of CBT ± SSRI
post-AMI (24 weeks) - No effect on event rate (death or
(61 y, 66% m) recurrent MI)
CREATE [76] n = 284 1) IPT + UC vs. UC only -Antidepressant efficacy of SSRI + UC
chronic CAD 2) Citalopram vs. placebo - No benefit of IPT over UC
(58 y, 75% m) (12 weeks)
MIND-IT [77] n = 331 Mirtazapin (1. Choice) or SSRI vs. placebo - No improvement of depression or
post-AMI (18 months) cardiac prognosis
(58 y, 75% m)
EsDEPACS [78] n = 217 Escitalopram vs. placebo - Antidepressant efficacy according to
ACS (24 weeks) HAMD scores and MADRS scores
(59 y, 60% m) vs. placebo
- Safety of the SSRI escitalopram
EsDEPACS n = 300 Escitalopram vs. placebo - Lower risk of MACE (all-cause
long-term ACS (24 weeks) mortality, cardiac death, MI, and PCI)
follow-up [79••] (60 y, 60% m) Median follow-up 8.1 y vs. placebo
- Lower risk of MI
SADHART-CHF n = 469 Sertraline vs. placebo; simultaneous nurse-based care in both - No improvement of depression vs.
[80] CHF study groups placebo
(62 y, 69% m) (12 weeks) - No effect on cardiac status
- No effect on event rate (cardiovascular
death or hospitalization)
MOOD-HF [81••] n = 372 Escitalopram vs. placebo - No improvement of depression vs.
CHF (24 months) placebo
(62 y, 76% m) - Possible unfavorable effects of
escitalopram on cardiac status
(exploratory analysis)
- No effect on event rate (all-cause death
or hospitalization)
Cognitive behavioral therapy
Freedland KE et al. n = 158 CBT vs. UC - CBT improved depressive symptoms
2015 [82] CHF (24 weeks) - No effects on HF self-management or
(54 y, 56% m) physical functioning
MOSAIC [83] n = 183 Low intensity telephone-based multi-component - Intervention improved quality of life,
CAD and CHF with collaborative care intervention/disease management vs. depressive symptoms, and general
depression and/or enhanced UC (24 weeks) functioning
anxiety - No effect on anxiety and adherence
(60 y, 47% m)
Physical exercise
HF-ACTION [84] n = 2322 Aerobic training vs. UC - Physical exercise reduced depressive
CHF (12 months) symptoms and improved prognosis
(61 y, 69% m)
Tu et al. n = 3226 Training alone or as part of cardiac rehabilitation program vs. - Training decreased symptoms of
2014 [85] CHF UC or education only control group depression

ACS, acute coronary syndrome; AMI, acute myocardial infarction; CAD, coronary artery disease; CBT, cognitive behavioral therapy; CHF, chronic heart
failure; HAMD, Hamilton Depression Scale; IPT, interpersonal psychotherapy; m, male; MACE, major adverse cardiovascular events; MADRS,
Montgomery–Åsberg Depression Rating Scale; MI, myocardial infarction; PCI, percutaneous coronary intervention; RCT, randomized controlled trial;
SSRI, selective serotonin reuptake inhibitors; UC, usual care; vs., versus; y, years

improved survival and reduced mortality and cardiovascu-
lar rehospitalization rates [92]. Whether supplementing
omega-3 fatty acids could improve depression as well as
survival and other cardiovascular outcomes in HF patients
requires further prospective study.
Interestingly, recent meta-analysis indicates that omega-3
fatty acids might also help to reduce the clinical symptoms of
anxiety [93]. However, further prospective studies are required
in populations who have anxiety as their main symptom.
The question of whether depressive symptoms in patients
with CVD (including HF) or other severe chronic diseases
represent a truly independent causal risk factor or rather a risk
marker for adverse prognosis has so far remained unanswered.
Future research needs to focus on mechanisms that may ac-
count for the adverse prognostic significance of depressive
symptoms, in particular if persistent. Observations from the
SADHART-CHF and the MOOD-HF trials support the con-
cept of alternative pathophysiological pathways for mood dis-
orders in severe chronic somatic illnesses, with depressive
symptoms less responsive or even unresponsive to sertraline
or escitalopram the more advanced the cardiac disease is, and
the more severe the depressive symptoms [80, 81••]. Results
from the recent Chronic Kidney Disease Antidepressant
Fig. 2 Multimodal holistic therapy of the heart failure syndrome. Somatic
and psychological problems, and subjective symptoms of heart failure
Curr Heart Fail Rep
Sertraline (CAST) trial evaluating the effects of sertraline on
depressive symptoms in patients with major depression and
chronic kidney disease, who also had multiple other condi-
tions such as diabetes, coronary disease, or HF, strengthen this
theory [94••, 95]. In the 12-week CAST study, antidepressant
treatment was no more effective than placebo and was also
associated with unfavorable side effects [94••]. Placebo-
controlled trials for approval of antidepressants have, in the
past, often excluded patients with severe chronic somatic ill-
nesses. Therefore, it is becoming increasingly apparent that the
efficacy results of such studies are not necessarily transferable
to individuals with advanced chronic somatic illnesses in
whom antidepressants are often prescribed in clinical practice.
Despite evidence for a relationship between anxiety and
adverse clinical outcomes in patients with CVD [25–31] evi-
dence from randomized controlled trials is lacking that anxi-
olytic pharmacotherapy could improve clinical outcomes in
such populations.
Psychotherapy
Psychotherapy as an interactive process to influence psycho-
logical comorbidities includes a variety of treatment
and its complications and comorbidities require an individualized
approach to care (modified from [102])
Curr Heart Fail Rep
modalities. None of these has so far been shown to have any
significant beneficial effect on prognosis in HF patients.
However, although relevant effects on event rates could not
be identified, patients did benefit from CBT in some studies,
showing improved mood, anxiety, and quality of life, espe-
cially when CBT was combined with physical activity [82–83,
96].
Physical Exercise
The effects of exercise on depression in HF patients have been
determined in a systematic review and meta-analysis of ran-
domized controlled clinical trial data [85]. Data from 19 stud-
ies in 3447 patients showed that exercise training significantly
decreased depressive symptoms. Obviously, physical exercise
can improve perfusion of the frontal cortex and cognitive
functions [97–99]. Positive systemic effects with improve-
ment of endothelial function, inflammation, neurohumoral ac-
tivity, and function of the skeletal muscle further modulate
biological mechanisms of depression [97, 100].
In the HF-ACTION trial [84], exercise three times per
week over 3 months significantly decreased depressive symp-
toms and reduced mortality and hospitalization rates, com-
pared with guideline-based usual care. The results of a meta-
analysis of physical exercise in middle-aged and elderly wom-
en demonstrated that low- to moderate-intensity exercise re-
duces depressive symptoms [101]. In addition to the positive
biological effects of exercise [97, 100], the psychosocial ef-
fects of the training situation should not be underestimated.
Individualized physical training may restore confidence in the
body and training in groups may be experienced as socially
supportive. In the real-world setting, motivation to adhere to
physical exercise is often the greatest problem, but physical
training should be recommended regularly to help breaking
the vicious cycle of dyspnea-anxiety-inactivity-depression.
Comprehensive Care
Depression and anxiety have many somatic correlates [12]
and prevalence, incidence, and severity are closely related to
the severity of HF symptoms and HRQOL [12, 13].
Therefore, comprehensive care addressing the multifaceted
HF syndrome appears to be a meaningful primary therapeutic
approach. This includes effective management of physical
symptoms alongside standard disease-modifying treatment
of HF and associated comorbidities (Fig. 2). The goal of mul-
tidisciplinary collaborative disease management is to integrate
patients’ medical and social surroundings, thereby improving
psychosocial functioning, healthcare competence, and self-
empowerment [7]. This approach has proven efficacious in
patients with HF and was associated with improved HRQOL
and survival [7], although hospitalization rates are not always
reduced in randomized trials that included patients early after
a hospitalization for cardiac decompensation [7, 103]. As
healthcare competence and symptoms improve, depression,
anxiety, and cognitive dysfunction are reduced. Management
using a multidisciplinary approach incorporating psychoso-
matic factors should play a key role in the care of HF patients
and is central to managing psychological comorbidities.
Conclusion
Although much more common in cardiac patients compared
with the general population, psychological comorbidities are
often underdiagnosed and are rarely treated in routine clinical
care. This is due, at least partly, to commonality of symptoms
between CVD and mood disorders. In HF, psychological co-
morbidities are associated with frequent decompensations and
are associated with a higher risk of death and hospitalization.
Pathogenetic mechanisms are not fully understood, but bi-
directional interactions between somatic and mental disorders
are assumed, which are modulated by individual resilience
and demographic, biological, behavior-related, and psychoso-
cial factors. Screening tools facilitate early detection.
Multidisciplinary, individualized disease management pro-
moting patient engagement in self-care and regular physical
activity may improve outcomes. To date, psychotropic phar-
macotherapy has not generally shown beneficial effects on
mood and prognosis in HF populations. Recent evidence sug-
gests, however, that the SSRI escitalopram may improve de-
pressive symptoms and long-term clinical outcomes in pa-
tients with less severe CVD and depressive symptoms.
Acknowledgments With permission of the publisher, this article is an
updated and extended version of a chapter included in Cardv. Med.,
David S. Feldman and Paul Mohacsi (Eds): Heart Failure, 978-3-319-
98182-6, 335068_1_En, (Chapter 13, Wallenborn J, Angermann CEA.
Psychological Comorbidities in Heart Failure). Springer Nature 2018.
Compliance With Ethical Standards
Conflict of Interest The authors declare no conflicts of interest.
Christiane E. Angermann is a section editor of Current Heart Failure
Reports.
Human and Animal Rights and Informed Consent This article does not
contain any studies with human or animal subjects performed by any of
the authors.

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