Personalized medicine in psychiatry 1–2 (2017) 11–25
Contents lists available at ScienceDirect
Personalized medicine in psychiatry
journal homepage: www.elsevier.com/locate/pmip
Depression as a systemic disease
Jorge Luis Sotelo a,⇑, Charles B. Nemeroff b
a
b
Department of Psychiatry and Behavioral Sciences, Leonard M. Miller School of Medicine, University of Miami, United States
Leonard M. Miller School of Medicine, University of Miami, United States
a r t i c l e
i n f o
Article history:
Available online 25 November 2016
a b s t r a c t
Depression is now conceptualized as a systemic illness because of neurobiological mechanisms that
explain how it influences other medical illnesses. Significant research has been conducted to explain
the mechanisms by which depression increases the risk of, and complicates, already established medical
illness. Biological processes as diverse as inflammation, neuroendocrine regulation, platelet activity,
autonomic nervous system activity, and skeletal homeostasis are influenced by depression. In this review
we aim to elucidate the mechanisms through which depression affects patients with heart disease, cancer, stroke, diabetes, and osteoporosis. These are conditions in which the interplay between depression
and medical illness continues to be investigated.
Ó 2016 Elsevier Inc. All rights reserved.
Introduction
Major depressive disorder is one of the leading causes of disability worldwide [1]. According to the World Health Organization
(WHO), it will become the second leading cause of disabilityadjusted life years lost by the year 2020 [2]. Depression is believed
to increase the risk, accelerate the progression and portend a
poorer treatment response of a variety of medical disorders,
including cardiovascular disease [4–6], stroke, cancer, renal disease
and diabetes [7]. Processes as diverse as inflammation, neuroendocrine dysregulation, altered platelet activity, alterations in autonomic nervous system activity and decreased bone density may
play a role in complicating the prognosis of major depression,
especially in the setting of comorbid medical illness (Tables 1
and 2).
Depression and heart disease
According to the WHO Global Burden of Disease Survey, coronary heart disease and major depressive disorder are currently
the two leading causes of disability in developed countries and it
is estimated that this will apply to all countries throughout the
world by the year 2020 [9,10]. A bidirectional association between
depression and heart disease has been established and reviewed
[12–20]. Ample evidence suggests that depression is highly prevalent in patients with congestive heart failure (CHF) [21–23], atrial
fibrillation (AF) [24], post-myocardial infarction (MI) [20,25],
⇑ Corresponding author.
E-mail addresses: jsotelo@med.miami.edu (J.L. Sotelo), cnemeroff@med.miami.
edu (C.B. Nemeroff).
http://dx.doi.org/10.1016/j.pmip.2016.11.002
2468-1717/Ó 2016 Elsevier Inc. All rights reserved.
post-coronary-artery bypass graft surgery (CABG), and that it has
an adverse effect on morbidity and mortality in these populations
[26–28].
Multiple studies have demonstrated that depression increases
the risk of developing cardiovascular disease in healthy individuals. Depression is a significant independent risk factor for coronary
artery disease (CAD)-related morbidity and mortality, with an
increased adjusted relative risk (RR) of 1.5- to 2-fold [36–42]. In
addition, an important study of over 2800 adults without history
of heart disease and a mean follow-up of 12.4 years showed that
depressed mood and hopelessness were associated with an
increased risk of fatal (RR 1.5, 95% CI 1.0–2.3) and nonfatal (RR
1.6, 95% CI 1.1–2.4) ischemic heart disease after adjusting for other
risk factors [36]. Major depression was also a predictor of development of CAD (RR 2.12, 95% CI 1.24–3.63, P < 0.01) and MI (RR 2.12,
95% CI 1.11–4.06, P < 0.01) in subjects who were followed for
40 years [39] and the depression-associated risk was independent
of traditional risk factors. A review of 13 prospective studies of
40,000 healthy subjects over a mean of 10 years found that depression was a significant independent risk factor for the development
of CAD morbidity and mortality with an adjusted RR for major
depression showing a 4- to 4.5-fold increase [43]. In another study
with a median follow up of 8.5 years, patients with major depression were 2.7 times more likely to die from ischemic heart disease
[45]. In addition, data from the Danish Psychiatric Central Research
Register showed positive associations between depression and
acute MI (incidence rate ratio [IRR] 1.16, 95% CI 1.10–1.22,
P < 0.0001), as well as anxiety and acute MI (IRR 1.56, 95% CI
1.35–1.79, P < 0.0001) [46]. Data from the Swedish Twin Registry
(over 30,000 twin pairs) revealed that onset of major depression
resulted in an increase in the risk of concurrent (HR 2.53, 95% CI
12
J.L. Sotelo, C.B. Nemeroff / Personalized medicine in psychiatry 1–2 (2017) 11–25
Table 1
Pathophysiology of depression.
Changes observed in depression
": proinflammatory cytokines
": formation of kynurenine metabolites
": clotting diathesis, annexin V protein binding to platelets, surface expression of P-selectin, activation of platelet fibrinogen receptor integrin a-IIb-b3 complex,
platelet-leukocyte aggregates, platelet reactivity to ADP
": subclinical hypothyroidism
": HPA axis activity
;: glucocorticoid receptor sensitivity
SNP within vWf gene
Early life adversity
HPA: Hypothalamic-pituitary-adrenal.
SNP: Single-nucleotide polymorphism.
vWf: von Willebrand factor.
Table 2
Mechanisms through which depression affects medical illness.
Illness
Pathophysiology
Heart
disease
Coronary artery disease
": CRP, proinflammatory cytokines, inflammatory genes, plasma
VEGF, tryptophan/kynurenine ratio, serum b-thromboglobulin,
PF4
;: plasma and saliva cortisol, tryptophan
Coronary artery calcification
AA phenotype of SNP of BDNF gene
Myocardial infarction
": CRP, IL-6
Heart failure
": CRP, IL-2, IL-4, IL-6, IFN-c, TNF-a, MCAP1, MIP-1b
;: IL-10
Atrial fibrillation
": CRP
Cancer
": CRP, IL-1, IL-6, IL-8, TNF-a, soluble IL-2 receptor a chain,
soluble IL-6 receptor, sTNFR2, activation of NF-jB regulated
genes, nocturnal cortisol
;: diurnal cortisol slope
SNP of serotonin transporter gene
Early life adversity
Bone
health
": fall risk, salivary cortisol, bone NE, PTH, bone resorption
markers, osteocalcin
;: BMD, GHRH, GnRH, 25-hydroxyvitamin D, ionized calcium
SSRIs linked to falls, bone loss and fractures
Stroke
Endothelial dysfunction
Fibrinogen dysregulation
Exaggerated platelet reactivity
Diabetes
Inflammation
Abnormal glucose metabolism
Subclinical hypercortisolism
Prolonged hypercortisolemia
Blunted diurnal cortisol rhythm
Hypocortisolism
Impaired glucocorticoid sensitivity
Increased catecholamines
HPA axis activation
ADP: Adenosine diphosphate.
BDNF: Brain-derived neurotrophic factor.
BMD: Bone mineral density.
CRP: C-reactive protein.
GHRH: Growth hormone-releasing hormone.
GnRH: Gonadotropin-releasing hormone.
HPA: hypothalamic-pituitaryadrenal.
IFN: interferon.
IL: interleukin.
MCAP1: monocyte chemoattractant protein 1.
MIP: macrophage inflammatory protein.
NE: norepinephrine.
PF4: platelet factor 4.
PTH: parathyroid hormone.
SNP: single-nucleotide polymorphism.
sTNFR2: soluble tumor necrosis factor receptor 2.
TNF: tumor necrosis factor.
VEGF: vascular endothelial growth factor.
1.7–3.78, P < 0.001) and ongoing (HR 1.17, 95% CI 1.04–1.31,
P = 0.008) CAD [47]. Moreover, a 2013 study of 45 young adults
at increased risk of depression showed evidence of altered cardiovascular risk profile even in the absence of depressive symptoms
[48].
Depression has been recognized as a negative prognostic factor
associated with an increased risk of cardiovascular related morbidity and mortality [43,49,50]. Doering et al. [51] demonstrated that
co-morbid anxiety and depression were predictive of all-cause
mortality in patients with CAD. A study of 610 patients treated
for ischemic heart disease revealed that depression was associated
with an increased hazard rate for all-cause mortality (HR 1.96). In
addition, depression was associated with time to first hospitalization, total number of hospitalizations, and cumulative length of
hospital stay. Depression was also independently associated with
an increased risk for 5-year all-cause mortality [52]. Beach et al.
[53] demonstrated that higher initial Patient Health
Questionnaire-9 (PHQ-9) scores were significantly associated with
subsequent rehospitalization at 6 months in patients with acute
coronary syndrome, heart failure, or arrhythmia. These scores were
also associated with increased risk of composite outcome of cardiac readmission or mortality. The PHQ-9 score was more strongly
associated with adverse cardiac outcome than other variables. In
addition, a meta-analysis of 30 studies [18] found a pooled RR of
coronary heart disease of 1.30 (95% CI, 1.22–1.40) and a pooled
RR of MI of 1.30 (95% CI, 1.18–1.44) in patients with depression.
The prevalence of depression in patients with heart failure is
also increased, as are the morbidity and mortality of that patient
population. Approximately 20% of outpatients with heart failure
fulfill criteria for major depression and up to 48% experience
depressive symptoms [58]. In addition, more than half of patients
with heart failure have significant anxiety or depression symptoms
[59–61]. In patients with CHF, major depressive disorder is an
independent risk factor for reduced quality of life, adverse health
outcomes, and elevated risk of mortality [63–68]. Previous studies
have documented an association between depression and mortality in outpatients [69–72] and hospitalized patients with heart failure [73,63]. A recent study reported on 1260 patients with heart
failure on whom data was collected over 12 months [75]. More
than half (52.9%) of the participants had anxiety, 32.5% had depression, and 26.8% had both anxiety and depression. Patients with
heart failure with comorbid anxiety and depression were 2.6 times
more likely to die compared with those who were neither
depressed nor anxious.
Increased inflammation has been identified in patients with
depression and in patients with heart disease [76–79]. Proinflammatory cytokines play significant roles in the development and
clinical progression of CHF [80,81]. Inflammation also plays a central role in the pathogenesis of CAD and is involved in all stages of
atherosclerosis. Patients with CAD exhibit higher circulating proin-
J.L. Sotelo, C.B. Nemeroff / Personalized medicine in psychiatry 1–2 (2017) 11–25
flammatory cytokines, higher C-reactive protein (CRP) levels, and
increased expression of inflammatory genes [82,83]. Elevated CRP
levels have been associated with an increased risk of major adverse
cardiac events in the 2 years after an acute coronary syndrome
event [84].
Proinflammatory cytokines have been shown to be elevated in
major depressive disorder and there is a positive association
between severity of depressive symptoms and various markers of
inflammation [50,85–92]. Increased inflammation induces depressive symptoms by several mechanisms, including effects on the
serotonergic system [106,107]. In response to inflammation, tryptophan metabolism shifts towards the formation of kynurenine
metabolites
[108]
with
an
increased
production
of
3-hydroxykynurenine and quinolinic acid [109]. Excessive inflammation due to impaired glucocorticoid receptor sensitivity has also
been found in patients with major depressive disorder [110,111],
in the elderly [112] and in patients at risk for cardiovascular disease [113]. It has been postulated that glucocorticoid resistance
may occur as a result of chronic stress and prolonged exposure
to inflammatory cytokines [114]. Moreover, a meta-analysis of
articles published between 1967 and 2008 showed a positive correlation between inflammatory markers and depression in groups
of patients with depression and in community-based cohorts [97].
Chronic inflammatory states might mediate the increased risk
of CAD in depression [98–100]. Downregulation of the antiinflammatory cytokine interleukin-10 (IL-10) and upregulation of
the proinflammatory cytokines IL-6 and tumor necrosis factor
alpha (TNF-a) have been reported in heart failure patients with
depressive symptoms [101]. In addition, MI patients have
increased plasma IL-6 and CRP concentrations and altered response
to the anti-inflammatory properties of glucocorticoids, which independently correlate with depressive symptoms [102]. The Gutenberg Health Study (n = 10,000; ages 35–74) [115] revealed that
CRP concentrations were higher in patients with AF (3.6 vs 2.9)
and there was an association between the degree of depressive
symptoms and AF. Self-reported physical health status and mental
health status were lower in patients with AF and were related to
depression symptom severity. Evidence suggests that depressive
symptoms are related to the recurrence of AF episodes [116] and
of complications, such as heart failure and death [24]. Psychological distress may influence hemodynamics, vascular function, autonomic tone, inflammatory activity, and hemostasis [117–119], all
of which play a role in the pathogenesis and complications of AF.
Nikkheslat et al. [120] reported on CAD patients with (n = 28)
and without (n = 55) depression. CAD patients with depression
had higher levels of CRP, IL-6 gene expression, and plasma vascular
endothelial growth factor (VEGF) and lower plasma and saliva cortisol levels. The CAD depressed group also exhibited a reduction in
glucocorticoid receptor expression and sensitivity. Finally, tryptophan levels were significantly lower and tryptophan/kynurenine
ratios were increased in patients with depression. In this study,
CAD patients with depression had elevated levels of inflammation
in the context of HPA axis hypoactivity, glucocorticoid receptor
resistance, and increased kynurenine pathway activation. Reduced
cortisol bioavailability and decreased expression and sensitivity of
glucocorticoid receptors may lead to insufficient glucocorticoid
signaling and increased inflammation [120]. Furthermore, Xiong
et al. [121] reported on 155 patients (25 nondepressed; 130
depressed) admitted for acute heart failure exacerbations. Major
depressive disorder was associated with elevated IL-2, IL-4, IL-6,
interferon (IFN)-c, monocyte chemoattractant protein 1, macrophage inflammatory protein 1b, and TNF-a.
Platelets may also play a role in the interplay between depression, inflammation and heart disease. They recruit inflammatory
cells that contribute to atherosclerosis [122–124]. Platelets also
contribute to artery remodeling and atheroma formation by
13
producing growth factors that promote the proliferation of smooth
muscle cells in the atheroma [125–128]. Unchecked inflammation
can induce recruitment of monocyte progenitor cells [125–127],
which can become activated macrophages capable of inducing
apoptosis of smooth muscle cells within the arterial wall [129].
Alterations in platelet activation and aggregation in the clotting
cascade observed in patients with depression result in an increased
clotting diathesis [5]. Patients with major depression also exhibit
increased annexin V protein binding to platelets, increased surface
expression of P-selectin, and increased activation of the platelet
fibrinogen receptor integrin a-IIb-b3 complex, the final common
pathway for platelet activation [130,131]. In patients with depression, studies have shown significant increases in platelet activation
and circulating platelet-leukocyte aggregates and enhanced platelet reactivity to ADP [132]. Marked elevations of serum bthromboglobulin and platelet factor 4 (PF4) have also been shown
in elderly patients with depression and CAD compared with elderly
nondepressed patients with CAD and in healthy young controls
[133].
Overt and subclinical hypothyroidism are associated with an
increased risk of cardiovascular disease and related mortality
[155]. In depressed patients, considerable evidence suggests an
increased prevalence of subclinical hypothyroidism [156,157].
Many patients with depression also exhibit hypothalamicpituitaryadrenal (HPA) axis hyperactivity [158]. Increased cortisol
levels are also associated with an increased risk of cardiovascular
mortality. In the CHIANTI study, urinary cortisol levels predicted
cardiovascular mortality risk, with participants in the highest tertile
of urinary cortisol levels exhibiting a fivefold increase in risk of cardiovascular death [159]. In a cohort of 382 patients hospitalized due
to depression, dexamethasone nonsuppression of cortisol secretion
and elevated baseline cortisol levels both predicted mortality from
cardiovascular disease [160]. Another study revealed that cortisol
awakening response is negatively correlated with HRV [161].
One single-nucleotide polymorphism (SNP), rs216873, located
within the von Willebrand factor gene has been associated with
severe depression based on Beck Depression Inventory score
[162]. von Willebrand factor recruits platelets to damaged
endothelium during the pathogenesis of atherosclerosis [163].
Other SNPs associated with inflammation, endothelial function,
and platelet aggregation have also been identified as suggestive
of an association with depression [164]. Twin studies have suggested that depression, elevations in plasma lipids, and HRV may
share genetic mechanisms [165,166]. A study of patients with
CAD revealed that the AA phenotype of the Val66Met SNP of the
brain-derived neurotrophic factor (BDNF) gene predisposed to
CAD and CAD with depression in women [167].
Adverse events in early life, including childhood trauma, are
associated with an increased susceptibility to both depression
and cardiovascular disease [168]. A retrospective analysis of over
17,000 adults revealed a dose-response relationship between
adverse childhood experiences and ischemic heart disease [168].
This is of importance because childhood maltreatment is associated with a number of biological alterations that are similar to
depression and increase the risk for medical disorders. These
include inflammation and altered autonomic nervous system activity [169]. Such events lead to modification of the superstructure of
the chromatin through methylation, thus altering ultra-conserved
nongenic regions of the genome and the accessibility of certain
genetic regions to transcriptional enzymes and microRNAs. These
molecular events might directly affect genes important for susceptibility to cardiovascular disease or could trigger additional molecular events that further modify the superstructure of the
chromatin and consequently increase susceptibility to cardiovascular disease. Early life trauma may therefore be the mechanism
through which some individuals develop heart disease.
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J.L. Sotelo, C.B. Nemeroff / Personalized medicine in psychiatry 1–2 (2017) 11–25
Finally, one study of 454 healthy individuals assessed for
depression over 10 years revealed that persistent depression was
associated with a two-fold increase in the risk of both detectable
and severe coronary artery calcification [170]. A study of 314
patients, ages 19–79, who presented with chest pain showed that
each 1 point increase in the Beck Depression Inventory score was
associated with a 5–6% increase in abnormal coronary angiographic findings or definitive CAD [171]. Other studies have found
associations between depression severity and intima-media thickness of the carotid bulb [172] and impaired endothelial function
[173].
Depression and cancer
Prevalence rates for depression in patients with cancer range
from 1.5% to 50%, with median point prevalence rates between
15% and 29% [174–178]. A study by Linden [179] and a review
by Ng [180] in over 9000 patients calculated prevalence rates of
10.8 and 12.9%, respectively. One large-scale prospective study
found that cancer diagnosis and treatment resulted in a four-fold
increase in depression occurrence during the first two years after
diagnosis [181]. It leads to a poorer quality of life and compromises
patient outcomes, resulting in higher mortality rates [182–185]. A
meta-analysis revealed that depression increases mortality rates in
cancer patients by up to 39% and even patients with few depressive
symptoms may be at a 25% increased risk [186]. In a recent study
of patients with a mixture of different cancer types, the most frequent initial psychiatric diagnoses were minor depression
(17.6%), major depressive disorder (15.8%), and adjustment disorder (15.8%) [187]. Cancer patients without psychiatric morbidity
in this study had a survival benefit of 2.24 months. After adjusting
for demographics and cancer stage, psychiatric comorbidity
remained associated with poorer survival (HR 4.13, 95% CI 1.32–
12.92). Depression may, in part, adversely affect medical outcomes
in these patients by resulting in an increase in length of hospitalizations, diminishing quality of life, a reduction in the ability to
care for oneself, and a decrease in adherence with treatments
[174,188–190].
In breast cancer, the prevalence of clinical depression is
between 10 and 30% within the first five years after diagnosis
[192] and it is associated with increased mortality [183]. Hung
et al. [194] found an increased risk for mood disorders in older
women and women with comorbid conditions in over 26,000
women with breast cancer. A recent study of over 44,000 women
with breast cancer followed from 1998 to 2011 [195] found that
in the first year after diagnosis, the rate ratio for a hospital contact
for depression was 1.70 (95% CI, 1.41–2.05) and that for use of
antidepressant was 3.09 (95% CI, 2.95–3.22). These ratios were significantly increased after 3 and 8 years, respectively. A threefold
increased risk for first use of antidepressant was found close to
diagnosis, decreasing to a 20% significantly increased risk 8 years
after diagnosis. Comorbidity, node-positive disease, older age,
basic and vocational educational levels and living alone were associated with use of antidepressants. However, there was no association between type of surgery or adjuvant treatment and risk for
depression. Four other studies on factors associated with breast
cancer-related depression in populations ranging from 190 to
1933 women also found no associations with type of surgery
[196–198], or chemotherapy [196,197,199]. Associations between
increasing age, comorbid disease, and use of antidepressants were
also found in a study of over 8000 women treated with radiotherapy [200].
In men with prostate cancer, longitudinal studies [201–207]
have shown increased rates of anxiety, depression, cardiovascular
events, and suicide that may result from uncertainties regarding
treatment, cancer control, erectile dysfunction, or urinary incontinence following treatment. Depression symptoms are more common in older patients with prostate cancer, though younger
patients are more likely to report increased levels of psychological
distress [208]. Prasad et al. reported on 41,275 men diagnosed with
prostate cancer between 2004 and 2007, 4.6% of whom (1894) also
had a diagnosis of depressive disorder in the 2 years before cancer
diagnosis [209]. Men with depressive disorders were more likely to
have high-risk disease. In this study a pre-existing diagnosis of
depressive disorder was independently associated with treatment
choice and outcomes of localized prostate cancer. Men with prostate cancer and a recent diagnosis of depression were less likely
to undergo definitive treatment and experienced worse overall
survival. Depressed men with intermediate and high-risk prostate
cancer were less likely to choose definitive therapy. Men with
depression were also more likely to receive androgen deprivation
therapy (ADT) alone as treatment, which increases psychological
distress and worsens quality of life in this patient population;
[210] but its use does not appear to worsen depressive symptoms
in men with prostate cancer and depression [211]. Men with a
diagnosis of depression had a significantly higher number of doctor
visits in the 2 years before prostate cancer diagnosis but were also
more likely to present with aggressive disease. Intervention and
improvement in symptoms is associated with improved survival
in patients with metastatic cancer [191,213].
As was highlighted above, proinflammatory cytokines may be
involved in depression in healthy and medically ill individuals,
including cancer patients [214–216,177]. The cytokine hypothesis
of depression suggests that behavioral changes in cancer patients
may be caused by proinflammatory cytokines, which influence
neuroendocrine pathways, resulting in depression and other
comorbidities [217,90,218–221]. This hypothesis is supported by
studies showing a correlation between serum levels of proinflammatory cytokines and depressive symptoms in pancreatic and
ovarian cancer patients [90,222]. Epidemiological studies have
shown that chronic inflammation predisposes to various types of
cancer. Inflammation has actually been linked to 15–20% of all
deaths from cancer worldwide [223] and is associated with recurrence of cancer [224]. In addition, recent studies suggest that
blocking the effect of proinflammatory cytokines reduces symptoms of depression (especially fatigue) in cancer patients [227].
Tumor cells and cells in the tumor environment produce high
levels of IL-6 [228–231]. IL-6 promotes angiogenesis [228], invasion and attachment [230], and generation of tumor-associated
macrophages [232]. Elevations of IL-6 are also associated with
decreased time to recurrence and shorter survival time in ovarian
cancer patients [233–235]. An association has also been found
between IL-6 levels and vegetative signs and symptoms of depression, disability, and fatigue in patients with ovarian cancer [238]. In
one study of women undergoing radiation treatment of breast cancer, soluble IL-6 receptor levels were significantly elevated in
patients with severe versus mild depression [239]. Fatigue during
radiation treatment has also been associated with increased levels
of inflammatory markers [240,241].
NF-kB has also been implicated in cancer development and
treatment resistance [242,243]. Fatigued breast cancer survivors
demonstrate increased activation of NF-kB-regulated genes [244].
In addition, chemotherapy has been associated with NF-kB activation in breast cancer tissue and peripheral blood [227,245]. Prior
chemotherapy was associated with significantly higher depression
scores, increased expression of NF-kB regulated gene transcripts,
and increased levels of IL-6 and soluble TNF receptor 2 (sTNFR2)
in women undergoing breast cancer radiation treatment [246].
Moreover, IL-1 and IL-6 concentrations significantly correlate with
fatigue in patients with cancer treated with radiation or
chemotherapy [247,248].
J.L. Sotelo, C.B. Nemeroff / Personalized medicine in psychiatry 1–2 (2017) 11–25
In patients with breast, ovarian, cervical cancer and lymphoma,
dysregulated patterns of cortisol secretion have been observed
[249–252]. Elevated nocturnal cortisol and blunted diurnal cortisol
slope has been observed in ovarian cancer patients prior to surgery
[238,253]. Disruption of cortisol rhythms resulting in flattening of
the cortisol slope has been associated with shortened survival time
in patients with breast cancer [254]. In animal models, altered glucocorticoid receptor expression secondary to elevated cortisol has
been recognized as a likely mechanism in the initiation of ovarian
cancer [255], the failure of cancer cells to undergo apoptosis
[256–258], the development of chemotherapy resistance [259]
and accelerated tumor growth [260]. In addition, cortisol dysregulation has been associated with poor performance status [261],
fatigue [262], and depression [250] in cancer patients. Abnormal
cortisol rhythms have also been linked with symptoms of depression in patients with ovarian cancer [238,253].
Genetic factors may also play a role in determining vulnerability to depression in patients with cancer. The rs12150214 SNP of
the SLC6A4 serotonin transporter gene has been associated with
severity of depression symptoms as assessed with the Beck
Depression Inventory and elevated IL-6 levels in some populations
[263]. This polymorphism has also been associated with poor overall survival and decreased disease specific survival in patients with
colorectal cancer [264]. Patients with the C allele were at 57%
increased risk of death than their counterparts. This study suggests
that emotional or physiological stress (inflammation) and their
associated mechanisms can be modified by the availability of the
serotonin transporter protein, either by environmental factors or
variations in the SLC6A4 gene.
Individuals with a history of childhood abuse or neglect are at
increased risk for psychological distress when confronted with
new traumatic experiences, including a diagnosis of breast cancer
[265]. Childhood trauma may alter neurocircuitry during a time
when the brain is vulnerable to environmental stressors [266–
268]. As noted above, childhood abuse has been associated with
elevated markers of inflammation including CRP, IL-6, and TNF-a,
in adults. These biomarkers have been correlated with fatigue
and depression in breast cancer patients [246,244,268]. A cancer
diagnosis may trigger women with a history of childhood abuse
to experience higher levels of intrusive cancer-related thoughts,
images, emotions, and dreams during and after cancer treatment
[265]. A study of breast cancer patients confirmed that childhood
abuse predicted poorer quality of life, as well as severe fatigue,
depression, and stress during and after cancer therapy [270]. In
addition, two cross-sectional studies of breast cancer survivors
found that patients with childhood trauma reported reduced quality of life and greater fatigue and psychological distress following
cancer treatment [271,272]. Han et al. studied 20 women 18–
75 years of age with stage 0-IIIA breast cancer treated with
breast-conserving surgery followed by radiation therapy [273].
Patients with a history of childhood trauma exhibited significantly
greater fatigue. In addition, 50% of patients with childhood trauma
(vs 8% of patients without) had symptoms of moderate to severe
depression at some point during the study. Radiotherapy did not
significantly account for the fatigue, depression, or perceived stress
in patients with or without childhood trauma. However, significant
positive associations between severity of trauma on the Childhood
Trauma Questionnaire (CTQ) and depression scores were found.
CTQ symptom severity was the most significant predictor of perceived stress after controlling for covariates. In patients with childhood trauma significant positive correlations were also found
between fatigue scores and CRP and perceived stress scores and
CRP and IL-6. Childhood trauma patients exhibited alterations in
gene transcripts related to inflammatory signaling, including IL22, IL-17, and C-C chemokine receptor 5 signaling in macrophages
and T lymphocytes. They also exhibited an over-representation of
15
genes regulated by the NF-kB family transcription factor, RelA
(p65 subunit of NF-kB). This study confirmed that childhood abuse
was common in breast cancer patients and that it was associated
with inflammation-mediated fatigue and depression scores before,
during, and after radiotherapy. Another study of breast cancer
patients over a 9-month period [270] found that a history of childhood adversity was associated with increased fatigue, depression,
and perceived stress before and during treatment [270].
Depression and anxiety occur in approximately 30–40% of
patients with colorectal cancer [275,276]. High levels of proinflammatory cytokines in these patients suggest that cytokines also play
a role in the etiology and pathophysiology of depression and anxiety [277]. In a study of 20 adults recently diagnosed with colorectal cancer, a combination of severe anxiety and depression
symptoms was found in 65% of colorectal cancer patients. These
patients had 3.2- to 4.4-fold higher concentrations of the proinflammatory cytokines IL-1b, IL-6, IL-8, and TNF-a. Anxiety, depression, and combined anxiety and depression were positively
correlated with IL-1, IL-6, IL-8, and TNF-a. In advanced colorectal
cancer patients, increased serum levels of the soluble portion of
the IL-2 receptor a chain have been previously shown to correlate
with depression symptoms, suggesting that tumor-induced
immune activation contributes to depression [278].
Treatment of cancer may also predispose patients to depression.
There is a possible link between invasive surgical procedures and
higher levels of IL-6 and CRP [279,280]. In depressed patients
who underwent abdominal procedures, increased serum IL-6 concentrations correlated with depression severity scores [281]. However, these postsurgical mood changes and proinflammatory
alterations have not been replicated in other studies [282–284].
In contrast, cortisol and IL-6 levels decreased significantly over
the course of 1 year following surgery to treat ovarian cancer in
another study, and these changes were observed by 6 months
post-surgery. The decrease in IL-6 levels was associated with
decreased fatigue and vegetative signs of depression, and
decreased nocturnal cortisol concentration was significantly associated with decreased disability and fatigue [285]. Chemotherapy
is associated with increased proinflammatory cytokine levels,
which may be associated with fatigue and sleep disturbance
[268,286–288]. Fatigue, depression, and stress are commonly
reported side effects of radiotherapy [241,246,289,290]. Breast
cancer patients who develop fatigue and depression undergoing
radiotherapy have been found to have elevated proinflammatory
markers, including CRP, IL-6, IL-1 receptor antagonist, soluble NFj B DNA binding [239–241,246,290].
Depression and bone health
Depression has been linked to low bone mass [352] and there is
evidence that depression may lead to bone health deterioration
and increased fracture risk in adults [353–357] and that it could
even affect peak bone mass in children and adolescents [358].
Low bone mineral density (BMD) is prevalent even at early stages
of major depression [356,360]. After adjusting for osteoporosis risk
factors, BMD is negatively associated with depressive symptoms in
older patients [361]. This association has been observed in a variety of patient populations [351,355,356,361–367,362]. In men,
bone mass is generally lower in those with depression compared
to those who are not depressed [368–371].
Danielson et al. [372] measured the BMD of 207 motherdaughter pairs and found that the daughters of mothers with a
low BMD or who had suffered osteoporotic fractures also had
lower BMD. Two studies of postmenopausal women [367,373]
and one study of men [371] demonstrated a positive association
between depressive symptoms and a decrease in BMD. Two
16
J.L. Sotelo, C.B. Nemeroff / Personalized medicine in psychiatry 1–2 (2017) 11–25
[374,375] longitudinal studies reported that depression symptoms
were associated with a decrease in BMD at the total hip. One of
these studies [374] found that the number of depressive symptoms
correlated with rates of bone loss. In the other study [375], depressive symptoms in men were associated with lower BMD with and
without adjustment for medication use. Cizza et al. performed a
meta-analysis concluding that depression is associated with loss
of bone mass leading to osteoporosis [376]. Yirmiya and Bab
[377] evaluated data from 23 projects and found a significant association between depression and lower bone density. A review of
studies between 1994 and 2007 found a possible association
between depression and osteoporosis [378]. In another metaanalysis, Wu et al. showed a pooled lower BMD at the spine and
hip for depressed subjects compared to non-depressed controls
[357]. A study assessing determinants of osteoporotic fractures
suggests that depression can be considered a predisposing factor
with clinical significance and magnitude of impact similar to other
established risk factors [379].
Data summarized in the American Geriatrics Society guidelines
suggest that depression confers a higher mean relative risk for falls
(2.2) than cognitive impairment (1.8) or age 80 years and older
(1.7) [381]. The MOBILIZE Boston Study showed that the association of depressive symptoms with fall risk in older adults is mediated in part by chronic pain [382]. A bidirectional relationship of
depression with falls proposes the mechanism of excessive fear
of falling, which, through impairment of gait and balance, mediated through cognitive, sensory, and motor pathways, leads to further increase in fall risk [383].
The Multiple Outcomes of Raloxifene Evaluation (MORE) study
showed an increased prevalence of depression among patients
with osteoporosis, especially in postmenopausal women with vertebral fractures. The number of fractures resulted in a proportionately more severe score on the Geriatric Depression Scale [373]. In
a prospective study of older Mexican-American women, higher
levels of depression predicted self-reported fractures [385]. In a
prospective population-based study of Norwegian women aged
50 or older, those with the highest level of distress were at greater
risk for hip fracture [386]. In a large cohort of subjects aged 25–74
followed for 22 years, depression predicted hip fractures after
adjusting for age, gender, race, BMI, smoking, alcohol, and physical
activity [354]. Middle aged women with depression had a 40%
increase for non-vertebral fractures compared to women without
depression after adjusting for their increased likelihood of falling
[387]. In a longitudinal cohort study in Norway, both pre- and
post-menopausal women with mental distress had increased fracture risk [388].
Hypercortisolemia has been hypothesized to be an important
causative factor for the observed bone deficits in depression.
Depression is associated with a sustained and protracted activation
of the stress system and thereby leads to excessive activity of the
HPA and sympathoadrenal axes [363,391,392] with increased
corticotropin-releasing hormone (CRH) production [362]. A few
studies have observed increased plasma cortisol [393,394] or
increased UFC [391] though no differences were found in other
studies [393,356,395–397,360]. Salivary cortisol following a public
speech task was higher in 9 depressed postmenopausal women
compared to 10 non-depressed postmenopausal women [398].
Depressed women also had significantly lower total lumbar and
femur BMD, demonstrating a negative relationship between poststress salivary cortisol and BMD. Depression also results in suppression of the gonadal and somatotrophic axes with decreased
production of growth hormone-releasing hormone (GHRH) and
gonadotropin-releasing hormone (GnRH), which suppresses the
secretion of GH and gonadal steroids, respectively. CRH also stimulates catecholamine release, inducing IL-6 production. The hyperactivity of the HPA and sympathoadrenal axes, together with the
suppression of the somatotrophic and gonadal axes, results in
decreased bone formation [399].
Depression’s association with excessive adrenergic activity
results in an increase in bone norepinephrine levels accompanied
by restrained bone formation resulting from reduced osteoblast
number and skeletal deficiency. This mechanism suggests a role
for the sympathetic nervous system in the skeletal effects of
depression [400]. Treatment with SSRIs may also interfere with
5-HT uptake by bone [401,402]. It has been suggested that there
is a dual effect of 5-HT on bone metabolism with anabolic action
from the brain-derived substance and catabolic action from the
gut-produced circulating 5-HT [403], and this could determine
the basis for understanding the effects of SSRIs on bone health.
Leptin may play a role in the skeletal complications seen in
patients with depression. In animal models, leptin resulted in bone
loss by centrally inhibiting bone formation via activation of the
sympathetic nervous system [410]. In depressed subjects, reports
of serum leptin levels have been conflicting [368,393,411–413].
Evidence indicates that leptin acts centrally, through its receptor
in serotonin-producing neurons of the raphe nuclei, decreasing
the expression of tryptophan hydroxylase 2, the gene encoding
the initial enzyme for serotonin biosynthesis [363,407]. Thus leptin
regulation of bone metabolism and bone mass may be mediated
through its inhibition of nuclear serotonin synthesis [414]. Other
data on leptin suggest that it plays an anabolic role in bone formation and its administration increases insulin-like growth factor 1,
osteocalcin, osteoprotegerin and receptor activator of NFƙB ligand
(RANKL) [415].
There are multiple reports of reduced vitamin D concentrations
in depressed patients [418–425]. Low levels of 25-OH vitamin D
could lead to both depression and lower BMD [420]. Women with
depression had slightly higher PTH levels and had lower 25-OH
vitamin D and ionized calcium levels compared to controls [356].
Vitamin D receptors are present in several human brain areas
involved in neuroendocrine and autonomic functions [424], potentially supporting a direct role of vitamin D in modulating mood and
behavior in depression. Vitamin D deficiency and concurrent
hyperparathyroidism are known predisposing factors for osteoporosis [425]. No association of depression and PTH has been
shown in some [422,426,427] but not all studies [365]. However,
very recent reviews associate primary hyperparathyroidism with
depression and link parathyroidectomy with symptom alleviation
[428]. Since PTH receptors have been found in hypothalamic, limbic, and sensory brain regions that potentially exert an influence on
the neuroendocrine system [429], chronically elevated PTH levels
may have a direct effect on the nervous system, thus affecting
mood. On the other hand, an increase in bone remodeling, independent of vitamin D deficiency, may induce calcium release and
inhibition of parathyroid hormone secretion in patients with
depressive disorders [430].
Low bone mass in patients treated with antidepressants has
been reported since the 1990s [363]. The Women’s Health Initiative Observational Study [431] reported that antidepressant use
was associated with more fractures at the spine and other sites,
even in the absence of changes in BMD. SSRIs have collectively
been associated with osteoporosis and fractures [363,432,433]. In
the Study of Osteoporotic Fractures, elderly women treated with
SSRIs experienced greater bone loss at the hip, likely due to a
class-specific effect because no increase was observed in patients
treated with TCAs [434]. SSRIs have been linked to falls, bone loss,
and fractures [435,436,383,437]. A recent meta-analysis implicated the use of SSRIs with a twofold increase in fracture risk with
a dose-response relationship for SSRIs and an effect linked to the
affinity of each SSRI for the serotonin transporter. Compared to
non-SSRI users, SSRIs increase the relative risk of fracture by 72
% [436]. Use of SSRIs was associated with a 2.25-fold increase in
J.L. Sotelo, C.B. Nemeroff / Personalized medicine in psychiatry 1–2 (2017) 11–25
fracture risk in a large cohort study conducted in Rotterdam [438].
Serotonin transporters and receptors have been identified on
osteoblasts [439] suggesting a direct effect on bone mass. In addition, use of SSRIs and TCAs might induce fractures by increasing
risk of falls, especially in the elderly, possibly through arrhythmias
or postural hypotension [440]. A recent study of middle-aged
women initiating antidepressants did not find a significant
decrease in BMD in new users of SSRIs or TCAs [375].
Bone turnover markers (BTM) are products released during
bone matrix synthesis or degradation. In some studies, depressed
patients show increased urinary levels of bone resorption markers
[360,377] and serum osteocalcin, PTH and C-terminal telopeptide
(CTX) [430]. This probably reflects increased bone remodeling. In
a recent study, bone turnover markers, PTH and Receptor for
Nuclear Factor B Ligand were significantly higher in depressed
patients compared to controls, while serum levels of 25hydroxyvitamin D and osteoprotegerin were significantly lower
[366]. Two prospective studies have examined the relationship
between BTMs and antidepressant use. In the first study treatment
with escitalopram was associated with a significant decrease in the
bone resorption marker beta-CTX but only in participants whose
depression improved [450]. The second study, involving older
men and women, found that treatment with venlafaxine was associated with significantly increased levels of the bone resorption
marker only in participants whose depression did not remit
[451]. Furthermore, the bone formation marker did not change in
the overall group but it significantly decreased in individuals
genetically defined as having high transcription of the serotonin
transporter and low transcription of the serotonin 1B receptor, a
receptor known to be involved in bone formation [452]. These preliminary results suggest that antidepressant treatment leading to
remission of depression may have a positive effect on bone homeostasis, whereas unsuccessful antidepressant treatment may have
no or deleterious effects on bone resorption.
Lifestyle factors play a relatively small role in inducing bone
loss in subjects with depression. Studies report no differences in
dietary calcium intake [356,453,374,434,369] or calcium supplementation [387,362] in subjects with depression compared to controls. Smoking has been correlated with bone loss but most studies
found no differences between depressed and non-depressed subjects [373,356,395,396,374,434,370,365,361,454]. Alcohol intake
is also an established risk factor for osteoporosis and yet was found
to be either similar in subjects with depression and controls
[356,369–371,355,455], or significantly lower in subjects with
depression [354,387,361]. A systematic review of the English literature from 1990 to 2006 reported inconsistent or insufficient evidence to conclude that any of those factors are associated with
BMD [456].
Depression and stroke
Nearly one third of stroke survivors develop depression [292].
Conversely, depression has been linked to various risk factors for
stroke [293–296]. Prior studies have found that depression and
dementia are individually associated with increased risk of stroke
[296–306].
There is evidence suggesting that depressive symptoms or diagnoses consistently predict elevated risk of stroke onset [298–300].
Recent meta-analyses examining the effects of depression and
depressive symptoms on stroke risk estimated an adjusted HR of
1.45 (95% CI 1.29–1.63) and an overall adjusted HR of 1.34 (95%
CI 1.17–1.54). Depressive phenotypes have been linked with various physiological risk factors for stroke that develop slowly over
time, such as hypertension, atherosclerosis [293,307], dysregulation of the autonomic nervous system [294] and increased inflam-
17
matory responses [295,296]. Alternatively, depression may
influence stroke risk via short-term biological processes or stroke
triggers, such as cerebrovascular reactivity or AF [308]. Triggers
can spur stroke regardless of a person’s underlying vascular pathology [309] and may include infection [310] or AF [311,116]. Acute
infection, for example, can increase platelet reactivity and
platelet-leukocyte interactions, increasing platelet aggregation
[309]. Damage can also be incurred by indirect effects of depression on health behaviors, whereby depressed individuals are more
likely to engage in deleterious behavior such as smoking and physical inactivity [311].
A recent study found that persistent depression is associated
with twice the risk of stroke in adults over 50 [312]. Researchers
interviewed 16,178 initially stroke free participants over the age
of 50 in the Health and Retirement Study every 2 years from
1998 to 2010. Subjects with persistent depressive symptoms at
two consecutive interviews had twice the risk of having a first
stroke in the two years after assessment compared with participants with low depressive symptoms (adjusted HR of 2.14, 95%
CI 1.69–2.71). This increased risk was observed in all subgroups
analyzed, with a slightly higher risk in women (adjusted HR
2.59) than in men (adjusted HR 1.96). Risk of stroke was also
increased in those who had experienced depression at some point
but whose symptoms had remitted (HR1.66, 95% CI 1.22–2.26). The
risk of stroke in this study remained elevated even if depressive
symptoms had resolved, suggesting a long-term effect of
depression.
A recent retrospective-cohort study examined 7031 individuals
older than 50 years who participated in the Health and Retirement
Study [314]. After adjusting for demographic characteristics, cognitive impairment without dementia alone (OR 1.39, 95% CI 1.13–
1.71) and co-occurring depression and cognitive impairment without dementia (OR 1.76, 95% CI 1.33–2.32) remained associated
with increased odds of ischemic stroke, whereas dementia alone
and co-occurring depression and dementia were no longer significantly associated with odds of ischemic stroke. These associations
persisted after adjusting for medical comorbidities and health-risk
behaviors. This data identified cognitively impaired women as a
subgroup that may be at elevated risk, a finding consistent with
prior work [315]. The results of this study confirmed previous findings that individuals with co-occurring depression and cognitive
impairment are a uniquely at risk population for a wide range of
adverse outcomes, including cognitive decline, institutionalization
and mortality [316,317].
Co-occurring depression and cognitive impairment may be
associated with increased risk of ischemic stroke through several
mechanisms. A biologically plausible mediator is endothelial dysfunction and impaired regulation of coagulation pathways. Mild
cognitive impairment and depression have been associated with
fibrinogen dysregulation and exaggerated platelet reactivity
[130,318], both of which could predispose to vascular pathology
and ischemic stroke [319]. Prior work has established that depression in older adults with medical illnesses is frequently chronic
[323] and rates of depression among HRS participants have been
found to be fairly stable over time [324].
Depression and diabetes
The prevalence of depression is increased in patients with diabetes. Anderson et al. [326] performed a meta-analysis that
included studies of patients with type 1 and 2 diabetes. The overall
odds of depression were twice as high for patients with diabetes
compared to non-diabetic controls (OR = 2.0, 95% CI 1.8–2.2).
Pouwer et al. [327] found that the prevalence of depressive affect
was 25% and 30% for men and women, respectively, in type 1 dia-
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J.L. Sotelo, C.B. Nemeroff / Personalized medicine in psychiatry 1–2 (2017) 11–25
betes, when using the Center for Epidemiologic Studies Depression
Scale (CES-D) questionnaire. The prevalence of a major depressive
disorder was 8% when using the WHO Composite International
Diagnostic Interview (CIDI). In this study, depression was associated with the presence of proliferative retinopathy and suboptimal
glycemic control. In a large cross-sectional study that included
more than 200,000 adults, individuals with diabetes had an
increased risk of an episode of depressive symptoms (adjusted
OR 2.36, 95% CI 1.91–2.92). Comparable associations were found
in South American, Asian, and European countries [328].
Substantial evidence supports the hypothesis that depression is
a risk factor for the onset and exacerbation of diabetes [335,336].
Thirty-three articles published between 1991 and 2012 involving
over 2 million participants were reviewed in a recent metaanalysis [338]. This meta-analysis found that depression is associated with an increased risk for developing diabetes mellitus with a
pooled relative risk of 1.41 (95% CI, 1.25–1.59). Four similar metaanalyses also conducted recently [330,339–341] found such an
association with relative risk for type 2 diabetes mellitus of 1.25
(95% CI, 1.02–1.48) [339], 1.37 (95% CI, 1.14–1.63) [341], 1.60
(95% CI, 1.37–1.88) [340] and 1.38 (95% CI, 1.23–1.55) [330].
Comorbid diabetes and depression has been associated with
poorly controlled diabetes. Although there is a modest association
between depression and poorly controlled diabetes, there is a
stronger association between depressive symptoms and diabetes
complications including retinopathy, sexual dysfunction, and
nephropathy. Given the negative impact of depression upon diabetes, several investigators have also documented that patients
with depression and diabetes suffer premature mortality [332].
Multiple biological mechanisms may contribute to the relationship between depression and diabetes. These include activation of
inflammatory processes and the hypothalamic-pituitaryadrenal
(HPA) axis as well as abnormalities in glucose metabolism [333].
Depression and mental stress is associated with subclinical hypercortisolism, blunted diurnal cortisol rhythm, or hypocortisolism
with impaired glucocorticoid sensitivity, and increased catecholamines and inflammation secondary to hypothalamicpituitaryadrenal (HPA) axis activation [334]. Low-grade systemic
inflammation has been associated with the development of type
2 diabetes [342]. Prolonged hypercortisolemia is associated with
visceral adiposity, insulin resistance, dyslipidemia, and hypertension. It can also worsen atherosclerosis by increasing vessel fragility, changes in lipids and catecholamines, which increase heart
rate and contribute to increased risk for thrombus formation
through increased platelet aggregation. Adipose tissue and damaged vessels then release pro-inflammatory cytokines, which can
induce anhedonia, anorexia, sleep changes, and decreased social
interaction. All these biological pathways are activated in major
depression and are associated with insulin resistance.
It has been suggested that the key to metabolic syndrome, insulin resistance, and the development of type 2 diabetes is hypothalamic hyperactivity and excessive sympathetic drive [343]. HPA
axis hyperactivity has been posited as a contributing factor to
increasing abdominal obesity and stress has been hypothesized
to cause a more central distribution of fat, which in turn can give
rise to diabetes [344].
Serum BDNF concentrations are decreased in patients with
depression [346,347]. BDNF is also strongly associated with type
2 diabetes and obesity because it modulates the secretion and
activities of insulin, leptin, ghrelin, neurotransmitters, neuropeptides, and proinflammatory cytokines associated with energy
homeostasis [348]. In addition, animal studies have also shown
that BDNF has important effects on the regulation of eating behavior, suggesting that BDNF may also play a role in the development
of obesity and type 2 diabetes in humans [349].
Finally, the development of diabetes in people with depression
may be related to behaviors observed in depression (such as inactivity, poor diet, weight gain, poor medication adherence)
[337,350] or to the medications used to treat it, rather than to
the depression itself.
Conclusions
Depression is common in the general population. Depression
may be conceptualized as a systemic illness because of the several
biological mechanisms by which it can affect general health. A
bidirectional relationship between depression and some of the
medical disorders examined above has already been established
through an emerging literature reporting on the medical complications of depression. Enhanced inflammation, HPA axis hyperactivity, disrupted arterial wall repair, oxidative damage, decreased
heart rate variability, and sympathetic nervous system dysregulation are some of the findings that account for the extent to which
depression can increase susceptibility to, and complicate the prognosis of, other medical conditions. Heart disease, cancer, stroke,
diabetes, and osteoporosis are also common medical conditions
afflicting an increasingly aging population and the prevalence of
depression in patients with these disorders is greater than that
which is observed in the general population. Patients with these
conditions who exhibit depressive symptoms are at greater risk
for morbidity and mortality than their nondepressed counterparts.
Indeed depression has been identified as an independent risk factor for some of these conditions. Therefore, it is imperative that
depressive symptoms be treated aggressively in patients with
chronic medical conditions because their resolution may be
accompanied by general symptomatic improvement and an important decrease in complications and mortality risk.
The effects of childhood trauma in patients with general medical conditions need to be studied in greater detail. Not only are
early adverse experiences associated with an increased risk for
depression and anxiety syndromes later in life, they may also predispose patients to poorer medical outcomes through similar
mechanisms, such as increased inflammation and HPA axis
hyperactivity.
Depressed patients are also more likely to exhibit limited
adherence to treatment recommendations, such as lifestyle modifications (abstinence from tobacco, alcohol, and recreational drugs;
exercise; dietary changes), clinic appointments, and appropriate
medication compliance. Our review does not support a greater role
to these factors than the biological mechanisms described.
This review highlights the bidirectional mechanisms by which
depression and medical illness may affect each other. A recent
meta-analysis of randomized clinical trials (10 publications reporting on 14 trials and over 6200 participants) reviewed the effect of
anti-inflammatory treatments on depression [472]. Antiinflammatory treatments, in particular the selective cyclooxygenase 2 inhibitor celexoxib, reduced depressive symptoms compared with placebo. Biomarkers cannot yet reliably be used to
determine which patients may benefit from a specific treatment
or which treatments should be used in a particular patient. However, our understanding of depression has evolved from the days
of the monoaminergic hypothesis of the illness, paving the way
for new antidepressant treatments that could target the biological
mechanisms of disease outlined in this review. Such treatments
could hypothetically treat the symptoms of depression and
improve medical outcomes in patients with chronic medical illness, as well.
Future research focusing on the interplay between depression
and medical illness should further elucidate the underlying pathophysiology responsible for increased morbidity and mortality in
J.L. Sotelo, C.B. Nemeroff / Personalized medicine in psychiatry 1–2 (2017) 11–25
depressed and medically compromised individuals. Interventions
that target the biological alterations observed in depressed
patients could theoretically improve the course of illness in those
individuals.
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