Depression as a systemic disease

Major depressive disorder is one of the leading causes of disability worldwide []. According to the World Health Organization (WHO), it will become the second leading cause of disability-adjusted life years lost by the year 2020 []. 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 [, , ], stroke, cancer, renal disease and diabetes []. 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 (Table 1, Table 2).

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 [, ]. A bidirectional association between depression and heart disease has been established and reviewed [, , , , , , , , ]. Ample evidence suggests that depression is highly prevalent in patients with congestive heart failure (CHF) [, , ], atrial fibrillation (AF) [], post-myocardial infarction (MI) [, ], post-coronary-artery bypass graft surgery (CABG), and that it has an adverse effect on morbidity and mortality in these populations [, , ].

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 [, , , , , , ]. 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 []. 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 [] 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 []. 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 []. 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) []. 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 1.7–3.78, P < 0.001) and ongoing (HR 1.17, 95% CI 1.04–1.31, P = 0.008) CAD []. 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 [].

Depression has been recognized as a negative prognostic factor associated with an increased risk of cardiovascular related morbidity and mortality [, , ]. Doering et al. [] 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 []. Beach et al. [] 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 [] 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 []. In addition, more than half of patients with heart failure have significant anxiety or depression symptoms [, , ]. 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 [, , , , , ]. Previous studies have documented an association between depression and mortality in outpatients [, , , ] and hospitalized patients with heart failure [, ]. A recent study reported on 1260 patients with heart failure on whom data was collected over 12 months []. 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 [, , , ]. Proinflammatory cytokines play significant roles in the development and clinical progression of CHF [, ]. 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 proinflammatory cytokines, higher C-reactive protein (CRP) levels, and increased expression of inflammatory genes [, ]. 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 [].

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 [, , , , , , , , ]. Increased inflammation induces depressive symptoms by several mechanisms, including effects on the serotonergic system [, ]. In response to inflammation, tryptophan metabolism shifts towards the formation of kynurenine metabolites [] with an increased production of 3-hydroxykynurenine and quinolinic acid []. Excessive inflammation due to impaired glucocorticoid receptor sensitivity has also been found in patients with major depressive disorder [, ], in the elderly [] and in patients at risk for cardiovascular disease []. It has been postulated that glucocorticoid resistance may occur as a result of chronic stress and prolonged exposure to inflammatory cytokines []. 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 [].

Chronic inflammatory states might mediate the increased risk of CAD in depression [, , ]. Downregulation of the anti-inflammatory cytokine interleukin-10 (IL-10) and upregulation of the proinflammatory cytokines IL-6 and tumor necrosis factor alpha (TNF-α) have been reported in heart failure patients with depressive symptoms []. 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 []. The Gutenberg Health Study (n = 10,000; ages 35–74) [] 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 [] and of complications, such as heart failure and death []. Psychological distress may influence hemodynamics, vascular function, autonomic tone, inflammatory activity, and hemostasis [, , ], all of which play a role in the pathogenesis and complications of AF.

Nikkheslat et al. [] 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 []. Furthermore, Xiong et al. [] 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)-γ, monocyte chemoattractant protein 1, macrophage inflammatory protein 1β, and TNF-α.

Platelets may also play a role in the interplay between depression, inflammation and heart disease. They recruit inflammatory cells that contribute to atherosclerosis [, , ]. Platelets also contribute to artery remodeling and atheroma formation by producing growth factors that promote the proliferation of smooth muscle cells in the atheroma [, , , ]. Unchecked inflammation can induce recruitment of monocyte progenitor cells [, , ], which can become activated macrophages capable of inducing apoptosis of smooth muscle cells within the arterial wall []. Alterations in platelet activation and aggregation in the clotting cascade observed in patients with depression result in an increased clotting diathesis []. 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 α-IIb-β3 complex, the final common pathway for platelet activation [, ]. In patients with depression, studies have shown significant increases in platelet activation and circulating platelet-leukocyte aggregates and enhanced platelet reactivity to ADP []. Marked elevations of serum β-thromboglobulin 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 [].

Overt and subclinical hypothyroidism are associated with an increased risk of cardiovascular disease and related mortality []. In depressed patients, considerable evidence suggests an increased prevalence of subclinical hypothyroidism [, ]. Many patients with depression also exhibit hypothalamic-pituitaryadrenal (HPA) axis hyperactivity []. 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 []. 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 []. Another study revealed that cortisol awakening response is negatively correlated with HRV [].

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 []. von Willebrand factor recruits platelets to damaged endothelium during the pathogenesis of atherosclerosis []. Other SNPs associated with inflammation, endothelial function, and platelet aggregation have also been identified as suggestive of an association with depression []. Twin studies have suggested that depression, elevations in plasma lipids, and HRV may share genetic mechanisms [, ]. 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 [].

Adverse events in early life, including childhood trauma, are associated with an increased susceptibility to both depression and cardiovascular disease []. A retrospective analysis of over 17,000 adults revealed a dose-response relationship between adverse childhood experiences and ischemic heart disease []. 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 []. 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.

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 []. 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 []. Other studies have found associations between depression severity and intima-media thickness of the carotid bulb [] and impaired endothelial function [].

Prevalence rates for depression in patients with cancer range from 1.5% to 50%, with median point prevalence rates between 15% and 29% [, , , , ]. A study by Linden [] and a review by Ng [] 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 []. It leads to a poorer quality of life and compromises patient outcomes, resulting in higher mortality rates [, , , ]. 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 []. 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%) []. 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 [, , , ].

In breast cancer, the prevalence of clinical depression is between 10 and 30% within the first five years after diagnosis [] and it is associated with increased mortality []. Hung et al. [] 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 [] 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 [, , ], or chemotherapy [, , ]. Associations between increasing age, comorbid disease, and use of antidepressants were also found in a study of over 8000 women treated with radiotherapy [].

In men with prostate cancer, longitudinal studies [, , , , , , ] 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 []. 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 []. 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; [] but its use does not appear to worsen depressive symptoms in men with prostate cancer and depression []. 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 [, ].

As was highlighted above, proinflammatory cytokines may be involved in depression in healthy and medically ill individuals, including cancer patients [, , , ]. 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 [, , , , , ]. This hypothesis is supported by studies showing a correlation between serum levels of proinflammatory cytokines and depressive symptoms in pancreatic and ovarian cancer patients [, ]. 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 [] and is associated with recurrence of cancer []. In addition, recent studies suggest that blocking the effect of proinflammatory cytokines reduces symptoms of depression (especially fatigue) in cancer patients [].

Tumor cells and cells in the tumor environment produce high levels of IL-6 [, , , ]. IL-6 promotes angiogenesis [], invasion and attachment [], and generation of tumor-associated macrophages []. Elevations of IL-6 are also associated with decreased time to recurrence and shorter survival time in ovarian cancer patients [, , ]. 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 []. 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 []. Fatigue during radiation treatment has also been associated with increased levels of inflammatory markers [, ].

NF-kB has also been implicated in cancer development and treatment resistance [, ]. Fatigued breast cancer survivors demonstrate increased activation of NF-kB-regulated genes []. In addition, chemotherapy has been associated with NF-kB activation in breast cancer tissue and peripheral blood [, ]. 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 []. Moreover, IL-1 and IL-6 concentrations significantly correlate with fatigue in patients with cancer treated with radiation or chemotherapy [, ].

In patients with breast, ovarian, cervical cancer and lymphoma, dysregulated patterns of cortisol secretion have been observed [, , , ]. Elevated nocturnal cortisol and blunted diurnal cortisol slope has been observed in ovarian cancer patients prior to surgery [, ]. Disruption of cortisol rhythms resulting in flattening of the cortisol slope has been associated with shortened survival time in patients with breast cancer []. In animal models, altered glucocorticoid receptor expression secondary to elevated cortisol has been recognized as a likely mechanism in the initiation of ovarian cancer [], the failure of cancer cells to undergo apoptosis [, , ], the development of chemotherapy resistance [] and accelerated tumor growth []. In addition, cortisol dysregulation has been associated with poor performance status [], fatigue [], and depression [] in cancer patients. Abnormal cortisol rhythms have also been linked with symptoms of depression in patients with ovarian cancer [, ].

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 []. This polymorphism has also been associated with poor overall survival and decreased disease specific survival in patients with colorectal cancer []. 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 []. Childhood trauma may alter neurocircuitry during a time when the brain is vulnerable to environmental stressors [, , ]. As noted above, childhood abuse has been associated with elevated markers of inflammation including CRP, IL-6, and TNF-α, in adults. These biomarkers have been correlated with fatigue and depression in breast cancer patients [, , ]. 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 []. 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 []. 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 [, ]. 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 []. 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 IL-22, IL-17, and C-C chemokine receptor 5 signaling in macrophages and T lymphocytes. They also exhibited an over-representation of 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 [] found that a history of childhood adversity was associated with increased fatigue, depression, and perceived stress before and during treatment [].

Depression and anxiety occur in approximately 30–40% of patients with colorectal cancer [, ]. High levels of proinflammatory cytokines in these patients suggest that cytokines also play a role in the etiology and pathophysiology of depression and anxiety []. 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-1β, IL-6, IL-8, and TNF-α. Anxiety, depression, and combined anxiety and depression were positively correlated with IL-1, IL-6, IL-8, and TNF-α. In advanced colorectal cancer patients, increased serum levels of the soluble portion of the IL-2 receptor α chain have been previously shown to correlate with depression symptoms, suggesting that tumor-induced immune activation contributes to depression [].

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 [, ]. In depressed patients who underwent abdominal procedures, increased serum IL-6 concentrations correlated with depression severity scores []. However, these postsurgical mood changes and proinflammatory alterations have not been replicated in other studies [, , ]. 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 []. Chemotherapy is associated with increased proinflammatory cytokine levels, which may be associated with fatigue and sleep disturbance [, , , ]. Fatigue, depression, and stress are commonly reported side effects of radiotherapy [, , , ]. 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 NF-κ B DNA binding [, , , , ].