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Depression as a systemic disease

Published:November 24, 2016DOI:https://doi.org/10.1016/j.pmip.2016.11.002

      Highlights

      • Depression increases the risk and progression of a variety of medical disorders.
      • Increased inflammation is observed in cancer, heart disease and depression.
      • Childhood trauma predisposes to depression and increased inflammation.
      • Depression is a risk factor for osteoporosis and fractures in the elderly.

      Abstract

      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.

      Introduction

      Major depressive disorder is one of the leading causes of disability worldwide [
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      • Mathers C.
      • Murray C.J.
      Global burden of depressive disorders in the year 2000.
      ]. According to the World Health Organization (WHO), it will become the second leading cause of disability-adjusted life years lost by the year 2020 [
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      • Murray C.J.L.
      Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990–2013: a systematic analysis for the Global Burden of Disease Study.
      ]. 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 [
      • Lippi G.
      • Montagnana M.
      • Favalor E.J.
      • Franchini M.
      Mental depression and cardiovascular disease: a multifaceted, bidirectional association.
      ,
      • Musselman D.L.
      • Cowles M.K.
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      • Nemeroff C.B.
      ,
      • Kahn F.M.
      • Kulaksizoglu B.
      • Cilingiroglu M.
      Depression and coronary heart disease.
      ], stroke, cancer, renal disease and diabetes [
      • Cowles M.
      • Nemeroff C.B.
      • Pariente C.
      ]. 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).
      Table 1Pathophysiology 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 α-IIb-β3 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 2Mechanisms through which depression affects medical illness.
      IllnessPathophysiology
      Heart diseaseCoronary artery disease
      ↑: CRP, proinflammatory cytokines, inflammatory genes, plasma VEGF, tryptophan/kynurenine ratio, serum β-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-γ, TNF-α, MCAP1, MIP-1β
      ↓: IL-10
      Atrial fibrillation
      ↑: CRP
      Cancer↑: CRP, IL-1, IL-6, IL-8, TNF-α, soluble IL-2 receptor α chain, soluble IL-6 receptor, sTNFR2, activation of NF-κB 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
      StrokeEndothelial dysfunction
      Fibrinogen dysregulation
      Exaggerated platelet reactivity
      DiabetesInflammation
      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.

      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 [
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      ], post-coronary-artery bypass graft surgery (CABG), and that it has an adverse effect on morbidity and mortality in these populations [
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      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 [
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      ]. 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 [
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      ]. 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 [
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      ] 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 [
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      ]. 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 [
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      ]. 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) [
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      ]. 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 [
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      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 [
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      • Seta Y.
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      • Oral H.
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      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 [
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      Clinical depression and inflammatory risk markers for coronary heart disease.
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      • Lawson M.A.
      • Kelley K.W.
      Inflammation-associated depression: from serotonin to kynurenine.
      ,
      • Wichers M.C.
      • Maes M.
      The role of indoleamine 2,3-dioxygenase (IDO) in the pathophysiology of interpheron-alpha-induced depression.
      ]. In response to inflammation, tryptophan metabolism shifts towards the formation of kynurenine metabolites [
      • Lapin I.P.
      • Oxenkrug G.F.
      Intensification of the central serotoninergic processes as a possible determinant of the thymoleptic effect.
      ] with an increased production of 3-hydroxykynurenine and quinolinic acid [
      • Myint A.M.
      • Kim Y.K.
      Cytokine-serotonin interaction through IDO: a neurodegeneration hypothesis of depression.
      ]. Excessive inflammation due to impaired glucocorticoid receptor sensitivity has also been found in patients with major depressive disorder [
      • Pace T.W.
      • Hu F.
      • Miller A.H.
      Cytokine-effects on glucocorticoid receptor function: relevance to glucocorticoid resistance and the pathophysiology and treatment of major depression.
      ,
      • Stewart J.C.
      • Rand K.L.
      • Muldoon M.F.
      • Kamarck T.W.
      A prospective evaluation of the directionality of the depression-inflammation relationship.
      ], in the elderly [
      • Rohleder N.
      • Kudielka B.M.
      • Hellhammer D.H.
      • Wolf J.M.
      • Kirschbaum C.
      Age and sex steroid-related changes in glucocorticoid sensitivity of proinflammatory cytokine production after psychosocial stress.
      ] and in patients at risk for cardiovascular disease [
      • Carvalho L.A.
      • Urbanova L.
      • Hamer M.
      • Hackett R.A.
      • Lazzarino A.I.
      • Steptoe A.
      Blunted glucocorticoid and mineralocorticoid sensitivity to stress in people with diabetes.
      ]. It has been postulated that glucocorticoid resistance may occur as a result of chronic stress and prolonged exposure to inflammatory cytokines [
      • Miller A.H.
      • Pariante C.M.
      • Pearce B.D.
      Effects of cytokines on glucocorticoid receptor expression and function. Glucocorticoid resistance and relevance to depression.
      ]. 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 [
      • Howren M.B.
      • Lamkin D.M.
      • Suls J.
      Associations of depression with C-reactive protein, IL-1, and IL-6: a meta analysis.
      ].
      Chronic inflammatory states might mediate the increased risk of CAD in depression [
      • Currier M.B.
      • Nemeroff C.B.
      Inflammation and mood disorders: proinflammatory cytokines and the pathogenesis of depression.
      ,
      • Raison C.L.
      • Cowles M.K.
      • Miller A.H.
      ,
      • Raedler T.J.
      Inflammatory mechanisms in major depressive disorder.
      ]. 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 [
      • Parissis J.T.
      • Adamopoulos S.
      • Rigas A.
      • Kostakis G.
      • Karatzas D.
      • Venetsanou K.
      • et al.
      Comparison of circulating proinflammatory cytokines and soluble apoptosis mediators in patients with chronic heart failure with versus without symptoms of depression.
      ]. 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 [
      • Pizzi C.
      • Manzoli L.
      • Mancini S.
      • Costa G.M.
      Analysis of potential predictors of depression among coronary heart disease risk factors including heart rate variability, markers of inflammation, and endothelial function.
      ]. The Gutenberg Health Study (n = 10,000; ages 35–74) [
      • Schnabel R.B.
      • Michal M.
      • Wilde S.
      • Wiltink J.
      • Wild P.S.
      • Sinning C.R.
      • et al.
      Depression in atrial fibrillation in the general population.
      ] 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 [
      • Lange H.W.
      • Herrmann-Lingen C.
      Depressive symptoms predict recurrence of atrial fibrillation after cardioversion.
      ] and of complications, such as heart failure and death [
      • Frasure-Smith N.
      • Lespérance F.
      • Habra M.
      • Talajic M.
      • Khairy P.
      • Dorian P.
      • et al.
      Elevated depression symptoms predict long-term cardiovascular mortality in patients with atrial fibrillation and heart failure.
      ]. Psychological distress may influence hemodynamics, vascular function, autonomic tone, inflammatory activity, and hemostasis [
      • Jones A.
      • Steeden J.A.
      • Pruessner J.C.
      • Deanfield J.E.
      • Taylor A.M.
      • Muthurangu V.
      Detailed assessment of the hemodynamic response to psychosocial stress using real-time MRI.
      ,
      • Carney R.M.
      • Freedland K.E.
      • Veith R.C.
      • Cryer P.E.
      • Skala J.A.
      • Lynch T.
      • et al.
      Major depression, heart rate, and plasma norepinephrine in patients with coronary heart disease.
      ,
      • Whooley M.A.
      • de Jonge P.
      • Vittinghoff E.
      • Otte C.
      • Moos R.
      • Carney RMA
      • et al.
      Depressive symptoms, health behaviors, and risk of cardiovascular events in patients with coronary heart disease.
      ], all of which play a role in the pathogenesis and complications of AF.
      Nikkheslat et al. [
      • Nikkheslat N.
      • Zunszain P.A.
      • Horowitz M.A.
      • Barbosa I.G.
      • Parker J.A.
      • Myint A.M.
      • et al.
      Insufficient glucocorticoid signaling and elevated inflammation in coronary heart disease patients with comorbid depression.
      ] 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 [
      • Nikkheslat N.
      • Zunszain P.A.
      • Horowitz M.A.
      • Barbosa I.G.
      • Parker J.A.
      • Myint A.M.
      • et al.
      Insufficient glucocorticoid signaling and elevated inflammation in coronary heart disease patients with comorbid depression.
      ]. Furthermore, Xiong et al. [
      • Xiong G.L.
      • Prybol K.
      • Boyle S.H.
      • Hall R.
      • Streilein R.D.
      • Steffens D.C.
      • et al.
      Inflammation markers and major depressive disorder in patients with chronic heart failure: results from the sertraline against depression and heart disease in chronic heart failure study.
      ] 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 [
      • Goldschmidt-Clermont P.J.
      Loss of bone marrow-derived vascular progenitor cells leads to inflammation and atherosclerosis.
      ,
      • Goldschmidt-Clermont P.J.
      • Peterson E.D.
      On the memory of a chronic illness.
      ,
      • Asahara T.
      • Murohara T.
      • Sullivan A.
      • Silver M.
      • van der Zee R.
      • Li T.
      • et al.
      Isolation of putative progenitor endothelial cells for angiogenesis.
      ]. Platelets also contribute to artery remodeling and atheroma formation by producing growth factors that promote the proliferation of smooth muscle cells in the atheroma [
      • Ross R.
      Atherosclerosis – an inflammatory disease.
      ,
      • Lusis A.J.
      Atherosclerosis.
      ,
      • Libby P.
      Inflammation in atherosclerosis.
      ,
      • Goldschmidt-Clermont P.J.
      • Seo D.M.
      • Wang L.
      • Beecham G.W.
      • Liu Z.J.
      • Vazquez-Padron R.I.
      • et al.
      Inflammation, stem cells and atherosclerosis genetics.
      ]. Unchecked inflammation can induce recruitment of monocyte progenitor cells [
      • Ross R.
      Atherosclerosis – an inflammatory disease.
      ,
      • Lusis A.J.
      Atherosclerosis.
      ,
      • Libby P.
      Inflammation in atherosclerosis.
      ], which can become activated macrophages capable of inducing apoptosis of smooth muscle cells within the arterial wall [
      • Seshiah P.N.
      • Kereiakes D.J.
      • Vasudevan S.S.
      • Lopes N.
      • Su B.Y.
      • Flavahan N.A.
      • et al.
      Activated monocytes induce smooth muscle cell death role of macrophage colony-stimulating factor and cell contact.
      ]. Alterations in platelet activation and aggregation in the clotting cascade observed in patients with depression result in an increased clotting diathesis [
      • Musselman D.L.
      • Cowles M.K.
      • McDonald W.
      • Nemeroff C.B.
      ]. 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 [
      • Musselman D.L.
      • Tomer A.
      • Manatunga A.K.
      • Knight B.T.
      Exaggerated platelet reactivity in major depression.
      ,
      • Musselman D.L.
      • Marzec U.M.
      • Manatunga A.
      • Penna S.
      • Reemsnyder A.
      • Knight B.T.
      • et al.
      Platelet reactivity in depressed patients treated with paroxetine: preliminary findings.
      ]. In patients with depression, studies have shown significant increases in platelet activation and circulating platelet-leukocyte aggregates and enhanced platelet reactivity to ADP [
      • Morel-Kopp M.C.
      • McLean L.
      • Chen Q.
      • Tofler G.H.
      • Tennant C.
      • Maddison V.
      • et al.
      The association of depression with platelet activation: evidence for a treatment effect.
      ]. 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 [
      • Laghrissi-Thode F.
      • Wagner W.R.
      • Pollock B.G.
      • Johnson P.C.
      • Finkel M.S.
      Elevated platelet factor 4 and beta-thromboglobulin plasma levels in depressed patients with ischemic heart disease.
      ].
      Overt and subclinical hypothyroidism are associated with an increased risk of cardiovascular disease and related mortality [
      • Rondondi N.
      • et al.
      Subclinical hypothyroidism and the risk of coronary heart disease and mortality.
      ]. In depressed patients, considerable evidence suggests an increased prevalence of subclinical hypothyroidism [
      • Nemeroff C.B.
      • Simon J.S.
      • Haggerty Jr., J.J.
      • Evans D.L.
      Antithyroid antibodies in depressed patients.
      ,
      • Gillespie C.F.
      • Garlow S.J.
      • Schatzberg A.F.
      • Nemeroff C.B.
      ]. Many patients with depression also exhibit hypothalamic-pituitaryadrenal (HPA) axis hyperactivity [
      • Gutman D.A.
      • Nemeroff C.B.
      ]. 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 [
      • Vogelzangs N.
      • et al.
      Urinary cortisol and six-year risk of all-cause and cardiovascular mortality.
      ]. 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 [
      • Jokinen J.
      • Nordstrom P.
      HPA axis hyperactivity and cardiovascular mortality in mood disorder inpatients.
      ]. Another study revealed that cortisol awakening response is negatively correlated with HRV [
      • Stalder T.
      • Evans P.
      • Hucklebridge F.
      • Clow A.
      Associations between the cortisol awakening response and heart rate variability.
      ].
      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 [
      • Lopez-Leon S.
      • et al.
      Shared genetic factors in the co-occurrence of symptoms of depression and cardiovascular risk factors.
      ]. von Willebrand factor recruits platelets to damaged endothelium during the pathogenesis of atherosclerosis [
      • Yarnell J.
      • et al.
      Association of European population levels of thrombotic and inflammatory factors with risk of coronary heart disease: the MONICA Optional Haemostasis Study.
      ]. Other SNPs associated with inflammation, endothelial function, and platelet aggregation have also been identified as suggestive of an association with depression [
      • McCaffery J.M.
      • et al.
      Genetic predictors of depressive symptoms in cardiac patients.
      ]. Twin studies have suggested that depression, elevations in plasma lipids, and HRV may share genetic mechanisms [
      • Su S.
      • et al.
      Common genes contribute to depressive symptoms and heart rate variability: the Twins Heart Study.
      ,
      • Vaccarino V.
      • et al.
      Depressive symptoms and heart rate variability: evidence for a shared genetic substrate in a study of twins.
      ]. 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 [
      • Bozzini S.
      • et al.
      Coronary artery disease and depression: possible role of brain-derived neurotrophic factor and serotonin transporter gene polymorphisms.
      ].
      Adverse events in early life, including childhood trauma, are associated with an increased susceptibility to both depression and cardiovascular disease [
      • Dong M.
      • Giles W.H.
      • Felitti V.J.
      • et al.
      Insights into causal pathways for ischemic heart disease: adverse childhood experiences study.
      ]. A retrospective analysis of over 17,000 adults revealed a dose-response relationship between adverse childhood experiences and ischemic heart disease [
      • Dong M.
      • Giles W.H.
      • Felitti V.J.
      • et al.
      Insights into causal pathways for ischemic heart disease: adverse childhood experiences study.
      ]. 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 [
      • Danese A.
      • Pariante C.M.
      • Caspi A.
      • Taylor A.
      • Poulton R.
      Childhood maltreatment predicts adult inflammation in a life-course study.
      ]. 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 [
      • Hamer M.
      • Kivimaki M.
      • Lahiri A.
      • Marmot M.G.
      • Steptoe A.
      Persistent cognitive depressive symptoms are associated with 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 [
      • Vural M.
      • Satiroglu O.
      • Akbas B.
      • Goksel I.
      • Karabay O.
      Coronary artery disease in association with depression or anxiety among patients undergoing angiography to investigate chest pain.
      ]. Other studies have found associations between depression severity and intima-media thickness of the carotid bulb [
      • Kabir A.A.
      • et al.
      Association between depression and intima-media thickness of carotid bulb in asymptomatic young adults.
      ] and impaired endothelial function [
      • Paranthaman R.
      • et al.
      Vascular function in older adults with depressive disorder.
      ].

      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% [
      • Fann J.R.
      • Thomas-Rich A.M.
      • Katon W.J.
      • Cowley D.
      • Pepping M.
      • McGregor B.A.
      • Gralow J.
      Major depression after breast cancer: a review of epidemiology and treatment.
      ,
      • Massie M.J.
      Prevalence of depression in patients with cancer.
      ,
      • Miller A.H.
      • Ancoli-Israel S.
      • Bower J.E.
      • Capuron L.
      • et al.
      Neuroendocrine-immune mechanisms of behavioral comorbidities in patients with cancer.
      ,
      • Raison C.L.
      • Miller A.H.
      Depression in cancer: new developments regarding diagnosis and treatment.
      ,
      • Rooney A.G.
      • McNamara S.
      • Mackinnon M.
      • Fraser M.
      • Rampling R.
      • Carson A.
      • et al.
      Frequency, clinical associations, and longitudinal course of major depressive disorder in adults with cerebral glioma.
      ]. A study by Linden [
      • Linden W.
      • Vodermaier A.
      • Mackenzie R.
      • Greig D.
      Anxiety and depression after cancer diagnosis: prevalence rates by cancer type, gender, and age.
      ] and a review by Ng [
      • Ng C.G.
      • Boks M.P.
      • Zainal N.Z.
      • Wit N.J.
      The prevalence and pharmacotherapy of depression in cancer patients.
      ] 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 [
      • Polsky D.
      • Doshi J.A.
      • Marcus S.
      • Oslin D.
      • Rothbard A.
      • Thomas N.
      • et al.
      Long-term risk for depressive symptoms after a medical diagnosis.
      ]. It leads to a poorer quality of life and compromises patient outcomes, resulting in higher mortality rates [
      • Colleoni M.
      • Mandala M.
      • Peruzzotti G.
      • Robertson C.
      • Bredart A.
      • Goldhirsch A.
      Depression and degree of acceptance of adjuvant cytotoxic drugs.
      ,
      • Pinquart M.
      • Duberstein P.R.
      Depression and cancer mortality: a meta-analysis.
      ,
      • Stommel M.
      • Given B.A.
      • Given C.W.
      Depression and functional status as predictors of death among cancer patients.
      ,
      • Ariaratnam S.
      • Devi A.
      • Kaur G.
      • Sinniah D.
      • Suleiman A.
      • Thambu M.
      • et al.
      Psychiatric morbidity and survival in newly diagnosed treatment naive cancer patients – a study from Malaysia.
      ]. 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 [
      • Satin J.R.
      • Linden W.
      • Phillips M.J.
      Depression as a predictor of disease progression and mortality in cancer patients.
      ]. 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%) [
      • Chan C.M.H.
      • Ahmad W.
      • Azman W.
      • MD Yusof M.
      • Ho G.F
      • Krupat E.
      Effects of depression and anxiety on mortality in a mixed cancer group: a longitudinal approach using standardised diagnostic interviews.
      ]. 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 [
      • Fann J.R.
      • Thomas-Rich A.M.
      • Katon W.J.
      • Cowley D.
      • Pepping M.
      • McGregor B.A.
      • Gralow J.
      Major depression after breast cancer: a review of epidemiology and treatment.
      ,
      • Koenig H.G.
      • Shelp F.
      • Goli V.
      • Cohen H.J.
      • Blazer D.G.
      Survival and health care utilization in elderly medical inpatients with major depression.
      ,
      • Pelletier G.
      • Verhoef M.J.
      • Khatri N.
      • Hagen N.
      Quality of life in brain tumor patients: the relative contributions of depression, fatigue, emotional distress, and existential issues.
      ,
      • Stoudemire A.
      • Thompson T.L.
      Medication noncompliance: systematic approaches to evaluation and intervention.
      ].
      In breast cancer, the prevalence of clinical depression is between 10 and 30% within the first five years after diagnosis [
      • Mitchell A.J.
      • Chan M.
      • Bhatti H.
      • Halton M.
      • Grassi L.
      • Johansen C.
      • et al.
      Prevalence of depression, anxiety, and adjustment disorder in oncological, haematological, and palliative-care settings: a meta-analysis of 94 interview-based studies.
      ] and it is associated with increased mortality [
      • Pinquart M.
      • Duberstein P.R.
      Depression and cancer mortality: a meta-analysis.
      ]. Hung et al. [
      • Hung Y.P.
      • Liu C.J.
      • Tsai C.F.
      • Hung M.H.
      • Tzeng C.H.
      • Liu C.Y.
      • et al.
      Incidence and risk of mood disorders in patients with breast cancers in Taiwan: a nationwide population-based study.
      ] 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 [
      • Suppli N.P.
      • Johansen C.
      • Christensen J.
      • Kessing L.V.
      • Kroman N.
      • Dalton S.O.
      Increased risk for depression after breast cancer: a nationwide population-based cohort study of associated factors in Denmark, 1998–2011.
      ] 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 [
      • Kim S.H.
      • Son B.H.
      • Hwang S.Y.
      • Han W.
      • Yang J.H.
      • Lee S.
      • et al.
      Fatigue and depression in disease-free breast cancer survivors: prevalence, correlates, and association with quality of life.
      ,
      • Chen X.
      • Zheng Y.
      • Zheng W.
      • Gu K.
      • Chen Z.
      • Lu W.
      • et al.
      Prevalence of depression and its related factors among Chinese women with breast cancer.
      ,
      • Metcalfe K.A.
      • Semple J.
      • Quan M.L.
      • Vadaparampil S.T.
      • Holloway C.
      • Brown M.
      • et al.
      Changes in psychosocial functioning 1 year after mastectomy alone, delayed breast reconstruction, or immediate breast reconstruction.
      ], or chemotherapy [
      • Kim S.H.
      • Son B.H.
      • Hwang S.Y.
      • Han W.
      • Yang J.H.
      • Lee S.
      • et al.
      Fatigue and depression in disease-free breast cancer survivors: prevalence, correlates, and association with quality of life.
      ,
      • Chen X.
      • Zheng Y.
      • Zheng W.
      • Gu K.
      • Chen Z.
      • Lu W.
      • et al.
      Prevalence of depression and its related factors among Chinese women with breast cancer.
      ,
      • Ganz P.A.
      • Kwan L.
      • Stanton A.L.
      • Bower J.E.
      • Belin T.R.
      Physical and psychosocial recovery in the year after primary treatment of breast cancer.
      ]. Associations between increasing age, comorbid disease, and use of antidepressants were also found in a study of over 8000 women treated with radiotherapy [
      • Azzone V.
      • Frank R.G.
      • Pakes J.R.
      • Earle C.C.
      • Hassett M.J.
      Behavioral health services for women who have breast cancer.
      ].
      In men with prostate cancer, longitudinal studies [
      • Steginga S.K.
      • Occhipinti S.
      • Gardiner R.F.
      • Yaxley J.
      • Heathcote P.
      Prospective study of men’s psychological and decision-related adjustment after treatment for localized prostate cancer.
      ,
      • Potosky A.L.
      • Legler J.
      • Albertsen P.C.
      • Stanford J.L.
      • Gilliland F.D.
      • Hamilton A.S.
      • et al.
      Health outcomes after prostatectomy or radiotherapy for prostate cancer: results from the Prostate Cancer Outcomes Study.
      ,
      • Litwin M.S.
      • Lubeck D.P.
      • Spitalny G.M.
      • Henning J.M.
      • Carroll P.R.
      Mental health in men treated for early stage prostate carcinoma.
      ,
      • Litwin M.S.
      • Melmed G.Y.
      • Nakazon T.
      Life after radical prostatectomy: a longitudinal study.
      ,
      • Bill-Axelson A.
      • Garmo H.
      • Lambe M.
      • Bratt O.
      • Adolfsson J.
      • Nyberg U.
      • et al.
      Suicide risk in men with prostate-specific antigen–detected early prostate cancer: a nationwide population-based cohort study from PCBaSe Sweden.
      ,
      • Fang F.
      • Fall K.
      • Mittleman M.A.
      • Sparén P.
      • Ye W.
      • Adami H.O.
      • et al.
      Suicide and cardiovascular death after a cancer diagnosis.
      ,
      • Roth A.J.
      • Kornblith A.B.
      • Batel-Copel L.
      • Peabody E.
      • Scher H.I.
      • Holland J.C.
      Rapid screening for psychologic distress in men with prostate carcinoma.
      ] 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 [
      • Nelson C.J.
      • Weinberger M.I.
      • Balk E.
      • Holland J.
      • Breitbart W.
      • Roth A.J.
      The chronology of distress, anxiety, and depression in older prostate cancer patients.
      ]. 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 [
      • Prasad S.M.
      • Eggener S.E.
      • Lipsitz S.R.
      • Irwin M.R.
      • Ganz P.A.
      • Hu J.C.
      Effect of depression on diagnosis, treatment, and mortality of men with clinically localized prostate cancer.
      ]. 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; [
      • Herr H.W.
      • O’Sullivan M.E.
      Quality of life of asymptomatic men with nonmetastatic prostate cancer on androgen deprivation therapy.
      ] but its use does not appear to worsen depressive symptoms in men with prostate cancer and depression [
      • Timilshina N.
      • Breunis H.
      • Alibhai S.
      Impact of androgen deprivation therapy on depressive symptoms in men with nonmetastatic prostate cancer.
      ]. 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 [
      • Giese-Davis J.
      • Collie K.
      • Rancourt K.M.
      • Neri E.
      • Kraemer H.C.
      • Spiegel D.
      Decrease in depression symptoms is associated with longer survival in patients with metastatic breast cancer: a secondary analysis.
      ,
      • Li M.
      • Fitzgerald P.
      • Rodin G.
      Evidence-based treatment of depression in patients with cancer.
      ].
      As was highlighted above, proinflammatory cytokines may be involved in depression in healthy and medically ill individuals, including cancer patients [
      • Dantzer R.
      • O’Connor J.C.
      • Freund G.G.
      • Johnson R.W.
      • Kelley K.W.
      From inflammation to sickness and depression: when the immune system subjugates the brain.
      ,
      • Capuron L.
      • Dantzer R.
      Cytokines and depression: the need for a new paradigm.
      ,
      • Kiecolt-Glaser J.K.
      • Glaser R.
      Depression and immune function: central pathways to morbidity and mortality.
      ,
      • Raison C.L.
      • Miller A.H.
      Depression in cancer: new developments regarding diagnosis and treatment.
      ]. 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 [
      • Wedding U.
      • Koch A.
      • Röhrig B.
      • Pientka L.
      • Sauer H.
      • Höffken K.
      • et al.
      Depression and functional impairment independently contribute to decreased quality of life in cancer patients prior to chemotherapy.
      ,
      • Musselman D.L.
      • Miller A.H.
      • Porter M.R.
      • Manatunga A.
      • Gao F.
      • Penna S.
      • et al.
      Higher than normal plasma interleukin-6 concentrations in cancer patients with depression: preliminary findings.
      ,
      • Felger J.C.
      • Lotrich F.E.
      Inflammatory cytokines in depression: neurobiological mechanisms and therapeutic implications.
      ,
      • Illman J.
      • Corringham R.
      • Robinson Jr., D.
      • Davis H.M.
      • Rossi J.F.
      • Cella D.
      • et al.
      Are inflammatory cytokines the common link between cancer-associated cachexia and depression?.
      ,
      • Rich T.
      • Innominato P.F.
      • Boerner J.
      • Mormont M.C.
      • Iacobelli S.
      • Baron B.
      • et al.
      Elevated serum cytokines correlated with altered behavior, serum cortisol rhythm, and dampened 24-hour rest-activity patterns in patients with metastatic colorectal cancer.
      ,
      • Seruga B.
      • Zhang H.
      • Bernstein L.J.
      • Tannock I.F.
      Cytokines and their relationship to the symptoms and outcome of cancer.
      ]. This hypothesis is supported by studies showing a correlation between serum levels of proinflammatory cytokines and depressive symptoms in pancreatic and ovarian cancer patients [
      • Musselman D.L.
      • Miller A.H.
      • Porter M.R.
      • Manatunga A.
      • Gao F.
      • Penna S.
      • et al.
      Higher than normal plasma interleukin-6 concentrations in cancer patients with depression: preliminary findings.
      ,
      • Späth-Schwalbe E.
      • Hansen K.
      • Schmidt F.
      • Schrezenmeier H.
      • Marshall L.
      • Burger K.
      • et al.
      Acute effects of recombinant human interleukin-6 on endocrine and central nervous sleep functions in healthy men 1.
      ]. 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 [
      • Mantovani A.
      • Allavena P.
      • Sica A.
      • Balkwill F.
      Cancer-related inflammation.
      ] and is associated with recurrence of cancer [
      • Cole S.W.
      Chronic inflammation and breast cancer recurrence.
      ]. In addition, recent studies suggest that blocking the effect of proinflammatory cytokines reduces symptoms of depression (especially fatigue) in cancer patients [
      • Monk J.P.
      • Phillips G.
      • Waite R.
      • Kuhn J.
      • Schaaf L.J.
      • Otterson G.A.
      • et al.
      Assessment of tumor necrosis factor alpha blockade as an intervention to improve tolerability of dose-intensive chemotherapy in cancer patients.
      ].
      Tumor cells and cells in the tumor environment produce high levels of IL-6 [
      • Nilsson M.B.
      • Langley R.R.
      • Fidler I.J.
      Interleukin-6, secreted by human ovarian carcinoma cells, is a potent proangiogenic cytokine.
      ,
      • Offner F.A.
      • Obris P.
      • Stadlmann S.
      • Feichtinger H.
      • Klingler P.
      • Herold M.
      • et al.
      IL-6 secretion by human peritoneal mesothelial and ovarian cancer cells.
      ,
      • Obata N.H.
      • Tamakoshi K.
      • Shibata K.
      • Kikkawa F.
      • Tomoda Y.
      Effects of interleukin-6 on in vitro cell attachment, migration and invasion of human ovarian carcinoma.
      ,
      • Watson J.M.
      • Sensintaffar J.L.
      • Berek J.S.
      • Martínez-Maza O.
      Constitutive production of interleukin 6 by ovarian cancer cell lines and by primary ovarian tumor cultures.
      ]. IL-6 promotes angiogenesis [
      • Nilsson M.B.
      • Langley R.R.
      • Fidler I.J.
      Interleukin-6, secreted by human ovarian carcinoma cells, is a potent proangiogenic cytokine.
      ], invasion and attachment [
      • Obata N.H.
      • Tamakoshi K.
      • Shibata K.
      • Kikkawa F.
      • Tomoda Y.
      Effects of interleukin-6 on in vitro cell attachment, migration and invasion of human ovarian carcinoma.
      ], and generation of tumor-associated macrophages [
      • Jeannin P.
      • Duluc D.
      • Delneste Y.
      IL-6 and leukemia-inhibitory factor are involved in the generation of tumor-associated macrophage: regulation by IFN-γ.
      ]. Elevations of IL-6 are also associated with decreased time to recurrence and shorter survival time in ovarian cancer patients [
      • Lane D.
      • Matte I.
      • Rancourt C.
      • Piché A.
      Prognostic significance of IL-6 and IL-8 ascites levels in ovarian cancer patients.
      ,
      • Plante M.
      • Rubin S.C.
      • Wong G.Y.
      • Federici M.G.
      • Finstad C.L.
      • Gastl G.A.
      Interleukin-6 level in serum and ascites as a prognostic factor in patients with epithelial ovarian cancer.
      ,
      • Scambia G.
      • Testa U.
      • Panici P.B.
      • Foti E.
      • Martucci R.
      • Gadducci A.
      • et al.
      Prognostic significance of interleukin 6 serum levels in patients with ovarian cancer.
      ]. 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 [
      • Lutgendorf S.K.
      • Weinrib A.Z.
      • Penedo F.
      • Russell D.
      • DeGeest K.
      • Costanzo E.S.
      • et al.
      Interleukin-6, cortisol, and depressive symptoms in ovarian cancer patients.
      ]. 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 [
      • Courtier N.
      • Gambling T.
      • Enright S.
      • Barrett-Lee P.
      • Abraham J.
      • Mason M.D.
      Psychological and immunological characteristics of fatigued women undergoing radiotherapy for early-stage breast cancer.
      ]. Fatigue during radiation treatment has also been associated with increased levels of inflammatory markers [
      • Bower J.E.
      • Ganz P.A.
      • Tao M.L.
      • Hu W.
      • Belin T.R.
      • Sepah S.
      • et al.
      Inflammatory biomarkers and fatigue during radiation therapy for breast and prostate cancer.
      ,
      • Wratten C.
      • Kilmurray J.
      • Nash S.
      • Seldon M.
      • Hamilton C.S.
      • O’Brien P.C.
      • et al.
      Fatigue during breast radiotherapy and its relationship to biological factors.
      ].
      NF-kB has also been implicated in cancer development and treatment resistance [
      • DiDonato J.A.
      • Mercurio F.
      • Karin M.
      NF-κB and the link between inflammation and cancer.
      ,
      • Braunstein S.
      • Formenti S.C.
      • Schneider R.J.
      Acquisition of stable inducible up-regulation of nuclear factor-κB by tumor necrosis factor exposure confers increased radiation resistance without increased transformation in breast cancer cells.
      ]. Fatigued breast cancer survivors demonstrate increased activation of NF-kB-regulated genes [
      • Bower J.E.
      • Ganz P.A.
      • Irwin M.R.
      • Arevalo J.M.
      • Cole S.W.
      Fatigue and gene expression in human leukocytes: increased NF-κB and decreased glucocorticoid signaling in breast cancer survivors with persistent fatigue.
      ]. In addition, chemotherapy has been associated with NF-kB activation in breast cancer tissue and peripheral blood [
      • Monk J.P.
      • Phillips G.
      • Waite R.
      • Kuhn J.
      • Schaaf L.J.
      • Otterson G.A.
      • et al.
      Assessment of tumor necrosis factor alpha blockade as an intervention to improve tolerability of dose-intensive chemotherapy in cancer patients.
      ,
      • Hernández-Vargas H.
      • Rodríguez-Pinilla S.M.
      • Julián-Tendero M.
      • Sánchez-Rovira P.
      • Cuevas C.
      • Anton A.
      • et al.
      Gene expression profiling of breast cancer cells in response to gemcitabine: NF-κB pathway activation as a potential mechanism of resistance.
      ]. 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 [
      • Torres M.A.
      • Pace T.W.
      • Liu T.
      • Felger J.C.
      • Mister D.
      • Doho G.H.
      • et al.
      Predictors of depression in breast cancer patients treated with radiation: role of prior chemotherapy and nuclear factor kappa B.
      ]. Moreover, IL-1 and IL-6 concentrations significantly correlate with fatigue in patients with cancer treated with radiation or chemotherapy [
      • Bower J.E.
      • Ganz P.A.
      • Aziz N.
      • Fahey J.L.
      Fatigue and proinflammatory cytokine activity in breast cancer survivors.
      ,
      • Greenberg D.B.
      • Gray J.L.
      • Mannix C.M.
      • Eisenthal S.
      • Carey M.
      Treatment-related fatigue and serum interleukin-1 levels in patients during external beam irradiation for prostate cancer.
      ].
      In patients with breast, ovarian, cervical cancer and lymphoma, dysregulated patterns of cortisol secretion have been observed [
      • Abercrombie H.C.
      • Giese-Davis J.
      • Sephton S.
      • Epel E.S.
      • Turner-Cobb J.M.
      • Spiegel D.
      Flattened cortisol rhythms in metastatic breast cancer patients.
      ,
      • Jehn C.F.
      • Kühnhardt D.
      • Bartholomae A.
      • Pfeiffer S.
      • Schmid P.
      • Flath B.
      Association of IL-6, hypothalamus–pituitary–adrenal axis function, and depression in patients with cancer.
      ,
      • Mormont M.C.
      • Levi F.
      Circadian-system alterations during cancer processes: a review.
      ,
      • Palesh O.
      • Zeitzer J.M.
      • Conrad A.
      • Giese-Davis J.
      • Mustian K.M.
      • Popek V.
      • et al.
      Vagal regulation, cortisol, and sleep disruption in women with metastatic breast cancer.
      ]. Elevated nocturnal cortisol and blunted diurnal cortisol slope has been observed in ovarian cancer patients prior to surgery [
      • Lutgendorf S.K.
      • Weinrib A.Z.
      • Penedo F.
      • Russell D.
      • DeGeest K.
      • Costanzo E.S.
      • et al.
      Interleukin-6, cortisol, and depressive symptoms in ovarian cancer patients.
      ,
      • Weinrib A.Z.
      • Sephton S.E.
      • DeGeest K.
      • Penedo F.
      • Bender D.
      • Zimmerman B.
      • et al.
      Diurnal cortisol dysregulation, functional disability, and depression in women with ovarian cancer.
      ]. Disruption of cortisol rhythms resulting in flattening of the cortisol slope has been associated with shortened survival time in patients with breast cancer [
      • Sephton S.E.
      • Sapolsky R.M.
      • Kraemer H.C.
      • Spiegel D.
      Diurnal cortisol rhythm as a predictor of breast cancer survival.
      ]. In animal models, altered glucocorticoid receptor expression secondary to elevated cortisol has been recognized as a likely mechanism in the initiation of ovarian cancer [
      • Rae M.T.
      • Hillier S.G.
      Steroid signalling in the ovarian surface epithelium.
      ], the failure of cancer cells to undergo apoptosis [
      • Melhem A.
      • Yamada S.D.
      • Fleming G.F.
      • Delgado B.
      • Brickley D.R.
      • Wu W.
      • et al.
      Administration of glucocorticoids to ovarian cancer patients is associated with expression of the anti-apoptotic genes SGK1 and MKP1/DUSP1 in ovarian tissues.
      ,
      • Pan D.
      • Kocherginsky M.
      • Conzen S.D.
      Activation of the glucocorticoid receptor is associated with poor prognosis in estrogen receptor-negative breast cancer.
      ,
      • Schlossmacher G.
      • Stevens A.
      • White A.
      Glucocorticoid receptor-mediated apoptosis: mechanisms of resistance in cancer cells.
      ], the development of chemotherapy resistance [
      • Pang D.
      • Kocherginsky M.
      • Krausz T.
      • Kim S.Y.
      • Conzen S.
      Dexamethasone decreases xenograft response to Paclitaxel through inhibition of tumor cell apoptosis.
      ] and accelerated tumor growth [
      • Filipski E.
      • Lévi F.
      Circadian disruption in experimental cancer processes.
      ]. In addition, cortisol dysregulation has been associated with poor performance status [
      • Touitou Y.
      • Bogdan A.
      • Levi F.
      • Benavides M.
      • Auzeby A.
      Disruption of the circadian patterns of serum cortisol in breast and ovarian cancer patients: relationships with tumour marker antigens.
      ], fatigue [
      • Bower J.E.
      • Ganz P.A.
      • Dickerson S.S.
      • Petersen L.
      • Aziz N.
      • Fahey J.L.
      Diurnal cortisol rhythm and fatigue in breast cancer survivors.
      ], and depression [
      • Jehn C.F.
      • Kühnhardt D.
      • Bartholomae A.
      • Pfeiffer S.
      • Schmid P.
      • Flath B.
      Association of IL-6, hypothalamus–pituitary–adrenal axis function, and depression in patients with cancer.
      ] in cancer patients. Abnormal cortisol rhythms have also been linked with symptoms of depression in patients with ovarian cancer [
      • Lutgendorf S.K.
      • Weinrib A.Z.
      • Penedo F.
      • Russell D.
      • DeGeest K.
      • Costanzo E.S.
      • et al.
      Interleukin-6, cortisol, and depressive symptoms in ovarian cancer patients.
      ,
      • Weinrib A.Z.
      • Sephton S.E.
      • DeGeest K.
      • Penedo F.
      • Bender D.
      • Zimmerman B.
      • et al.
      Diurnal cortisol dysregulation, functional disability, and depression in women 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 [
      • Su S.
      • Zhao J.
      • Bremner J.D.
      • Miller A.H.
      • Tang W.
      • Bouzyk M.
      • et al.
      Serotonin transporter gene, depressive symptoms, and interleukin-6.
      ]. This polymorphism has also been associated with poor overall survival and decreased disease specific survival in patients with colorectal cancer [
      • Savas S.
      • Hyde A.
      • Stuckless S.N.
      • Parfrey P.
      • Younghusband H.B.
      • Green R.
      Serotonin transporter gene (SLC6A4) variations are associated with poor survival in colorectal cancer patients.
      ]. 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 [
      • Goldsmith R.E.
      • Jandorf L.
      • Valdimarsdottir H.
      • Amend K.L.
      • Stoudt B.G.
      • Rini C.
      • et al.
      Traumatic stress symptoms and breast cancer: the role of childhood abuse.
      ]. Childhood trauma may alter neurocircuitry during a time when the brain is vulnerable to environmental stressors [
      • Danese A.
      • McEwen B.S.
      Adverse childhood experiences, allostasis, allostatic load, and age-related disease.
      ,
      • Heim C.
      • Shugart M.
      • Craighead W.E.
      • Nemeroff C.B.
      Neurobiological and psychiatric consequences of child abuse and neglect.
      ,
      • Liu L.
      • Mills P.J.
      • Rissling M.
      • Fiorentino L.
      • Natarajan L.
      • Dimsdale J.E.
      • et al.
      Fatigue and sleep quality are associated with changes in inflammatory markers in breast cancer patients undergoing chemotherapy.
      ]. 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 [
      • Torres M.A.
      • Pace T.W.
      • Liu T.
      • Felger J.C.
      • Mister D.
      • Doho G.H.
      • et al.
      Predictors of depression in breast cancer patients treated with radiation: role of prior chemotherapy and nuclear factor kappa B.
      ,
      • Bower J.E.
      • Ganz P.A.
      • Irwin M.R.
      • Arevalo J.M.
      • Cole S.W.
      Fatigue and gene expression in human leukocytes: increased NF-κB and decreased glucocorticoid signaling in breast cancer survivors with persistent fatigue.
      ,
      • Liu L.
      • Mills P.J.
      • Rissling M.
      • Fiorentino L.
      • Natarajan L.
      • Dimsdale J.E.
      • et al.
      Fatigue and sleep quality are associated with changes in inflammatory markers in breast cancer patients undergoing chemotherapy.
      ]. 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 [
      • Goldsmith R.E.
      • Jandorf L.
      • Valdimarsdottir H.
      • Amend K.L.
      • Stoudt B.G.
      • Rini C.
      • et al.
      Traumatic stress symptoms and breast cancer: the role of childhood abuse.
      ]. 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 [
      • Janusek L.W.
      • Tell D.
      • Albuquerque K.
      • Mathews H.L.
      Childhood adversity increases vulnerability for behavioral symptoms and immune dysregulation in women with breast cancer.
      ]. 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 [
      • Fagundes C.P.
      • Lindgren M.E.
      • Shapiro C.L.
      • Kiecolt-Glaser J.K.
      Child maltreatment and breast cancer survivors: social support makes a difference for quality of life, fatigue and cancer stress.
      ,
      • Bower J.E.
      • Crosswell A.D.
      • Slavich G.M.
      Childhood adversity and cumulative life stress risk factors for cancer-related fatigue.
      ]. 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 [
      • Han T.J.
      • Felger J.C.
      • Lee A.
      • Mister D.
      • Miller A.H.
      • Torres M.A.
      Association of childhood trauma with fatigue, depression, stress, and inflammation in breast cancer patients undergoing radiotherapy.
      ]. 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 [
      • Janusek L.W.
      • Tell D.
      • Albuquerque K.
      • Mathews H.L.
      Childhood adversity increases vulnerability for behavioral symptoms and immune dysregulation in women with breast cancer.
      ] found that a history of childhood adversity was associated with increased fatigue, depression, and perceived stress before and during treatment [
      • Janusek L.W.
      • Tell D.
      • Albuquerque K.
      • Mathews H.L.
      Childhood adversity increases vulnerability for behavioral symptoms and immune dysregulation in women with breast cancer.
      ].
      Depression and anxiety occur in approximately 30–40% of patients with colorectal cancer [
      • Tsunoda A.
      • Nakao K.
      • Hiratsuka K.
      • Yasuda N.
      • Shibusawa M.
      • Kusano M.
      Anxiety, depression and quality of life in colorectal cancer patients.
      ,
      • Medeiros M.
      • Oshima C.T.F.
      • Forones N.M.
      Depression and anxiety in colorectal cancer patients.
      ]. High levels of proinflammatory cytokines in these patients suggest that cytokines also play a role in the etiology and pathophysiology of depression and anxiety [
      • Szkaradkiewicz A.
      • Marciniak R.
      • Chudzicka-Strugała I.
      • Wasilewska A.
      • Drews M.
      • Majewski P.
      • et al.
      Proinflammatory cytokines and IL-10 in inflammatory bowel disease and colorectal cancer patients.
      ]. 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 [
      • Allen-Mersh T.G.
      • Glover C.
      • Fordy C.
      • Henderson D.C.
      • Davies M.
      Relation between depression and circulating immune products in patients with advanced colorectal cancer.
      ].
      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 [
      • Jakeways M.S.R.
      • Mitchell V.
      • Hashim I.A.
      • Chadwick S.J.D.
      • Shenkin A.
      • Green C.J.
      • et al.
      Metabolic and inflammatory responses after open or laparoscopic cholecystectomy.
      ,
      • Kristiansson M.
      • Saraste L.
      • Soop M.
      • Sundqvist K.G.
      • Thörne A.
      Diminished interleukin-6 and C-reactive protein responses to laparoscopic versus open cholecystectomy.
      ]. In depressed patients who underwent abdominal procedures, increased serum IL-6 concentrations correlated with depression severity scores [
      • Kudoh A.
      • Katagai H.
      • Takazawa T.
      Plasma inflammatory cytokine response to surgical trauma in chronic depressed patients.
      ]. However, these postsurgical mood changes and proinflammatory alterations have not been replicated in other studies [
      • Padova F.
      • Pozzi C.
      • Tondre M.J.
      • Tritapepe R.
      Selective and early increase of IL-1 inhibitors, IL-6 and cortisol after elective surgery.
      ,
      • Fallowfield L.J.
      Psychosocial adjustment after treatment for early breast cancer.
      ,
      • Kruimel J.W.
      • Pesman G.J.
      • Sweep C.G.J.
      • Van der Vliet J.A.
      • Liem T.
      • Jansen J.B.M.J.
      • et al.
      Depression of plasma levels of cytokines and ex-vivo cytokine production in relation to the activity of the pituitary–adrenal axis, in patients undergoing major vascular surgery.
      ]. 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 [
      • Schrepf A.
      • Clevenger L.
      • Christensen D.
      • DeGeest K.
      • Bender D.
      • Ahmed A.
      • et al.
      Cortisol and inflammatory processes in ovarian cancer patients following primary treatment: Relationships with depression, fatigue, and disability.
      ]. Chemotherapy is associated with increased proinflammatory cytokine levels, which may be associated with fatigue and sleep disturbance [
      • Liu L.
      • Mills P.J.
      • Rissling M.
      • Fiorentino L.
      • Natarajan L.
      • Dimsdale J.E.
      • et al.
      Fatigue and sleep quality are associated with changes in inflammatory markers in breast cancer patients undergoing chemotherapy.
      ,
      • Mills P.J.
      • Ancoli-Israel S.
      • Parker B.
      • Natarajan L.
      • Hong S.
      • Jain S.
      • et al.
      Predictors of inflammation in response to anthracycline-based chemotherapy for breast cancer.
      ,
      • Mills P.J.
      • Dimsdale J.E.
      Sleep apnea: a model for studying cytokines, sleep, and sleep disruption.
      ,
      • Wang X.S.
      • Shi Q.
      • Williams L.A.
      • Mao L.
      • Cleeland C.S.
      • Komaki R.R.
      • et al.
      Inflammatory cytokines are associated with the development of symptom burden in patients with NSCLC undergoing concurrent chemoradiation therapy.
      ]. Fatigue, depression, and stress are commonly reported side effects of radiotherapy [
      • Wratten C.
      • Kilmurray J.
      • Nash S.
      • Seldon M.
      • Hamilton C.S.
      • O’Brien P.C.
      • et al.
      Fatigue during breast radiotherapy and its relationship to biological factors.
      ,
      • Torres M.A.
      • Pace T.W.
      • Liu T.
      • Felger J.C.
      • Mister D.
      • Doho G.H.
      • et al.
      Predictors of depression in breast cancer patients treated with radiation: role of prior chemotherapy and nuclear factor kappa B.
      ,
      • Stone P.C.
      • Minton O.
      Cancer-related fatigue.
      ,
      • Geinitz H.
      • Zimmermann F.B.
      • Stoll P.
      • Thamm R.
      • Kaffenberger W.
      • Ansorg K.
      • et al.
      Fatigue, serum cytokine levels, and blood cell counts during radiotherapy of patients with breast cancer.
      ]. 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 [
      • Courtier N.
      • Gambling T.
      • Enright S.
      • Barrett-Lee P.
      • Abraham J.
      • Mason M.D.
      Psychological and immunological characteristics of fatigued women undergoing radiotherapy for early-stage breast cancer.
      ,
      • Bower J.E.
      • Ganz P.A.
      • Tao M.L.
      • Hu W.
      • Belin T.R.
      • Sepah S.
      • et al.
      Inflammatory biomarkers and fatigue during radiation therapy for breast and prostate cancer.
      ,
      • Wratten C.
      • Kilmurray J.
      • Nash S.
      • Seldon M.
      • Hamilton C.S.
      • O’Brien P.C.
      • et al.
      Fatigue during breast radiotherapy and its relationship to biological factors.
      ,
      • Torres M.A.
      • Pace T.W.
      • Liu T.
      • Felger J.C.
      • Mister D.
      • Doho G.H.
      • et al.
      Predictors of depression in breast cancer patients treated with radiation: role of prior chemotherapy and nuclear factor kappa B.
      ,
      • Geinitz H.
      • Zimmermann F.B.
      • Stoll P.
      • Thamm R.
      • Kaffenberger W.
      • Ansorg K.
      • et al.
      Fatigue, serum cytokine levels, and blood cell counts during radiotherapy of patients with breast cancer.
      ].

      Depression and bone health

      Depression has been linked to low bone mass [
      • Cizza G.
      Major depressive disorder is a risk factor for low bone mass, central obesity, and other medical conditions.
      ] and there is evidence that depression may lead to bone health deterioration and increased fracture risk in adults [
      • Whooley M.A.
      • Simon G.E.
      Primary care: managing depression in medical outpatients.
      ,
      • Mussolino M.E.
      Depression and hip fracture risk: the NHANES I epidemiologic follow-up study.
      ,
      • Jacka F.N.
      • et al.
      Depression and bone mineral density in a community sample of perimenopausal women: Geelong Osteoporosis Study.
      ,
      • Eskandari F.
      • et al.
      Low bone mass in premenopausal women with depression.
      ,
      • Wu Q.
      • et al.
      Depresion and low bone mineral density: a meta-analysis of epidemiologic studies.
      ] and that it could even affect peak bone mass in children and adolescents [
      • Weller E.B.
      • et al.
      Impact of depression and its treatment on the bones of growing children.
      ]. Low bone mineral density (BMD) is prevalent even at early stages of major depression [
      • Eskandari F.
      • et al.
      Low bone mass in premenopausal women with depression.
      ,
      • Yazici K.M.
      • et al.
      Bone mineral density in premenopausal women with major depressive disorder.
      ]. After adjusting for osteoporosis risk factors, BMD is negatively associated with depressive symptoms in older patients [
      • Robbins J.
      • et al.
      The association of bone mineral density and depression in an older population.
      ]. This association has been observed in a variety of patient populations [
      • Schweiger U.
      • et al.
      Low lumbar bone mineral density in patients with major depression.
      ,
      • Jacka F.N.
      • et al.
      Depression and bone mineral density in a community sample of perimenopausal women: Geelong Osteoporosis Study.
      ,
      • Eskandari F.
      • et al.
      Low bone mass in premenopausal women with depression.
      ,
      • Robbins J.
      • et al.
      The association of bone mineral density and depression in an older population.
      ,
      • Michelson D.
      • et al.
      Bone mineral density in women with depression.
      ,
      • Cizza
      • et al.
      Depression: a major unrecognized risk factor for osteoporosis?.
      ,
      • Halbreich U.
      • et al.
      Decreased bone mineral density in medicated psychiatric patients.
      ,
      • Dorn L.D.
      • et al.
      Association of depressive symptoms and anxiety with bone mass and density in ever-smoking and never-smoking adolescent girls.
      ,
      • Atteritano M.
      • et al.
      Bone mineral density, quantitative ultrasound parameters and bone metabolism in postmenopausal women with depression.
      ,
      • Erez H.B.
      • et al.
      The relationship of depression, anxiety and stress with low bone mineral density in postmenopausal women.
      ,
      • Michelson D.
      • et al.
      Bone mineral density in women with depression.
      ]. In men, bone mass is generally lower in those with depression compared to those who are not depressed [
      • Esel E.
      • et al.
      Effects of antidepressant treatment and of gender on serum leptin in patients with major depression.
      ,
      • Mussolino M.E.
      • et al.
      Depression and bone mineral density in young adults: results from NHANES III.
      ,
      • Whooley M.A.
      • et al.
      Depressive symptoms and bone mineral density in older men.
      ,
      • Wong S.Y.
      • et al.
      Depression and bone mineral density: is there a relationship in elderly Asian men? Results from Mr. Os (Hong Kong).
      ].
      Danielson et al. [
      • Danielson
      • Michelle E.
      • et al.
      Familial resemblance of bone mineral density (BMD) and calcaneal ultrasound attenuation: the BMD in mothers and daughters study.
      ] measured the BMD of 207 mother-daughter 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 [
      • Erez H.B.
      • et al.
      The relationship of depression, anxiety and stress with low bone mineral density in postmenopausal women.
      ,
      • Silverman S.L.
      • et al.
      Prevalence of depressive symptoms in postmenopausal women with low bone mineral density and/or prevalent vertebral fracture: results from the Multiple Outcomes of Raloxifene Evaluation (MORE) study.
      ] and one study of men [
      • Wong S.Y.
      • et al.
      Depression and bone mineral density: is there a relationship in elderly Asian men? Results from Mr. Os (Hong Kong).
      ] demonstrated a positive association between depressive symptoms and a decrease in BMD. Two [
      • Diem S.J.
      • et al.
      Depressive symptoms and rates of bone loss at the hip in older women.
      ,
      • Diem S.J.
      • et al.
      Depression symptoms and rates of bone loss at the hip in older men.
      ] longitudinal studies reported that depression symptoms were associated with a decrease in BMD at the total hip. One of these studies [
      • Diem S.J.
      • et al.
      Depressive symptoms and rates of bone loss at the hip in older women.
      ] found that the number of depressive symptoms correlated with rates of bone loss. In the other study [
      • Diem S.J.
      • et al.
      Depression symptoms and rates of bone loss at the hip in older men.
      ], 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 [
      • Cizza G.
      • et al.
      Depression and osteoporosis: a research synthesis with meta-analysis.
      ]. Yirmiya and Bab [
      • Yirmiya R.
      • Bab I.
      Major depression is a risk factor for low bone mineral density: a meta-analysis.
      ] 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 [
      • Williams L.J.
      • et al.
      Depression and bone metabolism: a review.
      ]. In another meta-analysis, Wu et al. showed a pooled lower BMD at the spine and hip for depressed subjects compared to non-depressed controls [
      • Wu Q.
      • et al.
      Depresion and low bone mineral density: a meta-analysis of epidemiologic studies.
      ]. 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 [
      • Lapi F.
      • Simonetti M.
      • Michieli R.
      • Pasqua A.
      • Brandi M.L.
      • Frediani B.
      • et al.
      Assessing 5-year incidence rates and determinants of osteoporotic fractures in primary care.
      ].
      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) [
      • Kamholz B.
      • et al.
      Depression after hip fracture.
      ]. The MOBILIZE Boston Study showed that the association of depressive symptoms with fall risk in older adults is mediated in part by chronic pain [
      • Eggermont
      • Laura H.P.
      • et al.
      Depressive symptoms, chronic pain, and falls in older community-dwelling adults: the MOBILIZE Boston Study.
      ]. 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 [
      • Iaboni A.
      • Flint A.J.
      The complex interplay of depression and falls in older adults: a clinical review.
      ].
      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 [
      • Silverman S.L.
      • et al.
      Prevalence of depressive symptoms in postmenopausal women with low bone mineral density and/or prevalent vertebral fracture: results from the Multiple Outcomes of Raloxifene Evaluation (MORE) study.
      ]. In a prospective study of older Mexican-American women, higher levels of depression predicted self-reported fractures [
      • Tolea M.I.
      • et al.
      Depressive symptoms as a risk factor for osteoporosis and fractures in older Mexican-American women.
      ]. 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 [
      • Forsen L.
      • et al.
      Mental distress and risk of hip fracture. Do broken hearts lead to broken bones?.
      ]. 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 [
      • Mussolino M.E.
      Depression and hip fracture risk: the NHANES I epidemiologic follow-up study.
      ]. 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 [
      • Whooley M.A.
      • et al.
      Depression, falls, and risk of fracture in older women. Study of Osteoporotic Fractures Research Group.
      ]. In a longitudinal cohort study in Norway, both pre- and post-menopausal women with mental distress had increased fracture risk [
      • Sogaard A.J.
      • et al.
      Long-term mental distress, bone mineral density and non-vertebral fractures. The Tromso Study.
      ].
      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 [
      • Cizza
      • et al.
      Depression: a major unrecognized risk factor for osteoporosis?.
      ,
      • Amsterdam J.D.
      • Hooper M.B.
      Bone density measurement in major depression.
      ,
      • Warden S.J.
      • Robling A.G.
      • Haney E.M.
      • Turner C.H.
      • Bliziotes M.M.
      The emerging role of serotonin (5-hydroxytryptamine) in the skeleton and its mediation of the skeletal effects of low-density lipoprotein receptor-related protein 5 (LRP5).
      ] with increased corticotropin-releasing hormone (CRH) production [
      • Michelson D.
      • et al.
      Bone mineral density in women with depression.
      ]. A few studies have observed increased plasma cortisol [
      • Kahl K.G.
      • et al.
      Bone mineral density, bone turnover, and osteoprotegerin in depressed women with and without borderline personality disorder.
      ,
      • Altindag O.
      • et al.
      Relation of cortisol levels and bone mineral density among premenopausal women with major depression.
      ] or increased UFC [
      • Amsterdam J.D.
      • Hooper M.B.
      Bone density measurement in major depression.
      ] though no differences were found in other studies [
      • Kahl K.G.
      • et al.
      Bone mineral density, bone turnover, and osteoprotegerin in depressed women with and without borderline personality disorder.
      ,
      • Eskandari F.
      • et al.
      Low bone mass in premenopausal women with depression.
      ,
      • Kavuncu Vural
      • et al.
      Bone metabolism and bone mineral density in premenopausal women with mild depression.