Depression as a systemic disease

doi:10.1016/j.pmip.2016.11.002

Personalized Medicine in Psychiatry

Volumes 1–2, March–April 2017, Pages 11-25

https://doi.org/10.1016/j.pmip.2016.11.002 Get rights and content

Highlights

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Depression increases the risk and progression of a variety of medical disorders.
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Increased inflammation is observed in cancer, heart disease and depression.
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Childhood trauma predisposes to depression and increased inflammation.
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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 [1]. According to the World Health Organization (WHO), it will become the second leading cause of disability-adjusted life years lost by the year 2020 [2]. Depression is believed to increase the risk, accelerate the progression and portend a poorer treatment response of a variety of medical disorders, including cardiovascular disease [4], [5], [6], stroke, cancer, renal disease and diabetes [7]. Processes as diverse as inflammation, neuroendocrine dysregulation, altered platelet activity, alterations in autonomic nervous system activity and decreased bone density may play a role in complicating the prognosis of major depression, especially in the setting of comorbid medical illness (Table 1, Table 2).

Section snippets

Depression and heart disease

According to the WHO Global Burden of Disease Survey, coronary heart disease and major depressive disorder are currently the two leading causes of disability in developed countries and it is estimated that this will apply to all countries throughout the world by the year 2020 [9], [10]. A bidirectional association between depression and heart disease has been established and reviewed [12], [13], [14], [15], [16], [17], [18], [19], [20]. Ample evidence suggests that depression is highly

Depression and cancer

Prevalence rates for depression in patients with cancer range from 1.5% to 50%, with median point prevalence rates between 15% and 29% [174], [175], [176], [177], [178]. A study by Linden [179] and a review by Ng [180] in over 9000 patients calculated prevalence rates of 10.8 and 12.9%, respectively. One large-scale prospective study found that cancer diagnosis and treatment resulted in a four-fold increase in depression occurrence during the first two years after diagnosis [181]. It leads to a

Depression and bone health

Depression has been linked to low bone mass [352] and there is evidence that depression may lead to bone health deterioration and increased fracture risk in adults [353], [354], [355], [356], [357] and that it could even affect peak bone mass in children and adolescents [358]. Low bone mineral density (BMD) is prevalent even at early stages of major depression [356], [360]. After adjusting for osteoporosis risk factors, BMD is negatively associated with depressive symptoms in older patients

Depression and stroke

Nearly one third of stroke survivors develop depression [292]. Conversely, depression has been linked to various risk factors for stroke [293], [294], [295], [296]. Prior studies have found that depression and dementia are individually associated with increased risk of stroke [296], [297], [298], [299], [300], [301], [302], [303], [304], [305], [306].

There is evidence suggesting that depressive symptoms or diagnoses consistently predict elevated risk of stroke onset [298], [299], [300]. Recent

Depression and diabetes

The prevalence of depression is increased in patients with diabetes. Anderson et al. [326] performed a meta-analysis that included studies of patients with type 1 and 2 diabetes. The overall odds of depression were twice as high for patients with diabetes compared to non-diabetic controls (OR = 2.0, 95% CI 1.8–2.2). Pouwer et al. [327] found that the prevalence of depressive affect was 25% and 30% for men and women, respectively, in type 1 diabetes, when using the Center for Epidemiologic Studies

Conclusions

Depression is common in the general population. Depression may be conceptualized as a systemic illness because of the several biological mechanisms by which it can affect general health. A bidirectional relationship between depression and some of the medical disorders examined above has already been established through an emerging literature reporting on the medical complications of depression. Enhanced inflammation, HPA axis hyperactivity, disrupted arterial wall repair, oxidative damage,

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Combined influence of depression severity and low-grade inflammation on incident hospitalization and mortality risk in Italian adults
2021, Journal of Affective Disorders
Citation Excerpt :
Depression is comorbid with diverse common health conditions, such as cardiovascular disease (CVD)(Dhar and Barton, 2016), cancer (Young and Singh, 2018) and diabetes (Darwish et al., 2018). A bidirectional relationship has been hypothesized at the basis of these comorbidities, and inflammation has been proposed to play and important role in this link (Darwish et al., 2018; Dhar and Barton, 2016; Sotelo and Nemeroff, 2017; Young and Singh, 2018). Indeed, beyond the known association of circulating inflammation with the risk of being affected by these conditions (Darwish et al., 2018; Dhar and Barton, 2016; Young and Singh, 2018), high levels of circulating pro-inflammatory cytokines like interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α have been associated with depressive symptoms, as well as circulating levels of inflammatory markers like C-reactive protein (CRP)(Mora et al., 2018; Pfau et al., 2018; Strawbridge et al., 2017).
Depression and low-grade systemic inflammation are associated risk factors for hospitalizations and mortality, although the nature of this relationship is under-investigated.
We performed multivariable Cox regressions of first hospitalization/mortality for all and specific causes vs depression severity, in an Italian population cohort (N=13,176; age≥35 years; 49.4% men), incrementally adjusting for sociodemographic, health and lifestyle factors. We tested potential mediation, additive and interactive effects of INFLA-score, a composite circulating inflammation index, and potential concurrent mediations of main lifestyles and chronic conditions.
Over 4,856 hospitalizations (median follow-up 7.28 years), we observed an increased incident risk of events by 24% (CI=17-32%) and 59% (30-90%) for moderate and severe depression, which also showed a 125% (33-281%) increased risk of all-cause mortality (over 471 deaths, 8.24 years). These remained stable after adjustment for lifestyles, health conditions and INFLA-score, which explained 2.1%, 7.6%, 16.3% and 8%, 14.9% and 12% of depression influence on hospitalizations and mortality risk, respectively. These proportions remained substantially stable after reciprocal adjustments. INFLA-score showed significant additive (but not interactive) effects on both hospitalizations and mortality risk.
Depression severity was defined using a sub-version of Patient Health Questionnaire 9, which was validated here. Directionality links among exposures could not be established since they were collected simultaneously.
These findings suggest a combined influence of depression and low-grade inflammation on health, which is partly intertwined and dependent on lifestyles and chronic conditions. This suggests the existence of pathways other than inflammation through which depression may play its detrimental effect.
Links Between Child and Adolescent Psychiatric Disorders and Cardiovascular Risk
2020, Canadian Journal of Cardiology
Citation Excerpt :
MDD and/or attempted suicide was the strongest risk factor for women, and the fourth strongest risk factor (after obesity, smoking, and hypertension) for men. There appears to be evidence of dose-response effects, because greater burden of depression symptoms was associated with increased risk of CVD and CVD events.106,108-116 A meta-analysis of 11 studies showed elevated relative risk of depression in predicting new-onset coronary artery disease in adults was 1.64 (95% CI, 1.29-2.08).117
This narrative review, with an emphasis on children and adolescents, addresses the link between 5 psychiatric disorders and cardiovascular risk: attention deficit hyperactivity disorder, autism spectrum disorders, anxiety disorders, depression, and bipolar disorders. The evidence regarding cardiovascular risk factors, noninvasive measures of early atherosclerosis, and cardiovascular disease prevalence and/or mortality is summarized. Whereas multiple studies have examined stimulant treatment of attention deficit hyperactivity disorder in relation to cardiovascular death, and autonomic-vagal function in autism spectrum disorders, little is known regarding atherosclerotic cardiovascular disease in patients with these conditions. For anxiety disorders, there is a gap in knowledge regarding cardiovascular risk in clinical samples of youth. In contrast to the adult literature, there are few studies regarding depression diagnoses, as opposed to self-reported symptoms, in relation to cardiovascular risk in youth. For bipolar disorder, youth studies focused on epidemiologic samples and various mood-stabilizing medications are warranted. General recommendations for future research include: larger samples, prospective repeated measures studies, and the integration of clinical and biological mediators with noninvasive measures of early atherosclerosis. Overall, the potential implications of cardiovascular risk factors are multiplied in youth with psychiatric conditions, because these risk factors are relevant not only to cardiovascular disease but to mental health and cognitive function. A shift in thinking regarding treatment paradigms for youth with psychiatric disorders is warranted. Pending changes in clinical practice guidelines and care delivery models, patients, families, clinicians, and policy makers can act on currently available information to reduce cardiovascular risk among children and adolescents with psychiatric disorders.
Dans le cadre d’une revue non systématique centrée sur les enfants et les adolescents, nous avons étudié le lien entre le risque cardiovasculaire et cinq troubles psychiatriques : le trouble d'hyperactivité avec déficit de l'attention (THDA) les troubles du spectre de l’autisme, les troubles de l’anxiété, la dépression et les troubles bipolaires. Nous présentons une synthèse des données probantes relatives aux facteurs de risque cardiovasculaire, aux évaluations non invasives de l’athérosclérose précoce et à la prévalence de la maladie cardiovasculaire et/ou de la mortalité d’origine cardiovasculaire. Même si de multiples études ont examiné le lien entre le traitement du THDA au moyen d’un agent stimulant et le décès d’origine cardiovasculaire ou encore le rôle de la fonction du système nerveux parasympathique dans les troubles du spectre de l’autisme, on en sait peu sur la maladie cardiovasculaire athéroscléreuse chez les patients atteints de tels troubles psychiatriques. Dans le cas des troubles de l’anxiété, on dispose de peu de données sur le risque cardiovasculaire chez les jeunes formant les échantillons cliniques. Contrairement aux études menées chez les adultes, peu d’études réalisées auprès de jeunes examinent le lien entre le diagnostic de dépression, par opposition aux symptômes autodéclarés, et le risque cardiovasculaire. En ce qui concerne les troubles bipolaires, des études portant sur des échantillons épidémiologiques de jeunes patients et sur divers stabilisateurs de l’humeur s’imposent. Parmi les recommandations générales concernant la réalisation de futures études, citons : le recours à de plus vastes échantillons, la réalisation d’études prospectives à mesures répétées et l’intégration de mesures non invasives des médiateurs cliniques et biologiques de l’athérosclérose précoce. Dans l’ensemble, les répercussions possibles des facteurs de risque cardiovasculaire sont multipliées chez les jeunes atteints d’un trouble psychiatrique, parce que ces facteurs de risque intéressent non seulement la maladie cardiovasculaire, mais aussi la santé mentale et la fonction cognitive. Un changement de paradigme pour le traitement des jeunes atteints d’un trouble psychiatrique s’impose. D’ici à ce que les lignes directrices de pratique clinique et les modèles de prestation des soins soient mis à jour, les patients, leurs familles, les cliniciens et les décideurs peuvent intervenir en se fiant aux données existantes afin de réduire le risque cardiovasculaire chez les enfants et les adolescents atteints d’un trouble psychiatrique.
Cell Type–Specific Methylome-wide Association Studies Implicate Neurotrophin and Innate Immune Signaling in Major Depressive Disorder
2020, Biological Psychiatry
We sought to characterize methylation changes in brain and blood associated with major depressive disorder (MDD). As analyses of bulk tissue may obscure association signals and hamper the biological interpretation of findings, these changes were studied on a cell type–specific level.
In 3 collections of human postmortem brain (n = 206) and 1 collection of blood samples (N = 1132) of MDD cases and controls, we used epigenomic deconvolution to perform cell type–specific methylome-wide association studies within subpopulations of neurons/glia for the brain data and granulocytes/T cells/B cells/monocytes for the blood data. Sorted neurons/glia from a fourth postmortem brain collection (n = 58) were used for validation purposes.
Cell type–specific methylome-wide association studies identified multiple findings in neurons/glia that were detected across brain collections and were reproducible in physically sorted nuclei. Cell type–specific analyses in blood samples identified methylome-wide significant associations in T cells, monocytes, and whole blood that replicated findings from a past methylation study of MDD. Pathway analyses implicated p75 neurotrophin receptor/nerve growth factor signaling and innate immune toll-like receptor signaling in MDD. Top results in neurons, glia, bulk brain, T cells, monocytes, and whole blood were enriched for genes supported by genome-wide association studies for MDD and other psychiatric disorders.
We both replicated and identified novel MDD–methylation associations in human brain and blood samples at a cell type–specific level. Our results provide mechanistic insights into how the immune system may interact with the brain to affect MDD susceptibility. Importantly, our findings involved associations with MDD in human samples that implicated many closely related biological pathways. These disease-linked sites and pathways represent promising new therapeutic targets for MDD.
Depression and cardiovascular risk: Epidemiology, mechanisms, and implications
2019, Neurobiology of Depression: Road to Novel Therapeutics
Together, major depressive disorder (MDD) and cardiovascular disease (CVD) are among the most costly and burdensome medical conditions. The leading cause of death among those with MDD is CVD, and depression postcardiovascular event is associated with worse outcome. Cardiovascular risk factors (CVRFs) are similarly relevant to MDD. Depression is predictive of new-onset CVD and CVD mortality, independent of multiple potentially confounding variables. There is also evidence of dose-effects, with greater severity of depression symptoms associated with CVD risk and vascular function and structure. Several mechanisms may underlie the link between CVD and depression, including inflammation, oxidative stress, hypothalamic-pituitary-adrenal axis, metabolic dysfunction, and behavioral effects. Accordingly, pharmacological treatments have assessed these mechanisms as potential avenues for drug targets, for both depression and CVD. The CVD-MDD link may offer insights that inform our understanding of diagnosis, etiopathology, and treatment.
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Depression as a systemic disease

Highlights

Abstract

Introduction

Section snippets

Depression and heart disease

Depression and cancer

Depression and bone health

Depression and stroke

Depression and diabetes

Conclusions

Biol Psychiatry

J Am Coll Cardiol

J Cardiac Fail

J Thorac Cardiovasc Surg

J Affect Disord

Gen Hosp Psychiatry

Am J Cardiol

Int J Cardiol

J Psychosom Res

J Psychosom Res

J Am Coll Cardiol

J Card Fail

Heart Lung J Acute Crit Care

J Am Coll Cardiol

J Am Coll Cardiol

J Psychosom Res

Psychosomatics

Prog Neuropsychopharmacol Biol Psychiatry

J Card Fail

Am J Clin Nutr

Biol Psychiatry

Am J Cardiol

Biol Psychiatry

Biol Psychiatry

Am J Cardiol

Am J Cardiol

Psychoneuroendocrinology

Lancet

Med Hypotheses

Brain Behav Immun

Brain Behav Immun

J Neuroimmunol

Psychoneuroendocrinology

J Psychosom Res

Biol Psychiatry

Brain Behav Immun

Am Heart J

Global burden of depressive disorders in the year 2000

Br J Psychiatry

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

Lancet

Mental depression and cardiovascular disease: a multifaceted, bidirectional association

Semin Thromb Hemost

Depression and coronary heart disease

Curr Atheroscler Rep

Controversies in community-based psychiatric epidemiology: let the data speak for themselves

Arch Gen Psychiatry

Depression and cardiovascular disease: co-occurrence of shared genetic substrates?

Mol Psychiatry

The relationship of depression to cardiovascular disease: epidemiology, biology, and treatment

Arch Gen Psychiatry

Treatment of depression in cardiovascular disease

Depress Anxiety

Heartache and heartbreak—the link between depression and cardiovascular disease

Nat Rev Cardiol

The interface of depression and cardiovascular disease: therapeutic implications

Ann N Y Acad Sci

Cardiac risk markers and response to depression treatment in patients with coronary heart disease

Psychosom Med