Elsevier

Psychiatry Research

Volume 229, Issues 1–2, 30 September 2015, Pages 27-36
Psychiatry Research

Review article
Examining the role of neuroinflammation in major depression

https://doi.org/10.1016/j.psychres.2015.06.009Get rights and content

Highlights

  • Review recent literature regarding the connection between inflammation and MDD.

  • Hyperactivity of the HPA axis is associated with MDD in various populations.

  • Increased TNF-α, CRP and IL-6 are generally exhibited in MDD patients.

  • Highlight the need for further studies to improve early and accurate diagnosis.

Abstract

Recent findings have established a connection between inflammation and major depression and specifically the role of the hypothalamic–pituitary–adrenal (HPA) axis in depression. This article reviews clinical and experimental studies examining the role of the HPA axis, HPA hyperactivity (resulting in increased cortisol levels), as well as the proinflammatory cytokines tumor necrosis factor, C-reactive protein, and the interleukins, in depressed patients. Similarly this paper will review data supporting increased cytokine levels in depression and specifically differential effects in treatment-resistant patients, as well as potentially distinguishing in particular depression subtypes. Understanding the role of the immune system and inflammation in patients with major depression is essential in order to develop efficacious treatments potentially targeting inflammation in relation to the depression in order to reduce patient symptomatology and comorbidities.

Introduction

The prevalence of mental health disorders continues to rise worldwide, such that it is estimated that 1 in 4 individuals will be affected by a mental health disorder at some point in their lifetime (World Health Organization, 2011). Research has found that the most prevalent mental health disorders are depressive and anxiety disorders (Kessler et al., 2012), both of which hinder an individual’s functioning on multiple domains.

Depression is estimated to significantly impact 350 million people worldwide and it is projected to become the primary cause of global disease burden by 2030 (World Health Organization, 2012). Furthermore, the Global Burden of Disease Study found that depressive disorders were the second leading cause of Years Lived with Disability (YLDs) and the leading cause of Disability Adjusted Life Years (DALYs) globally (Ferrari et al., 2013). Depressive disorders, according to the Diagnostic and Statistical Manual of Mental Disorders (DSM IV) (American Psychiatric Association, 2000), include Major Depressive Disorder (MDD) and Dysthymia. MDD is characterized by Major Depressive Episodes (MDE) that are symptomatic almost all day, every day for periods of at very least 2 weeks, whereas dysthymia is described as a milder but more chronic form of depression lasting for at least 2 years (Ferrari et al., 2013). Changes with the DSM-5 (American Psychiatric Association, 2013), have included the insertion of Persistent Depressive Disorder (that includes both Dysthymia, and chronic and unremitted Major Depressive Disorder), as well as including a variety of specifiers, such as with anxious distress,” in which the presence of anxiety symptoms suggests potentially higher risks of complications in diagnosis, as well as a higher likelihood of chronicity (Lamers et al., 2011).

With medical comorbidities being very common in MDD, growing interest has been placed on the role of the immune system and inflammation and its relation to psychiatric disorders. Although it has generally been said that genetic and environmental factors may play a significant role in the cause of depression (Lesch, 2004), recent research has focused on the role of cytokines and immune biomarkers (Felger and Lotrich, 2013) as predictors of the disorder. The present commentary will review the current scientific literature in regard to immune mediated theories in depression.

Section snippets

Methods

The present review is aimed at evaluating and interpreting literature regarding depressive disorders and the role of the immune system, specifically, HPA activity and a variety of inflammatory cytokines. A PubMed, MEDLINE, and PsycINFO literature search was performed for the past decade (2004 to 2014), for clinical studies in depressed patients assessing the role of the immune system. Keywords for this review included: major depression, immune system, inflammation, cytokines, TNF, interleukin,

The immune system and cytokines

The role of cytokines can be understood simply as hormonal messengers responsible for most of the biological effects in the immune system. They can be functionally divided into two groups: those that are proinflammatory and those, which are essentially anti-inflammatory, but may also promote allergic or autoimmune responses.

Lymphocytes (the primary cells of the immune response) are of two types, the T and B lymphocytes, both of which specifically tailor their responses to each pathogenic insult

Cortisol and the HPA axis

Major Depressive Disorder (MDD) is a severely debilitating disorder that imposes a significant burden on one’s quality of life. MDD is often comorbid with both psychiatric illnesses (Kessler et al., 2012), as well as medical illnesses including metabolic syndrome (Park et al., 2014), cancer, diabetes and cardiovascular diseases (Benton et al., 2007). Individuals with MDD are at an increased risk of developing coronary artery disease, as well as of having poorer outcomes when suffering with

C-reactive protein in depression

C-reactive Protein (CRP) has been utilized as a biomarker for detecting inflammation, in which levels exceeding 10 mg/L are considered to predict inflammatory states (Pepys and Hirschfield, 2003, Nordestgaard, 2009), and is a significant predictor of coronary heart disease (Tracy et al., 1997, Koenig et al., 1999, Ridker et al., 2000, Danesh et al., 2004). Given the relationship between depressive disorders, inflammatory disease, and cardiac disease, researchers have begun investigating the

Inflammatory response to antidepressant treatment

Various studies have been conducted in MDD patients to specifically examine the effect of antidepressant treatment on the HPA axis, as well as on cytokine activity (see Table 6). Fluoxetine response was evaluated in 20 premenopausal females with MDD in a study in which they were administered 750 mg of metyrapone on 2 separate intervals, followed by 20 mg of fluoxetine for a 4 week period; nonresponders (50% or less decrease in HAM-D scores) at week 4 were increased to 40 mg for the final two weeks

Conclusion

Depressive disorders continue to increase in prevalence globally and cause substantial impairments in an individual’s functioning, as well as significant economic burden. It is therefore essential to comprehensively understand the mechanisms that contribute to these disorders in order to develop efficacious treatment strategies. Research focused on neuroimmunology has provided important information, specifically in regard to HPA activity, as well as inflammatory and anti-inflammatory properties.

Conflict of interest

Dr. Katzman has participated on advisory boards and/or similar committees for GlaxoSmithKline Inc., Wyeth Pharmaceuticals, Lundbeck Canada Inc., Eli Lilly, Organon, AstraZeneca, Janssen-Ortho Inc., Shire, Bristol-Myers Squibb, Pfizer, Biovail, Genuine Health, Boehringer Ingelheim, and Solvay; has received research funding from CIHR, Sick Kids Foundation, Centre for Addiction and Mental Health Foundation, Canadian Psychiatric Research Foundation, Canadian Foundation for Innovation,

References (79)

  • J. Krogh et al.

    The association between depressive symptoms, cognitive function, and inflammation in major depression

    Brain, Behavior, and Immunity

    (2014)
  • K. Markopoulou et al.

    The ratio of cortisol/DHEA in treatment resistant depression

    Psychoneuroendocrinology

    (2009)
  • M.S. McKay et al.

    The impact of treatment on HPA axis activity in unipolar major depression

    Journal of Psychiatric Research

    (2010)
  • O. Milstein et al.

    CTLs respond with activation and granule secretion when serving as targets for T-cell recognition

    Blood

    (2011)
  • S.M. O’Brien et al.

    Plasma cytokine profiles in depressed patients who fail to respond to selective serotonin reuptake inhibitor therapy

    Journal of Psychiatric Research

    (2007)
  • C.M. Pariante et al.

    The HPA axis in major depression: classical theories and new developments

    Trends in Neurosciences

    (2008)
  • S. Park et al.

    Metabolic syndrome and elevated C-reactive protein levels in elderly patients with newly diagnosed depression

    Psychosomatics

    (2014)
  • L. Pavón et al.

    Th2 cytokine response in Major Depressive Disorder patients before treatment

    Journal of Neuroimmunology

    (2006)
  • D.G. Perahia et al.

    Switching to duloxetine in selective serotonin reuptake inhibitor non- and partial-responders: effects on painful physical symptoms of depression

    Journal of Psychiatric Research

    (2009)
  • T.R. Powell et al.

    Tumor necrosis factor and its targets in the inflammatory cytokine pathway are identified as putative transcriptomic biomarkers for escitalopram response

    European Neuropsychopharmacology

    (2013)
  • S. Rudolf et al.

    Elevated IL-6 levels in patients with atypical depression but not in patients with typical depression

    Psychiatry Research

    (2014)
  • S. Saarijarvi et al.

    Alexithymia and depression: a 1-year follow-up study in outpatients with major depression

    Journal of Psychosomatic Research

    (2001)
  • R. Yoshimura et al.

    Higher plasma interleukin-6 (IL-6) level is associated with SSRI- or SNRI-refractory depression

    Progress in Neuro-Psychopharmacology & Biological Psychiatry

    (2009)
  • E.A. Young et al.

    HPA axis activation in major depression and response to fluoxetine: a pilot study

    Psychoneuroendocrinology

    (2004)
  • M. Adzic et al.

    Acute or chronic stress induce cell compartment-specific phosphorylation of glucocorticoid receptor and alter its transcriptional activity in Wistar rat brain

    Journal of Endocrinology

    (2009)
  • Diagnostic and Statistical Manual of Mental Disorders

    (2000)
  • Diagnostic and Statistical Manual of Mental Disorders

    (2013)
  • T. Benton et al.

    Medical co-morbidity in depressive disorders

    Annals of Clinical Psychiatry

    (2007)
  • A. Berger

    Th1 and Th2 responses: what are they?

    BMJ

    (2000)
  • G. Cizza et al.

    Plasma CRP levels in premenopausal women with major depression: a 12-month controlled study

    Hormone and Metabolic Research

    (2009)
  • P.J. Cowen

    Cortisol, serotonin and depression: all stressed out?

    The British Journal of Psychiatry

    (2002)
  • J. Danesh et al.

    C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease

    The New England Journal of Medicine

    (2004)
  • K. Dannehl et al.

    The predictive value of somatic and cognitive depressive symptoms for cytokine changes in patients with major depression

    Journal of Neuropsychiatric Disease and Treatment

    (2014)
  • A.J. Ferrari et al.

    Burden of depressive disorders by country, sex, age, and year: findings from the global burden of disease study 2010

    PLoS Medicine

    (2013)
  • P. Fitzgerald et al.

    Cutaneous glucocorticoid receptor sensitivity and pro-inflammatory cytokine levels in antidepressant-resistant depression

    Psychological Medicine

    (2006)
  • G. Gartlehner et al.

    Comparative benefits and harms of second-generation antidepressant for treating major depressive disorder: an updated meta-analysis

    Annals of Internal Medicine

    (2011)
  • R. Grassi-Oliveira et al.

    Increased soluble tumor necrosis factor-alpha receptors in patients with major depressive disorder

    Psychiatry and Clinical Neurosciences

    (2009)
  • A. Hess et al.

    Blockade of TNF-α rapidly inhibits pain responses in the central nervous system

    Proceedings of the National Academy of Sciences

    (2011)
  • K. Honkalampi et al.

    Is alexithymia a permanent feature in depressed outpatients? Results from a 6-month follow-up study

    Psychotherapy and Psychosomatics

    (2000)
  • Cited by (0)

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