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At the end of this article, readers should be able to:
1. Understand the correlation between inflammation and treatment-resistant depression.
2. Describe the clinical factors associated with treatment non-response and how these factors correlate with inflammation.
3. Identify the mechanisms that lead to nonresponse.
Major depression is a disease that affects approximately 20 million adults in the US and has a devastating impact on personal and public health.1 Although successful treatment substantially reduces functional impairment and economic burden, up to one-third of depressed patients are resistant to treatment with conventional antidepressants (eg, serotonin and/or norepinephrine reuptake inhibitors), even in the context of standardized attempts such as switching medications and/or augmenting with thyroid hormone, mood stabilizers, and atypical antipsychotics.2 Thus, roughly 7 million adults in the US are considered to have treatment-resistant depression (TRD), which emphasizes the need to develop new conceptual frameworks and new therapeutic targets to improve treatment outcome.
One factor that has received increasing attention regarding TRD is inflammation. A significant percentage of patients with TRD exhibit increased markers of inflammation, and clinical factors that are linked with treatment nonresponse are associated with inflammation. Inflammatory cytokines, which are critical mediators of the inflammatory response, have been found to sabotage and circumvent many of the mechanisms of action of conventional antidepressants. These findings provide powerful evidence that inhibition of inflammation or its downstream effects on mood may open up a host of new approaches to treatment for depression, especially for patients with TRD.
Invaluable to survival in the short term, chronic inflammation can lead to significant damage to multiple organ systems in the body—including the brain. Recognizing chronic inflammation as a common mechanism of disease, including cardiovascular disease, diabetes, and cancer, is one of the major insights of the past decade.3 Nevertheless, psychiatry began recognizing the role of inflammation in TRD only recently—as both the problem and a solution.
The correlation between TRD and inflammation
A number of clinical factors have been associated with TRD, including obesity, childhood maltreatment, anxiety disorders, personality disorders/neuroticism, bipolar disorder, and medical comorbidities (Table 1). Data show a dose-response relationship between BMI and TRD—the higher the BMI, the lower the response rate.4 Early life stress is also associated with poor treatment outcome. Childhood maltreatment has been associated with a significantly decreased likelihood of response or remission during antidepressant treatment.5 Likewise, anxiety disorders, including PTSD, obsessive-compulsive disorder, generalized anxiety disorder, and panic disorder, were found to be negative predictors of response in step 1 and especially in step 2 of the STAR*D.6
Comorbid personality disorders and high levels of neuroticism have also been shown to predict TRD.7 In addition, a significant percentage of patients with TRD have hidden bipolar disorder, for which antidepressants are often less effective and poorly tolerated.8 A dose-response relationship appears to exist between severity or degree of medical comorbidity and treatment resistance. For each organ system affected by illness, there is an approximately 20% decrease in the likelihood of antidepressant treatment response.9
Not only is there a dose-response relationship between BMI and a number of inflammatory markers, but also there is an array of inflammatory mediators that are released by fat cells, including the inflammatory cytokines tumor necrosis factor (TNF)-α, and interleukin (IL)-6 as well as the chemokine monocyte chemoattractant protein-1, which is a potent attractant for macrophages that accumulate in fatty tissue and sustain inflammatory responses.10 Childhood maltreatment has also been associated with increased markers of inflammation in depression, under resting conditions, and following stress. Depressed patients with a history of childhood maltreatment were found to exhibit increased plasma levels of the acute phase protein C-reactive protein (CRP), which is released by the liver during an inflammatory response.11 After exposure to a laboratory psychosocial stressor, persons with a history of childhood maltreatment showed increased plasma IL-6 levels and increased DNA binding of nuclear factor-κB (NF-κB) in peripheral blood mononuclear cells compared with controls.12 NF-κB is a lynchpin signaling molecule in the inflammatory cascade.
An increase of inflammatory markers has also been seen in patients with anxiety and personality disorders. Bipolar disorder has been associated with increased blood inflammatory markers as well as increased inflammatory cytokines, NF-κB, and markers of microglial activation in postmortem brain tissue.13 Patients with medical illnesses are well known to exhibit increased inflammation secondary to infection and the tissue damage and destruction that can activate the inflammatory response. The data indicate that treatment resistance may be in part a function of activation of inflammatory pathways. The clinical factors that may alert the clinician to which patients are most likely to exhibit increased inflammatory biomarkers and risk for treatment resistance include obesity, childhood maltreatment, bipolar disorder, and comorbid medical illness (Figure 1).
Multiple lifestyle, environmental, psychiatric, and medical factors contribute to and are a function of an inflammatory milieu associated with increased inflammatory cytokines, which can reduce the availability of monoamines, inhibit neurogenesis, and increase glutamate. Conventional antidepressants act on monoamine pathways to increase monoamine availability and require neurogenesis for efficacy. Moreover, glutamate is not a primary target of conventional antidepressant therapy. Cytokine effects on these biological processes thus conspire to sabotage and circumvent the mechanism of action of conventional antidepressants, leading to treatment resistance.
Dr Raison is Associate Professor of Psychiatry and Family and Consumer Sciences, Department of Psychiatry, University of Arizona College of Medicine, Tucson; Dr Felger is a Senior Associate in the Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta; and Dr Miller is William P. Timmie Professor of Psychiatry and Behavioral Sciences, Director of Psychiatric Oncology at the Winship Cancer Institute, and Director of the Emory Mind-Body Program.
Charles L. Raison, MD, reports that he is a steering committee member for NACCME, and he is involved in the creation of CME material for NACCME and CME Incite.
Jennifer C. Felger, PhD, has no disclosures to report.
Andrew H. Miller, MD, has no disclosures to report.
Ebrahim Haroon, MD (peer/content reviewer), reports that he receives grant support from the National Institute of Mental Health and the National Center for Complementary and Alternative Medicine.
1. Centers for Disease Control and Prevention. Current depression among adults—United States, 2006 and 2008. MMWR Morb Mortal Wkly Rep. 2010;59:1229-1235.
2. Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163:1905-1917.
3. Couzin-Frankel J. Inflammation bares a dark side. Science. 2010;330:1621.
4. Oskooilar N, Wilcox CS, Tong ML, Grosz DE. Body mass index and response to antidepressants in depressed research subjects. J Clin Psychiatry. 2009;70:1609-1610.
5. Nanni V, Uher R, Danese A. Childhood maltreatment predicts unfavorable course of illness and treatment outcome in depression: a meta-analysis [published correction appears in Am J Psychiatry. 2012;169:439]. Am J Psychiatry. 2012;169:141-151.
6. Rush AJ, Wisniewski SR, Warden D, et al. Selecting among second-step antidepressant medication monotherapies: predictive value of clinical, demographic, or first-step treatment features. Arch Gen Psychiatry. 2008;65:870-880.
7. Bock C, Bukh JD, Vinberg M, et al. The influence of comorbid personality disorder and neuroticism on treatment outcome in first episode depression. Psychopathology. 2010;43:197-204.
8. Correa R, Akiskal H, Gilmer W, et al. Is unrecognized bipolar disorder a frequent contributor to apparent treatment resistant depression? J Affect Disord. 2010;127:10-18.
9. Iosifescu DV, Nierenberg AA, Alpert JE, et al. The impact of medical comorbidity on acute treatment in major depressive disorder. Am J Psychiatry. 2003;160:2122-2127.
10. Shelton RC, Miller AH. Eating ourselves to death (and despair): the contribution of adiposity and inflammation to depression. Prog Neurobiol. 2010;91:275-299.
11. Danese A, Moffitt TE, Pariante CM, et al. Elevated inflammation levels in depressed adults with a history of childhood maltreatment [published correction appears in Arch Gen Psychiatry. 2008;65:725]. Arch Gen Psychiatry. 2008;65:409-415.
12. Miller AH, Maletic V, Raison CL. Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol Psychiatry. 2009;65:732-741.
13. Stertz L, Magalhães PV, Kapczinski F. Is bipolar disorder an inflammatory condition? The relevance of microglial activation. Curr Opin Psychiatry. 2013;26:19-26.
14. Lanquillon S, Krieg JC, Bening-Abu-Shach U, Vedder H. Cytokine production and treatment response in major depressive disorder. Neuropsychopharmacology. 2000;22:370-379.
15. Eller T, Vasar V, Shlik J, Maron E. Pro-inflammatory cytokines and treatment response to escitalopram in major depressive disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2008;32:445-450.
16. Raison CL, Rutherford RE, Woolwine BJ, et al. A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers. JAMA Psychiatry. 2013;70:31-41.
17. Zhu CB, Lindler KM, Owens AW, et al. Interleukin-1 receptor activation by systemic lipopolysaccharide induces behavioral despair linked to MAPK regulation of CNS serotonin transporters. Neuropsychopharmacology. 2010;35:2510-2520.
18. Sublette ME, Galfalvy HC, Fuchs D, et al. Plasma kynurenine levels are elevated in suicide attempters with major depressive disorder. Brain Behav Immun. 2011;25:1272-1278.
19. O’Connor JC, Lawson MA, André C, et al. Induction of IDO by bacille Calmette-Guérin is responsible for development of murine depressive-like behavior. J Immunol. 2009;182:3202-3212.
20. Haroon E, Raison CL, Miller AH. Psychoneuroimmunology meets neuropsychopharmacology: translational implications of the impact of inflammation on behavior. Neuropsychopharmacology. 2012;37:137-162.
21. Perera TD, Dwork AJ, Keegan KA, et al. Necessity of hippocampal neurogenesis for the therapeutic action of antidepressants in adult nonhuman primates. PLoS One. 2011;6:e17600.
22. Koo JW, Duman RS. IL-1beta is an essential mediator of the antineurogenic and anhedonic effects of stress. Proc Natl Acad Sci U S A. 2008;105:751-756.
23. Sanacora G, Treccani G, Popoli M. Towards a glutamate hypothesis of depression: an emerging frontier of neuropsychopharmacology for mood disorders. Neuropharmacology. 2012;62:63-77.
24. Tilleux S, Hermans E. Neuroinflammation and regulation of glial glutamate uptake in neurological disorders. J Neurosci Res. 2007;85:2059-2070.
25. Ida T, Hara M, Nakamura Y, et al. Cytokine-induced enhancement of calcium-dependent glutamate release from astrocytes mediated by nitric oxide. Neurosci Lett. 2008;432:232-236.
26. Hardingham GE, Bading H. Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders. Nat Rev Neurosci. 2010;11:682-696.
27. Guillemin GJ. Quinolinic acid, the inescapable neurotoxin. FEBS J. 2012;279:1356-1365.
28. Raison CL, Dantzer R, Kelley KW, et al. CSF concentrations of brain tryptophan and kynurenines during immune stimulation with IFN-alpha: relationship to CNS immune responses and depression. Mol Psychiatry. 2010;15:393-403.
29. Steiner J, Walter M, Gos T, et al. Severe depression is associated with increased microglial quinolinic acid in subregions of the anterior cingulate gyrus: evidence for an immune-modulated glutamatergic neurotransmission? [published correction appears in J Neuroinflammation. 2013;10:34]. J Neuroinflammation. 2011;8:94.
30. Harrison NA, Brydon L, Walker C, et al. Inflammation causes mood changes through alterations in subgenual cingulate activity and mesolimbic connectivity. Biol Psychiatry. 2009;66:407-414.
31. Ressler KJ, Mayberg HS. Targeting abnormal neural circuits in mood and anxiety disorders: from the laboratory to the clinic. Nat Neurosci. 2007;10:1116-1124.
32. Miller AH, Haroon E, Raison CL, Felger JC. Cytokine targets in the brain: impact on neurotransmitters and neurocircuits. Depress Anxiety. 2013;30:297-306.
33. Eisenberger NI, Lieberman MD. Why rejection hurts: a common neural alarm system for physical and social pain. Trends Cogn Sci. 2004;8:294-300.
34. Yirmiya R, Goshen I. Immune modulation of learning, memory, neural plasticity and neurogenesis. Brain Behav Immun. 2011;25:181-213.
35. Warner-Schmidt JL, Vanover KE, Chen EY, et al. Antidepressant effects of selective serotonin reuptake inhibitors (SSRIs) are attenuated by antiinflammatory drugs in mice and humans [published correction appears in Proc Natl Acad Sci U S A. 2011;108:11297]. Proc Natl Acad Sci U S A. 2011;108:9262-9267.
36. Pearson TA, Mensah GA, Alexander RW, et al; Centers for Disease Control and Prevention; American Heart Association. Markers of inflammation and cardiovascular disease: application to clinical and public health practice: a statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation. 2003;107:499-511.
37. Miyaoka T, Wake R, Furuya M, et al. Minocycline as adjunctive therapy for patients with unipolar psychotic depression: an open-label study. Prog Neuropsychopharmacol Biol Psychiatry. 2012;37:222-226.
38. Ching AS, Kuhnast B, Damont A, et al. Current paradigm of the 18-kDa translocator protein (TSPO) as a molecular target for PET imaging in neuroinflammation and neurodegenerative diseases. Insights Imaging. 2012;3:111-119.
39. Rethorst CD, Toups MS, Greer TL, et al. Pro-inflammatory cytokines as predictors of antidepressant effects of exercise in major depressive disorder. Mol Psychiatry. 2012 Aug 28; [Epub ahead of print].
40. Pace TW, Negi LT, Adame DD, et al. Effect of compassion meditation on neuroendocrine, innate immune and behavioral responses to psychosocial stress. Psychoneuroendocrinology. 2009;34:87-98.
41. Reardon C, Duncan GS, Brüstle A, et al. Lymphocyte-derived ACh regulates local innate but not adaptive immunity. Proc Natl Acad Sci U S A. 2013;110:1410-1415.