Old friends hypothesis – modern world – depression
In this paper, Raison et al. explore evidence that the ‘old friends’ theory, heretofore associated with allergic and autoimmune diseases, can also be applied to major depression.
The ‘old friends’ theory suggests that immune interactions with pseudocommensal mycobacterial species, gut flora members and helminthes regulate the immune system, thus explaining lower rates of atopic (Th2-mediated) and autoimmune (Th1/Th17-mediated) diseases prior to the implementation of invigorated sanitation practices in developed countries in the early 20th century. The authors cite various studies demonstrating that addition of ‘old friends’ to the gut led to decreased plasma pro-inflammatory cytokine levels (IL-1beta, TNF-alpha, and IL-6) and increased anti-inflammatory IL-10 production, likely by enhancing Treg proliferation while attenuating Th1, Th17, and Th2 activity.
The crux of the authors’ argument is that psychosocial stress triggers a pro-inflammatory cascade, and major depressive disorder, along with atopic and autoimmune diseases, represents an inflammatory state, even in individuals who are otherwise medically healthy. Supporting findings include, to name a few: factors associated with depression (stress, illness, obesity, etc.) tend to increase peripheral inflammatory markers, while treatments (anti-depressants, psychotherapy, ECT, and exercise) lead to decreased inflammatory markers. Also, the authors cite studies supporting the idea that pro-inflammatory cytokine exposure decreases tolerance of psychosocial adversity – depression is a well-known side effect of interferon alpha therapy.
Thus, in a genetically vulnerable individual, psychosocial stressors can trigger an inappropriately aggressive inflammatory response given a deficit of tolerogenic immune training in industrialized societies. Future research directions include formally testing the potential of preparations made from ‘old friends’ to improve not only allergic and autoimmune diseases comorbid with major depression, but also major depression in medically healthy subjects.
SOURCE: Arch Gen Psychiatry 2010 Dec, 67: 1211
An update
In a 2011 review Charles L Raison and Andrew H Miller develop the idea that inflammation only contributes to depression in a subset of patients versus the possibility that the depressogenic effect of inflammatory activation is more widespread and varies depending on the degree of vulnerability any given individual evinces in interconnected physiologic systems known to be implicated in the etiology of major depressive disorder (MDD). Finally, the treatment implications of these various possibilities are discussed.
In this review, the authors highlighted that activation of inflammatory processes is neither necessary nor sufficient to reliably produce the syndrome we currently define as depression. Rather, data show that groups of depressed individuals demonstrate elevated levels of multiple inflammatory biomarkers because there are more individuals with these elevations within depressed populations than comparison groups.
The authors have provided data that support two opposing explanations for this phenomenon: first that individuals with increased inflammation comprise a physiologically discrete depressive subtype, and second that because inflammatory pathways are fully integrated into larger mind– body systems evolved to cope with environmental danger, it may be the case that even low levels of inflammatory stimulation may be depressogenic in individuals with vulnerability patterns in nonimmune elements of these larger systems.
The authors conclude by noting that studies under way to determine the efficacy of anti-inflammatory interventions for depression will at one and the same time confirm or refute a role for inflammatory signaling pathways in MDD, and help resolve the important question of whether inflammation contributes to depression on a broad scale or in a far more circumscribed manner relevant only to individuals with measurably increased indices of inflammatory activation.
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Immunoregulating Microbes and Stress Resilience
Magnified Peripheral IL-6 Response Linked To Stress Susceptibility and Higher Risk of Depression
Image Credit (Left panel): Illustration by Elisa Morsch (G’20), from Harmony in the Gut-Brain Relationship, By Irene Sanchez-Brualla and Jane Varner Malhotra, Georgetown University.