The ‘Old Friends’ Hypothesis and Why Living in the Modern World May Increase Vulnerability to Major Depression

The ‘Old Friends’ Hypothesis and Why Living in the Modern World May Increase Vulnerability to Major 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

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