We have all bumped up against the limits of the current model of antidepressant treatments for depression: the patient who comes in with a laundry list of failed medication trials, or a number of other complaints depicting a portrait of malaise—aches, pains, anhedonia, fatigue, brain fog, digestive woes—that don’t really respond to currently available agents. What if shifting our thinking about underlying causes might hold the answer to treatment of these individuals?
It may be time to refine—perhaps even to discard—the monoamine hypothesis and explore a new perspective on chronic depression: the inflammatory model. First introduced in 1991 (Smith RS, Med Hypotheses 1991;35:298–306) and ripe to address the complexity and heterogeneity of what we call “depression,” the inflammatory model may hold clues for the understanding and treatment of this scourge, as it has for such conditions as cardiovascular disorders, diabetes, cancer, and autoimmune pathology.
Alterations in serotonin-related physiology and stress hormones, the targets for our current treatments, may actually be downstream manifestations of this more primary driver. In other words, clinical depression may be the “fever” for which there are many disparate but related triggers. Let’s take a tour of the basic tenets.
Relief Through Reduction of Inflammation
For starters, an increasing number of trials have examined the role of anti-inflammatory agents in the treatment of depression. In one recent randomized, controlled trial, a subset of patients resistant to antidepressant treatment and identified by serum markers of inflammation, most notably C-protein (CRP) >3mg/L, were responsive to treatment with the TNF-alpha antagonist infliximab (Remicade) (Raison CL et al, JAMA Psychiatry 2013;70:31–41). Elevations in CRP were also shown to precede the onset of depressed mood in asymptomatic elderly patients without a history of the illness (van den Biggelaar AH et al, Exp Gerontol 2007;42:693–701).
Celecoxib (Celebrex), the anti-inflammatory COX-2 inhibitor, has been found in randomized, placebo-controlled trials to be superior to placebo in antidepressant augmentation (Müller N et al, Mol Psychiatry 2006;11:680–684). In the setting of psoriasis treatment with etanercept (Enbrel), mood was improved independent of psoriatic relief (Tyring S et al, Lancet 2006;367:29–35). Thinking of depression as an inflammatory syndrome, therefore, may lend itself to more effective interventions, particularly in cases unresponsive to or incompletely responsive to antidepressants (Caravalho LA et al, J Affect Disord 2013;148(1):136–140).
Similarly, several studies show SSRIs may work primarily through immunomodulatory pathways and not through “serotonin reuptake,” as classically believed. Antidepressants may downregulate inflammatory cytokines such as interleukin 6 (IL-6) and enhance secretion of anti-inflammatory immune messengers such as IL-10 (DeBerardis D et al, Int J Immunopath Pharmacol 2010;23(2):417–422).
In addition, antidepressants can activate growth factors like brain-derived neurotrophic factor (BDNF), and they have been found to enhance glucocorticoid receptor sensitivity, bringing the HPA axis back in line for some patients, but potentially overshooting with chronic exposure (Carmine M et al, Psychoneuroendocrinology 2004:29;423–447).
Even outside of the pharmaceutical realm, curcumin, a bioflavinoid in the Indian spice turmeric with elaborate anti-inflammatory mechanisms, was recently found to be as effective as fluoxetine (Prozac), at a dose of 1 g daily, in small a randomized study (Sanmukhani et al, Phytother Res 2013, online ahead of print).
While not yet rigorously studied, anti-inflammatory diets may also play a significant role in reversing mood and anxiety symptoms. Perhaps the greatest leverage comes from elimination of gluten-containing grains. A significant proportion of celiac patients suffer from depression and neuropsychiatric disease (including OCD and ataxia), possibly related to greater intestinal permeability, local and systemic inflammation, and immune complexes that compromise blood-brain barrier function. When patients with celiac disease are maintained on lab-standard, gluten free diets, these symptoms frequently improve (Jackson et al, Psychiatr Q 2012;83(1):91–102).
Case reports have been in the literature for over a decade describing dramatic clinical benefits from dietary modification, particularly from low carb (<40 g daily), high natural fat, moderate protein or “ketogenic diets” (Phelps JR et al, Neurocase 2013;19(5):423–426). Probiotics may also serve to enhance anti-inflammatory effects and self-nonself recognition patterns, while diminishing intestinal permeability and modifying behavioral symptoms such as anxiety (Messaoudi et al, Br J Nutr 2011;105:755–764).
Inflammatory Cytokines: Associative and Causative
The efficacy of anti-inflammatory drugs and diets raises the possibility that inflammatory cytokines may lie at the heart of the biology of depression. As an example, one of the most predictable side effects of interferon therapy for hepatitis C is depression. In fact, 45% of patients on interferon develop clinical depression, which appears to be related to elevated levels of IL-6 and TNF (Alavi M et al, J Gastroenterol Hepatol 2012;27(5):957–965).
Cytokines can also be induced by lipopolysaccharide (LPS), an endotoxin produced by gram-negative bacteria, and which is used in animal models to induce depression-like syndromes. Mice that lack IL1-B (a cytokine that mediates inflammatory response), however, are protected against these LPS-mediated “depressive symptoms” (ie, lost interest in sugar water), suggesting that these inflammatory messengers may be a key part of the depression equation (Lawson et al, J Neuroinflammation 2013;10:54).
A primary concept in the inflammatory model of depression is the bidirectional nature of immune signals in the peripheral and central nervous system. As we all remember from our immunology courses, inflammation is triggered by the presentation of environmental antigens to T-cells. Since our greatest interface with the environment is the 70%-plus of our immune system housed in our gut wall, disturbances in gut microbiota can trigger systemic inflammation, as can autoimmunity, head injury, childbirth, and infection.
Cytokines such as IL-1, IL-6, and TNF-alpha are the messengers of distress and have all been shown to be elevated in a linear, dose-dependent way and in the setting of depression, (reviewed in Howren MB et al, Psychosomat Med 2009;71:171–186). These cytokines can traverse the blood brain barrier and may also stimulate afferent neurons (those that send sensory information toward the brain) such as the vagus (Wilson et al, J Am Geriatr Soc 2002;50:2041–2056).
Once there, glial cells called microglia, which act as the immune regulators of the brain, are activated. In activated microglia, an enzyme called IDO (indoleamine 2 3-dioxygenase) has been shown to direct tryptophan away from the production of serotonin and melatonin and toward the production of an NMDA agonist called quinolinic acid (Christmas DM et al, Neuropsych Dis Treat 2011:7;431– 439).
In the postpartum period, for instance, IDO activation is related to symptoms of anxiety and depression, and is also thought to account for stimulation of NMDA receptors in the limbic system, which may contribute to intrusive thoughts/images and symptoms of anxiety. Furthermore, in a one-two punch of neurotoxicity, glial cells called astrocytes that are charged with removing excess glutamate through excitatory amino acid transporters are thought to be downregulated in the setting of inflammatory microglial activation (McNally et al, CNS Spectr 2008:13:6 501–510).
Stress as a Final Pathway for Inflammation?
We all know about the putative role of the hypothalamus-pituitary-adrenal (HPA) axis in depression, but interestingly, the monoamine hypothesis of depression has very little to say about HPA disruption. In the context of inflammation, however, cortisol, prolactin, and sex hormones are often dysregulated. In this model, depression is thought to represent a hypercortisolemic state which may result from elevated levels of inflammatory cytokines. Peripheral glucocorticoid resistance may exacerbate this elevation in cortisol and immune response, simultaneously, which would also drive changes in progesterone, insulin, and androgens.
This concept is reflected in the overlap between depression and “sickness syndrome” described by Miller, Raison, and Maes (Miller et al, Biol Psychiatry 2009;65(9):732–741) and characterized by lethargy, sleep disturbance, anorexia, anhedonia, and decreased social activity, mobility, and libido. They theorize that immune system hyperresponsivity has served us evolutionarily, but that the transduction of psychological stress into immune response, coupled by shifts in our relationship to our microbial environment, have rendered this system somewhat maladaptive. This may, in part, explain the efficacy of exercise (Cooney GM et al, Cochrane Database Syst Rev 2013;9:CD004366) and yoga (Yadav RK et al, J Alt Comp Med 2012;18(7):662– 667) in the treatment of depression, as well as meditation in downregulation of inflammation (Dusek JA et al, PLoS One 2008;3(7):e2576).
Evidence suggests that inflammatory mediators acting on the brain may result in sickness behavior, depletion of tryptophan and monoamines, oxidative stress, and cellular dysfunction and apoptosis (Maes et al, Metab Brain Dis. 2009;24(1):27–53). Given the fundamental lack of clarity around etiology of depressive symptoms; the likelihood that depression represents a heterogeneous clinical entity with multiple different potential contributors; and the often limited benefits and notable side effects of today’s antidepressants, consideration of inflammatory models may provide a new and more effective way of thinking about depression and its treatment.
TCPR’S VERDICT: The inflammatory hypothesis of depression paves the way for the study of effective interventions—diet, exercise, meditation, medications, such as NSAIDs—that have already shown promise in the treatment of metabolic inflammatory disorders and may represent a shift towards thinking of depression as a complex disorder with contributions from behavioral, neuroendocrine, and immune pathways.