Inflammation in depression: is adiposity a cause?

Keywords: overweight, obesity, adiposity, inflammation, depression, cytokine, adipocytokine, fatty acid, lipid

Table I. Inflammatory and noninflammatory diseases associated with elevated rates of depression. *Particularly in the context of combined chemoradiation.

Access to the brain

Peripheral immune activation, such as that seen with local infection, wounding and/or psychological stress, induces release of IL-1α, IL-1β, IL-6, and TNF-α.^5,25-27 However, these cytokines are too large to freely pass through the blood-brain barrier, which raises the question of how a centrally mediated behavioral effect is achieved. Several pathways by which cytokine signals can access the brain have been identified. Local release of cytokines can stimulate peripheral afferent nerve fibers such as the vagus that innervate peripheral tissues, ultimately leading to activation of microglia, which can produce cytokines in the brain. In addition, “leaky” regions in the blood brain barrier such as the circumventricular organs^6,28 allow access of peripheral inflammatory mediators to the brain. Cytokines in the peripheral circulation can also cross the blood-brain barrier via saturable active transport molecules expressed on brain endothelial cells.²⁹ Finally, in the context of chronic immune stimulation, microglia activated by peripheral TNF-α can produce the chemokine, monocyte chemoattractant protein (MCP)-1, which in turn, can attract monocytes into the brain parenchyma.³⁰

Impact on neurotransmitter metabolism

Once cytokine signals reach the brain, there is a rich literature indicating that they can interact with virtually every pathophysiologic domain relevant to depression, including marked effects on brain monoamines, which are the target of conventional antidepressant medications. Indeed, cytokines have been shown to influence central monoamine synthesis, release, and synaptic reuptake.

The anti-inflammatory effects of antidepressant treatments and the antidepressant effects of anti-inflammatories

There have been a number of in vitro and in vivo studies of antidepressant medications^82-98 and other antidepressant treatments such as electroconvulsive therapy⁹⁹

indicating that antidepressant treatments can reduce proinflammatory factors including IL2, IL-6, TNF-α, and IFN-γ.¹ In fact, the available evidence indicates that many antidepressant therapies induce a shift from a Th1 (proinflammatory) to a TH2/TH3 (anti-inflammatory) pattern.^{82,87,88,100,101} The IFN-α to IL10 or IL4 ratio is a measure of relative TH1 to TH2-3 activity, and a number of studies indicate that antidepressants decrease this ratio.^82,87,88 Because these effects have been observed both in vitro and in vivo, they do not appear to be dependent on the actions of these drugs on monoamines such as norepinephrine or serotonin, suggesting a direct impact of antidepressant medications on cytokines.⁹⁵ Therefore, the mechanism of antidepressant action in the context of inflammation-induced depression may be a direct effect on inflammatory factors themselves.

There is also a small but significant literature indicating that anti-inflammatory drugs may produce antidepressant effects. Cyclooxygenase 2 (COX-2) activity is increased by proinflammatory cytokines, particularly IL-6, and it, in turn, activates the release of IL-1β and TNF-α¹⁰⁰ as well as prostaglandin E2 (PGE2), a central mediator of sickness behavior.⁶ COX-2 inhibitors have been shown to reverse depression-like behaviors in animal models.^102-104 In addition, the COX-2 rofecoxib has been shown to reduce depressive symptoms in patients with osteoarthritis.¹⁰⁵ Adjunctive treatment, the nonselective COX-1 and -2 antagonist acetylsalicylic acid (aspirin), increased remission rates in one open-label study of depressed patients previously nonresponsive to fluoxetine alone.¹⁰⁶ A prospective, double-blind, placebocontrolled trial of the COX-2 antagonist celecoxib (400 mg. per day) added to the norepinephrine reuptake inhibitor antidepressant reboxetine (4-10 mg per day) for 6 weeks showed greater effects of the combination treatment than reboxetine alone.¹⁰⁷

TNF receptor antagonists such as infliximab, adalimumab, golimumab, and certolizumab pegol, and the TNF receptor fusion protein etanercept have been developed in recent years to treat inflammatory and autoimmune diseases such as psoriasis, rheumatoid arthritis, and Crohn's disease. Direct actions in depressed patients have not yet been reported. However, one study of etanercept treatment of psoriasis did examine antidepressant effects.¹⁰⁸ Six hundred and eighteen patients with moderate to severe psoriasis received double-blind treatment with placebo or 50 mg twice weekly infusion treatment with etanercept for 12 weeks. Patients on etanercept had greater improvements on measures of depression (as measured by Beck Depression Inventory) than those on placebo. Notably, these improvements were not associated with reduction in psoriatic plaques or joint pain, which indicates a primary effect of TNF antagonism on depression, not simply a cosmetic or analgesic effect.¹⁰⁸ These effects were confirmed in subsequent longer term studies in psoriasis patients^109,110 and in patients with rheumatoid arthritis.¹¹¹ A similar effect has been shown with the TNF-α monoclonal antibody infliximab.^112,113

Obesity as an inflammatory state

Adipose tissue is now understood as being a very complex organ system.¹²⁷ White adipose tissue (WAT) is the main location for long-term fat storage in the body. WAT, particularly in the abdomen, is the main contributor to metabolic diseases.^122,128,129 Adipocytes in WAT secrete a variety of hormones, inflammatory factors including cytokines (referred to as adipocytokines or adipokines).^130,131 These factors include hormones traditionally associated with adipose tissue such as leptin, adiponectin, resistin, and visfatin; however, adipocytes can also secrete IL-6 and TNF-α.^130,130 Nevertheless, one of the primary mechanisms for the induction of inflammation in adipose tissue is the secretion of chemokines, particularly MCP-1. MCP-1 attracts leukocytes such as macrophages, T lymphocytes, and dendritic cells to adipose tissue, which in turn secrete cytokines including IL1, IL6, and TNF-α.^132,133 Thus, chemokines and cytokines produced by WAT may contribute to widespread immune activation, potentially causing or exacerbating diseases associated with inflammation such as type 2 diabetes, cardiovascular disease, cancer, and depression.¹³⁰

Leptin is another important peptide produced by adipocytes that regulates dietary intake. It regulates appetite by acting on leptin receptors in brain, particularly the hypothalamus.¹³⁴ In the case of obesity, a state of leptin resistance develops in which circulating levels are actually increased but responsiveness is reduced. Excess calories in the diet lead to leptin resistance; however, high-fructose feeding is a major contributor.^135,136 Leptin is a member of the type I cytokine superfamily;^137,138 it is involved in the modulation of white blood cell response, including T-cell activation and a shift to Th1 cytokine production.^137,138 Resistin is another proinflammatory adipocytokine produced by both WAT and monocytes.¹³⁰ It sets up a positive inflammatory feedback system in which the secretion of resistin is increased by proinflammatory cytokines such as IL-1, IL-6, and TNF-α, but it also increases the production of these same cytokines by macrophages. ^130,139 By contrast, adiponectin increases fatty acid oxidation and reduces the synthesis of glucose in the liver.^137,138 Adiponectin, whose levels are reduced in obese persons,¹³⁷ has a predominantly inhibitory role in Th1 immune responses, including the inhibition of IL-6 and TNF-α production and an increase in the anti-inflammatory cytokine IL10.¹³⁰ Therefore, dietary excess, leading to expansion of WAT, produces a shift in the pro- and anti-inflammatory mediators such as leptin, resistin, adiponectin, and other adipocytokines, leading to a general proinflammatory state.¹⁴ This, then, contributes to metabolic derangements and disease such as dyslipidemias, cardiovascular disease, and type 2 diabetes.^{123,130,140,141}

The activation of inflammatory factors related to obesity also appears to induce the IDO-KYN pathway. Plasma tryptophan concentrations are reduced¹⁴² and the KYN/tryptophan ratio is increased in obese relative to lean individuals, indicating IDO activation^142,143 Weight reduction by diet¹⁴² or bariatric surgery¹⁴³ restores a normal KYN/tryptophan balance. This is likely to be the result of a reduction in the proinflammatory state after weight loss.¹⁴³ It, then, appears that, like other inflammatory diseases, the immune activation found in obesity may shift metabolism from tryptophan to KYN, which may contribute to depression.

Adiposity and depression

Both depression and obesity, then, are associated with Th1 activation. However, is there evidence of a causal link in either direction - ie, from depression to obesity of viceversa? Some larger-scale epidemiological studies have failed to find a strong association between obesity and depression.^144,145 Nevertheless, while cross-sectional studies do not show strong correlations between depression and obesity, longitudinal studies tell a very different story^146-149 A recent meta-analysis of 15 longitudinal studies showed a bidirectional association between depression and obesity (especially abdominal adiposity) in which prior obesity increases the risk for depression and depression increases the likelihood of subsequent obesity¹⁵⁰

To further investigate this bidirectional relationship especially as it pertains to inflammation, Miller et al¹⁵¹ conducted a mediational analysis¹⁵² evaluating the relationship between serum inflammatory markers (including IL-1β, IL-6, TNF-α, CRP, and MCP-1) in 50 physically healthy young adults with depression and 50 matched controls. IL-6, CRP, and BMI were elevated in the depressed sample compared with controls. When the relationship between depression and both IL-6 and CRP (but not IL-1β) were adjusted for BMI, the results became nonsignificant, indicating a mediational role for adiposity in the relationship between depression and IL-6 and CRP elevation.¹⁵¹ A separate analysis of the same dataset¹⁵³ using structural equation modeling (SEM) estimated the relationship among depression, adiposity, leptin, and inflammation (IL-6 and CRP). The best fit model indicated that the primary causal pathway was from depression to adiposity to inflammation. This was interpreted as indicating that depression leads to increased adiposity (possibly through inactivity) which, in turn, leads to an increase in inflammatory markers.

Diet and depression

Diets in much of the world have shifted to high carbohydrates and a reduction in omega-3 (n-3) (unsaturated) compared with omega-6 (n-6) (saturated) fatty acids.¹⁵⁴ The intake of fish and other sources of n-3 fatty acids appear to be somewhat protective from certain metabolic conditions,^155-163 and epidemiological studies have associated an increased relative intake of fish with a reduced risk for depression.¹⁶⁴ However, it does not seem to be primarily intake of fish per se, but so-called fatty fish with high n-3 concentration (eg, anchovy, sea bass, carp, dogfish, eel, halibut, herring, mackerel, mullet, fish, roe, salmon, sardine, trout, and tuna) that lend protection against both metabolic diseases and depression.^{162,163,165,166}

The benefits of the Mediterranean diet pattern

Recent studies have found particular health benefits, including reduction in risk of depression, associated with the so-called Mediterranean Diet Pattern (MDP).¹⁶⁷ As noted in the seminal work by Willett et al,¹⁶⁷ this pattern of eating has been associated historically with good general health and longer life expectancy. This method “is based on food patterns typical of Crete, much of the rest of Greece, and southern Italy in the early 1960s” and “included regular physical activity... abundant plant foods (fruit, vegetables, breads, other forms of cereals, potatoes, beans, nuts, and seeds), fresh fruit as the typical daily dessert, olive oil as the principal source of fat, dairy products (principally cheese and yogurt), and fish and poultry consumed in low to moderate amounts, zero to four eggs consumed weekly, red meat consumed in low amounts, and wine consumed in low to moderate amounts, normally with meals.” This pattern of eating is characterized by lower saturated and total fat content. This manner of eating was shown recently to be associated with reduced risk for depression in a prospective study of the relationship between the MDP and health.^168,169 A sample of 10 094 healthy persons in Spain were assessed using a validated 136-item item food frequency questionnaire to determine the relative adherence to the MDP, and followed for 4.4 years. Using the lowest adherence to the MDP as the reference condition, adjusted hazard ratios for depression for the higher categories of adherence ranged from 0.74 for modest adherence to 0.49. These results indicate a strong prospective protective effect for the MDP. Of relevance, earlier research found a strong inverse relationship between adherence to the MDP and serum IL-6 with a trend for CRP.¹⁷⁰

These data indicate that diet is an important contributor to inflammatory load and risk for depression. In addition to the n-3 to n-6 fatty acid ratio in the diet is the relative intake of carbohydrates, particular simple sugars. Carbohydrates in Western diets have also increased substantially in recent years. While the intake of certain refined sugars such as cane sugar has declined over the last 40 years, the total caloric load from sweeteners has increased; this has primarily been in the form of fructose, particularly in the form of high-fructose corn syrup (also known as “corn sugar”).¹⁷¹ A high level of fructose intake is associated with obesity and metabolic diseases.^172-177 Although the specific role of fructose intake, as opposed to increased total calories, has been questioned,¹⁷⁸ it is increasingly clear that high intake of fructose contributes uniquely to problems of obesity¹⁷⁹ and metabolic diseases such as cardiovascular disease, dyslipidemia, and type 2 diabetes.^180-182 Fructose has a very high extraction ratio by the liver,¹⁸³ and does not contribute significantly to increases in insulin¹⁸⁴ or satiety signaling.¹⁸⁵ High levels of fructose loading in the liver leads to the synthesis of triglycerides, which contribute to liver and abdominal fat.^181,184,186 The shift in intake from proteins and “healthy” fats to saturated fats and carbohydrates, particularly fructose, has contributed to the worldwide epidemic of obesity.

Does n-3 fatty acid supplementation reduce depression?

A recent study indicates that not all n-3 fatty acids reduce inflammation; this study actually showed that docosahexanoic acid, one constituent of fish oil, may actually increased the ratio of interferon gamma to IL-10, indicating a proinflammatory effect. However, eicospentaenoic acid (EPA) did not show this effect; EPA has shown to reduce depressive symptoms in a few, smallerscale studies. One study¹⁸⁷ randomized 70 persons with major depression not responsive to antidepressants to ethyl-eicosapentaenoic acid (e-EPA) (a specific n-3 fatty acid) 1, 2, or 4 g per day or placebo as add-on therapy.¹⁸⁷ Curiously, the 1 mg per day, but not 2 or 4 mg./day doses was significantly better than placebo. Subsequent studies have supported these results.^188-190 Of note, a polymorphism in the gene for phospholipase A2, a key enzyme in the metabolism of polyunsaturated fatty acids, was associated with a 3-fold increase in the likelihood of developing major depression during IFN-α treatment as well as lower blood concentrations of EPA.¹⁹¹

Diet, adiposity, and risk for depression in children

The increase in obesity in adults has been paralleled in children and adolescents,¹¹⁹ along with an increase in inflammation^192,193 and inflammatory diseases previously thought to occur mostly in adults: type 2 diabetes, fatty liver disease, cardiovascular disease, and dyslipidemia.^121,194-200 As described earlier for adults, the current evidence suggests a bidirectional relationship between obesity and depression in children.²⁰¹ Prior depression in childhood is a relatively strong predictor of the subsequent development of obesity, metabolic syndrome, and related diseases in adult life.^202-204 Depression may increase risk by changes in diet, eating behavior, and inactivity.¹²⁶ Alternatively, baseline obesity may increase risk for depression via increases in inflammation as well as cultural aspects of beauty.²⁰⁵ Obesity negatively impacts self-esteem based on cultural aspects of beauty and desirability.²⁰⁵ Obesity also may contribute to risk for depression via effects on physical activity, sleep, and eating behavior.²⁰⁵

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