Inflammation and depression
An overwhelming amount of evidence indicates that depressed patients exhibit increased markers of innate immune system activation and inflammation.For example, in a meta-analysis of over 50 studies, Howren et al found that the majority of studies show that depressed patients have elevations in the proinflammatory cytokines, interleukin (IL)-6, and IL-1β as well as the acute phase protein, C-reactive protein (CRP). A recent meta-analysis has revealed that the proinflammatory cytokine, tumor necrosis factor (TNF)-α, is also increased in patients with major depression.
In addition to the simple association between depression and inflammatory markers, the administration of inflammatory cytokines such as the innate immune cytokine, interferon (IFN)-α, can induce depression in a high proportion of treated patients.In many ways this is parallel to what is referred to as sickness behavior in animals, which represents an adaptive response to acute infection and other sources of inflammation such as wounding. - The sickness response can be induced in laboratory animals by the acute administration of proinflammatory cytokines such as IL-1β or TNF-α - or indirectly via the induction of peripheral immune activation by stimuli such as bacterial endotoxin. , Acute administration of endotoxin as well as other immune stimuli including typhoid vaccination causes a similar sickness syndrome in humans that includes depressed mood, decreased social interaction, sleep disturbance, and anhedonia. , This constellation of symptoms, which parallels that found in major depression, has also been consistently observed during chronic administration of cytokines such as IFN-α and β for illnesses including hepatitis C, multiple sclerosis, and several types of cancers, including malignant melanoma. To explore the degree to which cytokine-induced depression parallels depression in ostensibly medically healthy individuals, Capuron et al compared 20 patients who were being treated with INFα for malignant melanoma with 28 medically healthy subjects with major depression using the Hamilton Rating Scale for Depression (HAM-D). Forty-five percent of the IFN-α-treated patients developed major depression during the 12-week follow-up period. There were minimal differences in the severity of individual depressive symptoms between patients who became depressed during IFN-α treatment versus medically healthy depressed individuals, although IFN-α-treated depressed patients did exhibit more psychomotor retardation and weight loss, and the medically healthy depressed group experienced greater feelings of guilt and thoughts of suicide. These results suggest that the depression induced by cytokines is remarkably similar to depression seen in medically healthy depressed patients.
Of note, the link between inflammation and depression may explain the frequent association between medical illnesses and depression.As shown in Table I, while there are many medical conditions associated with increased rates of depression, the majority of these illnesses are also associated with increased inflammation, including not only infectious diseases and cancer but also cardiovascular disease and diabetes, both of which are now recognized to have an inflammatory component. Of note, when depression occurs in the context of medical illness, it has been associated with increased concentrations of inflammatory cytokines. For example, several studies have shown that depressed patients with cancer - or cardiovascular disease have higher peripheral blood concentrations of IL6 and CRP. Moreover, depression scores have been shown to be strongly correlated with blood cytokine concentrations in these patients.
|Noninflammatory diseases||Inflammatory diseases|
|• Hypothyroidism||• Neurological diseases|
|• Cushing's disease||- Cerebrovascular disease|
|• Porphyria||- Multiple sclerosis|
|- Lewy body disease, etc|
|• Specific neoplasms|
|- Lymphoma, etc|
|• Cardiovascular disease|
|• Connective tissue diseases|
|- Lupus, psoriasis, etc|
|- Rheumatoid arthritis, etc|
|• Diabetes mellitus|
|• Inflammatory bowel diseases|
|- Crohn's, ulcerative colitis|
|• Infectious disease (HIV), etc|
How do cytokines cause depression?
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., - 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 , 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. 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.
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.
Serotonin is synthesized from tryptophan by tryptophan hydroxylase (TH) and aromatic amino acid decarboxylase (AAAD), and the amount of serotonin in brain is highly dependent on tryptophan availability.Specifically, depletion of tryptophan rapidly leads to reduced brain serotonin levels, which in turn can precipitate depressive symptoms in vulnerable individuals. Activation of the enzyme idoleamine 2,3-dioxygenase - IDO (and the related liver enzyme tryptophan 2,3dioxygenase) is an alternative pathway for tryptophan metabolism yielding kynurenine (KYN) and leading to tryptophan depletion and ultimately decreased serotonin in brain. , Several cytokines and their signaling pathways have been shown to activate IDO , (for a review see Shelton and Miller14). Interestingly, peripheral administration of the cytokine-inducer, lipopolysaccharide (LPS) to mice activates IDO and is associated with depressive-like behavior. These LPS-induced behavioral changes can be reversed by IDO inhibition using the IDO antagonist 1-methyltryptophan.
IDO activation also has other effects that may be relevant to depression. For example, KYN is metabolized to kynurenic acid (KYNA), which antagonizes α7 nicotinic acetylcholine receptorsand can reduce striatal dopamine release (see below) , KYN is also metabolized to quinolinic acid (QUIN); QUIN leads to the generation of toxic lipid peroxides and activates N-methylD-aspartic acid (NMDA) receptors and the release of glutamate, all of which can contribute to neurotoxicity. The impact of QUIN on neuronal integrity has been implicated in the pathophysiology of several degenerative neurological conditions including Alzheimer's, Huntington's, and Parkinson's diseases, amyotrophic lateral sclerosis, and human immunodeficiency virusrelated dementia. - Of note, IFN-α therapy has also been shown to increase KYN/tryptophan ratios in humans, and KYN has been found to access the brain in IFN-α-treated patients where it is associated with increased cerebrospinal fluid (CSF) concentrations of both QUIN and KYNA. , CSF KYN and QUIN were in turn correlated with depression in during IFN-α treatment.
Aside from its impact on tryptophan and serotonin synthesis, immune activation can also affect serotonin availability by acting on synaptic reuptake via the high-affinity serotonin transporter (5HTT).Activation of p38 mitogen activated protein kinase (MAPK) by both IL-1β- and TNF-α leads to phosphorylation of 5HTT and increased neuronal uptake of serotonin. Expression and trafficking of 5HTT to the cell surface is also increased by the activation of p38 MAPK. These effects of cytokines on 5HTT expression and function have been observed both in vitro and in vivo. Of note, polymorphisms in the 5HTT gene have also been associated with the development of depression during cytokine (IFN-α) administration. ,
The relevance of immune-serotonin interactions is further supported by the observation that serotonin reuptake inhibitors can block the development of depressive symptoms in the context of immune activation. For example, one studyrandomly assigned 40 patients undergoing IFN-α therapy for malignant melanoma to treatment with the selective serotonin reuptake inhibitor (SSRI) paroxetine or placebo for 12 weeks. Eleven percent of the patients treated with paroxetine developed depression as compared to 45% of the placebo group. Almost all studies of SSRIs - in the context of immune activation have demonstrated benefit in reversing or preventing immunotherapy-induced depressive symptoms.
In addition to serotonin, cytokine effects on dopamine metabolism may also be important in the pathophysiology of inflammation-induced depression. Reduced prefrontal and striatal dopamine activity is thought to be associated with symptoms of depression such as decreased motivation, psychomotor slowing, fatigue, and lack of response to rewarding stimuli., Positron emission tomography imaging studies in humans undergoing IFN-α therapy show increased striatal resting state glucose metabolism, , which is believed to represent increased ocillatory burst activity in neurons normally under tonic inhibition by dopamine. Increased striatal resting state glucose metabolism is also found in other dopamine depletion states including Parkinson's disease. , Animal studies show that immune stimulation by TNF-α and IFN-α reduce brain and CSF dopamine and its metabolites. , In addition, prodopaminergic agents such as levodopa or psychostimulants improve fatigue and depression symptoms in patients undergoing IFN-α therapy as well as a variety of other conditions associated with inflammation including cancer and systemic HIV infection. -
There are several mechanisms by which dopamine may be depleted in the CNS during immune activation, aside from decreased dopamine release secondary to the α7 nicotinic acetylcholine receptor mechanism described above.For example, IFN-α administration to rodents has been associated with depletion of tetrahydrobiopterin (BH4), a cofactor for tyrosine hydroxylase, the rate-limiting enzyme in dopamine synthesis. Also, in a mechanism similar to the effects of immune activation on 5HTT, phosphorylation of the dopamine transporter (DAT) by MAPK kinase (MEK) has been shown to increase cell surface expression of DAT and uptake of dopamine. Therefore, relative depletion of synaptic dopamine (via reduced synthesis and release and increased reuptake) may underlie some of the neurovegetative symptoms of sickness behavior and depression, such as low energy, reduced motivation, and reduced response to rewarding stimuli. ,
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- and other antidepressant treatments such as electroconvulsive therapy
indicating that antidepressant treatments can reduce proinflammatory factors including IL2, IL-6, TNF-α, and IFN-γ.In fact, the available evidence indicates that many antidepressant therapies induce a shift from a Th1 (proinflammatory) to a TH2/TH3 (anti-inflammatory) pattern. , , , , 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. , , 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. 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-αas well as prostaglandin E2 (PGE2), a central mediator of sickness behavior. COX-2 inhibitors have been shown to reverse depression-like behaviors in animal models. - In addition, the COX-2 rofecoxib has been shown to reduce depressive symptoms in patients with osteoarthritis. 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. 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.
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.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. These effects were confirmed in subsequent longer term studies in psoriasis patients , and in patients with rheumatoid arthritis. A similar effect has been shown with the TNF-α monoclonal antibody infliximab. ,
Adiposity as a possible causal pathway to depression
In considering possible sources of inflammation leading to depression, there has been increasing interest in the role of obesity. Rates of overweight and obesity have increased tremendously in recent years in both adults and children.- Along with this has been an epidemic of related metabolic conditions like type 2 diabetes, dyslipidemias, cardiovascular and fatty liver disease, and certain forms of cancer. - The bulk of evidence links obesity and its attendant complications to inflammation. - The possible relationship between depression and obesity appears to be bidirectional, as evidence indicates that being depressed also increases the risk for the subsequent development of obesity, probably mediated, in part, by inactivity.
Obesity as an inflammatory state
Adipose tissue is now understood as being a very complex organ system.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. , , Adipocytes in WAT secrete a variety of hormones, inflammatory factors including cytokines (referred to as adipocytokines or adipokines). , 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. , 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. , 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.
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.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. , Leptin is a member of the type I cytokine superfamily; , it is involved in the modulation of white blood cell response, including T-cell activation and a shift to Th1 cytokine production. , Resistin is another proinflammatory adipocytokine produced by both WAT and monocytes. 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. , By contrast, adiponectin increases fatty acid oxidation and reduces the synthesis of glucose in the liver. , Adiponectin, whose levels are reduced in obese persons, 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. 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. This, then, contributes to metabolic derangements and disease such as dyslipidemias, cardiovascular disease, and type 2 diabetes. , , ,
The activation of inflammatory factors related to obesity also appears to induce the IDO-KYN pathway. Plasma tryptophan concentrations are reducedand the KYN/tryptophan ratio is increased in obese relative to lean individuals, indicating IDO activation , Weight reduction by diet or bariatric surgery restores a normal KYN/tryptophan balance. This is likely to be the result of a reduction in the proinflammatory state after weight loss. 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., Nevertheless, while cross-sectional studies do not show strong correlations between depression and obesity, longitudinal studies tell a very different story - 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 obesity
To further investigate this bidirectional relationship especially as it pertains to inflammation, Miller et alconducted a mediational analysis 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. A separate analysis of the same dataset 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.The intake of fish and other sources of n-3 fatty acids appear to be somewhat protective from certain metabolic conditions, - and epidemiological studies have associated an increased relative intake of fish with a reduced risk for depression. 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. , , ,
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).As noted in the seminal work by Willett et al, 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. , 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.
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”).A high level of fructose intake is associated with obesity and metabolic diseases. - Although the specific role of fructose intake, as opposed to increased total calories, has been questioned, it is increasingly clear that high intake of fructose contributes uniquely to problems of obesity and metabolic diseases such as cardiovascular disease, dyslipidemia, and type 2 diabetes. - Fructose has a very high extraction ratio by the liver, and does not contribute significantly to increases in insulin or satiety signaling. High levels of fructose loading in the liver leads to the synthesis of triglycerides, which contribute to liver and abdominal fat. , , 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 studyrandomized 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. 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. - 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.
Diet, adiposity, and risk for depression in children
The increase in obesity in adults has been paralleled in children and adolescents,along with an increase in inflammation , and inflammatory diseases previously thought to occur mostly in adults: type 2 diabetes, fatty liver disease, cardiovascular disease, and dyslipidemia. , - As described earlier for adults, the current evidence suggests a bidirectional relationship between obesity and depression in children. Prior depression in childhood is a relatively strong predictor of the subsequent development of obesity, metabolic syndrome, and related diseases in adult life. - Depression may increase risk by changes in diet, eating behavior, and inactivity. Alternatively, baseline obesity may increase risk for depression via increases in inflammation as well as cultural aspects of beauty. Obesity negatively impacts self-esteem based on cultural aspects of beauty and desirability. Obesity also may contribute to risk for depression via effects on physical activity, sleep, and eating behavior.
Summary and conclusions
It seems clear at this point that inflammatory mediators, whether they are generated by specific diseases or administered exogenously (as with IFN therapy) can lead to depression. It also appears that a significant subset of depressed patients without known inflammatory disease have inherent upregulation of inflammatory factors, particularly IL-6, TNF-α, and CRP, without other known inflammatory disease., , As posited in this paper, one causal pathway for this increased inflammation may be overweight and obesity. Therefore, depression (and the inactivity and diet changes associated with it), obesity, and inflammation may represent a “vicious cycle” ( ). A person may enter this cycle at any pointobesity may lead to inflammation which leads to depression; depression may lead to inactivity and dietary changes, which lead to obesity leading to inflammation; inflammatory diseases may lead to both depression and inactivity, resulting in obesity. Western high-fat, high-carbohydrate diets and inactivity may lead to obesity inflammation, and depression. This cycle may also explain the common association between inflammatory diseases such as lupus or fibromyalgia and both depression and obesity - Therefore, multiple, interacting factors may lead to a general decline in mental and physical health.
However, this cycle also provides multiple nodal points for both treatment and prevention. For example, children and adolescents at risk for depression (ie, with positive family history or those who have been traumatized) may represent a group for whom targeted diet and exercise programs would be beneficial to help to prevent or reduce risk for depression. In addition, recent data indicate that overweight and obese patients have reduced response to antidepressant treatments. - For example, a recent combined analysis of outcomes in three clinical trials of marketed antidepressants divided participants into normal weight (BMI<25), overweight (BMI 25-<30), and obese (BMI > 30). The results indicated progressive resistance to antidepressant therapies from normal weight to obesity. Future interventions could target overweight and obesity as a possible remediable cause of treatment resistance. Depression is a complex condition with many potential causal pathways; two, possibly interrelated mechanisms, diet-associated overweight and obesity and inflammation have been reviewed. Although these mechanisms represent only two among many causal paths, they potentially explain many features, such as the common association between inflammatory diseases and depression risk. Nevertheless, there is cause for optimism for possible intervention strategies given the evidence for success of lifestyle modifications such as exercise, diet, and other weight loss approaches to inflammatory diseases a nd obesity. , , , , -