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Inflammation and the Phenomenology, Pathophysiology, Comorbidity, and Treatment of Bipolar Disorder: A Systematic Review of the Literature

J Clin Psychiatry 2009;70(8):1078-1090
10.4088/JCP.08r04505

Objective: To review extant literature implicating inflammation in the pathophysiology of bipolar disorder. Furthermore, we review evidence regarding the anti-inflammatory actions of mood-stabilizing medication, the putative reciprocal association of inflammation with behavioral parameters and medical burden in bipolar disorder, and the potential role of anti-inflammatory agents in the treatment of bipolar disorder.

Data Sources: MEDLINE and PubMed searches were conducted of English-language articles published from 1950 to April 2008 using the search terms bipolar disorder, manic, or mania, cross-referenced with inflammation, inflammatory, interleukin, cytokine, C-reactive protein, or tumor necrosis factor. The search, which was conducted most recently on August 20, 2008, was supplemented by manually reviewing reference lists from the identified publications.

Study Selection: Articles selected for review were based on adequacy of sample size, the use of standardized experimental procedures, validated assessment measures, and overall manuscript quality.

Data Extraction: Studies were reviewed for statistical comparisons of cytokines among persons with and without bipolar disorder, during symptomatic and non-symptomatic intervals and before and after pharmacologic treatment. Significant and nonsignificant findings were tabulated.

Data Synthesis: Available evidence indicates that bipolar disorder and inflammation are linked through shared genetic polymorphisms and gene expression as well as altered cytokine levels during symptomatic (i.e., mania and depression) and asymptomatic intervals. However, results are inconsistent. Several conventional mood stabilizers have anti-inflammatory properties. The cyclooxygenase-2–selective anti-inflammatory celecoxib may offer antidepressant effects. Inflammation is closely linked with behavioral parameters such as exercise, sleep, alcohol abuse, and smoking, as well as with medical comorbidities including coronary artery disease, obesity and insulin resistance, osteoporosis, and pain. Methodological limitations precluding definitive conclusions are heterogeneity in sample composition, cytokine assessment procedures, and treatment regimens. The inclusion of multiple ethnic groups introduces another source of variability but also increases the generalizability of study findings.

Conclusion:Inflammation appears relevant to bipolar disorder across several important domains. Further research is warranted to parse the reciprocal associations between inflammation and symptoms, comorbidities, and treatments in bipolar disorder. Studies of this topic among youth are needed and may best serve this purpose.


Received June 29, 2008; accepted Aug. 22, 2008. From the Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, Pa. (Dr. Goldstein); the Department of Psychiatry, Case Western Reserve University School of Medicine, Cleveland, Ohio (Dr. Kemp); the Mood Disorders Psychopharmacology Unit, University Health Network, and the Institute of Medical Science, University of Toronto, Ontario, Canada (Dr. McIntyre and Ms. Soczynska); and the Departments of Psychiatry and Pharmacology, University of Toronto, Ontario, Canada (Dr. McIntyre).

Dr. Kemp has received grant/research support from the National Institutes of Health and Takeda; has received honoraria from Servier; has been a consultant for Abbott, Bristol-Myers Squibb, and Wyeth; and has received other financial or material support from Organon. Dr. McIntyre has received grant/research support from the Stanley Medical Research Institute, NARSAD, and Eli Lilly; has been a member of the speakers/advisory boards for AstraZeneca, Bristol-Myers Squibb, the France Foundation, GlaxoSmithKline, Janssen-Ortho, Solvay/Wyeth, Eli Lilly, Organon, Lundbeck, Biovail, Pfizer, and Shire; and has received other financial or material support from AstraZeneca, Bristol-Myers Squibb, the France Foundation, 13CME, Solvay/Wyeth, and Physicians Postgraduate Press. Dr. Goldstein and Ms. Soczynska report no financial or other relationship relevant to the subject of this article.

Corresponding author and reprints: Benjamin I. Goldstein, M.D., Ph.D., Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, 3811 O’Hara Street, Pittsburgh, PA 16213 (e-mail: goldsteinbi@upmc.edu).

Inflammation and the Phenomenology, Pathophysiology, Comorbidity, and Treatment of Bipolar Disorder: A Systematic Review of the Literature

Objective: To review extant literature implicating inflammation in the pathophysiology of bipolar disorder. Furthermore, we review evidence regarding the anti-inflammatory actions of mood-stabilizing medication, the putative reciprocal association of inflammation with behavioral parameters and medical burden in bipolar disorder, and the potential role of anti-inflammatory agents in the treatment of bipolar disorder.

Data Sources: MEDLINE and PubMed searches were conducted of English-language articles published from 1950 to April 2008 using the search terms bipolar disorder, manic, or mania, cross-referenced with inflammation, inflammatory, interleukin, cytokine, C-reactive protein, or tumor necrosis factor. The search, which was conducted most recently on August 20, 2008, was supplemented by manually reviewing reference lists from the identified publications.

Study Selection: Articles selected for review were based on adequacy of sample size, the use of standardized experimental procedures, validated assessment measures, and overall manuscript quality.

Data Extraction: Studies were reviewed for statistical comparisons of cytokines among persons with and without bipolar disorder, during symptomatic and non-symptomatic intervals and before and after pharmacologic treatment. Significant and nonsignificant findings were tabulated.

Data Synthesis: Available evidence indicates that bipolar disorder and inflammation are linked through shared genetic polymorphisms and gene expression as well as altered cytokine levels during symptomatic (i.e., mania and depression) and asymptomatic intervals. However, results are inconsistent. Several conventional mood stabilizers have anti-inflammatory properties. The cyclooxygenase-2–selective anti-inflammatory celecoxib may offer antidepressant effects. Inflammation is closely linked with behavioral parameters such as exercise, sleep, alcohol abuse, and smoking, as well as with medical comorbidities including coronary artery disease, obesity and insulin resistance, osteoporosis, and pain. Methodological limitations precluding definitive conclusions are heterogeneity in sample composition, cytokine assessment procedures, and treatment regimens. The inclusion of multiple ethnic groups introduces another source of variability but also increases the generalizability of study findings.

Conclusion: Inflammation appears relevant to bipolar disorder across several important domains. Further research is warranted to parse the reciprocal associations between inflammation and symptoms, comorbidities, and treatments in bipolar disorder. Studies of this topic among youth are needed and may best serve this purpose.

J Clin Psychiatry 2009;70(8):1078–1090

Received June 29, 2008; accepted Aug. 22, 2008. From the Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, Pa. (Dr. Goldstein); the Department of Psychiatry, Case Western Reserve University School of Medicine, Cleveland, Ohio (Dr. Kemp); the Mood Disorders Psychopharmacology Unit, University Health Network, and the Institute of Medical Science, University of Toronto, Ontario, Canada (Dr. McIntyre and Ms. Soczynska); and the Departments of Psychiatry and Pharmacology, University of Toronto, Ontario, Canada (Dr. McIntyre).

Dr. Kemp has received grant/research support from the National Institutes of Health and Takeda; has received honoraria from Servier; has been a consultant for Abbott, Bristol-Myers Squibb, and Wyeth; and has received other financial or material support from Organon. Dr. McIntyre has received grant/research support from the Stanley Medical Research Institute, NARSAD, and Eli Lilly; has been a member of the speakers/advisory boards for AstraZeneca, Bristol-Myers Squibb, the France Foundation, GlaxoSmithKline, Janssen-Ortho, Solvay/Wyeth, Eli Lilly, Organon, Lundbeck, Biovail, Pfizer, and Shire; and has received other financial or material support from AstraZeneca, Bristol-Myers Squibb, the France Foundation, 13CME, Solvay/Wyeth, and Physicians Postgraduate Press. Dr. Goldstein and Ms. Soczynska report no financial or other relationship relevant to the subject of this article.

Corresponding author and reprints: Benjamin I. Goldstein, M.D., Ph.D., Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, 3811 O’Hara Street, Pittsburgh, PA 16213 (e-mail: goldsteinbi@upmc.edu).

The macrophage theory of depression was articulated nearly 20 years ago in an effort to consolidate several related observations, including a growing recognition that pro-inflammatory cytokines can precipitate depressive symptoms among healthy volunteers and that depression commonly occurs in illnesses associated with inflammation, such as coronary artery disease and rheumatoid arthritis.1 Since that time, accumulating evidence indicates that alteration in inflammation is salient to the pathogenesis and possibly treatment of major depressive disorder (MDD).2,3 Studies have also examined the role of inflammation in other neuropsychiatric illnesses, such as schizophrenia4 and Alzheimer’s disease.5 There is evidence that provocation of a pro-inflammatory response among healthy volunteers is accompanied by increased levels of affective symptoms and decreased neurocognitive performance.6

Taken together, studies regarding inflammation in MDD suggest that pro-inflammatory cytokines may subserve depressive symptomatology by activation of the hypothalamic-pituitary-adrenal (HPA) axis and by affecting central monoaminergic systems2,3 The interactions between cytokines, the HPA axis, and monoamines are complex, however, and are thought to involve multiple factors, including glutamate, calcium, and protein kinase C, among others.7 Activation of astrocytes and microglia cells and disruption of the blood-brain barrier have similarly been implicated in the role of cytokines in psychiatric disorders.8 The role of inflammation in neuronal damage and degeneration is well established9,10 and may be particularly pronounced among those with disturbances in other interacting metabolic networks.11

Figure 1. Citations Regarding Bipolar Disorder and Inflammation by 5-Year Epochs

Figure 1

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Until recently, however, few studies had examined the potential role of inflammation in bipolar disorder (Figure 1). Bipolar disorder is a severe and impairing neuropsychiatric illness with onset that is frequently early in life and whose diagnosis and treatment are often delayed by more than 10 years.12–14 In addition to frequent psychiatric comorbidity of bipolar disorder15,16 co-occurring medical conditions are also common.17 In a recent editorial, Miller and Manji18 concluded that “the relevance of inflammatory processes to disorders of the brain and body may thus serve as an important touchstone for increasing integration of psychiatry and medicine.” Indeed, previous authors19 have hypothesized that systemic inflammation may be associated with early natural death in bipolar disorder. Given these findings and observations, we set out to examine the topic of inflammation as it relates to bipolar disorder. Our primary objective was to systematically review the literature regarding the association between inflammation and bipolar disorder. Our secondary objective was to selectively examine evidence implicating anti-inflammatory actions of conventional pharmacotherapy in bipolar disorder, putative reciprocal associations of inflammation with behavioral parameters and medical burden in bipolar disorder, and the potential role of conventional anti-inflammatory agents as possible therapeutic avenues in bipolar disorder.

Method

MEDLINE and PubMed searches were conducted of English-language articles published between 1950 and April 2008 using the following search terms: bipolar disorder, manic, or mania, cross-referenced with inflammation, inflammatory, interleukin (IL), cytokine, C-reactive protein (CRP), or tumor necrosis factor (TNF). Articles selected for review were based on adequacy of sample size, the use of standardized experimental procedures, validated assessment measures, and overall manuscript quality. In addition, reference lists from the identified publications were then manually reviewed. The search was conducted most recently on August 20, 2008.

Inflammation and Bipolar Disorder

The central findings from the 27 studies identified are summarized in Table 1a and Table 1b. Table 2 depicts the findings regarding individual cytokines during mania, depression, and euthymia and as they relate to treatment and/or changes in symptoms. Consistent themes in these findings are highlighted below. Cytokines are small proteins released by cells that play a role in inflammation via specific effects on the interactions and communications between cells. ILs, CRP, and TNF-α are examples of cytokines. For parsimony, the appellation pro-inflammatory markers (PIMs) is used here to describe factors associated with increased inflammation. Cytokines ascertained via in vitro exposure of macrophages or plasma to mitogen, lipopolysaccharide, or phytohemagglutinin are described as stimulated.

Table 1. Characteristics and Findings of Studies Regarding Inflammatory Markers and Bipolar Disorder

Table 1a

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Table 1 (continued). Characteristics and Findings of Studies Regarding Inflammatory Markers and Bipolar Disorder

Table 1b

aWhere not otherwise indicated, PIM levels were ascertained only from serum/plasma without stimulation.
Abbreviations: BD = bipolar disorder, BMI = body mass index, CRP = C-reactive protein, hsCRP = high-sensitivity CRP, IFN = interferon, IL = interleukin, IL-1RA = interleukin-1 receptor antagonist, MDD=major depressive disorder, NS = not significant, PIMs = pro-inflammatory markers, SCZ = schizophrenia, sIL-2 = soluble interleukin-2, sIL-2R = soluble interleukin-2 receptor, sIL-6R = soluble interleukin-6 receptor, TNF = tumor necrosis factor, YMRS = Young Mania Rating Scale.

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Table 2. Summary of Findings Regarding Inflammatory Markers and Bipolar Disordera

Table 2

aEach arrow signifies a study that found statistically significant between-group differences. Relative increases are noted with a ↑, whereas decreases are noted with a ↓.
bIncluding correlation with symptom severity and/or change in levels following treatment; each separate study denoted by +.
Abbreviations: BD = bipolar disorder, CRP = C-reactive protein, IFN = interferon, IL = interleukin, IL-1RA = interleukin-1 receptor antagonist, sIL-2R = soluble interleukin-2 receptor, sIL-6R = soluble interleukin-6 receptor, TNF = tumor necrosis factor.

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Inflammation During Mania or Depression

Taken together, findings regarding PIMs during mania generally provide evidence for increased PIMs, particularly CRP, soluble IL-2 receptor (sIL-2R), IL-6, and TNF-α. Findings regarding anti-inflammatory markers (such as IL-4, IL-10), or imbalance between pro- and anti-inflammatory markers, are less consistent. For example, 2 studies have found increased levels of IL-4 among subjects with mania compared to controls,31,39 whereas a third study37 found that subjects with bipolar disorder demonstrated significantly higher levels of IL-6 and TNF-α, significantly lower levels of IL-4, and significantly greater ratios of pro- vs. anti-inflammatory cytokines versus controls. Relatively fewer studies have examined inflammation during bipolar depression, although elevations in several PIMs appear to overlap with those elevated during mania, including sIL-2R, IL-6, IL-8, CRP, and TNF-α (see Table 1a and Table 1b; e.g., Kim et al.,31 Papiol et al.,44 and Middle et al.47). Finally, there is preliminary evidence of increased IL-1β and IL-6 during depression versus mania, and increased sIL-2R, IL-4, and CRP during mania versus depression.44,55,56

Changes in Inflammation After Treatment and/or Symptomatic Improvement

Most studies that have tested for associations between PIMs and treatment and/or resolution of symptoms have not reported significant findings. The nature of this association may vary between cytokines. Several studies regarding sIL-2R and IL-6 suggest that changes in these PIMs are associated with treatment and/or symptom resolution.29,45,54 In contrast, although several studies49,53,55 have found increased levels of TNF-α during mania and bipolar depression, significant associations with treatment and/or symptom resolution have not been reported.

Inflammation During Euthymia

Few studies have reported findings regarding inflammation during euthymia. Breunis and colleagues29 found that sIL-2R is elevated among euthymic bipolar disorder subjects versus controls, similar to findings during mania and depression. Although no significant findings have been reported regarding the anti-inflammatory cytokine IL-10 during mania or depression, one study30 reported decreased levels of IL-10 among euthymic subjects with bipolar disorder under lithium treatment. The same study also found decreased levels of IL-2, -6, and -10 during euthymia. A preliminary Canadian study41 examined serum cytokines in relation to cognitive performance among 20 euthymic subjects with bipolar disorder. The researchers found that TNF-α is associated with intrusions on California Verbal Learning Test (CVLT), that IL-8 is associated with repetitions on CVLT, and that recollection deficits are negatively associated with IFN-γ. Finally, IL-1RA was significantly associated with self-reported cognitive deficits. There were no significant cytokine differences between cognitively impaired (≥ 1 SD below the norm on the CVLT) versus nonimpaired subjects, and there was no significant association of CRP with cognitive performance.

Lack of Association Between Cytokines and Demographic or Clinical Variables

Several studies34,46,50 examined whether cytokines are associated with a variety of clinical variables other than changes in symptoms, such as duration of illness, age at bipolar disorder onset, smoking, and obesity. Similarly, many studies34,46,50 examined whether cytokines are associated with demographic variables such as age and sex. However, to date, no demographic or clinical correlates of inflammation among subjects with bipolar disorder have been reported. As acknowledged in the Summary section below, the literature is constrained by important methodological limitations, and these limitations may explain in part the lack of association with demographic or clinical variables. In particular, modest sample sizes and heterogeneity in sample characteristics and methodologies may be contributory.

Evidence for Glucocorticoid Resistance

A recent study34 from the Netherlands examined the impact of dexamethasone suppression on stimulated sIL-2R expression among 54 subjects with bipolar disorder and 29 controls. At low concentrations of dexamethasone, sIL-2R was reduced by 35.8% among subjects with bipolar disorder as compared with an 18.9% reduction among controls. That a significant difference in suppression was observed at low, but not high, concentrations of dexamethasone suggests relative resistance. This finding is noteworthy given the evidence that cytokines may lead to glucocorticoid resistance through direct effects on glucocorticoid receptor expression and function.42,43 No demographic variables or clinical variables such as mood state, duration of illness, or duration of treatment were significantly correlated with dexamethasone suppression. Of note, although serum sIL-2R concentrations were elevated among subjects with bipolar disorder compared to controls, this difference disappeared after 72-hour in vitro culture. This observation suggests the possibility that subjects with bipolar disorder had a pro-inflammatory in vivo milieu.

Inflammation-Related Genetic Polymorphisms and Expression

Papiol and colleagues,44 from Spain, examined a polymorphism in the promoter region of the IL1B gene and the variable nucleotides tandem repeat (VNTR) polymorphism of the IL1RA gene among 88 subjects with bipolar disorder, 78 subjects with schizophrenia, and 176 controls. They found a significant excess of the haplotypic combination among subjects with bipolar disorder and schizophrenia compared to controls. The highest prevalence of this haplotype was observed among subjects with bipolar disorder with family history of bipolar disorder, schizophrenia, or MDD. The authors concluded that IL1 cluster genetic variability may comprise shared genetic susceptibility for bipolar disorder and schizophrenia. In contrast, Kim and colleagues,45 from Korea, examined the IL1RA VNTR polymorphism among 83 subjects with bipolar disorder, 269 subjects with schizophrenia, and 297 controls and found a significant association with schizophrenia but not with bipolar disorder.

Another study46 from Korea examined the TNFA 308 polymorphism among 89 subjects with bipolar disorder and 125 controls. The TNF2 allele was significantly more common among subjects with bipolar disorder in comparison to controls (21.3% vs 7.2%). In contrast, a previous United Kingdom study of women with BD with (N = 116) or without (N = 56) puerperal psychosis, compared to healthy controls (N = 72), found no significant association between either bipolar disorder or puerperal psychosis and the TNFA 308 polymorphism.47 Meira-Lima and colleagues,48 from Brazil, similarly found no significant association between this polymorphism and bipolar disorder (N = 161), although this variant was more common among subjects with schizophrenia (N=186) versus controls (N = 657).

Padmos and colleagues 49 identified a signature of 19 aberrantly expressed messenger RNAs for inflammatory genes. Subjects included 42 adults with bipolar disorder, 25 adult controls, 54 adolescent or young adult offspring of parents with bipolar disorder (of whom 16 had a mood disorder at baseline or during follow-up), and 70 adolescent or young adult controls. The pro-inflammatory signature was observed among 52% of bipolar disorder adults, 18% of control adults, 88% of bipolar disorder offspring with mood disorder, 45% of bipolar disorder offspring without mood disorder, and 19% of control adolescents. The IL6 gene was among the strongest variables distinguishing bipolar disorder adults from controls. IL6 differed significantly between the bipolar disorder offspring (with and without mood disorders) and controls, and between bipolar disorder offspring with versus without mood disorder.

In summary, genetic findings suggest that bipolar disorder is associated with IL1 and IL6 genetic polymorphisms and that there have been contradictory findings for TNFA polymorphisms. Moreover, aberrant expression of inflammatory genes may comprise an endophenotype or biologic marker for bipolar disorder, although replication studies are needed.

Inflammation and Mood Stabilizers

Several clinical and pre-clinical studies suggest that the mechanism of action of mood stabilizing medications (e.g., antipsychotics, carbamazepine, lamotrigine, lithium, and valproate) may include cyclooxygenase 2 (COX-2) inhibition and reduction in inflammatory cytokines.50–59 Several studies have also examined the association between lithium treatment and markers of inflammation among subjects with bipolar disorder, although some of these studies have included subjects taking other medications as well.

Hornig and colleagues22 found that significantly fewer subjects taking lithium were considered CRP-positive as compared to subjects not taking lithium. There was a similar trend among subjects taking lithium in addition to an antidepressant. Rapaport and colleagues23 found that lithium treatment resulted in increased IL-2, sIL2R, and soluble IL-6R (sIL6R) among healthy controls. There were trends toward significant diagnosis-by-treatment interaction (p < .10) for both sIL2R and sIL6R. The authors speculated that, in healthy controls, lithium may stimulate these inflammatory markers by decreasing the levels of cyclic adenosine monophosphate, which has an inhibitory effect on cytokines such as IL6.

Knijff and colleagues38 found that in vitro addition of lithium to monocytes from healthy subjects dose-dependently down-regulated lipopolysaccharide and stimulated IL-1β production but did not influence IL-6 production. A recent study30 from Greece examined IL-2, IL-6, IL-10, and IFN-γ among 50 euthymic subjects with bipolar disorder (N = 40 taking long-term lithium, N = 10 medication-naive) and 20 controls. Lithium-treated subjects with bipolar disorder had significantly lower levels of IL-2, IL-6, IL-10, and IFN-γ compared to controls. Subsequent treatment of medication-naive subjects with bipolar disorder with lithium results in decreased cytokine production after 3 months of treatment, and this decrease in production was observed in all of the cytokines examined. In vitro stimulation with lithium did not have a significant effect among subjects with bipolar disorder or controls. Finally, Padmos and colleagues49 found that treatment with lithium and antipsychotics down-regulated expression of most inflammatory genes examined.

In summary, it appears that lithium attenuates the pro-inflammatory milieu in bipolar disorder, although the opposite effect may be observed among nonbipolar disorder subjects. Although studies of bipolar disorder have examined changes in inflammation following medication treatment, to our knowledge, none have examined whether inflammation is a moderator or mediator of treatment response. Preliminary data from MDD indicate that treatment response may be predicted by certain baseline IL-6 levels, whereas TNF-α levels correlate with changes in depression symptoms during treatment.60 It remains to be determined whether the same correlations are true in bipolar disorder.

Medical Burden in bipolar disorder

Figure 2. Putative Role of Inflammation in Bipolar Disorder

Figure 2

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The excessive burden of medical conditions in bipolar disorder is increasingly recognized.17 Examples of medical conditions that are both prevalent in bipolar disorder and related to inflammation include cardiovascular illness, obesity and insulin resistance/diabetes, pain, arthritis, and headache. Similarly, alcohol use disorders (AUDs) are both prevalent in bipolar disorder and related to inflammation. A conceptual framework for understanding the inter-relationships between all of these factors is depicted in Figure 2.

Cardiovascular Illness

For over 25 years, studies have demonstrated increased mortality due to cardiovascular disease in bipolar disorder,61–63 with the most recent estimates suggesting standardized mortality ratios of 1.9 and 2.6 for men and women, respectively.64 The onset of cardiovascular illness may also be earlier than in the general population.65 Inflammation is an antecedent of cardiovascular disease among men66 and women67 and may independently predict mortality among persons experiencing acute coronary syndromes.68,69 Fortunately, reducing inflammation may improve cardiac outcomes independent of other factors such as cholesterol.70 For this reason, measurement of inflammatory markers has become part of the clinical biomarker armamentarium in cardiology.71

Obesity and Insulin Resistance/Diabetes

The majority of adults with bipolar disorder are overweight or obese,72,73 and epidemiologic data suggest mutually increased prevalence of bipolar disorder and obesity.74,75 Similarly, the prevalence of diabetes is elevated in bipolar disorder,76,77 even after controlling for psychotropic medications.78,79 Inflammatory markers, particularly CRP, IL-6, and TNF-α, are elevated in obesity.80 Most research has been cross-sectional81; however, there is evidence for a bidirectional association between inflammation and obesity. Subcutaneous fat releases inflammatory markers such as IL-6,82 but stress-induced inflammation may also lead to obesity.83 There may also be an association between inflammation and diabetes/insulin resistance independent of obesity.84 Evidence of genetic inflammatory diathesis has been reported for obesity85 and type II diabetes.86 A recent review concluded that increased TNF-α is a consequence, rather than a cause, of antipsychotic-induced weight gain.87 To our knowledge, however, cytokines such as IL-6 have yet to be examined as they relate to medication-induced weight gain.

Antidiabetic agents may also provide future treatment options. A recent study found that rosiglitazone, a thiazolidinedione, results in rapid and significant reduction in CRP levels independent of its effect on glycemia, and that this change was associated with regression of carotid artery intima-media thickness.88 Studies are currently underway that examine the impact of these medications on mood disorders.89,90

Pain, Arthritis, and Headache

There is evidence for elevated burden of several pain conditions, including arthritis, backache, and headache, in bipolar disorder.91–94 There is abundant evidence that pathologic pain is mediated by cytokines, particularly IL-1β, IL-6, and TNF-α.95 Similarly, inflammation has been implicated in migraine headaches,96,97 rheumatoid arthritis,98 and osteoarthritis.99

Smoking and Alcohol Use

In addition to these medical comorbidities, comorbid AUDs (i.e., alcohol abuse or dependence) are prevalent among the majority of individuals with bipolar disorder at some point during their lifetime. Alcohol is the most common substance of abuse in bipolar disorder, and bipolar disorder is arguably the Axis I psychiatric disorder most strongly associated with AUDs.100,101 Epidemiologic data indicate that the lifetime prevalence of daily smoking among adults with bipolar disorder is 82.5%, more than twice as high as that of adults with no mental illness (39.1%) and higher than that of adults with lifetime major depression (59%).102 Unfortunately, the cessation rate for adults with bipolar disorder (16.6%) is substantially lower than for adults with no mental illness (42.5%) or those with lifetime major depression (38.1%).102 Both cigarette smoking103 and heavy alcohol use104 are associated with increased systemic inflammation.

Other Factors

Other factors that relate to the association between inflammation and bipolar disorder include osteoporosis, physical activity, and sleep. Little is known about osteoporosis and bipolar disorder, but the illness is thought to have a direct effect on bone density in addition to the effects of lithium (disturbed calcium metabolism and parathyroid hormone secretion), anticonvulsants (increased vitamin D catabolism), and antipsychotic medication (hyperprolactinemia).105 Accordingly, inflammation is a recognized factor in the pathophysiology of osteoporosis.106 Recent findings that inflammation contributes to decreased bone mass among premenopausal women with depression may extend to bipolar disorder as well.107

In addition to medication-related weight gain, decreased physical activity is one factor that has been implicated in the high rates of obesity.108–111 It is therefore worthwhile noting that, in addition to any direct impact on obesity, physical fitness has been associated with smaller inflammatory responses to acute mental stress.112

Finally, sleep is a variable that is closely linked with bipolar disorder and inflammation. Even during euthymia, the majority of patients with bipolar disorder experience significant sleep difficulties including impaired sleep efficiency113 and variability in sleep duration and night wake time.114 Sleep disturbances result in significantly increased IL-6115,116 and TNF-α, as well as increased transcription of messenger RNA for these variables.116

In summary, comorbid medical illnesses, smoking, and excessive alcohol use, which differentially affect individuals with bipolar disorder, are also associated with altered inflammatory networks. The same is true of decrements in physical activity and sleep parameters. In some cases, such as obesity, there is a bidirectional association between inflammation and comorbidity. In other cases, such as smoking and alcohol use, inactivity, and sleep disturbance, inflammation is generally a consequence rather than a cause. Nonetheless, the latter behavioral parameters are inherent to bipolar disorder and may contribute significantly to the cumulative burden of inflammation in bipolar disorder.

Potential Role for Anti-Inflammatory Medications in Bipolar Disorder

The potential role of anti-inflammatory agents in the treatment of psychiatric illness has been suggested by results from several recent studies. For example, celecoxib has shown promise as an adjunctive treatment in bipolar disorder, MDD, and schizophrenia.117–120

A recent 6-week, double-blind, randomized, placebo-controlled study117 examined the efficacy of adjunctive celecoxib 400 mg/day for the treatment of depressive or mixed episodes among adults with bipolar disorder.117 The celecoxib-treated subjects evinced a greater numerical improvement when compared to the placebo-treated subjects in the first week of therapy using intention-to-treat analysis. Amongst individuals who completed the full duration of treatment, celecoxib-treated subjects exhibited a significantly greater improvement from baseline to endpoint. However, the small sample size (N = 28) increases the probability of a type II error. Moreover, 64% of the sample had comorbid substance use disorders indicative of a more complex illness presentation.

A separate 6-week, double-blind, randomized, placebo-controlled study examined the efficacy of celecoxib 400 mg/day as an adjuvant to reboxetine (4–10 mg) for the treatment of MDD among 40 subjects (93% inpatients) with MDD.118 Celecoxib-treated subjects demonstrated a significantly greater decrease in depressive symptoms compared to placebo-treated subjects. The advantage of celecoxib was also apparent on secondary outcome measures (e.g., response rates).

Adjunctive celecoxib (in addition to atypical antipsychotics) has also shown promise in the treatment of schizophrenia. Two studies have found that celecoxib-treated (400 mg/day) subjects exhibited a reduction in overall positive and negative symptoms when compared to placebo, and that celecoxib was well tolerated.119,120 A third negative study was reported that included continuously ill outpatients (versus acutely ill inpatients) who were older when compared to the positive studies.121 Attempts to identify predictors of response indicated that celecoxib responders exhibited increased sIL-2R after 5 weeks of treatment and lower pretreatment levels of TNF-α receptor.122 Data regarding cytokines from the Rapaport study suggest that celecoxib combined with olanzapine may result in a transient increase in TNF-α and IL-2.123

Taken together, the findings regarding celecoxib suggest that the principal benefit of adjunctive treatment may be the acceleration of treatment response among acutely ill patients at early stages of the illness. Larger controlled studies are warranted to corroborate and extend these findings. Future studies of celecoxib and other anti-inflammatory medications are need to identify predictors of response such as age, duration of illness, comorbidity, inflammation-related genotypes, and cytokine levels in order to maximize the risk-benefit ratio of these medications. Similarly, studies are needed to evaluate whether changes in cytokine levels mediate treatment response.

Neuroprotection

Neuroprotective effects of celecoxib against macrophage toxicity toward motor neurons have been reported,124 as have neuroprotective effects of rofecoxib against induced excitotoxicity of cholinergic neurons.125 COX-2 inhibitors may also have neuroprotective effects in brain regions that are more directly related to bipolar disorder. A study of celecoxib in a rat model of depression found that celecoxib treatment was associated with significantly lower hypothalamic IL-1β and IL-10 concentrations. Celecoxib treatment also resulted in significantly lower prefrontal cortical TNF-α and IL-1β and higher IL-10.126 Another preclinical study found that celecoxib normalizes age-related increase of hippocampal TNF-α and IL-1β, as well as corticosterone.127 These foregoing changes paralleled reduced aversive behavior in a conflict situation and improved cognitive ability in a spatial learning test.

“Somatoprotection”

Given the vastly increased burden of medical illness in bipolar disorder,17 it is important to consider the potential impact of new medications on medical problems that are common in this population. Indeed, recent studies suggest that celecoxib may have tumoricidal and anti-angiogenic properties,128–130 in addition to analgesic and anti-arthritic properties.131 Celecoxib also enhances glucocorticoid receptor function.132 This fact is important in light of glucocorticoid dysregulation in manic, depressed, and euthymic phases of bipolar disorder,133 the known effects cytokines have on glucocorticoid receptor expression and function,32,42 and the impact that glucocorticoid dysregulation has on allostatic load.134,135 It remains to be determined how celecoxib’s analgesic, anti-inflammatory, and other medically beneficial properties relate to its putative benefits in psychiatric illness. Nonetheless, treatment with celecoxib is not without risks. Although it does not appear that celecoxib shares the same propensity for cerebrovascular events as does rofecoxib, all nonsteroidal anti-inflammatories, including celecoxib, carry a “black-box” warning contained in the product insert underscoring the cardiovascular risks.

Other Anti-Inflammatory Treatments

TNF-α has been proposed as a possible pharmacologic target in bipolar disorder.136 For example, the TNF antagonist etanercept has U.S. Food and Drug Administration approval for the treatment of rheumatoid arthritis in both pediatric and adult populations. There have been no studies to date regarding its effect in the treatment of mood disorders per se. However, preliminary findings related to its mood-modulating properties have been reported from a large placebo-controlled trial (N = 618) for psoriasis.137,138 Although the study excluded patients with diagnosed psychiatric illness, subjects treated with etanercept demonstrated a significant reduction in Beck Depression Inventory (bipolar I disorder) and Hamilton Rating Scale for Depression (HAM-D) scores. Moreover, the proportion of bipolar I disorder responders (55% vs. 39%) and the proportion of subjects with minimal depressive symptoms (84% vs. 75%) were significantly greater in the etanercept group vs. placebo. Similar significant differences were observed with the HAM-D. Effect sizes for bipolar I disorder and HAM-D were 0.22 and 0.25, respectively.138 As with other anti-inflammatory medications, etanercept has been associated with treatment-emergent mania.139 In addition, etanercept is being evaluated for possible increased risk of lymphoma among children and young adults.140

Another treatment option relating to inflammation is omega-3 fatty acids. Multiple studies have found that omega-3 fatty acids have beneficial effects in acute and chronic inflammatory conditions and that they alter cytokine production ex vivo.141 This alteration may explain in part the known benefits of omega-3 fatty acids on cardiovascular and endocrine-metabolic parameters.140,142 Placebo-controlled studies have yielded both positive143,144 and negative145 findings in bipolar disorder. A small trial144 (N = 30) found that a combination of ethyl-eicosapentanoic acid (EPA) 6.2 g/day and docosahexaenoic acid 3.4 g/day resulted in significantly longer duration of remission versus placebo. A larger study143 of bipolar depression found that treatment with ethyl-EPA 1 to 2 g/day (N = 49) resulted in significant improvements in HAM-D scores and Clinical Global Impression scale (CGI) scores versus placebo (N = 26). No significant differences were observed between subjects receiving 1 g/day (N = 24) or 2 g/day (N = 25) of ethyl-EPA. Indeed, Keck and colleagues145 hypothesized that the negative findings in their study of bipolar depression and rapid-cycling bipolar disorder (N = 116) may have been explained by the high ethyl-EPA dose of 6 g/day, which exceeded the 1–3 g/day effective dose in dose-ranging studies of MDD and schizophrenia.

In addition to examining anti-inflammatory medications, the effects of exercise on the association between inflammation and mood in bipolar disorder merit investigation. Recent findings suggest that exercise may attenuate inflammatory responses to acute mental stress in the general population,112 although it has yet to be shown that exercise affects inflammatory mediators in bipolar disorder.

Summary

The articles reviewed in this article provide early evidence that inflammation may explain, in part, the phenomenology, comorbidity, pathophysiology, and treatment response in bipolar disorder. However, it is important to acknowledge that, similar to other nascent areas of investigation, inferences and interpretations that can be drawn from the literature are constrained by several important limitations, which include heterogeneity in mood state, bipolar disorder subtype, cytokine ascertainment, nationality, and concurrent medications. Additionally, sample sizes are generally modest. The discrepancies of study findings may be explained in part by these methodological differences. Further, most studies do not control for known confounds, such as obesity and smoking. Studies that did include these variables did not find that they were significantly associated with inflammation. Previous authors have suggested that these variables may account in large part for the association between severe mental illness—including bipolar disorder—and inflammation.146 Again, the methodological limitations may explain why, to date, studies of bipolar disorder have not found these variables to be associated with inflammation. Finally, studies to date have excluded subjects with comorbid medical disorders and substance use disorders. Given the high prevalence of these disorders in bipolar disorder,147 these exclusion criteria limit the generalizability of the reviewed findings.

Despite the methodological limitations, the extant literature provides sufficient data to support the working hypothesis that altered inflammatory networks are salient to the pathophysiology and treatment of bipolar disorder. For example, there is evidence for either increased PIMs or an imbalance between pro- and anti-inflammatory markers in bipolar disorder. Second, genetic findings suggest that bipolar disorder may be associated with IL11 and IL6 genes, whereas findings for TNFAα polymorphisms are conflicting. There is preliminary evidence for aberrant expression of inflammatory genes in bipolar disorder, which may comprise a susceptibility marker for bipolar disorder. Third, medications such as lithium may serve to modulate the inflammatory milieu in bipolar disorder, and this effect may indeed be specific to persons with bipolar disorder. Fourth, regardless of the direction of the associations, the high prevalence of comorbid medical illnesses, smoking, and excessive alcohol use, combined with decrements in physical activity and sleep parameters, contribute to a pro-inflammatory milieu in bipolar disorder. Finally, conventional anti-inflammatory therapies may possess symptom-alleviating effects among acutely ill patients at early stages of their illness.

Future Directions: Focus on Youth and Early Adversity

At present, there is insufficient evidence to support a recommendation for ascertainment of cytokines as part of the usual clinical management of bipolar disorder. Further studies are needed to demonstrate the potential clinical utility of including cytokines as part of the diagnostic or monitoring armamentarium in bipolar disorder. For example, no study to date has examined whether changes in cytokines may precede the onset of mood episodes. Longitudinal studies are needed to evaluate whether inflammatory dysregulation may be a predictor of important clinical outcomes such as relapse, recurrence, or polarity switches.

Similarly, no previous study has specifically examined inflammation among children or adolescents with bipolar disorder (although the study by Padmos and colleagues49 did include some adolescent offspring of parents with bipolar disorder). Many of the studies from adults with bipolar disorder reviewed above included subjects with 20-year courses of illness. Drawing definitive conclusions from subjects with prolonged illnesses is problematic because of the possibility that long-term symptom burden and pharmacologic treatment alter the association between bipolar disorder and inflammation. Indeed, inflammation may potentially play a larger role early in the disease process. Testing this hypothesis has treatment implications, as the relative risks and benefits of adjunctive anti-inflammatory medication may differ for youth. Youth are extremely prone to weight gain and metabolic effects conferred by mood stabilizers and antipsychotics, particularly when used in combination.148 Therefore, the possibility of using anti-inflammatories as weight-neutral adjunctive treatments is particularly appealing in this population. Another advantage of examining this topic among youth is that this offers greater opportunity to detect differences between subjects with bipolar disorder and controls, as inflammation is extremely low among healthy youth.149 Findings from Padmos and colleagues49 suggest that offspring of parents with bipolar disorder are more than twice as likely to express an aberrant inflammation-related messenger RNA signature compared to offspring of controls. Future longitudinal studies are needed to examine whether inflammatory diathesis may predict subsequent mood disorders in this high-risk population.

Another question that arises is how to delineate persons with pro-inflammatory diathesis for genotypic, phenotypic, and therapeutic investigations. An emerging risk factor for increased inflammation among adults with MDD is childhood maltreatment.150,151 Unfortunately, childhood abuse is reported by approximately 50% of adults with bipolar disorder and is associated with increased illness severity as evidenced by substance abuse, rapid cycling, and suicide attempts.152,153 Future studies of bipolar disorder should examine the possibility that inflammation in part mediates the impact of childhood maltreatment on illness severity in bipolar disorder.

Conclusion

Inflammation has been hypothesized to signal the brain to produce neurochemical, neuroendocrine, and neuroimmune changes in the face of stress.154 Indeed, it is precisely the brain’s response to stress that is central to the kindling theory which suggests that psychosocial stress and recurrent mood episodes combine to leave a cumulative “residue” of biochemical and anatomical vulnerabilities in mood disorders.155 Recent work regarding allostatic load has extended the evidence that stress and recurrent mood episodes leave a residue of vulnerabilities on both the brain and the body.134,156 The association of inflammation with bipolar disorder, psychosocial stress, sleep, neurotoxicity, obesity, and insulin resistance provides evidence that inflammation may comprise an integral part of both the neuropsychiatric and metabolic residues of bipolar disorder. In addition to the potential importance of inflammation to the pathophysiology and treatment of bipolar disorder, its putative role in the increased medical burden and premature mortality of bipolar disorder lends further urgency to progress on this topic.

Drug names: carbamazepine (Carbatrol, Equetro, and others), celecoxib (Celebrex), dexamethasone (Maxidex and others), etanercept (Enbrel), lamotrigine (Lamictal and others), lithium (Eskalith, Lithobid, and others), olanzapine (Zyprexa), rosiglitazone (Avandia), valproate (Depacon and others).

References

1. Smith RS. The macrophage theory of depression. (published correction appears in Med Hypotheses 1991;36:178) Med Hypotheses. 1991;35:298–306. PubMed doi:10.1016/0306-9877(91)90272-Z

2. Schiepers OJG, Wichers MC, Maes M. Cytokines and major depression. Prog Neuropsychopharmacol Biol Psychiatry. 2005;29:201–217. PubMed doi:10.1016/j.pnpbp.2004.11.003

3. Raison CL, Capuron L, Miller AH. Cytokines sing the blues: inflammation and the pathogenesis of depression. Trends Immunol. 2006;27:24–31. PubMed doi:10.1016/j.it.2005.11.006

4. Potvin S, Stip E, Sepehry AA, et al. Inflammatory cytokine alterations in schizophrenia: a systematic quantitative review. Biol Psychiatry. 2008;63:801–808. PubMed doi:10.1016/j.biopsych.2007.09.024

5. McGeer PL, Rogers J, McGeer EG. Inflammation, anti-inflammatory agents and Alzheimer disease: the last 12 years. J Alzheimers Dis. 2006;9(suppl 3):271–276. PubMed

6. Reichenberg A, Yirmiya R, Schuld A, et al. Cytokine-associated emotional and cognitive disturbances in humans. Arch Gen Psychiatry. 2001;58:445–452. PubMed doi:10.1001/archpsyc.58.5.445

7. Barkhudaryan N, Dunn AJ. Molecular mechanisms of actions of interleukin-6 on the brain, with special reference to serotonin and the hypothalamo-pituitary-adrenocortical axis. Neurochem Res. 1999;24:1169–1180. PubMed doi:10.1023/A:1020720722209

8. Müller N, Ackenheil M. Psychoneuroimmunology and the cytokine action in the CNS: implications for psychiatric disorders. Prog Neuropsychopharmacol Biol Psychiatry. 1998;22:1–33. PubMed doi:10.1016/S0278-5846(97)00179-6

9. Aktas O, Ullrich O, Infante-Duarte C, et al. Neuronal damage in brain inflammation. Arch Neurol. 2007;64:185–189. PubMed doi:10.1001/archneur.64.2.185

10. Allan SM, Rothwell NJ. Cytokines and acute neurodegeneration. Nat Rev Neurosci. 2001;2:734–744. PubMed doi:10.1038/35094583

11. McIntyre RS, Soczynska JK, Konarski JZ, et al. Should depressive syndromes be reclassified as “Metabolic Syndrome Type II”? Ann Clin Psychiatry. 2007;19:257–264. PubMed doi:10.1080/10401230701653377

12. Hirschfeld RM, Lewis L, Vornik LA. Perceptions and impact of bipolar disorder: how far have we really come? results of the National Depressive and Manic-Depressive Association 2000 survey of individuals with bipolar disorder. J Clin Psychiatry. 2003;64:161–174. PubMed

13. Belmaker RH. Bipolar Disorder. N Engl J Med. 2004;351(5):476–486. PubMed doi:10.1056/NEJMra035354

14. Lish JD, Dime-Meenan S, Whybrow PC, et al. The National Depressive and Manic-Depressive Association (DMDA) survey of bipolar members. J Affect Disord. 1994;31:281–294. PubMed doi:10.1016/0165-0327(94)90104-X

15. Grant BF, Stinson FS, Hasin DS, et al. Prevalence, correlates, and comorbidity of bipolar I disorder and axis I and II disorders: results from the National Epidemiologic Survey on Alcohol and Related Conditions. J Clin Psychiatry. 2005;66:1205–1215. PubMed

16. Merikangas KR, Akiskal HS, Angst J, et al. Lifetime and 12-month prevalence of bipolar spectrum disorder in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2007;64(5):543–552. PubMed doi:10.1001/archpsyc.64.5.543

17. Kupfer DJ. The increasing medical burden in bipolar disorder. JAMA. 2005;293:2528–2530. PubMed doi:10.1001/jama.293.20.2528

18. Miller AH, Manji HK. On redefining the role of the immune system in psychiatric disease. Biol Psychiatry. 2006;60:796–798. PubMed doi:10.1016/j.biopsych.2006.09.013

19. Tsai SY, Lee CH, Kuo CJ, et al. A retrospective analysis of risk and protective factors for natural death in bipolar disorder. J Clin Psychiatry. 2005;66:1586–1591. PubMed

20. Rapaport MH. Immune parameters in euthymic bipolar patients and normal volunteers. J Affect Disord. 1994;32:149–156. PubMed doi:10.1016/0165-0327(94)90012-4

21. Maes M, Bosmans E, Calabrese J, et al. Interleukin-2 and interleukin-6 in schizophrenia and mania: effects of neuroleptics and mood stabilizers. J Psychiatr Res. 1995;29:141–152. PubMed doi:10.1016/0022-3956(94)00049-W

22. Hornig M, Goodman DBP, Kamoun M, et al. Positive and negative acute phase proteins in affective subtypes. J Affect Disord. 1998;49:9–18. PubMed doi:10.1016/S0165-0327(97)00180-8

23. Rapaport MH, Guylai L, Whybrow P. Immune parameters in rapid cycling bipolar patients before and after lithium treatment. J Psychiatr Res. 1999;33:335–340. PubMed doi:10.1016/S0022-3956(99)00007-2

24. Tsai S-Y, Chen K-P, Yang Y-Y, et al. Activation of indices of cell-mediated immunity in bipolar mania. Biol Psychiatry. 1999;45:989–994. PubMed doi:10.1016/S0006-3223(98)00159-0

25. Tsai SY, Yang YY, Kuo CJ, et al. Effects of symptomatic severity on elevation of plasma soluble interleukin-2 receptor in bipolar mania. J Affect Disord. 2001;64:185–193. PubMed doi:10.1016/S0165-0327(00)00252-4

26. Kim YK, Suh IB, Kim H, et al. The plasma levels of interleukin-12 in schizophrenia, major depression, and bipolar mania: effects of psychotropic drugs. Mol Psychiatry. 2002;7:1107–1114. PubMed doi:10.1038/sj.mp.4001084

27. Su K-P, Leu S-JC, Yang Y-Y, et al. Reduced production of interferon-gamma but not interleukin-10 in bipolar mania and subsequent remission. (published correction appears in J Affect Disord 2003;73:299) J Affect Disord. 2002;71:205–209. PubMed doi:10.1016/S0165-0327(01)00369-X

28. Wadee AA, Kuschke RH, Wood LA, et al. Serological observations in patients suffering from acute manic episodes. Hum Psychopharmacol. 2002;17(4):175–179. PubMed doi:10.1002/hup.390

29. Breunis MN, Kupka RW, Nolen WA, et al. High numbers of circulating activated T cells and raised levels of serum IL-2 receptor in bipolar disorder. Biol Psychiatry. 2003;53(2):157–165. PubMed doi:10.1016/S0006-3223(02)01452-X

30. Boufidou F, Nikolaou C, Alevizos B, et al. Cytokine production in bipolar affective disorder patients under lithium treatment. J Affect Disord. 2004;82:309–313. PubMed doi:10.1016/j.jad.2004.01.007

31. Kim Y-K, Myint A-M, Lee B-H, et al. T-helper types 1, 2, and 3 cytokine interactions in symptomatic manic patients. Psychiatry Res. 2004;129:267–272. PubMed doi:10.1016/j.psychres.2004.08.005

32. Liu H-C, Yang Y-Y, Chou Y-M, et al. Immunologic variables in acute mania of bipolar disorder. J Neuroimmunol. 2004;150:116–122. PubMed doi:10.1016/j.jneuroim.2004.01.006

33. O’Brien SM, Scully P, Scott LV, et al. Cytokine profiles in bipolar affective disorder: focus on acutely ill patients. J Affect Disord. 2006;90:263–267. PubMed doi:10.1016/j.jad.2005.11.015

34. Knijff EM, Breunis MN, van Geest MC, et al. A relative resistance of T cells to dexamethasone in bipolar disorder. Bipolar Disord. 2006;8:740–750. PubMed doi:10.1111/j.1399-5618.2006.00359.x

35. Dickerson F, Stallings C, Origoni A, et al. Elevated serum levels of C-reactive protein are associated with mania symptoms in outpatients with bipolar disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2007;31:952–955. PubMed doi:10.1016/j.pnpbp.2007.02.018

36. Huang T-L, Lin F-C. High-sensitivity C-reactive protein levels in patients with major depressive disorder and bipolar mania. Prog Neuropsychopharmacol Biol Psychiatry. 2007;31:370–372. PubMed doi:10.1016/j.pnpbp.2006.09.010

37. Kim Y-K, Jung H-G, Myint A-M, et al. Imbalance between pro-inflammatory and anti-inflammatory cytokines in bipolar disorder. J Affect Disord. 2007;104:91–95. PubMed doi:10.1016/j.jad.2007.02.018

38. Knijff EM, Nadine Breunis M, Kupka RW, et al. An imbalance in the production of IL-1B and IL-6 by monocytes of bipolar patients: restoration by lithium treatment. Bipolar Disord. 2007;9:743–753. PubMed doi:10.1111/j.1399-5618.2007.00444.x

39. Ortiz-Dominguez A, Hernandez ME, Berlanga C, et al. Immune variations in bipolar disorder: phasic differences. Bipolar Disord. 2007;9:596–602. PubMed doi:10.1111/j.1399-5618.2007.00493.x

40. Cunha AB, Andreazza AC, Gomes FA, et al. Investigation of serum high-sensitive C-reactive protein levels across all mood states in bipolar disorder. Eur Arch Psychiatry Clin Neurosci. 2008;258:300–304. PubMed doi:10.1007/s00406-007-0797-0

41. McIntyre RS, Muzina DJ, Kemp DE, et al. Bipolar disorder and suicide: research synthesis and clinical translation. Curr Psychiatry Rep. 2008;10:66–72. PubMed doi:10.1007/s11920-008-0012-7

42. Miller AH, Pariante CM, Pearce BD. Effects of cytokines on glucocorticoid receptor expression and function: glucocorticoid resistance and relevance to depression. Adv Exp Med Biol. 1999;461:107–116. PubMed doi:10.1007/978-0-585-37970-8_7

43. Pariante CM, Pearce BD, Pisell TL, et al. The proinflammatory cytokine, interleukin-1alpha, reduces glucocorticoid receptor translocation and function. Endocrinology. 1999;140:4359–4366. PubMed doi:10.1210/en.140.9.4359

44. Papiol S, Rosa A, Gutierrez B, et al. Interleukin-1 cluster is associated with genetic risk for schizophrenia and bipolar disorder. J Med Genet. 2004;41:219–223. PubMed doi:10.1136/jmg.2003.012914

45. Kim SJ, Lee HJ, Koo HG, et al. Impact of IL-1 receptor antagonist gene polymorphism on schizophrenia and bipolar disorder. Psychiatr Genet. 2004;14:165–167. PubMed doi:10.1097/00041444-200409000-00009

46. Pae CU, Lee KU, Han H, et al. Tumor necrosis factor alpha gene-G308A polymorphism associated with bipolar I disorder in the Korean population. Psychiatry Res. 2004;125:65–68. PubMed doi:10.1016/j.psychres.2003.06.002

47. Middle F, Jones I, Robertson E, et al. Tumour necrosis factor alpha and bipolar affective puerperal psychosis. Psychiatr Genet. 2000;10:195–198. PubMed doi:10.1097/00041444-200010040-00008

48. Meira-Lima IV, Pereira AC, Mota GF, et al. Analysis of a polymorphism in the promoter region of the tumor necrosis factor alpha gene in schizophrenia and bipolar disorder: further support for an association with schizophrenia. Mol Psychiatry. 2003;8:718–720. PubMed doi:10.1038/sj.mp.4001309

49. Padmos RC, Hillegers MHJ, Knijff EM, et al. A discriminating messenger RNA signature for bipolar disorder formed by an aberrant expression of inflammatory genes in monocytes. Arch Gen Psychiatry. 2008;65:395–407. PubMed doi:10.1001/archpsyc.65.4.395

50. Lee H-J, Ertley R, Rapoport S, et al. Chronic administration of lamotrigine downregulates COX-2 mRNA and protein in rat frontal cortex. Neurochem Res. 2008;33:861–866. PubMed doi:10.1007/s11064-007-9526-3

51. Rao JS, Lee HJ, Rapoport SI, et al. Mode of action of mood stabilizers: is the arachidonic acid cascade a common target? Mol Psychiatry. 2008;13:585–596. PubMed doi:10.1038/mp.2008.31

52. Maes M, Song C, Lin AH, et al. In vitro immunoregulatory effects of lithium in healthy volunteers. Psychopharmacology (Berl). 1999;143:401–407. PubMed doi:10.1007/s002130050965

53. Bosetti F, Weerasinghe GR, Rosenberger TA, et al. Valproic acid down-regulates the conversion of arachidonic acid to eicosanoids via cyclooxygenase-1 and -2 in rat brain. J Neurochem. 2003;85:690–696. PubMed

54. Bosetti F, Rintala J, Seemann R, et al. Chronic lithium downregulates cyclooxygenase-2 activity and prostaglandin E(2) concentration in rat brain. Mol Psychiatry. 2002;7:845–850. PubMed doi:10.1038/sj.mp.4001111

55. Rapaport MH, Manji HK. The effects of lithium on ex vivo cytokine production. Biol Psychiatry. 2001;50:217–224. PubMed doi:10.1016/S0006-3223(01)01144-1

56. Ghelardoni S, Tomita YA, Bell JM, et al. Chronic carbamazepine selectively downregulates cytosolic phospholipase A2 expression and cyclooxygenase activity in rat brain. Biol Psychiatry. 2004;56:248–254. PubMed doi:10.1016/j.biopsych.2004.05.012

57. Ichiyama T, Okada K, Lipton JM, et al. Sodium valproate inhibits production of TNF-alpha and IL-6 and activation of NF-kappa B. Brain Res. 2000;857:246–251. PubMed doi:10.1016/S0006-8993(99)02439-7

58. Pollmacher T, Haack M, Schuld A, et al. Effects of antipsychotic drugs on cytokine networks. J Psychiatr Res. 2000;34:369–382. PubMed doi:10.1016/S0022-3956(00)00032-7

59. Himmerich H, Koethe D, Schuld A, et al. Plasma levels of leptin and endogenous immune modulators during treatment with carbamazepine or lithium. Psychopharmacology (Berl). 2005;179:447–451. PubMed doi:10.1007/s00213-004-2038-9

60. Lanquillon S, Krieg JC, Bening-Abu-Shach U, et al. Cytokine production and treatment response in major depressive disorder. Neuropsychopharmacology. 2000;22:370–379. PubMed doi:10.1016/S0893-133X(99)00134-7

61. Weeke A, Vaeth M. Excess mortality of bipolar and unipolar manic-depressive patients. J Affect Disord. 1986;11:227–234. PubMed doi:10.1016/0165-0327(86)90074-1

62. Weeke A, Juel K, Vaeth M. Cardiovascular death and manic-depressive psychosis. J Affect Disord. 1987;13:287–292. PubMed doi:10.1016/0165-0327(87)90049-8

63. Tsuang MT, Woolson RF, Fleming JA. Causes of death in schizophrenia and manic-depression. Br J Psychiatry. 1980;136:239–242. PubMed doi:10.1192/bjp.136.3.239

64. Osby U, Brandt L, Correia N, et al. Excess mortality in bipolar and unipolar disorder in Sweden. Arch Gen Psychiatry. 2001;58:844–850. PubMed doi:10.1001/archpsyc.58.9.844

65. Kilbourne AM, Cornelius JR, Han X, et al. Burden of general medical conditions among individuals with bipolar disorder. Bipolar Disord. 2004;6:368–373. PubMed doi:10.1111/j.1399-5618.2004.00138.x

66. Ridker PM, Cushman M, Stampfer MJ, et al. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med. 1997;336:973–979. PubMed doi:10.1056/NEJM199704033361401

67. Ridker PM, Hennekens CH, Buring JE, et al. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med. 2000;342:836–843. PubMed doi:10.1056/NEJM200003233421202

68. Sabatine MS, Morrow DA, de Lemos JA, et al. Multimarker approach to risk stratification in non-ST elevation acute coronary syndromes: simultaneous assessment of troponin I, C-reactive protein, and B-type natriuretic peptide. Circulation. 2002;105:1760–1763. PubMed doi:10.1161/01.CIR.0000015464.18023.0A

69. Morrow DA, Rifai N, Antman EM, et al. C-reactive protein is a potent predictor of mortality independently of and in combination with troponin T in acute coronary syndromes: a TIMI 11A substudy. J Am Coll Cardiol. 1998;31:1460–1465. PubMed doi:10.1016/S0735-1097(98)00136-3

70. Ridker PM, Cannon CP, Morrow D, et al. C-reactive protein levels and outcomes after statin therapy. N Engl J Med. 2005;352:20–28. PubMed doi:10.1056/NEJMoa042378

71. Pearson TA, Mensah GA, Alexander RW, et al. Markers of inflammation and cardiovascular disease: application to clinical and public health practice: a statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation. 2003;107:499–511. PubMed doi:10.1161/01.CIR.0000052939.59093.45

72. Fagiolini A, Frank E, Houck PR, et al. Prevalence of obesity and weight change during treatment in patients with bipolar I disorder. J Clin Psychiatry. 2002;63:528–533. PubMed

73. McElroy SL, Frye MA, Suppes T, et al. Correlates of overweight and obesity in 644 patients with bipolar disorder. J Clin Psychiatry. 2002;63:207–213. PubMed

74. Simon GE, Von Korff M, Saunders K, et al. Association between obesity and psychiatric disorders in the US adult population. Arch Gen Psychiatry. 2006;63:824–830. PubMed doi:10.1001/archpsyc.63.7.824

75. McIntyre RS, Konarski JZ, Wilkins K, et al. Obesity in bipolar disorder and major depressive disorder: results from a national community health survey on mental health and well-being. Can J Psychiatry. 2006;51:274–280. PubMed

76. van Winkel R, De Hert M, Van Eyck D, et al. Prevalence of diabetes and the metabolic syndrome in a sample of patients with bipolar disorder. Bipolar Disord. 2008;10:342–348. PubMed doi:10.1111/j.1399-5618.2007.00520.x

77. Cassidy F, Ahearn E, Carroll J. Elevated frequency of diabetes mellitus in hospitalized manic-depressive patients. Am J Psychiatry. 1999;156:1417–1420. PubMed

78. Regenold WT, Thapar RK, Marano C, et al. Increased prevalence of type 2 diabetes mellitus among psychiatric inpatients with bipolar I affective and schizoaffective disorders independent of psychotropic drug use. J Affect Disord. 2002;70(1):19–26. PubMed doi:10.1016/S0165-0327(01)00456-6

79. Ruzickova M, Slaney C, Garnham J, et al. Clinical features of bipolar disorder with and without comorbid diabetes mellitus. Can J Psychiatry. 2003;48:458–461. PubMed

80. Das UN. Is obesity an inflammatory condition? (comments appear in Nutrition 2001:17:974–976) Nutrition. 2001;17(11–12):953–966. PubMed doi:10.1016/S0899-9007(01)00672-4

81. Pou KM, Massaro JM, Hoffmann U, et al. Visceral and subcutaneous adipose tissue volumes are cross-sectionally related to markers of inflammation and oxidative stress: the Framingham Heart Study. Circulation. 2007;116:1234–1241. PubMed doi:10.1161/CIRCULATIONAHA.107.710509

82. Mohamed-Ali V, Goodrick S, Rawesh A, et al. Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor-alpha, in vivo. J Clin Endocrinol Metab. 1997;82:4196–4200. PubMed doi:10.1210/jc.82.12.4196

83. Brydon L, Wright CE, O’Donnell K, et al. Stress-induced cytokine responses and central adiposity in young women. Int J Obes. 2007;32:443–450. doi:10.1038/sj.ijo.0803767

84. Greenfield JR, Campbell LV. Relationship between inflammation, insulin resistance and type 2 diabetes: ‘cause or effect’? Curr Diabetes Rev. 2006;2:195–211. PubMed doi:10.2174/157339906776818532

85. Wolford JK, Colligan PB, Gruber JD, et al. Variants in the interleukin 6 receptor gene are associated with obesity in Pima Indians. Mol Genet Metab. 2003;80:338–343. PubMed doi:10.1016/j.ymgme.2003.07.003

86. Huth C, Heid IM, Vollmert C, et al. IL6 gene promoter polymorphisms and type 2 diabetes: joint analysis of individual participants’ data from 21 studies. Diabetes. 2006;55:2915–2921. PubMed doi:10.2337/db06-0600

87. Baptista T, Beaulieu S. Are leptin and cytokines involved in body weight gain during treatment with antipsychotic drugs? Can J Psychiatry. 2002;47:742–749. PubMed

88. Stocker DJ, Taylor AJ, Langley RW, et al. A randomized trial of the effects of rosiglitazone and metformin on inflammation and subclinical atherosclerosis in patients with type 2 diabetes. Am Heart J. 2007;153:445. PubMed doi:10.1016/j.ahj.2006.11.005

89. McIntyre RS, Soczynska JK, Woldeyohannes HO, et al. Thiazolidinediones: novel treatments for cognitive deficits in mood disorders? Expert Opin Pharmacother. 2007;8:1615–1628. PubMed doi:10.1517/14656566.8.11.1615

90. McIntyre RS, Soczynska JK, Lewis GF, et al. Managing psychiatric disorders with antidiabetic agents: translational research and treatment opportunities. Expert Opin Pharmacother. 2006;7:1305–1321. PubMed doi:10.1517/14656566.7.10.1305

91. Carney CP, Jones LE. Medical comorbidity in women and men with bipolar disorders: a population-based controlled study. Psychosom Med. 2006;68:684–691. PubMed doi:10.1097/01.psy.0000237316.09601.88

92. Kilbourne AM. The burden of general medical conditions in patients with bipolar disorder. Curr Psychiatry Rep. 2005;7:471–477. PubMed doi:10.1007/s11920-005-0069-5

93. McIntyre RS, Konarski JZ, Wilkins K, et al. The prevalence and impact of migraine headache in bipolar disorder: results from the Canadian Community Health Survey. Headache. 2006;46:973–982. PubMed doi:10.1111/j.1526-4610.2006.00469.x

94. Low NCP, Du Fort GG, Cervantes P. Prevalence, clinical correlates, and treatment of migraine in bipolar disorder. Headache. 2003;43:940–949. PubMed doi:10.1046/j.1526-4610.2003.03184.x

95. Zhang J-M, An J. Cytokines, inflammation, and pain. Int Anesthesiol Clin. 2007;45:27–37. PubMed doi:10.1097/AIA.0b013e318034194e

96. Peroutka SJ, Price SC, Jones KW. The comorbid association of migraine with osteoarthritis and hypertension: complement C3F and Berkson’s bias. Cephalalgia. 1997;17:23–26. PubMed doi:10.1046/j.1468-2982.1997.1701023.x

97. Waeber C, Moskowitz MA. Migraine as an inflammatory disorder. Neurology. 2005;64(suppl 2):S9–S15. PubMed

98. Choy EHS, Panayi GS. Cytokine pathways and joint inflammation in rheumatoid arthritis. N Engl J Med. 2001;344:907–916. PubMed doi:10.1056/NEJM200103223441207

99. Sturmer T, Brenner H, Koenig W, et al. Severity and extent of osteoarthritis and low grade systemic inflammation as assessed by high sensitivity C reactive protein. Ann Rheum Dis. 2004;63:200–205. PubMed doi:10.1136/ard.2003.007674

100. Grant BF, Stinson FS, Dawson DA, et al. Prevalence and co-occurrence of substance use disorders and independent mood and anxiety disorders: results from the National Epidemiologic Survey on Alcohol and Related Conditions. Arch Gen Psychiatry. 2004;61:807–816. PubMed doi:10.1001/archpsyc.61.8.807

101. Regier DA, Farmer ME, Rae DS, et al. Comorbidity of mental disorders with alcohol and other drug abuse: results from the Epidemiologic Catchment Area (ECA) Study. JAMA. 1990;264:2511–2518. PubMed doi:10.1001/jama.264.19.2511

102. Lasser K, Boyd JW, Woolhandler S, et al. Smoking and mental illness: a population-based prevalence study. JAMA. 2000;284:2606–2610. PubMed doi:10.1001/jama.284.20.2606

103. Gan WQ, Man SFP, Sin DD. The interactions between cigarette smoking and reduced lung function on systemic inflammation. Chest. 2005;127:558–564. PubMed doi:10.1378/chest.127.2.558

104. Imhof A, Froehlich M, Brenner H, et al. Effect of alcohol consumption on systemic markers of inflammation. Lancet. 2001;357:763–767. PubMed doi:10.1016/S0140-6736(00)04170-2

105. Misra M, Papakostas GI, Klibanski A. Effects of psychiatric disorders and psychotropic medications on prolactin and bone metabolism. J Clin Psychiatry. 2004;65:1607–1618. PubMed

106. Mundy GR. Osteoporosis and inflammation. Nutr Rev. 2007;65(12 Pt 2):S147–S151. PubMed doi:10.1301/nr.2007.dec.S147-S151

107. Eskandari F, Martinez PE, Torvik S, et al. Low bone mass in premenopausal women with depression. Arch Intern Med. 2007;167:2329–2336. PubMed doi:10.1001/archinte.167.21.2329

108. Kilbourne AM, Rofey DL, McCarthy JF, et al. Nutrition and exercise behavior among patients with bipolar disorder. Bipolar Disord. 2007;9:443–452. PubMed doi:10.1111/j.1399-5618.2007.00386.x

109. Wildes JE, Marcus MD, Fagiolini A. Obesity in patients with bipolar disorder: a biopsychosocial-behavioral model. J Clin Psychiatry. 2006;67:904–915. PubMed

110. Morriss R, Mohammed FA. Metabolism, lifestyle and bipolar affective disorder. J Psychopharmacol. 2005;19(suppl 6):94–101. PubMed doi:10.1177/0269881105058678

111. Elmslie JL, Mann JI, Silverstone JT, et al. Determinants of overweight and obesity in patients with bipolar disorder. J Clin Psychiatry. 2001;62(6):486–491. PubMed

112. Hamer M, Steptoe A. Association between physical fitness, parasympathetic control, and proinflammatory responses to mental stress. Psychosom Med. 2007;69:660–666. PubMed doi:10.1097/PSY.0b013e318148c4c0

113. Harvey AG, Schmidt DA, Scarna A, et al. Sleep-related functioning in euthymic patients with bipolar disorder, patients with insomnia, and subjects without sleep problems. Am J Psychiatry. 2005;162:50–57. PubMed doi:10.1176/appi.ajp.162.1.50

114. Millar A, Espie CA, Scott J. The sleep of remitted bipolar outpatients: a controlled naturalistic study using actigraphy. J Affect Disord. 2004;80:145–153. PubMed doi:10.1016/S0165-0327(03)00055-7

115. Motivala SJ, Sarfatti A, Olmos L, et al. Inflammatory markers and sleep disturbance in major depression. Psychosom Med. 2005;6:187–194. doi:10.1097/01.psy.0000149259.72488.09

116. Irwin MR, Wang M, Campomayor CO, et al. Sleep deprivation and activation of morning levels of cellular and genomic markers of inflammation. Arch Intern Med. 2006;166:1756–1762. PubMed doi:10.1001/archinte.166.16.1756

117. Nery FG, Monkul ES, Hatch JP, et al. Celecoxib as an adjunct in the treatment of depressive or mixed episodes of bipolar disorder: a double-blind, randomized, placebo-controlled study. Hum Psychopharmacol. 2008;23:87–94. PubMed doi:10.1002/hup.912

118. Muller N, Schwarz MJ, Dehning S, et al. The cyclooxygenase-2 inhibitor celecoxib has therapeutic effects in major depression: results of a double-blind, randomized, placebo controlled, add-on pilot study to reboxetine. Mol Psychiatry. 2006;11:680–684. PubMed doi:10.1038/sj.mp.4001805

119. Muller N, Riedel M, Scheppach C, et al. Beneficial antipsychotic effects of celecoxib add-on therapy compared to risperidone alone in schizophrenia. Am J Psychiatry. 2002;159:1029–1034. PubMed doi:10.1176/appi.ajp.159.6.1029

120. Akhondzadeh S, Tabatabaee M, Amini H, et al. Celecoxib as adjunctive therapy in schizophrenia: a double-blind, randomized and placebo-controlled trial. Schizophr Res. 2007;90:179–185. PubMed doi:10.1016/j.schres.2006.11.016

121. Rapaport MH, Delrahim KK, Bresee CJ, et al. Celecoxib augmentation of continuously ill patients with schizophrenia. Biol Psychiatry. 2005;57:1594–1596. PubMed doi:10.1016/j.biopsych.2005.02.024

122. Muller N, Ulmschneider M, Scheppach C, et al. COX-2 inhibition as a treatment approach in schizophrenia: immunological considerations and clinical effects of celecoxib add-on therapy. Eur Arch Psychiatry Clin Neurosci. 2004;254:14–22. PubMed doi:10.1007/s00406-004-0478-1

123. Bresee CJ, Delrahim K, Maddux RE, et al. The effects of celecoxib augmentation on cytokine levels in schizophrenia. Int J Neuropsychopharmacol. 2006;9:343–348. PubMed doi:10.1017/S1461145705005808

124. Huang Y, Liu J, Wang LZ, et al. Neuroprotective effects of cyclooxygenase-2 inhibitor celecoxib against toxicity of LPS-stimulated macrophages toward motor neurons. Acta Pharmacol Sin. 2005;26:952–958. PubMed doi:10.1111/j.1745-7254.2005.00136.x

125. Scali C, Giovannini MG, Prosperi C, et al. The selective cyclooxygenase-2 inhibitor rofecoxib suppresses brain inflammation and protects cholinergic neurons from excitotoxic degeneration in vivo. Neuroscience. 2003;117:909–919. PubMed doi:10.1016/S0306-4522(02)00839-4

126. Myint AM, Steinbusch HW, Goeghegan L, et al. Effect of the COX-2 inhibitor celecoxib on behavioural and immune changes in an olfactory bulbectomised rat model of depression. Neuroimmunomodulation. 2007;14:65–71. PubMed doi:10.1159/000107420

127. Casolini P, Catalani A, Zuena AR, et al. Inhibition of COX-2 reduces the age-dependent increase of hippocampal inflammatory markers, corticosterone secretion, and behavioral impairments in the rat. J Neurosci Res. 2002;68:337–343. PubMed doi:10.1002/jnr.10192

128. Ferrario A, Fisher AM, Rucker N, et al. Celecoxib and NS-398 enhance photodynamic therapy by increasing in vitro apoptosis and decreasing in vivo inflammatory and angiogenic factors. Cancer Res. 2005;65:9473–9478. PubMed doi:10.1158/0008-5472.CAN-05-1659

129. Shishodia S, Koul D, Aggarwal BB. Cyclooxygenase (COX)-2 inhibitor celecoxib abrogates TNF-induced NF-kappa B activation through inhibition of activation of I kappa B alpha kinase and Akt in human non-small cell lung carcinoma: correlation with suppression of COX-2 synthesis. J Immunol. 2004;173:2011–2022. PubMed

130. Mao JT, Roth MD, Serio KJ, et al. Celecoxib modulates the capacity for prostaglandin E2 and interleukin-10 production in alveolar macrophages from active smokers. Clin Cancer Res. 2003;9:5835–5841. PubMed

131. Alvarez-Soria MA, Largo R, Santillana J, et al. Long term NSAID treatment inhibits COX-2 synthesis in the knee synovial membrane of patients with osteoarthritis: differential proinflammatory cytokine profile between celecoxib and aceclofenac. Ann Rheum Dis. 2006;65:998–1005. PubMed doi:10.1136/ard.2005.046920

132. Hu F, Wang X, Pace TWW, et al. Inhibition of COX-2 by celecoxib enhances glucocorticoid receptor function. Mol Psychiatry. 2005;10:426–428. PubMed doi:10.1038/sj.mp.4001644

133. Cervantes P, Gelber S, Kin FN, et al. Circadian secretion of cortisol in bipolar disorder. J Psychiatry Neurosci. 2001;26:411–416. PubMed

134. Kapczinski F, Vieta E, Andreazza AC, et al. Allostatic load in bipolar disorder: implications for pathophysiology and treatment. Neurosci Biobehav Rev. 2008;32:675–692. PubMed doi:10.1016/j.neubiorev.2007.10.005

135. McEwen BS. Protective and damaging effects of stress mediators. N Engl J Med. 1998;338:171–179. PubMed doi:10.1056/NEJM199801153380307

136. Brietzke E, Kapczinski F. TNF-alpha as a molecular target in bipolar disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2008;32:1355–1361. PubMed doi:10.1016/j.pnpbp.2008.01.006

137. Krishnan R, Cella D, Leonardi C, et al. Effects of etanercept therapy on fatigue and symptoms of depression in subjects treated for moderate to severe plaque psoriasis for up to 96 weeks. Br J Dermatol. 2007;157:1275–1277. PubMed doi:10.1111/j.1365-2133.2007.08205.x

138. Tyring S, Gottlieb A, Papp K, et al. Etanercept and clinical outcomes, fatigue, and depression in psoriasis: double-blind placebo-controlled randomised phase III trial. Lancet. 2006;367:29–35. PubMed doi:10.1016/S0140-6736(05)67763-X

139. Kaufman KR. Etanercept, anticytokines and mania. Int Clin Psychopharmacol. 2005;20:239–241. PubMed doi:10.1097/00004850-200507000-00008

140. Center for Drug Evaluation and Research, US Food and Drug Administration. Early communication about an ongoing safety review of tumor necrosis factor (TNF) blockers (marketed as Remicade, Enbrel, Humira, and Cimzia). Available at: www.fda.org/CDER/drug/early_comm/TNF_blockers.htm. Accessed April 20, 2009

141. Mori TA, Beilin LJ, Mori TA, et al. Omega-3 fatty acids and inflammation. Curr Atheroscler Rep. 2004;6:461–467. PubMed doi:10.1007/s11883-004-0087-5

142. White P, Marette A. Is omega-3 key to unlocking inflammation in obesity? Diabetologia. 2006;49:1999–2001. PubMed doi:10.1007/s00125-006-0346-9

143. Frangou S, Lewis M, McCrone P. Efficacy of ethyl-eicosapentaenoic acid in bipolar depression: randomized double-blind placebo-controlled study. Br J Psychiatry. 2006;188:46–50. PubMed doi:10.1192/bjp.188.1.46

144. Stoll AL, Severus WE, Freeman MP, et al. Omega 3 fatty acids in bipolar disorder: a preliminary double-blind, placebo-controlled trial. Arch Gen Psychiatry. 1999;56:407–412. PubMed doi:10.1001/archpsyc.56.5.407

145. Keck JPE, Mintz J, McElroy SL, et al. Double-blind, randomized, placebo-controlled trials of ethyl-eicosapentanoate in the treatment of bipolar depression and rapid cycling bipolar disorder. Biol Psychiatry. 2006;60:1020–1022. PubMed doi:10.1016/j.biopsych.2006.03.056

146. Haack M, Hinze-Selch D, Fenzel T, et al. Plasma levels of cytokines and soluble cytokine receptors in psychiatric patients upon hospital admission: effects of confounding factors and diagnosis. J Psychiatr Res. 1999;33:407–418. PubMed doi:10.1016/S0022-3956(99)00021-7

147. Krishnan KRR. Psychiatric and medical comorbidities of bipolar disorder. Psychosom Med. 2005;67:1–8. PubMed doi:10.1097/01.psy.0000151489.36347.18

148. Correll CU. Weight gain and metabolic effects of mood stabilizers and antipsychotics in pediatric bipolar disorder: a systematic review and pooled analysis of short-term trials. J Am Acad Child Adolesc Psychiatry. 2007;46:687–700. PubMed doi:10.1097/chi.0b013e318040b25f

149. Lilic D, Cant AJ, Abinun M, et al. Cytokine production differs in children and adults. Pediatr Res. 1997;42:237–240. PubMed doi:10.1203/00006450-199708000-00018

150. Danese A, Moffitt TE, Pariante CM, et al. Elevated inflammation levels in depressed adults with a history of childhood maltreatment. Arch Gen Psychiatry. 2008;65:409–415. PubMed doi:10.1001/archpsyc.65.4.409

151. Pace TWW, Mletzko TC, Alagbe O, et al. Increased stress-induced inflammatory responses in male patients with major depression and increased early life stress. Am J Psychiatry. 2006;163:1630–1633. PubMed doi:10.1176/appi.ajp.163.9.1630

152. Garno JL, Goldberg JF, Ramirez PM, et al. Impact of childhood abuse on the clinical course of bipolar disorder. (published correction appears in Br J Psychiatry 2005;186:357) Br J Psychiatry. 2005;186:121–125. PubMed doi:10.1192/bjp.186.2.121

153. Leverich GS, McElroy SL, Suppes T, et al. Early physical and sexual abuse associated with an adverse course of bipolar illness. (comment appears in Biol Psychiatry 2002;52:843) Biol Psychiatry. 2002;51:288–297. PubMed doi:10.1016/S0006-3223(01)01239-2

154. Kronfol Z, Remick DG. Cytokines and the brain: implications for clinical psychiatry. Am J Psychiatry. 2000;157:683–694. PubMed doi:10.1176/appi.ajp.157.5.683

155. Post RM. Transduction of psychosocial stress into the neurobiology of recurrent affective disorder. Am J Psychiatry. 1992;149:999–1010. PubMed

156. McEwen BS. Stress, adaptation, and disease: allostasis and allostatic load. Ann N Y Acad Sci. 1998;840:33–44. PubMed doi:10.1111/j.1749-6632.1998.tb09546.x