Whether or not bipolar disorder should be considered an inflammatory condition will depend on an unambiguous definition of inflammatory condition and immune response. Inflammation is a part of the nonspecific immune response that takes place after any type of bodily injury or microbial invasion. Many of these reactions involve cytokines, especially interleukin-1 (IL-1), tumor necrosis factor-alpha (TNF-α) and IL-6, produced by dendritic cells, macrophages, and other types of cells. Inflammatory responses are also accompanied by increased levels of acute-phase reactants [such as high sensitivity C-reactive protein (hsCRP)] and complement factors [1▪].
The immune system is often involved with inflammatory disorders, such as allergic reactions and skin disorders, many of which result in abnormal inflammation. Wounds and infections would never heal without inflammation, but chronic inflammation, if not controlled, can also lead to a number of pathological conditions, such as inflammatory bowel disease and rheumatoid arthritis. This is one of the reasons why the inflammation is so closely regulated by the body.
Over the past decade, bipolar disorder has been consistently associated with clinical comorbidities . Recent data from the Systematic Treatment Enhancement Program for Bipolar Disorder show that over 50% of patients with chronic bipolar disorder have at least one associated comorbidity [3▪]. Prominent in this group are cardiovascular disease, diabetes, obesity, dyslipidemia, and insulin resistance – all metabolic syndrome components [2,4▪]. This overlap is one of the reasons why great emphasis has been placed on systemic mechanisms related to bipolar disorder-related impairment [4▪]. Up to the present moment, two clinical studies, one conducted at a specialized clinic [5▪] and another assessing the general population [6▪], have shown that subtle proinflammatory states are characteristic of the peripheral pathophysiology of bipolar disorder [7▪].
Progressive impairment of different cognitive functions has been consistently described in bipolar disorder, corroborating a potential role of neuroinflammation in this illness [8,9]. Immune signaling in the brain is of special interest because it provides a relevant explanatory link between progressive dysfunction, cognitive impairment, medical comorbidity, and premature mortality . Neurocognitive alterations include impairment of attention, executive function, and verbal memory [11▪]. These changes can be influenced by inflammatory mediators through the shaping of synaptic transmissions. Inflammation can influence the role of microglia in synaptogenesis (synaptic formation) and pruning, that is, reduction of the overall number of neurons and synapses, leaving only more efficient synaptic configurations [12▪▪,13▪▪]. Also, TNF-α influences dendritic arborization, modulates long-term potentiation (a mechanism of memory consolidation), and affects neurotransmitter pathways [14▪▪].
Many of these impairments and comorbidities have been described in clinical populations after the occurrence of mood episodes. Because the pathophysiology of bipolar disorder tends to differ in early versus late stages, the term neuroprogression has been used to describe these changes [7▪]. Structural and functional modifications change as the illness progresses and as patient age increases. MRI studies have suggested abnormal neural development already in the early stages of the disorder, with progressive changes as mood episodes occur [15▪]. Neuroprogression in bipolar disorder underlies changes in inflammatory cytokines and neurotrophins, mitochondrial dysfunction, oxidative stress, and epigenetic effects [7▪]. These parameters can be sensitive to the progression of illness and have, therefore, been used as first biochemical indicators in the staging of bipolar disorder .
In this review, we will focus on lines of investigation that establish a link between neuroinflammation and peripheral toxicity in bipolar disorder, in an attempt to define bipolar disorder as an inflammatory or a noninflammatory condition, using data published mainly in the past 18 months.
MICROGLIAL ACTIVATION AND NEUROINFLAMMATION
In the framework of the nervous system, inflammation can be viewed as a collection of immune responses aimed at dealing with a threat to the neuronal environment. Inflammation is accompanied by synaptic degeneration and neuronal loss (for a detailed revision on the role of inflammation in the developing brain, see Harry and Kraft [17▪▪]), and it can be induced by disease, physical trauma, ischemia/hypoxia, or cellular damage due to multiple initiating stimuli, including exposure to neurotoxicants [18▪▪].
The brain is rich in resident macrophages, called microglia, which become activated in response to tissue damage or brain infections and can be the first to detect critical changes in neuronal activity and health [17▪▪]. The microglial activation can be divided into two types: classical M1 (first line of defense) and alternative M2 (anti-inflammatory). In the M2 case, microglia increase the production and release of anti-inflammatory cytokines and neurotrophic factors, and the production of cytoactive factors involved in repairing and restructuring damaged extracellular matrix in the brain [19▪]. In the M1 case, microglial activation leads to the synthesis of an array of proinflammatory mediators, which can clear infections and repair tissues. However, if not controlled, this response may perpetrate bystander neural insult [20▪▪].
Activated microglia secrete innate proinflammatory cytokines TNF-α and IL-1β, which can directly injure neurons at supraphysiological levels [20▪▪]. TNF-α, for instance, interacts with two receptors: p55 (TNF-RI) and p75 (TNF-RII). Binding of TNF-α to either receptor can activate an apoptotic signaling cascade when ligand binding occurs. The TNF-R then associates with the TNF receptor-associated death domain. This results in recruitment and internalization of Fas, activation of caspase-8, and cell death .
The threshold for microglial activation, however, may be higher than that of macrophage activation in other tissues. Healthy neurons maintain microglia in an inactive state via secreted and membrane-bound signals, including CD200, CX3CL1 (fractalkine), neurotransmitters, and neurotrophins [17▪▪]. If this control fails (e.g., as a result of neuronal injury or loss of regulatory signals), activated microglia may participate in a form of chronic neuroinflammation, which has been implicated in the pathoetiology of a number of neurodegenerative diseases [20▪▪].
There is recent, still limited, evidence indicating the involvement of neuroinflammation in bipolar disorder. A 2010 study reported that markers of neuroinflammation were significantly upregulated in post-mortem frontal cortex from patients with bipolar disorder. In particular, those authors observed the activation of the IL-1 receptor (IL-1R) cascade involved in microglial activation. The same work found increased astroglial and microglial markers (glial fibrillary acidic protein, inducible nitric oxide synthase, c-fos, and CD11b), another evidence of microglial activation . Recently, patients experiencing one or more manic/hypomanic episodes during the previous year were shown to have significantly higher levels of IL-1β in cerebrospinal fluid levels when compared with patients without a recent manic/hypomanic episode. This indicates a relationship between the presence of acute episodes and activation of the IL-1R cascade [23▪].
The mechanisms described above suggest microglial activation in bipolar disorder. Some forms of cognitive decline, including the one observed in bipolar disorder [24▪], involve remodeling or destruction of specific regions of neuronal dendrites in response to changes in synaptic activity, neurite dysfunction, or excess extracellular neurotransmitters. Microglia monitor synaptic activity and may contribute to the remodeling of impaired synapses [18▪▪]. In this vein, the activation induced by the IL-1R cascade could indicate not only an inflammation process but also a ‘synaptic adaptation attempt’ to cope with the insult caused by the acute episode (Fig. 1a).
The understanding of severe psychiatric disorders as systemic conditions is not a recent trend. Since the publication in 2002 of an article that already has classic status , emphasis has been placed on early mortality due to natural causes and the burden related to medical comorbidities in patients with bipolar disorder [11▪,26▪] – parts of a spectrum that we have been calling systemic toxicity . As we have earlier proposed, systemic toxicity consists of an increase in the levels of several peripheral markers implicated in bipolar disorder as mediators of allostasis (the adaptation by which living organisms maintain homeostasis) [7▪]. Inflammatory markers account for some of the primary components of this cumulative load. Table 1[1▪,5▪,23▪,28▪,29▪▪,30▪,31▪] describes the primordial functions of cytokines and recent alterations found in bipolar disorder.
Most evidence supporting the implication of inflammation in the pathophysiology of psychiatric disorders comes from circulating inflammatory markers, especially TNF-α. Serum TNF-α levels seem to be elevated not only during acute episodes [28▪] but also in response to treatment with lithium. A significant increase in TNF-α levels has been observed in patients with a poor response to lithium when compared with those with a good response [29▪▪].
Additionally, studies have demonstrated that bipolar disorder is associated with both cytokine alterations and acute-phase reactants, such as hsCRP, produced by the liver in response to IL-1 and IL-6 [1▪,30▪]. Serum hsCRP levels are significantly higher in bipolar patients (in both acute mania and partial remission) when compared with controls [30▪]. Moreover, hsCRP levels are positively associated with hypomanic/manic symptoms [31▪]. Recently, investigators from the Psychiatric Center Copenhagen published an extensive systematic review and meta-analysis on cytokine alterations in bipolar disorder. The authors found that altered levels of TNF-α, soluble TNF receptor type 1 and soluble IL-2 receptor were most strongly associated with bipolar disorder [28▪].
ANTI-INFLAMMATORY POTENTIAL OF ESTABLISHED TREATMENTS AND CURRENT EVIDENCE ON NEW ADJUNCTIVE TREATMENTS
There is considerable preliminary evidence suggesting that traditional mood stabilizers modulate neuroinflammation. Very recently, lithium was shown to have neuroprotective activity in two preclinical studies [32▪▪,33]. In rat glial cells, pretreatment with lithium showed a significant anti-inflammatory potential, decreasing lipopolysaccharides-induced secretion of TNF-α, IL1-β, prostaglandin E (2), and nitric oxide. Similarly, in an intracerebral hemorrhage model, lithium reduced cell death, cyclooxygenase (COX) 2 expression, and reactive microglia in perihematomal regions in rats. Interestingly, valproate has also shown anti-inflammatory properties in preclinical models, modulating both systemic and central nervous system (CNS) responses [34▪]. Nevertheless, not enough clinical evidence exists to support that these would exert neuroprotective effects in general, and specifically through immune and inflammatory pathways in particular .
The adjunctive use of drugs with anti-inflammatory properties, such as omega-3 fatty acids (fish oil), COX inhibitors, minocycline, and statins, is another arena that has recently started to be explored [36▪▪]. Omega-3 are nutritionally important fatty acids that include α-linolenic acid (C18 : 3), docosahexaenoic acid (DHA, C22 : 6), and eicosapentaenoic acid (EPA, C20 : 5). A recent meta-analysis showed that EPA is a more effective component in the treatment of major depressive episodes than DHA [37▪]. These molecules are supposed to compete for the biotransformation of inflammatory eicosanoids (such as prostaglandins and leukotrienes). In fact, competition for the biosynthesis of inflammatory mediators could be partially responsible for their anti-inflammatory effects [38▪]. Although current evidence does not support the adjunctive use of omega-3 in the treatment of bipolar mania, some studies have demonstrated its efficacy in bipolar depression [39▪,40▪].
The antibiotic and anti-inflammatory effects of minocycline inhibit apoptosis by attenuating microglial release of proinflammatory cytokines IL-1β, TNF-α, and IL-6, while at the same time promoting release of anti-inflammatory cytokine IL-10. However, the efficacy of minocycline has not been formally tested in mood disorders [41▪▪]. Recently, a clinical trial with minocycline and aspirin was proposed and is currently underway [42▪▪].
Acetylsalicylic acid (ASA) irreversibly inhibits COX-1 and modifies the enzymatic activity of COX-2. COX-1 and COX-2 differentially modulate leukocyte recruitment during neuroinflammation. The clinical use of low-dose ASA has been primarily driven by its role as an antithrombotic and thrombolytic agent. Given the high rates of death from cardiovascular events in bipolar disorder, this action might be potentially advantageous in the management of bipolar disorder. Nevertheless, recent literature also supports the use of low-dose ASA in the management of the mood disorder itself, more specifically to ameliorate depressive symptoms [42▪▪]. The COX-2 inhibitor celecoxib was tested in the treatment of depressive or mixed episodes in bipolar disorder in a short-term randomized controlled trial . That study showed some benefits of celecoxib in the treatment of depressive symptoms, but it remains unclear whether those benefits outweigh the risks at this point. Another trial is currently underway [36▪▪].
PROBLEMS WITH THE INFLAMMATORY SYSTEM OR WITH NEGATIVE FEEDBACK?
The immune system is a good example of how connections between the brain and the body can have multiple relevant facets. Communication with the peripheral immune system occurs via vagal afferents, circumventricular organs, and directly at the blood–brain barrier [44▪▪]. For instance, systemic administration of CCL11, a proinflammatory chemokine, may decrease adult neurogenesis and impair learning and memory in young mice [45▪▪]. Also, vagal afferent stimulation by systemic inflammation elicits ‘sickness behavior’ in healthy humans, for example, sleep and appetite disturbances, psychomotor slowing, and memory impairment [46▪]. At the same time, efferent processes from the CNS affect and regulate inflammatory response by inducing the secretion of glucocorticoids, epinephrine, norepinephrine, and α-melanocyte-stimulating hormone, all of which inhibit the production of cytokines. Another descending mechanism occurs via the vagal efferent arm, regulating cytokine production, controlling the immune response system, and preventing excessive inflammation .
Altogether, these lines of evidence allow us to consider the role of inflammation in the pathophysiology of bipolar disorder (Fig. 1). At first, different insults, perhaps caused by the acute episode itself, may trigger inflammatory signaling and microglial activation. These events can induce a proinflammatory environment that may change or damage surrounding neurons and synapses. Microglial activation may affect synaptic transmission through proteolytic modifications of the synaptic environment or by synaptic pruning (Fig. 1a). After several acute episodes, the negative feedback control system may fail, and systemic toxicity occurs. These alterations may be related to microglial senescence and their inability to perform normal activities, or to an excessive production of proinflammatory cytokines, exceeding the downregulatory capacity of the system in response to an acute induction [18▪▪] (Fig. 1b). This state of toxicity may contribute to a better understanding of bipolar disorder in which the management of the disorder does not depend only on the correct use of medications, but also on a number of other palliative measures, such as the control of comorbidities and of a persistent proinflammatory state.
The original question contained in our title still remains: is bipolar disorder an inflammatory condition? We believe it is not, or at least not a primarily inflammatory condition. On the basis of the data currently available, the inflammatory changes observed in bipolar disorder appear to be associated with disease progression rather than to integrate a causal model. Microglial activation and its role in the disorder are not yet completely understood and deserve further investigation. However, systemic inflammation does not seem to be the only key aspect of bipolar disorder. The inefficacy of anti-inflammatory drugs in the treatment of acute manic episodes does not necessarily mean that these patients will not benefit from this approach. Rather, inflammation may be one of the reasons why patients in more advanced stages of the disorder do not properly respond to treatment (i.e., as a result of disease progression). At present, clinicians should be aware from the outset that the early use of mood-stabilizing medication may help prevent comorbid conditions, ultimately resulting in better outcomes. For patients in late bipolar disorder stages, there is a possibility that adjunctive treatments could ameliorate symptoms [48▪]. The adjunctive use of anti-inflammatory drugs, however, still needs to be formally tested.
L.S. is the recipient of a scholarship from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Brazil. P.V.S.M. is the recipient of a postdoctoral scholarship from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Brazil. Professor F.K. has received grant/research support from Astra-Zeneca, Eli Lilly, the Janssen-Cilag, Servier, CNPq, CAPES, NARSAD, and the Stanley Medical Research Institute; he has also been a member of the speakers’ boards for Astra-Zeneca, Eli Lilly, Janssen and Servier; and has served as a consultant for Servier.
We thank MSc Dinler Amaral Antunes for his support in creatingFig. 1. We also thank MSc Gabriel Rodrigo Fries for reviewing and suggesting improvements to the article.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
▪ of special interest
▪▪ of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 125–126).
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