Neuroinflammation in bipolar disorders

Introduction

Mood disorders along with anxiety disorders are considered “stress disorders”.[7] The organism responds to stress in an integrated manner, involving the cooperation among the nervous, endocrine, and immune systems,[8] and stress disorders are believed to be underpinned by derangements in this integration.[9]

Stress and inflammation

Inflammation is a process described since antiquity, meaning burningin both Greek (φλόγωσις) and Latin (inflammation), and characterised by swelling (tumor), redness (rubor), heating (calor), pain (dolor), and impaired function (functiolæsa). It is a general reaction to pathogens in a tissue involving an innate response of cells residing within that tissue. In the acute phase, the process entails the extravasation of immune cells, permeability changesin blood vessels, and the production of chemical mediators, including acute phase proteins, vasoactive amines, eicosanoids, bradykinin and other tachykinins, and chemical attractors. The nonspecific response usually leads to resolution and repair, with restitution to integrity. The inability to restore the previous healthy state may ensue in chronic inflammation, characterised by shifts from the main participating cells towards mononuclear (monocytes, macrophages, lymphocytes, plasma) cells and fibroblasts and from the main participating molecules towards interferon-γ, interleukins, growth factors, nitric oxide, and hydrolytic enzymes.[10]

The stress concept was developed from the work of Hans Selye,[11-12] who viewed the body in Cannon’s frame.[13] Stress, like inflammation, was proposed to be the body’s response to “diverse nocuous agents”,[11] a general adaptation syndrome characterised by an integrated neuroendocrine and immune response tending to restore homœostasis. Selye[12] showed that the response also involves the immune system, which constitutes another parallel with the inflammatory response. Currently, the stress response is considered to be evolutionary and likely to amplify an organism’s resistance to environmental stressors. Like inflammation, the inability of an organism to adequately address stress may lead to a stress disorder, which in psychiatry is represented by post-traumatic stress disorder, anxiety disorders, and mood disorders such asdepression.

In recent years, there has been an increasing recognition of altered immunological parameters in many psychiatric disorders, including depression, bipolar disorder, autism spectrum disorders, and schizophrenia.[14,15] The rationale is that chronic inflammation, by releasing cytokines, may set brain function into a “sickness mode”, thus causing psychiatric disorders. However, how this is carried-out is not explained, so it remains an interesting paradigm with no demonstration so far.

What do we intend by “neuroinflammation”?

Neuroinflammation is defined as inflammation of the central nervous system (CNS). It consists of increased glial activation, pro-inflammatory cytokine content, blood-brain-barrier permeability, and leucocyte extravasation. The process is believed to be driven by interleukin-1 beta (IL-1β), a cytokine that has been found to be increased in neurodegenerative disorders like Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis. IL-1β stimulates the IL-1 receptor/IL-1 accessory protein complex to increase glia NFkB-dependent transcription of pro-inflammatory cytokines, such as tumour necrosis factor (TNF)-α, IL-6, and interferons, as well as the neutrophil-recruiting chemokines CXCL1 and CXCL2. The whole process appears however to be mediated through stress,[16] which is a very general term, but it is essential to understand neuroinflammation as part of a whole in the pathophysiology of various disorders, and disease in general.

There has been evidence that neuroinflammation is reflected inchanges in peripheral immunity,[17] but the reverse may not be true, hence, evidence of peripheral immunological alterations cannot be taken to indicate the presence of neuroinflammation. There is no consensus as to whether central and peripheral immunity are specular, and arecent study that adequately addressed the issue showed that brain immune markers were found to be independent from the peripheral activity of the immune system.[18]

Summarising, stress may lead to the establishment of a chronic inflammatory reaction, which may occur in the brain in parallel to the periphery, thus setting brain function in a sickness mode that may substitute default activity and perpetuate the disorder. This does not explain the oscillatory mood activity. The presence of neuroinflammation in the brain in patients with bipolar disorder can help to answer whether neuroinflammation is a general way by which manic-depressive symptoms are produced. It is not sufficient evidence to demonstrate some of these symptoms in people with autoimmune neuroinflammation or other disorders showing both neuroinflammation and cognitive or mood alterations proper of bipolar disorder. Instead, convincing evidence requires the demonstration of neuroinflammation in a population of patients with bipolar disorders who have no other comorbidity. For this reason, we consider studies that point to the existence of neuroinflammation in bipolar disorder only those studies investigating microglial activation or showing increased presence of neuroinflammatory markers in the human brain, in people with bipolar disorder compared to healthy or nonpsychiatric controls. These may be post-mortem studies or studies in living humans that involve the cerebrospinal fluid (CSF) or brain imaging.

Having this in mind, we aimed to review the evidence for neuroinflammation in the pathogenesis of bipolar disorder.

Our search strategy to investigateneuroinflammation in bipolar disorder

We performed a careful PubMed search using the following strategy: (Neuroinflammat* or glia* or microglia* or [(CXCL1 or CXCL2 or IL-1b* or IL-6 or interleukin* or interferon* or tumor necrosis factor or TNF* or NKκB) and (brain or cerebrospinal fluid or CSF)] and (“bipolar disorder” or mania or manic or “recurrent depression”). There were no restrictions as to publication date or language. To be included, the paper had to be an original article and carried-out in humans. We did not restrict our search to human studies using the related PubMed function, because in our experience this practice does not exclude completely animal studies, but is likely to conceal some relevant human investigations instead. Hence, animal studies were subsequently excluded on the basis of evidence. Furthermore, we excluded reviews and meta-analyses, opinion/speculative papers, animal studies, case reports, as well as papers conducted without respect of the 1964 Declaration of Helsinki Principles of Human Rights, reviews and meta-analyses, opinion/speculative papers, animal studies, as well as case reports. However, their references, especially those of reviews/meta-analyses were searched for possible further includible papers. This review followed the bureaucratic Prisma statement[19,20] when appropriate. We inverted the order recommended for screening, i.e. first exclude duplicates and then screen. We first classified studies according to their type, then excluded animal studies, reviews and studies of peripheral immunity, and included only human studies with data, including clinical and post-mortem, but not in vitro experiments on cell lines. We also excluded and classified as unfocused those post-mortem studies investigating glia in the brain without telling microglia from other types of glial cells. We excluded all non-peer reviewed literature, as it could constitute a source of bias. We considered as duplicates only studies that reported the same results in different published reports. When different studies by the same research group progressively report on increasingly larger samples and when the past used sample is used and accrued, we adopt the strategy to disregard the first appearing papers, including only the last study with the larger sample, provided its quality of evidence is high. Papers reporting on the same samples, but on different measures, were considered as different studies and included if appropriate. Contrary to the distinction made by the Prisma statement between records and full-text articles, we considered all papers emerging from our research as papers to obtain in full text and carefully searched for any data that conformed to our aims. Our experience is that you can never say if you only read the abstract, especially for not so recently published papers.

Contrariwise to what Prisma dictates, we did not label our review as “systematic” and did not attempt to carry-out a meta-analysis, both because the concepts of quantitative and qualitative syntheses are quite weak in Prisma, and their definitions fuzzy and because we were subsequently faced with an extreme heterogeneity of study designs and results that cannot be meta-analysed.

What did the search produce?

The PubMed search yielded 316 papers as of the 11th of July, 2015. The search of the reference lists of these papers produced further 40 potentially interesting papers. Of the total output of 356 papers, 100 were completely unfocused and were captured for the presence of spandrels in the search strategy (however, we chose not to modify the strategy by adopting a more specific approach, since this would result in a potential loss of otherwise eligible material), 98 were excluded because they were reviews or meta-analyses, 16 because they were opinion papers-editorials or speculative with no experimental data, 55 were animal studies, 5 were case studies or case series, 7 did not include patients with bipolar disorder separately or did not investigate neuroinflammation at all, 50 were investigations of peripheral markers, 1 was a duplicate, and 4 were carried-out in vitro on human glial cells. The flow diagram in Figure 1 shows the search strategies and papers selected for review according to a modified Prisma algorithm. A total final number of 20 papers were found to be eligible and were analysed. The search output spanned from 1982 to 2015; recalling that the first occurrence in PubMed of the term neuroinflammatory was in 1983, that of neuroinflammation was in 1995, and that microglial activation and related terms appeared during 1973-75, we may presume that there was a dearth of focused papers in the first years, i.e. prior to 2000. However, one of the includible papers was dated 1997. This was the case (19 papers up to 1999 and 337 from 2000 on) and the trend is one of increase through the years, witnessing an increasing interest of the scientific community inthe neuroinflammation issue in psychiatric disorders in general, and in bipolar disorder in particular. Of interest, 2 of the included papers were not identified by the PubMed search despite the strategy was appropriate for singling them out. The included papers are shown in Tables 1 and 2. They fell into two broad categories, post-mortem (n = 15) and in vivo (n = 5), the latter comprising 4 studies of neuroinflammatory mediators in the CSF and one was an ingenuous positron emission tomography (PET) study of the binding of a neuroinflammatory marker in the brain. The only study we excluded as a duplicate was Rolstad et al.[21] which focused on the correlation between CSF neuroinflammatory markers and cognitive performance and admittedly reported data previously reported in Jakobsson et al.,[18] despite differences in sample size.

Based on the search, is there any evidence for neuroinflammation in bipolar disorder?

This review attempted to answer the question of whether neuroinflammation plays a role in the pathophysiology of bipolar disorder.

We may not speak of conclusive evidence of neuroinflammatory mechanisms in bipolar disorder when the obtained evidence is too indirect. For example, when a molecule like N-acetylcysteine is found to have some therapeutic activity in bipolar disorder, we may not specify whether this is related to its antineuroinflammatory, anti-oxidative stress, or antiapoptotic effect or to its mitochondrial dysfunction countering or glutamate/dopamine balancing actions,[44] unless accompanied by evidence of neuroinflammatory markers moving in the desired direction (and the demonstration of their alteration at baseline). Furthermore, the evidence of abnormal peripheral inflammatory reactivity cannot be taken as evidence of neuroinflammation.

Our search yielded a high number of interesting articles, but few of them suited the purpose of this review. This was due to the fact that our search strategy was over-inclusive to avoid missing anysuitable article. It proved to be more tiresome to download all papers, but this allowed us to identify two papers that would otherwise have gone undetected. Surprisingly, the majority of suitable articles regarded postmortem studies. These studies (n = 15) [Table 1] favoured the idea of the existence of neuroinflammation in bipolar disorder in their majority. Two provided indirect evidence for microglial activation, while four were not consistent with the presence of neuroinflammation in bipolar disorder. However, in one of these,[23] it is possible that treatment could have set-off neuroinflammation. In fact, patients were receiving drugs like lithium and valproate, which both interfere with the arachidonic acid cascade,[45] one of the cross-roads of excitotoxicity and neuroinflammation.[46] The evidence stemming from in vivo studies (n = 5) is consistent with the presence of neuroinflammation in bipolar disorder, also in consideration of the fact that most patients were sampled/tested when euthymic. The demonstration of peripheral benzodiazepine receptor alterations in bipolar I disorder patients may constitute a definitive demonstration,[43] but it should also be considered that such alterations in the brain of people with bipolar disorder, which are consistent with microglial activation, may not be specifically related to the pathogenesis of bipolar disorder or any diagnosis, but rather to disease activity.[47]

Causality effects, that is, whether it is bipolar disorder that once established triggers neuroinflammation, either through the adoption of a reckless lifestyle that is likely to promote a metabolic syndrome that facilitates the onset of neuroinflammation, or rather it is neuroinflammation, that has always existed in a given individual, that eventually ensued in bipolar behaviour and disorder, cannot be probed. In fact, to demonstrate causality we need longitudinal study designs, and in the case of neuroinflammation and bipolar disorder all relevant articles were based on cross-sectional articles. While this was mandatory for post-mortem studies, it was not for studies investigating living humans. Future studies should be able to tackle the causality questionby studying the same patients across the various phases of their illness. However, the fact that the supposed neuroinflammation was present to some extent also when bipolar disorder was in its euthymic phases strongly argues against the lack of involvement of the brain immune system in bipolar disorder.

The studies included in our review were methodologically different and their sample sizes were much variable. Investigations of neuroinflammatory markers in the CSF were all but one carried-out in Sweden and conducted by the same Karolinska-Gothenburg group. One of these studies had to be excluded due to sample and data duplication,[21] but all these studies were quite consistent in their conclusions, supporting the existence of neuroinflammation in bipolar disorder. This might have introduced a site bias. The markers tested each time in post-mortem studies differed, even when the same research groups were involved. Hence we had no population overlap, with the same group first reporting on some people and then on a bigger sample that comprised the formerly reported cases. We found no duplicates even when data referred to the same population in post-mortem studies. There was a tendency in Bethesda-based groups to support neuroinflammation while the German groups were more sceptical about it [Table 1].

Despite our care to avoid studies of peripheral immunity in bipolar disorder, many of these studies appeared through our search. This was due to the fact that many of these papers speak about neuroinflammation without actually showing it. In many of these fascinating and fashionable papers, the question of how chronic inflammation and immune derangement would “enter” the brain and produce neuroinflammation is much talked-about, but not proved. Another striking result of our search is the high number of reviews (n = 96), and especially of those focusing on this issue (n = 40). Most reviews mix-up peripheral and brain studies, reaching unwarranted conclusions. The activation of microglia must not be taken only as evidence of neuroinflammation, because it might also be consistent with a host of other functions, like remoulding the brain microstructure, contributing to plasticity and synaptic formation, and responses to environmental challenges.[48] So it is possible that neuroglial activation, and precisely aberrant neuroglial function, may be responsible for some neuronal miswiring that is consistent with some psychotic symptoms that are frequently observed in bipolar disorder.

Summarising, the evidence for the existence of neuroinflammation in bipolar disorder is more yes than no. However, the hypothesis of a pre-existing peripheral inflammation passing in the brain and establishing a disease mode function, thus maintaining the disorder, is a mere supposition that is not based on evidence. Whereas neuroinflammation might lead to bipolar symptoms, it is not always true that neuroinflammation causes bipolar disorder, and it might be that only rarely is so. It is more likely that stress interacts with personal constitution and epigenetic factors to cause both neuroimmune dysreactivity and bipolar disorder in susceptible individuals. As de Baumont et al.[36] stated, schizophrenia and bipolar disorder may “arise from shared genetic factors, but that the resulting clinical phenotype is modulated by additional alterations mediated by microglia, possibly caused by interference of environmental factors at different times during neurodevelopment and early life, and/or epistatic interactions among groups of genes and environment”. All this should be borne in mind when projecting investigations to explore the relationship between neuroinflammation and bipolar disorder.

Conclusion

This review attempted to answer the question of whether neuroinflammation plays a role in the pathophysiology of bipolar disorder. Direct and indirect evidence points to some degree of possibility that this is the case, but studies heretofore are much heterogeneous in their methodology and conclusions, thus suggesting caution. It appears that the topic of neuroinflammation in bipolar disorder is a much under-investigated but over debated and highly reviewed issue. Finally, PubMed should be trusted, but alternative search engines should be used, lest precious articles are lost.

Acknowledgments

The authors wish to thank Ms. Mimma Ariano, Ms. Ales Casciaro, Ms. Teresa Prioreschi, and Ms. Susanna Rospo, Librarians of the Sant’Andrea Hospital, School of Medicine and Psychology, Sapienza University, Rome, for rendering precious bibliographic material accessible, as well as their Secretary Ms. Lucilla Martinelli for her assistance during the writing of the manuscript.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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