Review
Can bipolar disorder be viewed as a multi-system inflammatory disease?

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Abstract

Background

Patients with bipolar disorder are known to be at high risk of premature death. Comorbid cardio-vascular diseases are a leading cause of excess mortality, well above the risk associated with suicide. In this review, we explore comorbid medical disorders, highlighting evidence that bipolar disorder can be effectively conceptualized as a multi-systemic inflammatory disease.

Methods

We conducted a systematic PubMed search of all English-language articles recently published with bipolar disorder cross-referenced with the following terms: mortality and morbidity, cardio-vascular, diabetes, obesity, metabolic syndrome, inflammation, auto-antibody, retro-virus, stress, sleep and circadian rhythm.

Results

Evidence gathered so far suggests that the multi-system involvement is present from the early stages, and therefore requires proactive screening and diagnostic procedures, as well as comprehensive treatment to reduce progression and premature mortality. Exploring the biological pathways that could account for the observed link show that dysregulated inflammatory background could be a common factor underlying cardio-vascular and bipolar disorders. Viewing bipolar disorder as a multi-system disorder should help us to re-conceptualize disorders of the mind as “disorders of the brain and the body”.

Limitations

The current literature substantially lacks longitudinal and mechanistic studies, as well as comparison studies to explore the magnitude of the medical burden in bipolar disorder compared to major mood disorders as well as psychotic disorders. It is also necessary to look for subgroups of bipolar disorder based on their rates of comorbid disorders.

Conclusions

Comorbid medical illnesses in bipolar disorder might be viewed not only as the consequence of health behaviors and of psychotropic medications, but rather as an early manifestation of a multi-systemic disorder. Medical monitoring is thus a critical component of case assessment. Exploring common biological pathways of inflammation should help biomarkers discovery, ultimately leading to innovative diagnostic tools, new methods of prevention and personalized treatments.

Introduction

Bipolar disorder is known to be associated with substantial functional impairment, high health care costs, and also premature mortality (Roshanaei-Moghaddam and Katon, 2009). The recent WHO update (2008) highlights the global burden of bipolar disorder to be the fourth highest burden throughout both high as well as low and middle income countries. The morbidity, mortality and personal suffering associated with bipolar disorder are not simply the result of psychiatric symptoms, but are also the consequence of a wide range of psychiatric and medical comorbid disorders. Emerging data show that bipolar disorder is associated with highly prevalent co-occurring psychiatric and substance use disorders, ranging from 57% to 74% (Bauer et al., 2005), but also with medical comorbidities which occur in over 80% of bipolar patients (Kilbourne et al., 2004, Kupfer, 2005). Patients with these co-occurring disorders experience worse prognosis with less favorable response to treatment, unemployment and thus higher cost than those without comorbidity (Angst et al., 2002, Tsai et al., 2005, Williams et al., 2011).

Despite this very important medical burden, under-recognition and inattention to physical diseases and their risk factors still prevails. As bipolar I patients are almost always treated only in mental health settings, most psychiatrists, physicians and health policy makers are not aware that these comorbid medical disorders are probably more prevalent in bipolar disorder that in any other major psychiatric disorders.

As the detection of these highly prevalent comorbid medical disorders could drastically change mental health organization by reinforcing the links with medical care, by modifying the education of psychiatrists, and by opening up new avenues of research, this article reviews research related to medical comorbid disorders in bipolar disorder. We thus conducted a systematic PubMed search of all English-language articles recently published with bipolar disorder cross-referenced with the following terms: mortality and morbidity, cardio-vascular, diabetes, obesity, metabolic syndrome, immuno-inflammatory, auto-antibody/auto-immunity, retro-virus, stress, sleep and circadian rhythm. In this report we have explored the issue of comorbid medical disorders in bipolar disorder asking three major questions related first, to the magnitude of these comorbid disorders, second, to the staging and timing of occurrence of these disorders across the life-span, and third, describing some of the possible mechanisms underlying these co-occurring disorders in order to ascertain whether the patho-physiology of bipolar disorder itself explains the clustering of medical disorders.

Section snippets

Is there evidence of excess medical co-morbidity and mortality in bipolar disorder?

A growing number of studies have demonstrated that patients with bipolar disorder are at high risk of premature death, unrelated to suicide. Excess mortality rates due to medical causes are between 1.5 and 3 times higher in adults with bipolar disorder compared to the general population (Correll, 2008), higher than those with major depression (Roshanaei-Moghaddam and Katon, 2009). This has been observed across diverse cultural and socioeconomic backgrounds (Ohaeri and Akani, 2011). Among

Results

This review highlights evidence that the magnitude of early and severe medical burden in bipolar disorder is an indication that it might better be viewed as a multi-system disorder. Secondly, it asks whether inflammation might plausibly explain the link between bipolar and cardio-vascular disorders. Although there are gaps in the evidence to support this hypothesis, the review provides an important first step in framing critical questions that could be tested in future research and changes that

Role of funding source

This research was supported by “Institut National de la Santé et de la Recherche Médicale” (INSERM), the FondaMental Foundation (Fondation de Coopération Scientifique de Recherche et de Soins en Santé Mentale) and by grants from the National Institute of Mental Health MH081003, DA027508-03 and from the Agence Nationale pour la Recherche, (ANR; NEURO 2009, V.I.P. project).

Conflict of interest

All the authors declare they have no conflict of interest with regard to this paper.

Acknowledgment

We thank Kim Bauer and Kasey Dickenson who assisted us with literature search and preparation and proof-reading of the manuscript.

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