Acta Psychiatr Scand 2015: 1–12 © 2015 John Wiley & Sons A/S.

2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
All rights reserved ACTA PSYCHIATRICA SCANDINAVICA
DOI: 10.1111/acps.12414

Clinical overview

Are medical comorbid conditions of bipolar

disorder due to immune dysfunction?
Rosenblat JD, McIntyre RS. Are medical comorbid conditions of J. D. Rosenblat1,2
bipolar disorder due to immune dysfunction? R. S. McIntyre1,2
1
Department of Psychiatry and Pharmacology, University
Objective: Epidemiological data have shown a clear association of Toronto, and 2Mood Disorder Psychopharmacology
between bipolar disorder (BD) and medical comorbidities. The aim of Unit, University Health Network, Toronto, ON, Canada
this article was to assess the evidence of immune dysfunction as a key
mediator of this observed association.
Method: For this narrative clinical overview, the MEDLINE/PubMed,
EMBASE, Google Scholar, and ClinicalTrials.gov databases were
searched for relevant articles.
Results: Bipolar disorder has been shown to have an increased
prevalence in patients with autoimmune disorders, cardiovascular
disease, and metabolic dysfunction. Further, an elevation in
proinflammatory cytokines in BD has been repeatedly demonstrated.
Several mechanisms have been proposed to explain the effect of immune
dysfunction on mood and cognition. Anti-inflammatory agents
including TNF-a inhibitors, non-steroidal anti-inflammatory drugs
(NSAIDs), minocycline and omega-3 polyunsaturated fatty acids
(O3PUFA) are being investigated for their use as novel treatment of BD Key words: bipolar disorder; inflammation; autoimmune
in patients with immune dysfunction. disease; cardiovascular disease; diabetes; obesity
Conclusion: Immune dysfunction appears to be an important mediator Roger S. McIntyre, Head, Mood Disorders
of the association observed between BD and medical comorbidities. It Psychopharmacology Unit, University Health Network,
therefore serves as a potential novel target for treatment of BD. 399 Bathurst Street, MP 9-325, Toronto, ON M5T 2S8,
Canada. E-mail: roger.mcintyre@uhn.ca
Further, the observed bidirectional interaction merits screening for
psychiatric disorders in patients with immune dysfunction and vice
versa to allow for early detection and treatment of this at risk
population. Accepted for publication February 24, 2015

Clinical recommendations
• Epidemiological studies reveal a strong association between BD and several medical comorbidities
including autoimmune diseases, obesity, type II diabetes mellitus (T2DM) and cardiovascular dis-
ease.
• Immune dysfunction appears to be a key pathoetiologic factor facilitating the bidirectional interac-
tion between BD and medical comorbidities.
• Several anti-inflammatory agents show promise in the treatment of BD; however, there is insufficient
evidence to recommend any of these agents for clinical use as of yet.

Additional comments
• While inflammation presents one important nexus mediating the connections between BD and medi-
cal comorbidities, several other pathways may be mediating this pathway and may also present novel
targets.
• Screening for medical comorbidities in patients with BD and vice versa may lead to early detection,
treatment, and improved clinical outcomes.

1
Rosenblat and McIntyre
Introduction
Bipolar disorder (BD) is a severe mental illness
associated with high levels of morbidity and mor-
tality (1, 2). Epidemiological data have long sup-
ported a strong correlation between BD and a
number of medical comorbidities (2–9). The rele-
vance of this particular epidemiological correlation
is further emphasized through the observed
increased rate of mortality and resultant shortened
life span secondary to the increased prevalence of
cardiovascular disease (2, 3, 8, 10) and metabolic
dysfunction (most specifically, insulin resistance
and obesity) (4, 5, 11–13) in BD patients.
The nature of the connection between BD and
various medical comorbidities is yet to be fully
understood (2). While the pathophysiological
mechanisms underlying the link between BD and
medical comorbidities is likely to be multifactorial,
immune dysfunction has recently been proposed as
a key nexus between BD and medical comorbidity
(14–16).
The inflammatory response is an essential part
of human physiology that has evolved to protect
the host from potential pathogens (17). As such,
the immune system has developed to detect patho-
gens and initiate a systemic response through the
release of proinflammatory cytokines (17). This
systemic inflammatory response is counterbal-
anced by the release of anti-inflammatory cyto-
kines to prevent an exaggerated systemic response
that may lead to host tissue damage (16). With
appropriate immune function, this process allows
for clearance of pathogenic organisms and materi-
als with minimal damage to host tissue. However,
in several disease processes, immune dysfunction is
noted where host tissue is inappropriately dam-
aged. Autoimmune disorders are one such example
where the immune system misrecognizes host tissue
as pathogenic, thus leading to host tissue destruc-
tion (17).
Several other disease processes have been noted
to involve immune dysfunction in their pathoetiol-
ogy where anti-inflammatory cytokines are inade-
quately counterbalancing an inflammatory
response or where the immune system is chroni-
cally in a low-grade inflammatory state. Cardio-
vascular disease (18) and metabolic dysfunction
(19) have both been shown to be associated with
immune dysfunction with chronic low-grade
inflammation. More recently, mood disorders have
also been shown to be associated with chronic low-
grade inflammation (20, 21). Several authors have
thus queried immune dysfunction as a potential
link between mood disorders and medical comor-
bidities (15, 16, 21).
2
A common and simple method for the evalua-
tion of immune dysfunction is the measurement of
inflammatory markers and cytokines. Serum levels
of inflammatory markers are commonly used clini-
cally in the evaluation of patients with inflamma-
tory disorders to aid with diagnosis and
prognostication (17). In research settings, blood
serum or cerebral spinal fluid (CSF) levels of
inflammatory cytokines have been increasingly
used in the setting of psychiatric patients to deter-
mine a correlation between inflammatory cytokine
profiles and psychiatric symptomatology (14, 20).
Of particular interest has been the effect of inflam-
matory cytokines on mood and cognition, com-
monly affected features of both major depressive
disorder (MDD) and BD (20, 21).
Aims of the study
The aim of this article was to assess the evidence of
immune dysfunction as a mediator of the interac-
tion between BD and medical comorbidity. Fur-
ther, the clinical implication of such an interaction
will be discussed as it relates to screening, preven-
tion, and treatment of BD.
Material and methods
For this narrative clinical overview, the MED-
LINE/PubMed, EMBASE, Google Scholar, and
ClinicalTrials.gov databases were searched from
inception through October 2014 for published
reviews, meta-analyses, and primary studies of the
relationship between BD, medical comorbidities,
and immune dysfunction. Also, randomized con-
trolled trials, open-label trials, meta-analyses, and
systematic reviews of anti-inflammatory agents for
the treatment of BD were searched for. Searches
terms included various combinations of the follow-
ing terms: bipolar disorder (BD), novel targets,
inflammation, immune dysfunction, infliximab,
cytokines, interleukin (IL), IL-1B, IL-6, tumor
necrosis factor alpha (TNF-a), anti-TNF-a, non-
steroidal anti-inflammatory drugs (NSAIDs),
celecoxib, acetylsalicylic acid (ASA), omega-3
polyunsaturated fatty acid (O3PUFA), curcumin,
oxidative stress, reactive oxygen species (ROS),
hypothalamic–pituitary–adrenal (HPA) axis, corti-
sol, metabolic syndrome, diabetes, cardiovascular
disease, autoimmune disease, systemic lupus eryth-
ematosus (SLE), rheumatoid arthritis (RA), psori-
asis, Guillain–Barre syndrome (GBS), Chron’s
disease, ulcerative colitis (UC), and inflammatory
bowel disease (IBD). Reference lists from included
papers were also manually searched for additional
pertinent references.

Results
Immune dysfunction in bipolar disorder
Systemic inflammation may be assessed by measur-
ing serum levels of cytokines, chemokines, cell
adhesion molecules, and acute phase reactants, as
previously discussed (17). In the context of BD,
several studies have repeatedly shown elevated lev-
els of proinflammatory cytokines indicative of a
chronic low-grade inflammatory state (14, 22).
Machado-Vieira et al. recently conducted a
detailed systematic review, extensively reviewing
the cytokine changes observed in BD patients (22).
In brief, there is robust evidence of increased
serum levels of proinflammatory cytokines IL-4,
TNF-a, sIL-2R, IL-1b, IL-6, and soluble receptor
of TNF-alpha type 1 (STNFR1, the circulating
form of TNFR1, which is responsible for the
majority of the action of TNF-alpha and is often
used to determine the overall production of TNF-
alpha) in BD patients compared to healthy con-
trols (22). Among these identified cytokines,
STNFR1 was most consistently shown to be ele-
vated in BD (22).
Of great interest have also been cytokine levels
depending on mood state (i.e., cytokine variability
during mania, depression, and euthymia for a
given BD patient). At baseline, during a euthymic
period, sTNFR1 is still consistently elevated indi-
cating a mild proinflammatory state at baseline
(22–24). During a manic episode, the level of
inflammation is increased with increased serum
levels of IL-6, TNF-a, sTNFR1, IL-ra, CXCL10,
CXCL11, and IL-4 (14, 22, 23, 25). During a
Mood level
Fig. 1. Hypothetical* inflammatory
and mood levels for BD patients with
comorbid immune dysfunction. As
depicted, BD patients may have low-
grade chronic inflammation with
inflammatory cytokine levels above
Inflammaon level
control levels, even during euthymic
periods. During mood episodes (mania
or depression), proinflammatory
cytokines may be further elevated
compared to euthymic periods. *Note:
Graph is purely hypothetical based on
evidence discussed in the text (14, 22)
and is not based on a patient data set.
Inflammation, BD and medical comorbidity
depressive episode, BD patients have elevated lev-
els of sTNFR1 and CXCL10 (14, 22); however,
much fewer studies have been conducted evaluat-
ing cytokine profiles of BD patients during depres-
sive episodes. Conversely, several studies have
been conducted for patients with MDD during
depressive episodes, consistently demonstrating
elevated levels of TNF-a, IL-6, and IL-1b (20, 26–
28). Taken together, serum cytokine profiles indi-
cate that BD patients have chronic low-grade
inflammation with increased levels of inflammation
during mood episodes (14) as hypothetically
depicted in Fig. 1.
Central cytokine levels as measured through
sampling cerebral spinal fluid (CSF) have also been
of interest as a more direct measure of central neur-
oinflammation. While CSF cytokine profiles are
undoubtedly a more direct indicator of neuroin-
flammation, the invasive nature of a lumbar punc-
ture (LP) compared to a venipuncture limits study
implementation. Only one study has directly evalu-
ated CSF cytokine levels in BD showing elevation
of IL-1b in BD type I (n = 15) and type II (n = 15)
during euthymic periods compared to healthy
controls (29). In another study, evaluating CSF of
suicide attempters (with variable diagnoses includ-
ing BD), IL-6 was found to be elevated and corre-
lated with symptom severity (30). In a separate
study, kynurenic acid, an end metabolite of trypto-
phan degradation (associated with inflammation),
was found to be elevated in the CSF of BD patients
after having a manic episode (31). In addition, BD
patients with a history of psychotic features
were found to have elevated CSF kynurenic acid
BD mood level
Mania Mood level of control
Inflammatory markers of BD paent
Inflammatory markers of control
Depression
Time
3
Rosenblat and McIntyre
levels during euthymic periods (31). Postmortem
studies have also evaluated central cytokine levels
in BD patients. Notably, two studies have shown
increased levels of inflammatory markers (IL-1b,
NF-jB, and microglial markers) in the frontal cor-
tex of BD patients postmortem (32, 33).
Taken together, a strong correlation between
inflammation (as measured by central and periph-
eral proinflammatory cytokine levels) and BD has
been identified. Moreover, further studies have
suggested bidirectional causality for this correla-
tion (i.e., inflammation may induce BD symp-
toms, and BD may lead to a proinflammatory
state) (14). Indeed, several studies have shown in
preclinical and clinical models that induction of a
proinflammatory state causes ‘sickness behavior’
resembling a depressive episode with sleep alter-
ation, appetite changes, anhedonia, depressed
mood, cognitive dysfunction, and psychomotor
changes (20, 26, 34). In human testing, a proin-
flammatory state has been induced using vaccina-
tions, endotoxins, lipopolysaccharide (LPS),
interferon (IFN), and IL-2 (35–38). The induction
of inflammation in these studies was confirmed by
measuring increased levels of proinflammatory
cytokines, namely TNF-a, IL-6, IL-1Ra, and IL-
10 (35–38). For example, in healthy individuals
injected with Salmonella abortus equi endotoxin
intravenously, an increase of TNF-a, IL-6, and
cortisol was observed (36). The subjects subse-
quently had appetite changes, increased anxiety,
depressed mood, and decreased cognitive function
(specifically decreased memory performance) (36).
Similar results were found with healthy volunteers
vaccinated with Salmonella typhi vaccine. A dose
response was also shown with variable levels of
LPS, showing a dose-dependent increase in IL-6,
IL-10, TNF-a, and cortisol with a dose-dependent
increase in anxiety and decrease in mood and cog-
nition (38).
Also of interest have been naturalistic studies of
mood changes postadministration of IFN in the
treatment of hepatitis C. Interferon is a potent pro-
inflammatory cytokine that has been shown to be
extremely depressogenic with a major depressive
episode being induced in 25–80% of patients on
IFN therapy in a dose-dependent manner (39–41).
Similarly, with cancer patients receiving immune
boosting IL-2 and/or IFN therapy, early depres-
sive symptoms have been consistently demon-
strated (27, 35, 42, 43).
Several mechanisms that facilitate the inflamma-
tory-mood axis have been elucidated in recent
years (20, 21, 44). Alteration in neurotransmitter
levels is one key mechanism involved. Elevated
inflammatory cytokines, notably IFN, IL-2, and
4
TNF-a, can induce indoleamine 2,3-dioxygenase
(IDO) leading to the breakdown of tryptophan to
tryptophan catabolites (TRYCATs), molecules
known to have depressogenic and anxiogenic prop-
erties (35). Further, the depletion of tryptophan
leads to decreased production of serotonin (as
shown in Fig. 2), a well-established feature of
mood disorder pathophysiology (45). This alter-
ation in neurotransmitter levels may provide one
mechanism whereby immune dysfunction facili-
tates mood and cognitive symptoms of BD.
Increased inflammatory cytokines also lead to
HPA overactivation (37, 46, 47). This HPA over-
activation leads to hypercortisolemia, which has
several detrimental downstream effects such as
decreased serotonin levels, impaired mood, insom-
nia, insulin resistance, and obesity (46, 48, 49).
Elevated systemic TNF-a also induces the acti-
vation of microglia (44, 50, 51). Microglia are the
macrophages of the central nervous system (50).
They serve a key role in protecting against infec-
tion and provide neuronal pruning of unused neu-
ronal connection (50). While playing a vital role
when appropriately activated, microglia may also
have detrimental effects on neuronal connectivity
via overpruning when they are inappropriately
activated (50–52). Stertz et al. (44) recently
reviewed pathological activation of microglia as a
potential mechanism subserving BD neuroprogres-
sion. In brief, microglia overactivation may be
induced by systemic proinflammatory cytokines
leading to overpruning of important neuronal cir-
cuits for mood and cognition (44). With each
mood episode, microglia are activated and neuro-
nal circuitry becomes increasing poorly, leading to
impaired neuroplasticity and impaired function in
the affected brain areas, notably the amygdala,
hippocampus, and prefrontal cortex affecting affec-
tive and cognitive function (50–52). The bulk of
the evidence supporting the microglial hypothesis
is through postmortem investigations showing
altered levels of glia nuclei in the aforementioned
brain regions (32, 33).
Taken together, a large amount of evidence sup-
ports the presence of immune dysfunction and a
proinflammatory state during mood episodes. Sev-
eral mechanisms have been proposed to explain
immune dysfunction as an etiologic factor for
impaired mood and cognition. Of note, potential
mechanisms are further reviewed elsewhere (20, 21,
44, 53).
Autoimmune disorders and bipolar disorder
The clearest examples of immune dysfunction are
autoimmune disorders. By definition, autoimmune
 Inflammation, BD and medical comorbidity

Stress AA Cytokines HPA

Mood disorders Inflammaon cPLA2 O3PUFA
COX-1/2 (TNF-α, IL-6, IL-1B) axis TDO
CVD, MeS
Autoimmune NSAIDs PGE2
Transport via acve transport
Blood brain barrier and through leaky regions

Infliximab

Microglial acvaon
Neurotoxicity Cytokines
ROS
Neuroplascity
RNS
BDNF
Glutamate modulaon Minocycline

5-HIAA
IDO
Kynerenic acid
5-HT Tryptophan Kynerenine
Quinolonic acid
Decreased serotonin
release

Fig. 2. Potential mechanisms of immune dysfunction in mood disorders with potential novel drug targets. Several triggers (infection,
stress, cardiovascular disease (CVD), metabolic syndrome (MeS), autoimmune disorders) may induce an inflammatory state whereby
arachidonic acid (AA) is converted to prostaglandin E2 (PGE2), which induces the release of proinflammatory cytokines. Inflamma-
tory cytokines activate microglial cells and the HPA axis and induce IDO. Induction of IDO converts tryptophan to kynurenine
which is broken down to kynurenic acid and quinolonic acid, which are known to be depressogenic. Further, depletion of tryptophan
decreases central levels of serotonin (5-HT). A similar effect is noted with induction of hepatic TDO with HPA activation. Microglial
activation also leads to neurotoxicity, decreased neuroplasticity, decreased brain-derived neurotrophic factor (BDNF), glutamate
modulation, and production of reactive oxygen and nitrogen species (ROS and RNS). (green arrows = promoting, red
arrows = inhibition, gray cell is presynaptic neuron, orange cell is a microglial cell).

disorders have dysfunctional immune systems that
episodically or continually misrecognize host tissue
as pathogenic, thus aberrantly attacking host tis-
sue, leading to tissue destruction and a systemic
inflammatory response (17). Therefore, under the
previous understanding of inflammation as an etio-
logic and perpetuating factor of BD as previously
discussed, one may expect patients with autoim-
mune disorders to have increased rates of BD and
vice versa. Indeed, this correlation is observed with
several autoimmune disorders as summarized in
Table 1 (7, 54–59). Further the effect may be bidi-
rectional; in a study of 347 BD patients, 48% were
found to have autoimmune or allergic disorders,
indicating that the occurrence of BD may increase
the relative risk of having an autoimmune disorder
(7).
Several epidemiological studies have found an
increased rate of BD in patients with various auto-
immune disorders (7, 54–56). In a large popula-
tion-based study of all people born in Denmark
between 1945 and 1996 (3.57 million people), the
relative risk for patients with any form of autoim-
mune disease having concurrent BD was 1.7 (54).
More specifically, a diagnosis of GBS, inflamma-
tory bowel disease (Chron’s or UC), autoimmune
hepatitis, multiple sclerosis (MS), and rheumatoid
arthritis (RA) was found to increase the relative
risk of BD as summarized in Table 1 (54). In a sep-
arate study, SLE was also found to increase the
prevalence of BD by four-fold (55). In addition,
autoimmune thyroiditis was found to increase the
relative risk of BD (56). In a study of 226 BD
patients, 252 healthy controls and 3190 psychiatric
in-patients of any diagnosis, the prevalence of
thyroperoxidase antibodies (TPO-Abs) was higher
in BD patients (28%) compared to health controls
and psychiatric in-patients (3–18%) (56). Notably,
the presence of TPO-Abs in BD patients was not
associated with lithium exposure (56). Psoriasis
has also been found to increase the relative risk of
BD by two-fold; however, the interpretation of this
association is unclear as lithium is associated with
a variety of cutaneous side-effects including psori-
asis (60, 61).
Taken together, epidemiological data from sev-
eral large-scale studies strongly suggest an associa-
tion between autoimmune disorders and BD. The
effect appears to be bidirectional in nature as
depicted in Fig. 3. These observations along with
the previously described immune-mood mecha-
nisms further support immune dysfunction as a
facilitator of the association between BD and co-
morbid medical conditions.

5
Rosenblat and McIntyre

Table 1. Medical comorbidities with immune dysfunction shown to be correlated with BD

Medical comorbidity Relationship to bipolar disorder*

GBS In a large population-based study of all people born in Denmark between 1945 and 1996 (3.57 million people), the relative risk of developing bipolar
disorder after an episode of GBS was 2.4 (54).
Chron’s Relative risk of developing bipolar disorder after or during an episode of IBD (Chron’s or UC) was 1.9 (54).
Autoimmune Relative risk of developing bipolar disorder after the development of autoimmune hepatitis was 3.0. (54).
hepatitis
MS Relative risk of developing bipolar disorder during an episode of MS was 2.0 (54). Also, in a prospective study of 658 MS patients, a 30-fold increase in
BD compared to healthy controls was found (58).
Rheumatoid arthritis Relative risk of developing concurrent bipolar disorder with RA was 1.8 (54). In addition, in a nationwide population-based study in Taiwan, the
(RA) incidence of bipolar disorder was found to be elevated compared to healthy controls [incidence rate ratio = 2.13, 95% confidence interval (CI) = 1.12
–4.24, P = 0.013] and was higher among patients with RA than among control patients (57).
Lupus (SLE) An increase in several mood and anxiety disorders was found in female patients with SLE with 4-fold increase in prevalence of BD (55).
Psoriasis A two-fold increase in the prevalence of BD in patients with moderate to severe psoriasis in a retrospective, matched case–control study, with 7971
patients with psoriasis and 39 855 control adults (61).
Autoimmune In a study of 226 BD patients, 252 healthy controls and 3190 psychiatric in-patients of any diagnosis, the prevalence of hyroperoxidase antibodies (TPO-
thyroiditis Abs) was more prevalent in bipolar patients (28%) than population and psychiatric controls (3–18%). The presence of TPO-Abs in bipolar patients
notably was not associated with lithium exposure (56).
Obesity Rates of obesity in BD patients have been shown in several studies to be 2- to 4-fold higher than the general population (11, 12, 59).
T2DM Numerous studies have repeatedly shown up to a three-fold increase of T2DM in BD patients (5, 64, 65).
Cardiovascular All patients with a hospital diagnosis of BD (n = 15 386) or MDD (n = 39 182) in Sweden from 1973 to 1995 were identified from the in-patient
disease register and linked with the national cause-of-death register to determine the date and cause of death. Patient with BD had a 2.3-fold increased rate
of mortality secondary to cardiovascular disease (6).

*Studies listed are not an exhaustive list.

prognostic indicator for poorer outcomes (62). On

Immune
dysfuncon
Medical Bipolar
comorbidity disorder
Fig. 3. Multidirectional interactions between BD, immune
dysfunction, and medical comorbidity. Immune dysfunction
may induce and perpetuate BD and medical comorbidity.
Medical comorbidity and BD have a bidirectional interaction
with each other, and immune dysfunction as both BD and
medical comorbidity can both promote and be promoted by
immune dysfunction.
Cardiovascular disease, metabolic dysfunction, and bipolar
disorder
In recent years, immune dysfunction has been
shown to be an integral part of cardiovascular dis-
ease, obesity, and insulin resistance as a chronic
low-grade inflammatory state has also been associ-
ated with these diseases (18, 19). Increased levels of
proinflammatory cytokines have been consistently
shown for both cardiovascular disease and meta-
bolic dysfunction (18, 19). Further, increased levels
of inflammatory markers such as C-reactive
protein (CRP) have been used clinically as a strong
a molecular level, atherosclerosis has been shown
to be an immune-mediated process (18). Obesity
and type II diabetes mellitus (T2DM) increase
inflammation through increasing levels of adipo-
kines (proinflammatory cytokines produced
mainly by adipose tissues), increasing mitochon-
drial dysfunction, and increasing the production of
reactive oxygen species (ROS), leading to oxidative
stress and an inflammatory response (19).
Cardiovascular disease has long been recognized
as an important and prevalent medical comorbidi-
ty of BD. The risk of death secondary to cardio-
vascular disease is 2.3-fold greater for BD patients
compared to the rest of the population (6). This
staggering increase in mortality further emphasizes
the importance of understanding what is mediating
the association between BD and cardiovascular
disease (6). As previously discussed, immune dys-
function is one potential link as both BD and car-
diovascular disease involve a chronic low-grade
inflammatory state, which may further perpetuate
both disease processes. From therapeutic and pre-
ventative perspectives, the inflammatory pathway
may be important to target to potentially ‘break
the cycle’ of both BD and cardiovascular disease
increasing inflammation and further worsening BD
and cardiovascular disease progression.
In terms of causality, BD is often diagnosed at a
young age, while cardiovascular disease manifests
later in life. This temporal relationship may sug-
gest that the increase level of inflammation associ-
ated with BD increases the risk of immune
dysfunction leading to atherosclerosis and

6

ultimately cardiovascular disease. However, the
relationship is likely multifactorial as behavioral
(smoking, overeating, decreased activity), environ-
mental (decreased access to health care, lower
socioeconomic status, early childhood adversity)
and iatrogenic factors (metabolic and cardiac side-
effects of mood stabilizer and second-generation
antipsychotics) are undoubtedly also contributory
(63).
Metabolic dysfunction, most notably obesity
and T2DM, has also been strongly linked to BD.
Numerous studies have repeatedly shown that the
prevalence of T2DM and obesity is greatly
increased (by two to four-fold) in the BD popula-
tion (5, 11, 12, 64, 65). Further, comorbid obesity
is believed to have a synergistic neurotoxic effect
with BD, as it is associated with poorer prognosis
with greater recurrence of depressive episodes, cog-
nitive dysfunction, and increased suicidality (12).
The interaction between metabolic dysfunction
and BD is complicated and is still being elucidated.
From an inflammatory perspective, both BD and
metabolic dysfunction may further perpetuate a
proinflammatory state, leading to neuroprogres-
sion of BD and worsening of metabolic function
through the previously described mechanisms (mi-
croglial activation, oxidative stress, etc.) (5, 13, 66,
67). Further, the proinflammatory state increases
HPA activity, leading to hypercortisolemia, which
directly increases the risk of insulin resistance,
obesity, and impaired mood and cognition (5, 13,
66, 67). Therefore, targeting the inflammatory
pathway may serve to dampen this damaging pro-
cess.
Of note, the interaction between BD and meta-
bolic dysfunction is also clearly multifactorial as
discussed for cardiovascular disease. The insulin
pathway has been another mechanism of interest
in this interaction and has been reviewed exten-
sively elsewhere (68, 69). Also of particular impor-
tance is the impact of psychotropic medications
used in BD on metabolic function (68–70). Most
notably, the profound effect of many second-gen-
eration antipsychotics on weight gain and develop-
ment of metabolic syndrome is an important effect
to consider (71). Nevertheless, immune dysfunc-
tion appears to also play a key causal role of the
observed association between BD and metabolic
dysfunction, independent of metabolic side-effects
of medications (15, 72).
In summary, cardiovascular disease and meta-
bolic dysfunction (obesity and insulin resistance)
have been strongly linked to BD. This association
is a particularly relevant one, as it is believed to be
the primary cause of decreased life expectancy of
patients with BD (1, 6). While the mechanism
Inflammation, BD and medical comorbidity
linking BD with these medical comorbidities is
likely multifactorial, immune dysfunction appears
to be an extremely important pathophysiologic
factor mediating the progression and interaction of
BD, cardiovascular disease, and metabolic dys-
function.
Implications for treatment and prevention
Psychopharmacologic therapies for BD are cur-
rently suboptimal with high levels of treatment
refractoriness and mood episode recurrence and
poor side-effect profiles that often worsen medical
comorbidities (for example, second-generation an-
tipsychotics worsening obesity, insulin resistance,
and cardiovascular disease) (10, 73, 74). The focus
of treatment has always been symptom manage-
ment. That is to say, there are no ‘disease-modify-
ing’ treatments currently available for BD.
Patients with BD are usually placed on lifelong
pharmacotherapy. Often if patients stop taking
medications, their symptoms quickly resume indic-
ative of the underlying disease process prevailing
throughout treatment (74). In other fields of
medicine, such as rheumatology, a new class of dis-
ease-modifying agents have evolved that target
underlying disease processes instead of only pre-
senting symptoms (75). The basic idea is to target a
different area of the pathophysiology (for example,
target the upstream cause of the pain, such as
inflammation, instead of the neuronal perception
of the pain, the primary target of acetaminophen)
to actually induce disease modification. With
regard to mood disorders, no disease-modifying
agents are currently available; however, immune
modulators have been proposed as a potential
therapeutic class that may mechanistically be tar-
geting the cause of the symptoms more than the
symptoms themselves and may therefore have dis-
ease-modifying potential (20).
Given the demonstrated importance of immune
dysfunction in the pathophysiology of several co-
morbid medical conditions and BD, immunomod-
ulation has been investigated as a potential
treatment avenue (15). Given the hypothesis that
the neuroprogression of BD may be facilitated by
a proinflammatory state, anti-inflammatory agents
may be theoretically repurposed to treat and pre-
vent progression of BD in patients with immune
dysfunction (15, 16). Therefore, several anti-
inflammatory agents are currently being investi-
gated for treatment of mood disorders.
Non-steroidal anti-inflammatory drugs (NSA-
IDs) have become of interest for the treatment of
mood disorders. Celecoxib, a cyclooxygenase-2
(COX-2)-specific inhibitor, has been of particular
7
Rosenblat and McIntyre
interest for the treatment of BD. Through the inhi-
bition of COX-2, there is decreased production of
prostaglandins and therefore decreased production
of proinflammatory cytokines (76). Animal models
have suggested improved mood and cognition with
the treatment of COX-2 inhibitors (77). Further, in
a double-blind, randomized, placebo-controlled,
add-on study, Nery et al. found the addition of cel-
ecoxib to standard treatment was associated with a
faster improvement of depressive symptoms com-
pared to standard therapy alone for BD patients in
a depressive or mixed episode (78). Another
NSAID of interest has been aspirin (ASA), which
is currently being investigated for its effect as an
adjunct to the treatment of BD (ClinicalTrials.gov:
NCT01429272, NCT01797575).
Minocycline, a tetracycline antibiotic with anti-
inflammatory, antioxidant, antiglutamatergic, and
neuroprotective effects (79, 80), has also become of
interest for treating both MDD and BD. The
mechanism of action and preclinical data were
recently reviewed by Soczynska et al. (80). In brief,
the potent anti-inflammatory and neuroprotective
effects show great promise for treating underlying
molecular mechanisms subserving BD pathogene-
sis (80). While no clinical trials have yet to be com-
pleted, multiple trials are currently underway
evaluating minocycline as an adjunct in the treat-
ment of BD (NCT01429272, NCT01514422,
NCT01403662) and MDD (NCT01574742).
Also of interest have been omega-3 polyunsatu-
rated fatty acids (O3PUFA), a dietary fatty acid
that cannot be endogenously produced. Omega-3
polyunsaturated fatty acids exhibit an anti-inflam-
matory effect by competing with arachidonic acid
(AA) for COX enzymes, thereby decreasing pros-
taglandin E2 (PGE2) levels and thus decreasing
proinflammatory cytokine production (81).
Omega-3 polyunsaturated fatty acids with >60%
eicosapentaenoic acid (EPA) content have shown
the greatest promise with several trials and meta-
analyses showing a significant antidepressant effect
with a benign side-effect profile when used as an
adjunct to SSRI therapy in the treatment of MDD
(20, 82–84) and BD (85–87). Of note, O3PUFAs
have also been shown to exhibit some cardio-pro-
tective effects, decreasing the formation and propa-
gation of atherosclerotic plaques (88). Therefore,
O3PUFAs may potentially be used as an adjunct
to simultaneously improve outcomes BD and car-
diovascular disease.
Currently, clinical trials of immune-based thera-
pies for BD are limited, and much more studies
have been conducted for immunomodulation as a
treatment for MDD (20). In a recent meta-analysis
of the effect of anti-inflammatory agents on MDD,
8
fourteen well-designed randomized controlled
trials were identified (89). The pooled results
(n = 6262) indicated a positive effect on depressive
symptoms without risk of increased adverse events
(89). The inflammatory-mood axis is believed to be
ubiquitous among mood disorders, and as such,
the promising results of immune-based therapies
for treatment of MDD may possibly be translated
into therapies for BD (21).
Of particular interest for the treatment of MDD
have been TNF-a inhibitors. In theory, blocking
TNF-a would decrease microglial activation,
decrease ROS production, and prevent inflamma-
tion-induced neurotransmitter-level changes (20).
In a proof-of-concept clinical trial, Miller & Rai-
son used infliximab, a TNF-a inhibitor, as an add-
on therapy for treatment-resistant MDD (90). The
trial was negative as the overall difference in remis-
sion was not statistically significant. However,
when analyzing the subgroup of patients with ele-
vated CRP levels (indicative of an inflammatory
state), a statistically significant increase in remis-
sion rates was noted for patients treated with
adjunctive infliximab vs. standard therapy alone
(90). This key study suggested that anti-inflamma-
tory agents might only be applicable to a subpopu-
lation of mood disorder patients, namely those
with immune dysfunction. Therefore, in the design
and interpretation of clinical trials moving for-
ward, selecting an appropriate sample population
may allow for more meaningful results, subtracting
the added ‘noise’ in the data set caused by mood
disorder patients with normal immune function.
Aside from pharmacological treatments for
patients with BD with medical comorbidity, the
data discussed would also suggest that improved
screening practices for BD in patients with medical
conditions (particularly conditions with known
immune dysfunction, such as autoimmune, cardio-
vascular, and metabolic disorders) and vice versa
would be beneficial. Identifying patients with BD
in general medical clinics may allow for early treat-
ment and prevention of neuroprogression and ulti-
mately improved outcomes. Similarly, identifying
immune dysfunction and medical comorbidity in
the BD population may also allow for early detec-
tion and treatment and thus improved outcomes
and potentially even improved life expectancy for
these patients (20).
Discussion
In summary, BD has a strong association with sev-
eral medical comorbidities including many autoim-
mune disorders, cardiovascular disease, obesity,
and T2DM, all of which are associated with a

A Immune
B
dysfuncon
Bipolar Medical
disorder comorbidity
C venting the development of comorbidity in BD
Fig. 4. Venn diagram depicting overlap of BD, immune dys-
function, and medical comorbidity. (a) Patients with BD and
immune dysfunction may be candidates for immune-based
therapies. For this subgroup that has immune dysfunction
without medical comorbidity, the underlying reason for this
resilience would be of interest. (b) Patients with immune dys-
function and medical comorbidity with no psychiatric disor-
ders would be of interest in studying mechanisms of resilience,
which prevent the development of psychiatric disorders in this
at risk population. (c) Patients with BD, medical comorbidity,
and immune dysfunction likely may respond to immune-based
therapies to potentially simultaneously improve outcomes of
their BD and medical comorbidity. For this subgroup, immune
dysfunction is likely facilitating the co-occurrence of BD and
medical comorbidity.
chronic inflammatory state. Immune dysfunction
has significant molecular, cellular, physiological,
structural, and functional effects centrally leading
to impaired mood and cognition as seen in BD.
The interaction between BD and medical comor-
bidities is multifactorial; however, immune dys-
function presents as an important factor mediating
the epidemiologic observation of increased medical
comorbidity in BD patients.
Therefore, immune dysfunction serves as a
potential novel target in the treatment of BD
patients with inflammatory medical comorbidities.
Indeed, several agents discussed show promise to be
used as adjuncts for the treatment of BD in patients
with immune dysfunction, however; with the cur-
rent evidence presented, none of the agents dis-
cussed have enough evidence as of yet to support
their use in the treatment of BD as further clinical
studies are required to support or refute their use.
When using immune-based therapy, the impor-
tance of personalized medicine must be empha-
sized. While immune dysfunction is prevalent in
BD patience, not all BD patients have immune
Inflammation, BD and medical comorbidity
dysfunction as hypothetically depicted in Fig. 4.
Therefore, immune-based therapies are unlikely to
be helpful for all BD patients (i.e., anti-inflamma-
tory therapies may only be beneficial to BD
patients with immune dysfunction). Further, strati-
fying patients based on immune dysfunction may
aid in design of clinical trials that may yield more
relevant data, potentially preventing false-negative
trials of agents that may actually be therapeutically
beneficial to a subgroup of BD patients.
Also of interest in future studies would be to
understand the mechanisms that subserve resil-
ience in patients with BD who do not have comor-
bid immune dysfunction and/or medical
comorbidity. As depicted in the Venn diagram in
Fig. 4, there are individuals who have BD who do
not develop medical comorbidity. The process pre-
patients would thus be of great interest. Con-
versely, patients with immune dysfunction and/or
medical conditions who never develop psychiatric
disorders would be a population of interest.
Understanding the mechanisms which prevent
these individuals from developing mood disorders
may allow for insight into potential preventative
mechanisms that may be used to decrease the prev-
alence of psychiatric comorbidity in patients with
general medical conditions.
Given the high co-prevalence of BD with inflam-
matory diseases, regular screening for mood symp-
toms in patients with known inflammatory disease
is recommended. In addition, for patients with
BD, screening for medical comorbidity and
immune dysfunction at initial presentation and fol-
low-up visits would be extremely important. Fur-
ther, with the development of medical
comorbidities, practitioners must consider modifi-
cation of current therapies to prevent further
development of medical comorbidities.
Acknowledgement
This article was not directly supported by any grants or schol-
arships. JDR and RSM contributed equally to this paper.
Declaration of interest
JDR has no conflict of interests to declare. RSM declares that
he has been on advisory boards and/or received honoraria for
educational activities and/or research grants from AstraZene-
ca, Bristol-Myers Squibb, Janssen-Ortho, Eli Lily, Forest,
Lundbeck, Pfizer, Shire, Merck, Sepracor, and Otsuk.
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