Psychiatry Clin Neurosci - 2016 - Sigitova - Biological Hypotheses and Biomarkers of Bipolar Disorder

Psychiatry and Clinical Neurosciences 2017; 71: 77–103 doi:10.1111/pcn.
12476
Review Article
Biological hypotheses and biomarkers of bipolar disorder

Ekaterina Sigitova, MD, Zdenek Fišar, MSci, PhD,* Jana Hroudová, MPharm, PhD,
Tereza Cikánková, MPharm and Jiří Raboch, MD, DSc
Department of Psychiatry, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague,
Czech Republic
The most common mood disorders are major nitrosative stress; cellular bioenergetics; and mem-
depressive disorders and bipolar disorders (BD). The brane or vesicular transport. Current biological
pathophysiology of BD is complex, multifactorial, hypotheses of BD are summarized, including related
and not fully understood. Creation of new hypoth- pathophysiological processes and key biomarkers,
eses in the field gives impetus for studies and for which have been associated with changes in genet-
finding new biomarkers for BD. Conversely, new ics, systems of neurotransmitter and neurotrophic
biomarkers facilitate not only diagnosis of a disor- factors, neuroinflammation, autoimmunity, cyto-
der and monitoring of biological effects of treat- kines, stress axis activity, chronobiology, oxidative
ment, but also formulation of new hypotheses stress, and mitochondrial dysfunctions. Here we also
about the causes and pathophysiology of the BD. discuss the therapeutic hypotheses and mechanisms
BD is characterized by multiple associations of the switch between depressive and manic state.
between disturbed brain development, neuroplasti-
city, and chronobiology, caused by: genetic and Key words: bipolar disorder, hypothesis, mitochon-
environmental factors; defects in apoptotic, drial dysfunction, neuroinflammation, neuroplasticity.
immune-inflammatory, neurotransmitter, neurotro-
phin, and calcium-signaling pathways; oxidative and
neurogenesis.2 Pathways underlying neuroprogres-

T HE ETIOLOGY OF bipolar disorder
(BD) remains uncertain; both genetic back-
ground and environmental factors, such as stressful
sion in BD include the dopaminergic system,
inflammatory cytokines, oxidative and nitrosative
life events or substance abuse, are related to the risk stress, mitochondrial dysfunction and endoplasmic
of development of BD.1 Insights into the processes reticulum stress, alterations in cAMP response
underlying neuroprogression in BD have been pro- element-binding protein (CREB) and neurotrophic
vided by studies examining genetic and epigenetic system, dysregulation of calcium signaling, neuroin-
changes, structural and functional changes in the flammation, autoimmune processes, tryptophan and
brain, damage in neuronal circuits, disturbed circa- tryptophan metabolites, and hypothalamic–pitui-
dian rhythms, changes in immune and endocrine tary–adrenal (HPA) axis dysregulation (Fig. 1).3–5
systems, impairment in neuronal plasticity and resil- Current knowledge provides the background for
ience, increased apoptosis, disturbances of synaptic formulation of several biological hypotheses of
transmission and signal transduction, activation of BD based on the identification of biomarkers for
neurotoxic mechanisms, and changes in vulnerability, disease expression and course, and
treatment response. Biomarkers for BD are still
being researched: structural brain changes are
*Correspondence: Zdenek Fišar, MSci, PhD, Department of Psychiatry, searched for using neuroimaging methods; poly-
First Faculty of Medicine, Charles University and General University morphisms in a number of susceptibility genes
Hospital in Prague, Ke Karlovu 11, 120 00 Prague, Czech Republic.
Email: zfisar@lf1.cuni.cz
have been discovered in genetic studies; and neu-
Received 19 June 2016; revised 4 October 2016; rochemical biomarkers are studied in periphery
accepted 25 October 2016. above all.6,7
© 2016 The Authors 77

Psychiatry and Clinical Neurosciences © 2016 Japanese Society of Psychiatry and Neurology
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78 E. Sigitova et al. Psychiatry and Clinical Neurosciences 2017; 71: 77–103
Figure 1. Bipolar disorder is characterized by multiple associations between disturbed brain development and neuroplasticity
caused by genetic and environmental factors and activated apoptotic, immune-inflammatory, neurotransmitter, neurotrophin
and calcium signaling pathways, oxidative and nitrosative stress, and disturbed chronobiology, cellular bioenergetics and
transport.
Further research is needed to validate these after several manic episodes,12 progressive decline in
hypotheses and potential biomarkers prior to using hippocampal, fusiform, and cerebellar gray matter
them for clinical purposes. In this article we summa- density after repeated episodes,13 subregion-specific
rize our view of valid biological hypotheses for BD gray matter volume reductions in the prefrontal
based on findings from brain neuroimaging, genet- cortex,14 and increased rates of deep white matter
ics, neurophysiological, neurochemical, and neuro- hyperintensities.15
immuno-endocrinological approaches. Neuroimaging studies have consistently demon-
strated association of grey matter reduction in left
NEUROIMAGING rostral anterior cingulate cortex and right fronto-
Structural imaging studies in patients with BD insular cortex thickness; that is, the most robust grey
have identified anatomical and neuropathological matter reductions in BD occur in anterior limbic
abnormalities, which are associated with a neuro- regions, which may be related to executive control
progression. Moreover, previous mild traumatic and emotional processing abnormalities.16
brain injury has been identified as a risk factor In a large study of 1710 BD patients and 2594
for development of heterogeneous neuropsychiat- healthy controls, the volumes of the nucleus accum-
ric diseases, including BD.8 Disruptions to bens, amygdala, caudate, hippocampus, globus pal-
cortico–striatal–limbic circuits are the most lidus, putamen, thalamus, and lateral ventricles were
straightforward method of describing the patho- measured. BD patients have been found to have vol-
physiology and symptomatology of affective umetric reductions for the mean hippocampus and
disorders.9–11 thalamus and enlarged lateral ventricles.17 However,
Morphometric measurements discover in BD brain volume may be altered by environmental fac-
patients enlargement of lateral and third ventricles tors, including medication.
© 2016 The Authors

Psychiatry and Clinical Neurosciences 2017; 71: 77–103 Hypotheses of bipolar disorder 79
Imaging data suggest that decreased activity in The meta-analysis of genetic association studies on
prefrontal cortical areas may result in inadequate BD showed the lack of robust findings. Single poly-
modulation of limbic/subcortical areas, which con- morphisms in four different genes, BDNF, DRD4,
tributes to depressed mood and inadequate cogni- DAOA, and TPH1 (encoding BDNF, dopamine recep-
tive coping. Both regional gray-matter and tor D4, DAOA, and TPH 1, respectively) were found
white-matter changes appear to be present relatively to be nominally significant; however, none of these
early in BD development.18 findings were significant after correction for multiple
Functional magnetic resonance imaging (fMRI) testing. In a systematic review of genome-wide gene
confirmed that excessive activation in brain regions expression studies of BD, 11 genes were found to be
associated with emotional regulation may contrib- significant after correction for multiple testing.
ute to the affective symptoms of BD. Altered brain Among these were FKBP5 (encoding FK506 binding
activation was identified in various regions in the protein 5, which plays a role in immunoregulation,
cortico-limbic pathways; the most consistent find- protein folding and trafficking) and WFS1 (encoding
ings were overactivation of the amygdala, striatum, wolframin, which acts as a cation-selective ion chan-
and thalamus.19 All studies using fMRI in BD sup- nel). Both of these genes have been previously impli-
ported the cortico-limbic hypothesis and suggest cated in mood disorders.28
that connectivity can be more complex and that Findings in meta-analyses of BD depend on the
intra-regional disturbances should also be studied.20 method that was used to combine data. Recently,
among the 226 genes with significant effect in BD,
nine differed in expression in the dorsolateral pre-
GENETICS frontal cortex in patients with BD: CACNA1C
Genetic studies have suggested that many chromo- (encoding calcium channel, voltage-dependent, L
somal regions and candidate genes are related to type, α1C subunit), DTNA (encoding dystrobrevin
susceptibility to BD with each gene exerting a mild α), FOXP1 (encoding forkhead box protein P1),
to moderate effect.21 It is accepted that understand- GNG2 (encoding guanine nucleotide-binding pro-
ing of changes in regulation of gene expression tein Gi/Gs/Go subunit γ-2), ITPR2 (encoding inositol
(caused by mutations, polymorphisms, and epige- 1,4,5-trisphosphate receptor, type 2), LSAMP
netic changes) of specific components of signaling (encoding limbic system-associated membrane pro-
pathways may significantly contribute to recognition tein), NPAS3 (encoding transcription factor neu-
of processes responsible for disease onset and pro- ronal PAS domain protein 3), NCOA2 (encoding
gression. Twin and adoption studies consistently nuclear receptor coactivator 2), and NTRK3 (encod-
demonstrate a genetic influence on all major psychi- ing tropomyosin receptor kinase C). Intracellular
atric disorders.22 Based on twin studies, heritability signaling pathways have been identified that con-
of BD was estimated at 85%.23 tribute to risk for BD using genes with consistent
A number of plausible candidate genes have been evidence for association in multiple genome-wide
previously associated with BD, including genetic association studies (GWAS): glutamate receptor sig-
polymorphisms of key signaling components, such naling, phospholipase C (PLC) signaling,
as serotonin transporter (5-HTT, SERT), dopamine corticotrophin-releasing hormone (CRH) signaling,
transporter (DAT), brain-derived neurotrophic factor endothelin 1 signaling, cardiac β-adrenergic signal-
(BDNF), tryptophan hydroxylase (TPH), catechol-O- ing, and cardiac hypertrophy signaling. The pathway
methyltransferase (COMT), D-amino acid oxidase with the strongest evidence is the CRH signaling
activator (DAOA), and mutations of mitochondrial pathway.29 In another study, a meta-analysis con-
DNA (mtDNA).24–26 BD is seen as polygenic disor- firmed a significant gene effect for 46 genes (65 var-
ders underpinned by many genes of small effect size. iants) in BD, whereas the strongest gene effects for
Gene expression analysis in the post-mortem brains BD were reported for 21 genetic variants. The bio-
of BD patients indicates alterations in glutamate logical pathways implicated included cell activation
receptors, mitochondria-related genes, chaperone and proliferation and signal transduction, apoptosis
genes, oligodendrocyte genes, and markers of and chromatin modification, chemokine signaling,
GABAergic neurons.27 Epigenetic modifications and glutamate signaling and regulation, immunological
gene–environment interactions are studied to response, cell adhesion and migration, neurotrans-
explain genetic vulnerability that triggers BD. mitter degradation and tumor suppression.30
© 2016 The Authors

The GWAS studies confirmed a polygenic contri- supported by observation of elevated MAO-A den-
bution to risk of BD development. Preliminary ana- sity and reduced 5-HTT density during depressive
lyses of whole genome/exome sequencing have episode.46–48
supported the role of calcium, CREB, and potassium Hyperdopaminergic function has been reported
channels signaling pathways in BD.31 Several com- in BD. A dopamine hypothesis of BD was formu-
mon polymorphisms, including variants of genes lated that suggests a role of increased dopaminer-
CACNA1C, TENM4 (encoding teneurin transmem- gic transmission in mania and the converse in
brane protein 4, a protein promoting neurite out- depression.49,50 The hypothesis is supported by
growth and cell adhesion), NCAN (encoding the fact that altered availability of dopamine
neurocan, a significant component of the extracellu- transporter has been accepted as a biomarker
lar matrix), and ANK3 (encoding ankyrin G, a scaf- for BD.51
fold protein required for the normal clustering of Monoamine depletion studies, genetic association
voltage-gated sodium channels at the axon hillock studies, PET studies, and mechanism of action of
and for action potential firing), are significantly antidepressants supported an important role of dis-
associated with BD.32,33 The number of significant turbed monoamine neurotransmission in the patho-
common single nucleotide polymorphism (SNP) physiology of mood disorders but have not
associations detected in GWAS should rise as sample evidenced the primary role of monoaminergic sys-
sizes increase. Recently, two novel loci associated tem in development of the disorder. The molecular
with BD have been identified in the GWAS of changes underlying imbalances of neurotransmis-
40 000 individuals.34 sion in BD are not agreed upon; it is hypothesized
that alterations in excitatory amino acid transpor-
ters, 5-HTT, and dopamine transporter contribute to
NEUROTRANSMITTERS altered glutamatergic and monoaminergic function
The biological hypotheses of mood disorders are in BD patients.52
under development.35 The monoamine hypothesis The hypothesis that the dysfunctional muscarinic
was initially formulated as catecholamine36 and/or acetylcholine system is involved in the pathophysi-
indolamine37 deficiencies in the brain; that is, as the ology of BD has been supported by the finding that
neurotransmitter hypothesis. Later, the monoamine there is reduced muscarinic acetylcholine M2 recep-
hypothesis was revised to include the role of neuro- tor binding in subjects with BD,53 which could be
transmitter receptors, transporters, catabolizing accounted for by a reduction in M2 receptor affinity
enzymes (monoamine oxidase [MAO], and COMT), caused by genetic variation in the gene for M2
and other brain neurobiological systems.10,38–40 receptor.54
The monoamine hypothesis of mood disorder Glutamate and GABA systems are posited in the
posits that an imbalance in monoaminergic neuro- pathophysiology of major depression and BD that
transmission in the central nervous system is caus- extends beyond monoaminergic dysfunction.55 Glu-
ally related to the clinical features of depression or tamate levels were increased in the post-mortem
mania. This hypothesis has been supported by brains of subjects with BD, while the glutamate/glu-
mechanisms of action of antidepressants.35,41,42 tamine ratio was decreased following valproate treat-
Moreover, many candidate genes associated with BD ment, and GABA levels were increased after lithium
encode compounds influencing directly the monoa- treatment. The balance of excitatory/inhibitory neu-
mine neurotransmitter systems, for example, rotransmission seems to be central to the BD.56 A
SLC6A4 (encoding serotonin transporter), TPH2, meta-analysis confirmed that brain glutamate + glu-
DRD4, SLC6A3 (encoding dopamine transporter), tamine levels are elevated in BD patients,57 which
MAOA (encoding MAO type A, MAO-A), and supported an important role of glutamate in the
COMT.43–45 pathophysiology of BD. Due to the role of glutamate
The advanced monoamine hypothesis46 supposes in neurotransmission, brain energy metabolism,
that serotonin or norepinephrine concentrations in astrocyte function, neurotoxicity, neuroplasticity,
the brain are regulated by MAO-A activity, and that and learning, the glutamate hypothesis of mood dis-
the severity of symptoms of depression is linked to orders is expected to complement and improve the
changes in the activity of monoamine transporters prevailing monoamine hypothesis.58,59 The hypothe-
in specific brain regions. The hypothesis has been sis is supported by the observation that antagonists
© 2016 The Authors

of glutamate N-methyl-D-aspartate (NMDA) receptor decreased BDNF is part of the pathophysiology of

produce rapid antidepressant effect.60,61 BD.71 Several meta-analyses have shown that there
may be a correlation between low BDNF levels and
the emergence of BD.72–74 A systematic review and
NEUROTROPHIC FACTORS meta-analysis confirmed that peripheral BDNF levels
Neurotrophic factors are growth factors that pro- in BD are consistently reduced during manic and
mote neuroplasticity, neurogenesis, survival, differ- depressive episodes and plasma levels of BDNF are
entiation, and maintenance in healthy and recovered after treatment for acute mania, that is,
regenerating brain cells. They include nerve growth the BDNF plasma or serum levels are not different
factor (NGF), BDNF, neurotrophin-3 (NT-3), in euthymia when compared to controls.73,75,76
neurotrophin-4 (NT-4), glial cell line-derived neuro- Thus, reduction in serum BDNF may be a potential
trophic factor (GDNF), and ciliary neurotrophic fac- biomarker of acute episodes and could differentiate
tor (CNTF). They are two classes of neurotrophic patients in a manic or depressive episode from those
receptors: low-affinity nerve growth factor receptor in the euthymic phase. Moreover, serum BDNF may
(LNGFR, p75 neurotrophin receptor) and a family distinguish BD from unipolar depression,77 may be
of high-affinity tropomyosin receptor kinase (Trk, a biomarker of MD progression and severity,73,75,78
also tyrosine receptor kinase; types TrkA, TrkB, and may discriminate initial and advanced BD
TrkC). Activation of LNGFR by neurotrophins (NGF, episodes,79 and may reflect response to treat-
BDNF, NT-3, and NT-4) may induce apoptosis; acti- ment.76,80 The role of BDNF in the pathophysiology
vation of Trk receptors support cell growth and may of BD has been supported by findings that BDNF
be antiapoptotic (pro-survival). TrkA binds NGF, mRNA is decreased in cingulate and temporal cor-
TrkB binds BDNF, NT-3, and NT-4, and TrkC binds tices and in the hippocampus81,82 and that precursor
NT-3. protein proBDNF encoded by the BDNF gene has
Intracellular signaling pathways of growth factors been suggested as a biomarker of mood disorders.83
include: (i) Ras/mitogen activated protein kinase Note that BDNF levels in the blood could be
(MAPK) pathway; (ii) phosphatidylinositol-4,5- derived from its production by both brain and
bisphosphate 3-kinase (PI-3K)/protein kinase B peripheral tissues, such as skeletal muscle, liver, and
(Akt)/glycogen synthase kinase 3 (GSK-3) pathway; the cardiovascular system, and BDNF in the blood is
and (iii) phosphoinositide pathway (phospholipase stored predominantly in platelets.84 Nevertheless,
Cγ [PLCγ]/protein kinase C [PKC]) linked to MAPK, intact BDNF in the peripheral circulation crosses the
Akt, and/or Ca2+/calmodulin-dependent protein blood–brain barrier (BBB) by a high-capacity satura-
kinase (CaMK).62–66 An important intracellular reg- ble transport system85 and blood and plasma BDNF
ulator of apoptosis and cell survival in the develop- concentrations reflect brain-tissue BDNF levels.86
ing, adult, and injured nerve cells is the p53 protein BDNF plays a key role in the pathophysiology of
family.67 Neurotrophin signaling and vesicular stress-related mood disorders. Acute stress, such as
transport is linked; disturbances of vesicular trans- partial sleep deprivation, induced a fast increase in
port lead to disturbed neurotrophin signaling and to BDNF serum levels, whereas long-term stress led to
diseases of the nervous system.68 sleep disturbance and depression as well as
Disturbances in activities of neurotrophic factors decreased BDNF levels.87 The role of BDNF in the
and related impairment in plasticity and resilience pathophysiology of BD has been evidenced by eleva-
in brain cells has been reported in BD. Attention is tion of serum and brain BDNF levels by antidepres-
paid to neurotrophins and other growth factors that sant, mood stabilizers, and antipsychotics,88,89
regulate function of brain cells, such as BDNF, including lithium.90
GDNF, insulin-like growth factor 1 (IGF-1), and vas- The Val66Met polymorphism (refSNP Cluster
cular endothelial growth factor (VEGF).69,70 Report: rs6265) of the BDNF gene is a functionally
relevant SNP affecting the secretion of BDNF and is
implicated in differences in hippocampal volumes.
Brain-derived neurotrophic factor The hippocampal volumes were reduced signifi-
Post-mortem brains of BD patients have shown sig- cantly in association with the presence of the BDNF
nificantly decreased protein and mRNA levels of met allele and with BD diagnosis.91 However, a sys-
BDNF in the frontal cortex, which indicates that tematic meta-analytical review of findings on the
© 2016 The Authors

impact of the rs6265 SNP on hippocampal volumes Plasma VEGF levels were elevated in patients with
in patients with BD suggested that there is no associ- a manic episode of BD, which may be associated
ation between this BDNF polymorphism and hippo- with a neuroprotective role for VEGF.105 Increased
campal volumes.92 Another meta-analysis was expression of the VEGF gene was also found in a
performed to determine the overall strength of asso- depressive episode of BD compared to healthy con-
ciations between BDNF genetic polymorphism trol subjects.106 Lithium treatment led to decrease of
Val66Met and susceptibility to BD. It was concluded VEGF mRNA levels.107 These results indicate that
that there is no compelling evidence to support VEGF may vary with the episode of the disease and
Val66Met polymorphism in the BDNF gene playing may be associated with the pathophysiology
an important role in the susceptibility to BD.93 of BD.70
However, plasma BDNF levels were significantly It was reported that some members of the neuro-
negatively correlated with depression scores in trophin family, such as NGF, NT-3, and NT-4, can
patients with BD. It was supposed that plasma cross the BBB; NGF had the fastest influx rate and
BDNF in BD is not affected by BDNF Val66Met gene NT-3 the slowest.108 CNTF is saturably transported
variants, but by progression of the illness itself.94 across the BBB from blood to brain.109 IGF-1 enters
the CNS by a saturable transport system at the BBB,
which functions in synchrony with IGF-binding pro-
teins in the periphery to regulate the availability of
Other growth factors IGF-1 to the CNS.110 It indicates that peripheral
There are few studies that evaluate the role of NGF administration of some neurotrophins could have
in the pathophysiology of BD and the results are therapeutic effects within the CNS. In contrast,
inconsistent.70 For example, decreased plasma NGF GDNF and VEGF do not cross the BBB111; VEGF
was reported in BD in the manic episode,95 but enhances angiogenesis and promotes BBB leakage in
another study stated significantly higher IGF-1 in the ischemic brain.112
patients with bipolar I disorder and no changes in
NGF.96
Effects of NT-3 and NT-4 also require more Neurotrophic hypothesis
research. Serum NT-3 levels in drug-free and medi- Neurotrophic, neuroplasticity, and neurogenesis
cated patients were found to be increased when hypotheses were formulated, supposing a key role of
compared with controls and serum NT-3 levels did post-receptor and intracellular processes (regulating
not differ between drug-free and medicated intercellular and intracellular signaling) in the devel-
patients.97 Serum concentrations of NT-4 were opment of mood disorders. These hypotheses
reported to be significantly higher in BD patients emphasize the role of stress, growth factors and neu-
than in controls.98 At baseline, in bipolar depressed rogenesis in the pathophysiology of BD69,113–116
patients, there were no differences between respon- and they are supported by neurotrophic effects of
ders and non-responders to treatment with ketamine various antidepressants and mood stabilizers. Wnt
in serum BDNF, NGF, NT-3, NT-4, or GDNF.99 signaling pathway and GSK-3 activity have been
A study of GDNF in BD revealed that different implicated in both regulating neuroplasticity and
stages of the disorder and drug treatment can alter neuroprotection.117,118
activity of GDNF.70 Lower GDNF concentrations The neurogenesis hypothesis of depression pro-
might be involved in the pathophysiology of BD poses that depression can arise from impaired hip-
and drug treatment increases the GDNF.100 pocampal neurogenesis and that antidepressants
The evidence has been provided that IGF-1 plays stimulate neurogenesis. Coupling of hippocampal
a role in the pathophysiology of BD.70 The IGF1 neurogenesis to pathophysiology of depression
gene has been identified as a candidate gene for sus- requires further research to be confirmed.2,119–121
ceptibility to BD.101 Peripheral levels of IGF-1 were Neuroprogression is an important mechanism of
found to be unchanged in patients with BD com- BD, and neurotrophins are key regulators of neuro-
pared to controls102; however, it seems that lithium genesis and neuroplasticity.2,70,122 The neurotrophic
may regulate IGF-1 levels.103 Low expression of hypothesis69,113–115 postulates that mood disorders,
IGF1 has been suggested as a putative biomarker for such as BD, are associated with a lower activity of
lithium unresponsiveness.104 neurotrophic factors, such as BDNF. Vulnerability to
© 2016 The Authors

depression can arise as a result of neuronal damage with the inflammatory process associated with these
(e.g., after chronic stress, long-term increased levels autoimmune diseases.
of glucocorticoids, ischemia, hypoglycemia, viral Association of BD with autoimmune diseases may
infections, and action of neurotoxins) and therapeu- be partially explained by the finding that the fre-
tic effects of antidepressants may consist in activa- quency of regulatory T lymphocytes (CD4+ CD25+
tion of higher expression of neurotrophin BDNF Foxp3+) (cells related to the suppression of the pro-
and its receptor TrkB (e.g., through activation signal- liferation of effector T cells and suppression of exces-
ing pathways linked to monoaminergic systems) sive misguided immune responses, including
leading to increased neuronal plasticity, reactivation inhibition of the development of autoimmune dis-
of cortical plasticity, and resumption of neuronal eases) was reduced in BD patients.129
functions.123
Neuroinflammation
NEURO-IMMUNO-ENDOCRINOLOGICAL Chronic neuroinflammation, caused by neurotoxins,
APPROACH autoimmunity, aging, traumatic brain injury,
The initial episodes of BD are often precipitated by microbes and viruses, is associated with several
psychosocial stressor, which activates the HPA axis mental and neurodegenerative diseases. Both brain
and elevates cytokines. Cytokines, dopamine autoxi- cells (microglia, astrocytes, and neurons) and
dation, increased activation of glutamate ionotropic peripheral immune cells have been implicated in
receptors, and mitochondrial dysfunction cause neuroinflammation and the resulting oxidative and
increased production of ROS and oxidative stress. nitrosative stress. Neuroinflammation is typically
Cellular stress responses include upregulation of associated with activation of microglia, which are
molecular chaperones to protect biomolecules from major sources of ROS in the brain, and play crucial
degradation.124 roles in various brain diseases.130–132
The innate immune response in the brain seems Pro-inflammatory cytokines do not freely cross
to be a potentially pathogenic factor in a number of the BBB under physiological conditions. Thus, it is
CNS diseases that do have activated microglia and still unclear how the changes in the periphery
astrocytes (i.e. neuroinflammation is accepted as a affect pro-inflammatory processes in the CNS.
pathogenic factor in these diseases).125,126 The Post-mortem studies have shown that BD patients
exchange of signals between neurons and the glial present increased pro-inflammatory and decreased
cells at the CNS level is achieved by means of che- anti-inflammatory markers in the frontal
mokines, cytokines and the complement system. cortex.133,134
Dysregulation of cytokines has been linked to many Recently, BD has been discussed to be character-
diseases, including BD. The immunological distur- ized by glial pathology and neuroinflamma-
bance along the bipolar spectrum was most severe tion.135,136 BD patients present an episode-related
in BD-I patients.127 inflammatory syndrome137 (i.e. pro-inflammatory
state may be associated with BD). Really, the
immune dysfunctions and pro-inflammatory state
Autoimmunity have been implicated in the pathophysiology of BD,
Comorbidity of autoimmune diseases and BD sug- which was documented by increased frequency of
gests a possible autoimmune etiology. In a cohort of autoimmune diseases, distinct immune cell profile,
9920 cases of BD in Denmark, the degree was deter- cytokines released by stimulated mononuclear cells,
mined, to which 30 different autoimmune diseases elevated levels of circulating cytokines, and inflam-
are antecedent risk factors for BD.128 The significant matory changes in the CNS.4,138
familial association (genetic linkage) of autoim- Moreover, after injury and sustained release of
mune diseases to BD was not found (except for per- inflammatory factors, permeability of BBB may be
nicious anemia); however, the data suggest that increased and circulating blood components and
some autoimmune diseases, such as Guillain-Barré peripheral immune cells may enter into the brain,
syndrome, Crohn’s disease, and autoimmune hepa- which contributes to chronic neuroinflammation
titis, may precede onset of BD. This means that, in and neurodegeneration.139 The molecular regulation
some cases, the onset of BD arises in connection of neuroinflammation is strongly influenced by
© 2016 The Authors

epigenetic mechanisms (i.e. by DNA methylation, significantly increased in both BD and schizophrenia
histone modification, and noncoding RNA).140 compared to controls.154
The calcium-binding protein B (S100B), a growth In summary, data about the association of BD
and differentiation factor released by astrocytes and with peripheral immune system dysfunction are
oligodendrocytes, was found to be significantly ele- conflicting in individual studies. BD patients pre-
vated in BD during episodes of mania and depres- sented both increased and decreased plasma levels
sion, but not in euthymic patients.141,142 Serum of chemokines155 and it was evidenced that the
S100B has been linked to specific imaging para- release of various interleukins is altered in BD.156
meters in human white matter. Powerful whole Meta-analyses of blood cytokines have shown that
genome gene expression studies showed an increase levels of IL-2, IL-6, IL-10, TNF-α, soluble IL-2 recep-
in S100B gene expression in the hippocampus in tor (sIL-2R), TNF-α, sTNFR1, sIL-6R, IL-4, and IL-1
BD.143 receptor antagonist (IL-1RA) were significantly
Activation of microglia may mediate neuronal increased in acutely ill patients with bipolar mania
and glial cell injury and death through activation compared with controls.157–159 Following treatment
of pro-inflammatory factors, such as cytokines, che- of the acute illness, IL-1RA levels in bipolar mania
mokines, metalloproteinases, cytotoxic factors, or decreased. In chronically ill patients, the levels of IL-
complement system proteins.4,144,145 Upon activa- 6 were significantly increased in euthymic (but not
tion, microglia can produce pro-inflammatory depressed) BD compared with controls. The levels of
(at M1 polarization) or anti-inflammatory (at M2 IL-1β and sIL-2R were significantly increased in
polarization) cytokines. Mania and, to lesser euthymic BD.159
degree, depression are associated with a pro-
inflammatory state.146 BD patients in manic epi-
sode had higher concentrations of interleukin HPA axis
(IL) 6 (IL-6), interferon γ (IFN-γ), tumor necrosis There are evident abnormalities of HPA axis activity
factor α (TNF-α), IL-2, the soluble form of IL-6 in BD. Hypercortisolism and neurocytotoxic effects
receptor (sIL-6R), and soluble TNF receptor 1 - of cortisol may be central to the pathogenesis of
(sTNFR1),147–150 while IL-4 concentration was sig- depressive symptoms and cognitive deficits; manic
nificantly lower than normal controls.148 After episodes may be preceded by increased concentra-
treatment, IL-6 was normalized and TNF-α tions of adrenocorticotropic hormone and corti-
remained increased, which indicate that IL-6 might sol.160 A meta-analysis revealed moderate quality
be a state marker of manic episode.148 evidence of increased morning cortisol levels in BD
Inflammatory biomarkers are capable of discrimi- compared to controls, which suggests long-term
nating the initial stages of BD from those in pathology of the HPA axis that supports stress-
advanced stages (declined IL-10 and increased TNF- vulnerability models of the disease.161
α in advanced BD stages).151 TNF-α is a potential A recent systematic review and meta-analysis of
biomarker of BD progression. In addition, elevated HPA axis activity in BD confirmed that BD is associ-
levels of C-reactive protein were found during manic ated with abnormalities of stress-related pathways in
episodes as well as in the bipolar depressed the brain;162 BD is associated with HPA axis hyper-
group.152,153 activity (increased cortisol levels), most prominently
The analysis of biomarkers in cellular superna- in the manic episode, but also in remission. The
tants confirmed increased in vitro production of meta-analysis showed that variants of HPA-axis-
cytokines IL-2, IL-4, IL-6, IL-10, TNF-α, IFN-γ, and related genes seem not to be associated with the
IL-17 by isolated peripheral blood mononuclear direct risk of BD and HPA axis dysregulation and
cells stimulated with phytohaemagglutinin and con- that HPA axis abnormalities should not be consid-
firmed the dominance of T-helper type 1 (Th1) cyto- ered as an etiological factor or endophenotype of
kines in BD.129 BD, but seem to be related to environmental risk
There were similarities in the pattern of cytokine factors.
alterations in schizophrenia, BD, and major depres- Effects of glucocorticoids, increased due to activa-
sive disorder during acute and chronic phases of ill- tion of the HPA axis, on activity of cellular com-
ness. For example, plasma levels of sTNFR1 and von pounds included in neuroinflammation,
Willebrand factor (vWf ) were found to be neurotransmitter signaling pathways, or
© 2016 The Authors

bioenergetics may participate in the pathophysiol- anti-inflammatory state of microglial activation

ogy of BD. Interference of excessive glucocorticoid results in mood disorders. Pro-inflammatory state is
with BDNF signaling may be accomplished through defined by increased activity of cytokines (IL-1β, IL-
interaction of glucocorticoid receptors with TrkB.163 6, TNF-α) and chemokines (CCL2), release reactive
Progressive HPA axis dysfunction might participate oxygen species (ROS) and NO, activation of P2X
in the neuroprogression and the clinical and cogni- purinoceptor 7 and toll-like receptors, and
tive deterioration in BD. While HPA axis activity cyclooxygenase-2 (COX-2) upregulation. Anti-
responds to pharmacological treatment, targeting of inflammatory response to microglia activation is
the HPA axis may improve the outcome of BD in related to the release of IL-4, IL-10, IL-13, IGF-1,
the long term. TGF-β, and BDNF, increased microglial phagocyto-
sis, and increased synaptic pruning.150 It is possible
that microglial activation contributes to both patho-
Metalloproteinases physiology of BD and treatment responses.132,135
Proteins of the matrix metalloproteinase family are The underlying mechanisms of the immune acti-
involved in the breakdown of extracellular matrix in vation in BD may include both changes in frequency
normal physiological processes. Matrix metallopro- and activation of circulating lymphocytes. Defective
teinase 9 (MMP-9) has been implicated in neuroplas- neuroendocrine control over the immune system
ticity and a number of pathological conditions, may partially explain increased circulating levels of
including neuropsychiatric disorders, such as schizo- pro-inflammatory cytokines in BD patients.168 On
phrenia, BD, and multiple sclerosis. Molecular- the molecular level, it can be expected that cytokine
genetic studies of the functional polymorphism of signaling can influence neuro-glial interactions
MMP9 gene demonstrated an association of the poly- through ATP-gated ion channel P2X purinoceptor
morphism with a predisposition to BD.164 Bipolar 7156,170 and the T-cells of BD patients had an
patients, both during acute episode and in remission increased phosphorylated extracellular signal–
after depression, had significantly higher MMP-9 regulated kinases (ERK) signaling.129 Moreover, acti-
serum levels compared to those with manic episode vated microglia may promote expression of IFN-γ, a
and control subjects,165 which indicates serum potent activator of kynurenine pathway, whose role
MMP-9 as a possible marker for staging of BD. MMP- is described below.
7, which may be involved in regulation of inflamma-
tory processes, was found to be altered specifically in
mixed mood episodes of BD patients.166 New ‘serotonin’ hypothesis
Brain serotonin biosynthesis is carried out by
hydroxylation and decarboxylation of the amino
Inflammatory hypothesis acid tryptophan. Catabolism of tryptophan in the
The macrophage/T-cell hypothesis of depression states kynurenine pathway may cause depletion of brain
that chronically activated macrophages and T-cells in serotonin in depressive episode. Rate-limiting factor
periphery and microglia in the brain produce inflam- is the conversion of tryptophan to kynurenine,
matory cytokines, which modify brain functions and, which is catalyzed by tryptophan 2,3-dioxygenase
in conjunction with genetic and environmental factors, (TDO) and indoleamine 2,3-dioxygenase (IDO).
precipitate the symptoms of BD.167 Tryptophan catabolites (TRYCAT) produced in the
The hypothesis of a pro-inflammatory state- kynurenine pathway may be depressogenic and
induced BD supposes that elevated levels of a cyto- anxiogenic. Activation of the kynurenic pathway
kine cause manic and depressive symptoms. The (labeled also as the TRYCAT pathway) may be asso-
hypothesis has been supported by the finding that ciated with the development of depressive symp-
immune challenge with IFN-α during treatment of toms through both serotonin depletion and
hepatitis C induces the depressive or manic symp- detrimental effects of TRYCAT, such as activation of
toms in a significant number of patients.168,169 oxidative pathways, mitochondrial dysfunctions,
It is hypothesized that the immune system in BD and neurotoxicity.4,171,172
is chronically activated by microglia, which lead to Changes in the kynurenine pathway in BD have
increased production of cytokines and the imbal- been identified at the mRNA-expression, protein,
ance between the pro-inflammatory and the and metabolite levels. Whether these changes
© 2016 The Authors

represent biomarkers of disease or whether they rep- rhythms; however, melatonin is also a powerful
resent disease causation is not clear; however, psy- antioxidant, metal chelator, and anti-inflammatory
choses of several different etiologies involve agent.179 Melatonin secretion modulates the produc-
activation of this pathway. The significant changes tion of the thyrotropin and tuberalin hormone and
that had been identified for BD include increased induces synthesis of triiodothyronine (T3). Excessive
kynurenine and TDO173 (i.e. upregulation of the hypothalamic T3 may mediate mania, whereas
TRYCAT pathway). Nicotinamide, a kynurenine insufficient hypothalamic T3 may cause depression.
pathway end-product, was found to be significantly The hypothesis that internal desynchronization
elevated in the anterior cingulate cortex of bipolar and changes in melatonin rhythmicity participate in
patients who committed suicide within the bipolar the genesis of BD has been discussed.180,181 Distur-
group.174 bances of sleep timing are worse during mood epi-
IDO is induced by IFNγ, IL-6, TNFα, lipopolysac- sodes, but still apparent during euthymic periods.182
charides, and oxidative stress. The new ‘serotonin’ Recently, a hypothesis regarding separate oscillators
hypothesis of depression171 states that ROS and cell- for morningness and eveningness has been formu-
mediated immune activation (peripheral cell-mediated lated. The photoperiodic and circadian bifurcation
immune activation and microglial-mediated neuroin- hypothesis proposes that combined with genetic
flammation), which is characterized by an increased susceptibilities, abnormal light illumination triggers
production of IL-1β, IL-6, TNFα, and IFNγ, induce rapid-cycling BD, and perhaps most mania, by inter-
IDO and activate the kynurenine pathway. It leads to nal desynchronization or bifurcation of suprachias-
lower plasma and brain tryptophan (and thus lowered matic nucleus (SCN) circadian rhythms leading to
brain serotonin, N-acetylserotonin, and melatonin photoperiod malregulation and excess hypothalamic
synthesis) and an increased synthesis of detrimental T3 production.183
TRYCAT (e.g. kynurenine and quinolinic acid), both of Linkage of melatonin to the serotonin system may
which contribute to the onset of depression.175 The be through tryptophan metabolism as described
TRYCAT pathway is also activated following induction above. There are several ways by which melatonin
of TDO by glucocorticoids, which are elevated in and dopamine interact and modulate one
depression. another.184 These interactions and the antioxidant
There is interconnection of peripheral and central nature of melatonin may be beneficial in the treat-
immune, inflammatory, neuroendocrine, oxidative ment of monoamine-related mood disorders, such
and nitrosative stress pathways; e.g., the responsive- as BD. Due to the role of monoamine neurotrans-
ness of T-cells to the immune suppressive effect of mission in mood disorders and melatonin role in
dexamethasone is attenuated in BD, independently modulation of circadian rhythmicity, a proper
on the current mood state.176 approach to studying the pathophysiology of mood
disorders may be to consider the monoamine and
melatonin systems as one integrated system.
Chronobiological hypothesis Clock genes interact with each other in an intri-
Rhythmicity is a fundamental property of living cate manner generating oscillations of gene expres-
organisms.177 Virtually all patients with BD display sion. Genomic studies suggest an association of
significant disruption of circadian rhythms, such as circadian clock genes (BMAL1, CLOCK, NPAS2,
sleep, activity, hormonal secretion, and appetite, PER3, CRY1, RORA, and TIMELESS) with depressive
which suggest that circadian rhythms abnormalities disorder or BD.185 Moreover, expression of circadian
may play a role in precipitating periodic episodes of clock components was found to be affected by lith-
depression and mania. Lower levels of melatonin ium treatment.186 Transcription of the gene MAOA
were found in euthymic patients, depression epi- is regulated by the clock components BMAL1,
sodes and even mania when compared with healthy NPAS2, and PER2,187 which is another link between
controls.178 The circadian system might play an monoamine neurotransmission and circadian
important role in the pathogenesis of BD and this rhythms. The clock genes also provide a link
disorder should be effectively treated by melatonin between circadian rhythms and GSK-3β activity,
or agomelatine. which is an important factor in the etiology of
Melatonin (N-acetyl-5-methoxy tryptamine) is a BD.188 In summary, altered circadian rhythms may
hormone that influences circadian and seasonal be involved in the etiology of BD; however, it is
© 2016 The Authors

possible that both circadian disruptions and mood the key role of mitochondria in the cell energy
disorders are common effects of something else or metabolism, apoptosis, oxidative stress and calcium
the pleiotropic effects of common components.189 homeostasis. Data provide evidence for abnormal-
ities in mitochondrial structure and function in
BD. Mitochondrial dysfunctions in BD include:
OXIDATIVE STRESS (i) decreased mitochondrial respiration due to
Lowered antioxidant defenses (lowered concentra- reduced activity of mitochondrial complexes in elec-
tions of antioxidants, such as vitamin E, tryptophan, tron transport system; (ii) changes in mitochondrial
zinc, and coenzyme Q10; lowered activities of anti- morphology; (iii) increases in mtDNA polymorph-
oxidative enzymes) and increased oxidative and isms, deletions or mutations; and (iv) decreased
nitrosative stress causing lipid peroxidation, oxida- levels of high-energy phosphates and decreased pH
tion and nitration of proteins or nucleic acids, dam- in the brain.203
age to mitochondria and secondary autoimmune Post-mortem brains of BD patients have shown
responses are evident in BD.3,175,190,191 Serum lipid decreased expression and activity of electron trans-
hydroperoxides may be useful in the development port chain (ETC) and increased oxidative stress. BD
of clinically relevant peripheral biomarkers of is also associated with calcium dysregulation and
BD.192 Meta-analysis of oxidative stress markers in apoptosis. Neuroimaging studies confirmed an
BD confirmed that lipid peroxidation, DNA/RNA impaired energetic metabolism in brains of BD
damage, and nitric oxide were significantly increased patients. Mitochondrial dysfunctions in BD have
in BD patients compared to healthy controls.193 been supported by genetic findings; however, BD is
However, no significant effect sizes were observed not a classic mitochondrial disorder and mitochon-
for the antioxidant enzymes and products of oxida- drial functions seem to be regulated rather by
tive protein damage. expression of nuclear genes.204
Processes that may play a role in the increased Mitochondria are an important endogenous
oxidative and nitrosative stress in BD include acti- source of ROS. Increased oxidative and nitrosative
vation of immune-inflammatory and autoimmune stress is associated with mitochondrial dysfunc-
pathways, modulation of antioxidant defense tion.191 Damage of cellular functions due to
through activation of nuclear factor (erythroid- increased oxidative and nitrosative stress and/or
derived 2)-like 2 (Nrf2), activation of TRYCAT lowered levels of antioxidant protections are proba-
pathway, glutamate toxicity due to depletion of bly involved in the pathophysiology of
intracellular glutathione, mitochondrial dysfunc- depression.3,205,206
tions leading to increased production of ROS, and Both mitochondrial dysfunction and neuroinflam-
activation of toll-like receptors by lipopolysacchar- mation occur in BD. A potential link between mito-
ides or psychosocial stressors.194 chondrial dysfunctions and activation of the
Association of increased oxidative stress with inflammatory system may be the nod-like receptor
lower BDNF levels has been confirmed in pyrin domain-containing 3 (NLRP3) inflamma-
BD. Serum thiobarbituric acid reactive substances some.207 Increased production of ROS by mitochon-
(TBARS), which are formed as a byproduct of lipid dria (e.g. due to dysfunction of complex I) causes
peroxidation and may be used as biomarkers or pro- activation of NLRP3 and caspase 1 and formation of
gression of BD,141 were negatively correlated with inflammasome, which lead to activation of cyto-
serum BDNF levels in manic BD patients, but not in kines and alterations in neurotransmission.
healthy volunteers.195 There is a link between dys- BD is frequently comorbid with primary mito-
functional mitochondrial complex I, increased pro- chondrial and metabolic disorders, and mitochon-
duction of ROS, increased oxidative stress, and drial dysfunction has been implicated in its
decreased levels of brain BDNF.196 pathophysiology. A hypothesis of mitochondrial
dysfunction in BD is based on findings of magnetic
resonance spectroscopy that in the brains of BD
MITOCHONDRIAL DYSFUNCTIONS patients, high-energy phosphates are decreased, lac-
Mitochondrial and metabolic dysfunctions may be tate is elevated, and pH is decreased, which together
involved in the pathophysiology of different neuro- suggest impaired oxidative phosphorylation, a
psychiatric disorders, including BD,35,197–202 given decrease in total energy production and/or substrate
© 2016 The Authors

availability, and a shift toward glycolysis for energy studies provide a different perspective on BD as a
production.208,209 Moreover, proton magnetic reso- biologically diverse disease category.18 Genetic stud-
nance spectroscopy in patients with BD revealed ies have confirmed the polygenic model of BD with
decreased levels of N-acetylaspartate (NAA) in the a large number of genes with small effects, modified
basal ganglia; choline and creatine levels were not by epistasis, epigenetics, and environment. Struc-
altered.210 Oxidative stress is increased, calcium sig- tural and functional imaging findings have shown a
naling is dysregulated, and mitochondrial com- compromised integrity of frontal-subcortical and
plexes, especially complex I, are downregulated. The prefrontal-limbic circuits in BD. Changes in the
therapeutic effects of some drugs/mitochondrial immune system of BD patients are associated with
modulators, which are putative neuroprotective changes in glial and neuronal functions, disturbed
agents for use in treatment of BD, have been shown monoaminergic and glutamatergic neurotransmis-
to affect many of these processes.211–215 sion, and impaired neuroplasticity. An association
Monoamine, glutamate, mitochondrial, inflamma- has been confirmed between BD and circadian
tory, and other systems related to the pathophysiol- rhythm disturbances. Alterations in HPA axis activity
ogy of BD are interdependent. ATP derived from in BD lead to elevation of circulating cortisol; more-
glucose in brain mitochondria is essential for all other over, elevated inflammatory cytokines may desensi-
cellular processes and mitochondria play a key role tize glucocorticoid receptors in mood disorders. The
also in regulation of apoptosis, oxidative stress, and inflammatory mediators released by activated
calcium homeostasis. This leads to the tendency to microglia in response to peripheral inflammatory
assign new hypotheses of BD, such as mitochondrial. signals may induce the release of ATP and cytokines
It is hypothesized that the main contributors to neu- by astrocytes, which form a positive feedback loop
roprogression in BD include lower levels of BDNF, and further release of inflammatory cytokines from
decreased neurogenesis, increased neuronal and glial microglia. Moreover, activated astrocytes may be
cell death, higher excitotoxicity from excess of gluta- responsible for glutamate excitotoxicity. Activated
mate and lower GABA signaling, mitochondrial dys- microglia may increase IDO activity and the TRYCAT
function, oxidative stress, and neuroinflammation.216 pathway, which contribute to neurotoxicity and dis-
Intracellular calcium regulates multiple neuronal turbed serotonin signaling. Decreased expression of
functions, including synaptic transmission, neuronal the neurotrophin BDNF has been confirmed in both
plasticity and survival, and neurotoxicity.66,217 depressive and manic/hypomanic episodes, which
Uptake and release of cytosolic calcium ions are may be responsible for disturbances in release of ser-
included in basic mitochondrial functions and par- otonin, glutamate, and GABA in brain structures
ticipate in the control of cellular Ca2+-signals. included in pathophysiology of BD, such as cerebral
Calcium-phosphate complex in the mitochondrial cortex and hippocampus. There is a reciprocal rela-
matrix buffers the free Ca2+ and regulates calcium- tionship between BDNF and pro-inflammatory cyto-
dependent processes in cytosol. Excess of matrix Ca2+ kines in BD. Mitochondrial dysfunction has been
causes the mitochondrial permeability transition,218 supposed to be responsible for disturbances in bio-
which leads to inhibition of oxidative phosphoryla- energetics, calcium homeostasis, and ROS produc-
tion, inhibition of citric acid cycle enzymes, decrease tion in BD.
of ATP synthesis, increase of ROS production, and The integrated monoamine, neurotrophin, and
release of calcium and apoptogenic factor into cyto- cytokine hypothesis is based on reciprocal regula-
sol.219 The calcium and mitochondrial dysfunction tion of key components of these pathways: 5-HTT,
hypothesis of BD posits that mtDNA polymorph- BDNF, and pro-inflammatory cytokines.223 The
isms/mutations or mtRNA deletions caused by model supposes that: (i) under depression, stress, or
nuclear gene mutations can cause mitochondrial dys- inflammation, microglial cells and astrocytes
regulation of Ca2+ leading to symptoms of become activated and release pro-inflammatory
BD.220–222 cytokines; (ii) cytokine- and stress-dependent path-
ways enhance 5-HTT activity, as well as increase
5HTT gene expression; (iii) increased 5-HTT activity
INTEGRATED NEUROBIOLOGY OF BD results in a reduction of extracellular serotonin levels
Recently, the complexity of BD has been empha- and decreased activation of pre- and postsynaptic
sized based on the fact that various biological serotonin receptors; (iv) CREB-dependent BDNF
© 2016 The Authors

gene expression is reduced and BDNF levels are Patients with BD treated with lithium have
decreased, which leads to disturbed neuroplasticity reduced lipid peroxidation (TBARS), which indicates
and to depression-associated alteration of specific antioxidant effects of lithium in the prevention of
brain circuits. BD progression and clinical efficiency.234,235 Antiox-
idants, such as N-acetylcysteine (NAC) seem to be
beneficial in treatment of both major depressive epi-
THERAPEUTIC HYPOTHESES sodes236 and manic/hypomanic episodes.237 NAC is
The biological mechanism involved in the etiology a promising novel therapeutic option for BD and
of BD, such as monoaminergic dysfunctions, altered other neuropsychiatric disorders, because NAC tar-
glutamatergic neurotransmission, mitochondrial gets glutamatergic transmission, glutathione, neuro-
dysfunction and oxidative stress, increased inflam- trophins, apoptosis, mitochondrial function, and
mation, impaired cell signaling (inositol monopho- inflammatory pathways.238
sphatase, GSK-3, PKC, calcium channels) and Recent studies have provided data about the posi-
apoptosis, decreased neurogenesis, changed activa- tive effects of chronic treatment by mood stabilizers
tion of corticolimbic emotion control circuits, dis- on mitochondrial functions.203,239 Lithium
turbed sleep and circadian regulation, and increased the activity of electron transport chain
psychosocial variables, all facilitate the search for complexes I, II and III.240 Lithium and valproate
new therapeutics and understanding the mechan- enhanced mitochondrial function (respiration rate,
isms of their action.224,225 Conversely, the mechan- membrane potential, and mitochondrial oxidation),
isms of action of drugs used to treat BD or that are protected against mitochondria-mediated
able to induce a switch between episodes of the dis- methamphetamine-induced toxicity,241 and stabi-
ease provide the foundation for the formulation of lized intracellular calcium dynamics. Therefore, it is
new biological hypotheses or evidence to confirm expected that new drugs aimed at regulation of
existing hypotheses. mitochondrial function might be effective in the
Several reviews of the management of BD have treatment of BD.
been published.226–228 The therapeutic approach Impairments in neuroprotective, neurotrophic,
differs considerably for mania/hypomania, depres- cellular plasticity, and resilience pathways have been
sion, and euthymia. Pharmacological medication found to be associated with BD. Promising thera-
also differs between maintenance and the acute peutic strategies for treatment of BD include preven-
mood episode.227,229 Overall, antipsychotic drugs tion, treatment, or rectifying of these
(haloperidol, risperidone, and olanzapine mainly) pathophysiological changes. Lithium is targeted to
were significantly more effective than mood stabili- various factors in survival, neurotrophic, and neuro-
zers in treatment of acute mania.226,230 Olanzapine protective pathways, such as neurotrophic factors,
plus fluoxetine, and quetiapine, were the most effi- MAPK, phosphoinositide signaling, intracellular cal-
cacious treatment drugs for bipolar depres- cium, glutamate activity, antiapoptotic factor Bcl-2,
sion.227,231 In view of the efficacy in prevention of and proapoptotic GSK-3.232,242–245 Putative neuro-
both manic and depressive episodes relapse and protective agents for BD include beyond lithium
recurrence, lithium was recommended in the first- other known psychotropics (clozapine, aripiprazole,
line treatment in patients with BD.232,233 olanzapine, ziprasidone, and antidepressants), NAC,
New putative treatment of BD should be based aspirin, leptin, omega-3 polyunsaturated fatty acids,
on drug-induced modulation of multiple intracellu- and melatonin.211
lar targets included in pathophysiology of BD: dopa- Based on the inflammation/microglia hypothesis,
mine system, glutamate receptors, oxidative stress, anti-inflammatory agents are potential drugs for treat-
mitochondrial functions, neuroprotective factors, ment BD (i.e., the immune system seems to be a target
inflammatory pathways, and sleep and circadian of drugs developed for treatment of BD and antide-
rhythms. pressant effect of anti-inflammatory drugs has been
Drugs acting through glutamate signaling path- tested). Lithium ameliorates lipopolysaccharide-
ways, such as ketamine, could be used for treatment induced microglial activation via inhibition of toll-like
of the depressive episode.55 Currently, several new receptor 4 expression by activating the PI3K/Akt/
drugs exploring the glutamate pathway are in FoxO1 pathway.246 The anti-inflammatory effect of
development.225 valproate seems to be based on induction of apoptosis
© 2016 The Authors

Table 1. Putative biomarkers of bipolar disorder
Area Biomarkers References

13,14,16
Neuroimaging Grey matter reduction in left rostral anterior cingulate cortex and right fronto-insular
cortex thickness
12,17
Volumetric reductions of mean hippocampus and thalamus; enlarged lateral ventricles
15
Increased rates of deep white matter hyperintensities
257
Increased activation in ventral limbic regions in response to emotional stimuli
19,20
Overactivation of amygdala, striatum, and thalamus
71–76,78
Biochemistry Neurotrophic Decreased BDNF
70
factors Lower GDNF
70,105,106
Elevated VEGF
146–151,154,156–159
Immune Elevated IL-1β, IL-6, TNF-α, IL-2, IL-6, IL-10, sIL-2R, sIL-6R,
parameters sTNFR1, IL-4, IL-1RA, IL-1β, IFN-γ, vWf
141,142
Elevated S100B
152,153
Elevated C-reactive protein
171–174
Increased kynurenine and TDO
165,166
Matrix metalloproteinase 9, matrix metalloproteinase 7
46–48
Neurotransmitter Elevated MAO-A, reduced 5-HTT
51,52
systems Lower DAT availability
53
Reduced muscarinic acetylcholine M2 receptor binding
57
Elevated brain glutamate + glutamine levels
35,197–206,208,209
Mitochondrial Reduced activity of mitochondrial complexes (complex I mainly)
dysfunction Mitochondrial morphology
Decreased high-energy phosphates, elevated lactate, decreased pH
210
Decreased NAA
3,141,175,190–193,195
Oxidative stress Increased TBARS (lipid peroxidation)
Increased NO activity
Increased DNA/RNA damage
160–162
Neuroendocrine Increased cortisol
166,258
factors C-peptide, insulin, peptide YY
178
Chronobiology Lower melatonin
24–28,43–45,93
Genetics Candidate genes of SLC6A4, SLC6A3, BDNF, TPH1, TPH2, COMT, DAOA, DRD4, MAOA
28
key signaling FKBP5, WFS1
29,32,33
components CACNA1C, TENM4, NCAN, ANK3
29
DTNA, FOXP1, GNG2, ITPR2, LSAMP, NPAS3, NCOA2, NTRK3
101
IGF1
164
MMP9
185
Circadian clock BMAL1, CLOCK, NPAS2, PER3, CRY1, RORA, TIMELESS
genes
24,220–222
mtDNA polymorphisms, deletions or mutations; mtRNA deletions
Genes encoding: SLC6A4, serotonin transporter; SLC6A3, dopamine transporter; DAOA, D-amino acid oxidase activator;
MAOA, MAO type A; FKBP5, FK506 binding protein 5; WFS1, wolframin; CACNA1C, α subunit of the L-type calcium
channel; TENM4, teneurin transmembrane protein 4; NCAN, neurocan; ANK3, ankyrin G; DTNA, dystrobrevin α; FOXP1,
forkhead box protein P1; GNG2, guanine nucleotide-binding protein Gi/Gs/Go subunit γ-2; ITPR2, inositol 1,4,5-
trisphosphate receptor, type 2; LSAMP, limbic system-associated membrane protein; NPAS3, transcription factor neuronal
PAS domain protein 3; NCOA2, nuclear receptor coactivator 2; NTRK3, tropomyosin receptor kinase C; IGF1, insulin-like
growth factor 1; MMP9, matrix metalloproteinase 9; mtDNA, mitochondrial DNA.
5-HTT, serotonin transporter; BDNF, brain-derived neurotrophic factor; DAT, dopamine transporter; GDNF, glial cell line-
derived neurotrophic factor; IFN-γ, interferon γ; IL, interleukin; IL-1RA, IL-1 receptor antagonist; MAO, monoamine oxidase;
NAA, N-acetylaspartate; NO, nitric oxide; S100B, calcium-binding protein B; sIL-2R, soluble IL-2 receptor; sIL-6R, soluble form
of IL-6 receptor; sTNFR1, soluble tumor necrosis factor receptor 1; TBARS, thiobarbituric acid reactive substances; TDO, tryptophan
2,3-dioxygenase; TNF-α, tumor necrosis factor α; VEGF, vascular endothelial growth factor; vWf, von Willebrand factor.
© 2016 The Authors

in activated microglia. Ketamine is also a microglial (i) neuroimaging (loss of gray matter in cortical-
inhibitor, at least partially due to inhibition of ERK cognitive brain network, as well as increased activa-
phosphorylation.247 Adjunctive treatment with cele- tion in ventral limbic regions in response to emo-
coxib, a COX-2 inhibitor, may produce a rapid-onset tional stimuli); (ii) peripheral measurements
antidepressant effect in BD patients experiencing (decreased BDNF, increased pro-inflammatory cyto-
depressive or mixed episodes.248 Aspirin, a non- kines, markers of mitochondrial dysfunction and oxi-
steroidal anti-inflammatory drug that is an irreversible dative stress); and (iii) genetics (candidate genes
inhibitor of both COX-1 and COX-2 (it stimulates associated with increased risk for developing BD,
endogenous production of anti-inflammatory regula- involving circadian rhythm, neuronal development,
tory signals), is a potential new therapy for a range of and calcium metabolism). Selected potential biomar-
neuropsychiatric disorders, including BD.249 The anti- kers of BD, related to hypotheses presented
depressant efficacy of minocycline, a drug inhibiting in previous sections are summarized in the
microglia activation and showing neuroprotective and Table 1.3,12–17,19,20,24–29,32,33,35,43–48,51–53,57,70–76,78,93,101,
105,106,141,142,146–154,156–162,164–166,171–175,178,185,190–193,
immune-modulating properties, and of aspirin as an
adjunctive treatment, has been evaluated in BD.250 A 195,197–206,208–210,220–222,257,258
meta-analysis confirmed a moderate antidepressant The identification of biological markers for sub-
effect for various adjunctive anti-inflammatory agents sets of BD may be of importance. Recently, a system-
compared with conventional therapy alone in the atic review revealed that specific biomarkers
treatment of BD.251 (particularly in the field of neuroendocrine-immu-
Efficiency of antipsychotics in BD treatment nology, neuroimaging, and neuropsychology) exist
emphasizes the role of regulation of the dopamine for psychotic BD and that psychotic BD can be con-
system; however, the intrinsic anti-inflammatory sidered an intermediate phenotype between schizo-
and immunomodulatory effects of antipsychotic phrenia and mood disorders.259
drugs have been known for a long time.252 In vitro A large number of plasma biomarkers were identi-
studies have suggested the anti-inflammatory effects fied to be associated with distinct BD mood states.
of recent antipsychotics on microglial activation,253 For example, plasma levels of the hormones C-pep-
which may contribute to their therapeutic effect in tide, progesterone, and insulin and the inflamma-
BD. For example, aripiprazole and minocycline may tory protein cancer antigen 125 were altered in both
have antipsychotic effects through reducing oligo- manic and mixed mood states. The hormone pep-
dendrocyte damage caused by microglial activa- tide YY and the growth factor trafficking protein sor-
tion;254 quetiapine ameliorated the microglia tilin were changed only in manic episode. The
activation in various brain regions of mice exposed inflammation-related factors haptoglobin, chemo-
to cuprizone.255 Antipsychotics also target intracellu- kine CC4, and MMP-7 were altered specifically in
lar Ca2+ signaling (controlled by the endoplasmic mixed mood state.166 C-peptide, insulin, MMP-7,
reticulum and mitochondria), which is important and peptide YY were also found to be changed in
for microglial functions.256 As a result, modulating BD depressed patients,258 which suggests that these
microglia may be a novel therapeutic target in treat- proteins could be trait markers for BD. Thus, appli-
ment of BD. cation of individual biomarkers depends on the
stage of the disease.136,260–263
BIOMARKERS
In BD, both state markers related to various mood SWITCHING BETWEEN EPISODES
states (mania, depression, remission) and trait mar- A defining characteristic of BD is switching/cycling
kers related to BD as such may be useful in the early between the state of depression and mania/hypoma-
diagnosis of BD, control of disease progression, and nia with a tendency to recur and progress. Patients
treatment response. Biomarkers can be useful in with a previous history of mania/hypomania have
developing new medicines and treatments aimed at spontaneous switch rates of 21% (mania to depres-
reversing disease-related changes.2,206,211,249,251 The sion) to 29% (depression to mania); in prospective
most promising biomarkers were described by the studies the rates were around 30%.264 Currently, the
International Society for Bipolar Disorders Biomar- term ‘switch’ includes both the spontaneous process,
kers Network Task Force257 in three main areas: as a core feature of BD, and also treatment-emergent
© 2016 The Authors

affective switch (TEAS). Most studies of mechanisms The stress autonomy model and stress sensitiza-
of the switch process in BD refer to TEAS.265,266 The tion model were identified and both are frequently
risk of switching from mania to depression in BD referred to as ‘kindling.’275 The stress autonomy
has been little studied; a relatively small number model implies two parallel processes: (i) the associa-
(5.0%) of medicated patients with BD switch from a tion between stressful life events and onsets of
manic/mixed episode to depression during the depressive episodes weakens with each successive
12 weeks after a manic episode.267 depressive episode such that stressors eventually no
longer trigger recurrences; and (ii) depressive epi-
sodes become progressively decoupled from life
Allostatic load stress and may emerge autonomously, without an
apparent trigger. In contrast, the stress sensitization
Adaptive and maladaptive changes in the brain
model asserts that stressors become increasingly
attempt to compensate for pathological neurobio-
capable of triggering depressive symptoms and a
logical alterations in BD, which is considered an
likelihood of developing depression increases with
increase in the allostatic load. The concept of allo-
each successive depressive episode as the person
static load has been introduced into biological
becomes progressively more sensitized to stressful
hypotheses of BD, in order to explain the origin and
life events.
impact of recurrent mood episodes.268,269 Allostatic
load represents the physiological consequences of
chronic exposure to fluctuating or heightened neu-
ral, neuroendocrine, or immune response that Neurobiology of switching
results from repeated or chronic stress. For example,
A neurobiological mechanism for the switching
glucocorticoids, when chronically in excess, initiate
from depression to its opposite state, and vice versa,
a series of bodily dysfunctions that include decrease
is still poorly understood. An important reason is
in the expression of neuroprotective factors, oxida-
that the pathophysiology of mania remains incom-
tive stress, inflammation, and cortisol-related mito-
pletely elucidated.276 Recently, studies investigating
chondrial dysfunction.270 Allostatic load includes
the neurobiological mechanisms underlying cycling
epigenetic changes and modified response to exter-
from one episode to another were reviewed.277–280
nal (environmental) stimuli and affects both long-
Evidence suggests that tricyclic antidepressants, but
term cellular processes associated with changes in
not selective serotonin reuptake inhibitors or MAO
gene expression and rapid changes in the function
inhibitors, are more likely to trigger TEAS in BD
of neurons and neural circuits. The increase in allo-
patients. The role of catecholaminergic systems in
static load can support psychological and somatic
the switch process has been evidenced by the obser-
abnormalities and can contribute to both illness
vation that catecholamine depletion evokes a
progression and cycling between episodes.
rebound hypomania in BD patients. Increased post-
synaptic sensitivity of dopamine and norepineph-
rine receptors at high levels of catecholamines has
Kindling model also been hypothesized to trigger switch to manic
Kindling, a progressive strengthening of neuron episode in BD patients.278 Dopaminergic agonists,
responses to repetitive stimulation, was used to help such as psychostimulants, and precursors of catecho-
conceptualize how the ratio of pathological versus lamines, such as L-DOPA, have been associated with
adaptive factors at the level of alterations in gene TEAS.281,282 It was concluded that switch to mania/
expression in the brain may help to determine epi- hypomania is associated with increased catecholami-
sode recurrence or remission in BD. The kindling nergic neurotransmission (and maybe activation of
hypothesis271–273 has been tested in a number of the GSK-3 and PKC pathways), at least for some BD
different ways; however, support for the main prin- patients. However, the common precise mechanism
ciple of the hypothesis that psychosocial stressors underlying sudden spontaneous switching between
play a greater role in the initial episodes of BD, as episodes in BD remains unrecognized.
compared in subsequent episodes, has been incon- Dysfunctions in GABAergic and glutamatergic sys-
sistent (only eight of 14 studies detected a kindling tems are included in the pathophysiology and treat-
effect).274 ment of BD;55,115 however, it is not clear if
© 2016 The Authors

modulation of glutamate receptors might participate mechanism and the immediate stimulus for the
in the switching process. switching depends on the individual status of neuro-
An adrenergic-cholinergic balance hypothesis of transmitter signaling pathways and allostatic load.
BD, which is based on inhibitory effect of extracel- Immediate switching stimulus can come from dis-
lular acetylcholine on dopamine and norepineph- ruption of circadian and other chronobiological
rine activity, proposes that increased cholinergic rhythms and/or from the activation of the immuno-
functioning underlies depression, whereas increased neuroendocrine system by stress or by
catecholaminergic functioning underlies inflammation.
mania.283,284 Any factor causing an imbalance
between cholinergic and adrenergic systems was
hypothesized to trigger manic/hypomanic switching CONCLUSION
in BD.285 According to the revised balance hypoth-
Extended biological hypotheses have been proposed
esis of BD,284 the following factors have a poten-
to explain the role of several biomarkers for mood
tial to switch to and from depression and mania/
disorders and to test the probable causality of
hypomania through disturbance of
molecular processes responsible for disturbed stor-
catecholaminergic-cholinergic balance: (i) stress or
age, retrieval, and processing of information in the
inhibitors of acetylcholinesterase activity, an action
brain and disturbed function of specific neuronal
that results in depression due to acetylcholine-
circuits during episodes of BD. These hypotheses
induced decrease of catecholaminergic activity;
have been put in the context of changes in genetics,
(ii) activators of tyrosine hydroxylase activity
structure, function, physiology, and neurochemistry
(e.g. increased photoperiod exposure), an action
of the brain in BD, primarily changes in neuroplasti-
that results in a switch to manic/hypomanic epi-
city, neuroinflammation, intracellular signaling
sode due to increased biosynthesis of catechola-
pathways, bioenergetics, oxidative and nitrosative
mines; and (iii) factors altering susceptibility to
stress, apoptosis and proteolysis, calcium signaling,
external stimuli, such as polymorphisms in the
and membrane or vesicular transport. Future studies
gene for DAT or the CLOCK gene.
are expected to confirm the integrated models invol-
Sleep deprivation may induce rapid spontaneous
ving the correct causality of these processes in the
switch from depression into mania/hypomania in
development of BD or switching between episodes.
BD.286 Processes associated with sleep deprivation
Specific biomarkers for BD could lead to an early
seem to be closest to the neurobiology of spontane-
diagnosis and proper treatment of the disease;
ous switching. It has been suggested that rapid-eye-
although they are promising, they need to be veri-
movement sleep deprivation causes activation of the
fied in replicated studies.
noradrenergic system (by blockade α2 autoreceptors
in locus coeruleus), resulting in the rapid increase of
expression and activity of transcription factor CREB,
neurotrophin BDNF, and its receptor TrkB, which ACKNOWLEDGMENT
may lead to the switch into mania/hypoma- This study was supported by the Ministry of Health
nia.73,75,278,287 According to the circadian rhythm of the Czech Republic (15-28616A). All rights
hypothesis, circadian rhythm instability and the dys- reserved.
regulation of the HPA axis and monoamine systems
may increase individual susceptibility for switching
from depression to mania/hypomania.288 DISCLOSURE STATEMENT
In conclusion, it appears that polymorphisms in
The authors declare no conflicts of interest.
the CLOCK gene, along with sleep disruption and
resulting increase of CREB, BDNF, and TrkB, might
be decisive factors in the induction of the switch to
manic/hypomanic episode in BD patients.278,287 We AUTHOR CONTRIBUTIONS
suppose that disturbed activities of signaling path- Conception and design of the study: Z.F. and E.S.
ways regulated by monoamine neurotransmitters Drafting the manuscript or figures: E.S., Z.F., J.H.,
and BDNF (including MAPK/ERK, PI3K/Akt, IP3/ and T.C. Critical revision of the manuscript: all
DAG, and GSK-3) participate in the switching authors.
© 2016 The Authors

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Psychiatry Clin Neurosci - 2016 - Sigitova - Biological Hypotheses and Biomarkers of Bipolar Disorder

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Psychiatry and Clinical Neurosciences 2017; 71: 77–103 doi:10.1111/pcn.

Biological hypotheses and biomarkers of bipolar disorder

neurogenesis.2 Pathways underlying neuroprogres-

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of glutamate N-methyl-D-aspartate (NMDA) receptor decreased BDNF is part of the pathophysiology of

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bioenergetics may participate in the pathophysiol- anti-inﬂammatory state of microglial activation

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Table 1. Putative biomarkers of bipolar disorder

Area Biomarkers References

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