Articulo PDF

Braz J Psychiatry.
2020 Sep-Oct;42(5):536-551
doi:10.1590/1516-4446-2019-0732
Brazilian Psychiatric Association
0 0 0 0 -0 02-7316-1 85
SPECIAL ARTICLE
Neurobiology of bipolar disorders: a review of genetic

components, signaling pathways, biochemical changes,
and neuroimaging findings
Giselli Scaini,10 0 -0 0 -0 0 -0 0 Samira S. Valvassori,2 Alexandre P. Diaz,1,3 Camila N. Lima,1
Deborah Benevenuto,1 Gabriel R. Fries,1,4,50 0 -0 0 -0 0 -0 0 Joao Quevedo1,2,3,50 0 -0 0 -0 0 -0 0
1
Translational Psychiatry Program Louis A. Faillace, Department of Psychiatry and Behavioral Sciences at McGovern Medical School, The
University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA. 2Laboratório de Psiquiatria Translacional, Programa de
Pós-Graduação em Ciências da Saúde, Universidade do Extremo Sul Catarinense (UNESC), Criciúma, SC, Brazil. 3Center of Excellence on
Mood Disorders Louis A. Faillace, Department of Psychiatry and Behavioral Sciences at McGovern Medical School, UTHealth, Houston, TX,
USA. 4Center for Precision Health, School of Biomedical Informatics, UTHealth, Houston, TX, USA. 5Neuroscience Graduate Program,
Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, UTHealth, Houston, TX, USA.
Bipolar disorder (BD) is a chronic mental illness characterized by changes in mood that alternate
between mania and hypomania or between depression and mixed states, often associated with
functional impairment. Although effective pharmacological and non-pharmacological treatments are
available, several patients with BD remain symptomatic. The advance in the understanding of the
neurobiology underlying BD could help in the identification of new therapeutic targets as well as
biomarkers for early detection, prognosis, and response to treatment in BD. In this review, we discuss
genetic, epigenetic, molecular, physiological and neuroimaging findings associated with the neuro-
biology of BD. Despite the advances in the pathophysiological knowledge of BD, the diagnosis
and management of the disease are still essentially clinical. Given the complexity of the brain and the
close relationship between environmental exposure and brain function, initiatives that incorporate
genetic, epigenetic, molecular, physiological, clinical, environmental data, and brain imaging are
necessary to produce information that can be translated into prevention and better outcomes for
patients with BD.
Keywords: Bipolar disorder; mania; depression; genetics; epigenetics; neurotrophins; mitochondrial
dysfunction; oxidative stress; inflammation; hypothalamic-pituitary-adrenal axis; circadian rhythm;
neuroimaging
Introduction retardation. Mixed episodes manifest as simultaneous

states of mania and depression.4 About 14-59% of the
Bipolar disorder (BD) is a severe and chronic psychiatric individuals with BD report suicidal ideation5; 25 to 50%
illness that affects approximately 1-4% of the world attempt suicide, and almost 20% die due to suicide.6
population.1 It is characterized by changes in mood that Moreover, BD is also associated with increased risk of
alternate between mania and hypomania or between mortality by other medical conditions, such as cardiovas-
depression and mixed states, often associated with cular disease, diabetes mellitus, external causes of injuries,
functional impairment.1-3 Although depressive symptoms and respiratory diseases. Life expectancy is decreased by
typically predominate in individuals with BD, the clinical 9 years on average in individuals with BD as compared with
diagnostic hallmark is the presence of manic or hypo- the general population.7
manic episodes.4 During episodes of mania or hypoma- Despite the demonstrated efficacy of several drugs to
nia, the patient may present symptoms related to elevated treat BD, lithium (Li) is the only drug considered as a mood
mood, including euphoria, feelings of greatness, hyper- stabilizer by the Food and Drug Administration (FDA). More
activity, increased sexual activity, decreased need for than 70 years have passed since this salt was first
sleep, risky behaviors, irritability, and aggression. Con- proposed as a mood stabilizer. Li is effectively used in
versely, episodes of depression are characterized by anhe- BD for maintenance and treatment of acute mania
donia, sadness, vegetative symptoms, and psychomotor episodes; however, it has a modest antidepressant action.8
Correspondence: João Luciano de Quevedo, The University of How to cite this article: Scaini G, Valvassori SS, Diaz AP, Lima
Texas Health Science Center at Houston, McGovern Medical CN, Benevenuto D, Fries GR, et al. Neurobiology of bipolar
School, Faillace Department of Psychiatry and Behavioral Sciences, disorders: a review of genetic components, signaling pathways,
1941 East Road, Ste. 3216, Houston, TX 77054, USA. biochemical changes, and neuroimaging findings. Braz J Psychiatry.
E-mail: Joao.L.DeQuevedo@uth.tmc.edu 2020;42:536-551. http://dx.doi.org/10.1590/1516-4446-2019-0732
Submitted Sep 27 2019, accepted Dec 27 2019, Epub Apr 03 2020.
Underlying neurobiology of bipolar disorders 537
Anticonvulsants such as valproate (VPA) and carbamaze-

pine are also used to treat BD. Additionally, some typical
(e.g., haloperidol and chlorpromazine) and atypical anti-
psychotics (e.g., aripiprazole, clozapine, olanzapine, que-
tiapine, risperidone, ziprasidone, and asenapine) have also
shown efficacy.9-11 Of note, the treatment of depression
in BD is particularly challenging, as several drugs used
for treating depressive symptoms, such as selective
serotonin reuptake inhibitors (SSRI), can induce a switch
to hypomania or mania. Thus, these drugs are usually
combined with Li for acute treatment and maintenance of
bipolar depression.12 It is noteworthy that patients with
BD commonly face residual mood symptoms, cognitive
and functional impairment, psychosocial disability, and
decreased quality of life even with the best treatment
available.13,14 Figure 1 Etiology of bipolar disorders. The cause of bipolar
BD has been suggested as a progressive condition, disorder (BD) is still unknown. However, it has been esta-
and the delay in diagnosis as well as inappropriate treat- blished that the dynamic interplay between genetic, neuro-
ment can result in repeated mood episodes, persistent chemical, and environmental factors plays a role in the onset
subthreshold symptoms, development of co-morbidities, and progression of BD.
and progression of the disease with cognitive impairment
and functional decline.15-17 The term ‘‘neuroprogression’’ neuroprogression, and that over time recurrence may
has thus been conceptualized as the pathological rewiring exacerbate subsequent episodes, which are accompa-
of the brain that takes place in parallel with the functional nied by functional and cognitive impairment.20,36-38 An
and clinical deterioration that may occur in the course of underlying hypothesis is that changes in neuroplasticity,
BD; according to this concept, different stages of BD are with a decrease in neurotrophic factors combined with
associated with distinct neurobiological underpinnings.18-23 mitochondrial dysfunction, oxidative stress, inflammation,
Indeed, studies have shown that structural brain changes circadian rhythm abnormalities, and biological aging accel-
and cognitive deficits are not consistently found at illness eration, could be associated with the worsening of mood
onset, and appear to become more evident with chronicity episodes, refractoriness to treatment, cognitive impair-
and recurring episodes.24-27 Moreover, neuroprogression ment, and functional disability.20 This article seeks to
seems to be related to the cumulative effects of immune discuss studies addressing the neurobiological mechan-
dysfunction, enhanced oxidative stress, neurotrophic sup- isms of BD, providing an overview of genetic compo-
port breakdown, mitochondrial dysfunction, and impairment nents, major signaling pathways, biochemical changes,
of cellular resilience.20,21,28,29 Neuroprogression has been and neuroimaging findings associated with this disorder.
also associated with lower responsiveness to treatment,
especially with Li and cognitive behavioral therapy.30-32 In Genetics and epigenetics of bipolar disorder
this sense, Post et al.33 have suggested that multiple
episodes may lead to permanent alterations in neuronal Evidence suggests that BD presents a very strong genetic
activity, which may translate into greater liability to relapse component, with twin studies showing heritability rates
and poorer treatment response. Of note, such a progres- (i.e., the extent to which the disorder can be explained by
sive feature does not seem to be present across all genetic factors) as high as 70-80%.39,40 The strength of
patients, with some not experiencing as much cognitive or this genetic component is also supported by the increased
functional impairment as others.34 This poses the particular risk of BD noted in first-degree relatives of patients,
challenge of identifying specific subgroups of susceptible including offspring.41 The risk of BD is significantly higher
patients, which may require a deeper understanding of the in children of parents diagnosed with BD vs. offspring
biological basis of BD. of control parents42,43; indeed, a plethora of signs and
Although numerous factors and mechanisms have symptoms may accompany such familial risk even in the
been proposed to explain the pathophysiology of BD, its absence of a full-blown diagnosis of BD.44-48 This familial
definitive etiopathology remains unknown. Nonetheless, it aggregation suggests a potential relevance of both inheri-
is believed that the etiology of BD involves an interaction ted genes, which can be tested by molecular genetic
between multiple genetic, neurochemical, and environ- analyses, and the ‘‘inherited’’ familial environment, which
mental factors (Figure 1).35 Not only would a deep under- is also known to be potentially impaired in the face of
standing of the neurobiology of BD support the discovery parental psychopathology.49,50
of new targets for effective pharmacological and non- In the search for relevant BD-related genes, several
pharmacological therapies, it would also facilitate the genome-wide association studies (GWASs) conducted
identification of biomarkers for diagnosis, prognosis, and in the past years have identified multiple loci with a
response to specific treatments. The last years have small effect that may account for heritability,51-62 including
witnessed great progress in the understanding of BD 30 recently discovered loci encoding ion channels, neu-
pathophysiology. For instance, several lines of thought rotransmitter transporters, and synaptic components.63
have led us to believe that BD is associated with None of these single nucleotide polymorphisms (SNPs),
Braz J Psychiatry. 2020;42(5)

538 G Scaini et al.
however, has been shown to present high penetrance or peripheral biomarkers when assessed from neuron-
a large effect size, a finding that is consistent with the derived extracellular vesicles, which are currently being
complex multifactorial model that is believed to underlie investigated in BD patients.92,93 Altogether, these studies
the genetics of BD and other psychiatric disorders. More- suggest an important role for noncoding RNAs in BD
over, the difference in heritability rate calculated through pathophysiology, and also their potential as an important
twin studies (70-80%) and that calculated based on diagnostic and prognostic tool.
molecular genetics findings (approximately 30%) is quite
large, suggesting a role of other markers or mechan- Changes in neuroplasticity and neurotrophic
isms.64 These may include gene-by-gene interactions, signaling
rare genetic markers (current GWASs only assess
‘‘common’’ alterations), gene-by-environment interac- Neurotrophic factors comprise a group of proteins respon-
tions, and epigenetic markers. sible for regulating neuronal survival processes, neuronal
Epigenetic mechanisms encompass several pathways growth, synaptic formation, and cellular plasticity at the
that can mediate gene-by-environment interactions and central and peripheral nervous systems. Nerve growth
modulate gene expression and activity without altering factor (NGF), brain-derived neurotrophic factor (BDNF),
the DNA sequence. These include, among others, DNA glial-derived neurotrophic factor (GDNF), neurotrophin-3
methylation, histone modifications, chromatin remodeling, (NT-3), and neurotrophin-4 (NT-4) are the most common
and the actions of noncoding RNAs. Several of these neurotrophic factors studied in psychiatric disorders.
have been suggested to play significant roles in BD However, BDNF is undoubtedly the most studied neuro-
pathophysiology, especially DNA methylation.65-67 In trophin in BD. Neurotrophins are a specific type of neuro-
addition, several epigenetic alterations that may underlie trophic factor, and members of this family include BDNF,
risk/resilience mechanisms have been described in youth NGF, NT-3, and NT-4. Neurotrophins bind and activate
at high risk of BD, such as offspring of BD parents.68,69 a specific family of tyrosine kinase (Trk) receptors, thus
Specifically, DNA methylation is a fairly stable epigenetic promoting modulation of the central nervous system
alteration that has been implicated in BD pathogenesis (CNS). There are three specific Trk receptors: NGF binds
and progression,69-71 as well as in the mechanisms of to TrkA; BDNF and NT-4 bind to TrkB; and NT-3 binds to
action of several drugs used to treat patients.65,72-74 DNA the TrkC receptor.94
methylation in promoters is typically associated with the The strong interest in BDNF and other neurotrophins
repression of gene expression and may underlie at least in BD was triggered by the discovery that antidepressants
some of the transcriptomic changes reported for BD in and mood stabilizers could act on these molecules,
multiple tissues.75-79 Moreover, several preclinical and modulating their signaling pathways. Preclinical studies
clinical studies have shown that early-life traumatic expe- have shown that the chronic use of antidepressants and
riences can induce stable methylation alterations that mood stabilizers, such as Li and VPA, can increase NGF,
persist into adulthood, suggesting epigenetic-based BDNF, and GDNF levels in the rat brain.95-98 Currently, a
alterations as mediators of the clinical effects of early range of studies show decreased levels of BDNF and its
adversity.80-82 receptor TrkB in both blood and brain of patients with
Interestingly, one of the mechanisms by which methy- BD.99-103 Additionally, a BDNF gene polymorphism that
lomes have been shown to interfere with BD phenotype replaces a valine for a methionine (i.e., valine replacing
is the modulation of biological aging processes. Patients methionine) at codon 66 (Val66Met) has been repeatedly
with BD have been shown to present several clinical associated with BD.104 A previous study also demon-
markers that are suggestive of premature aging, including strated decreased plasma NGF levels in patients with
a higher rate of age-related conditions and faster cog- BD.105 Another clinical study showed that NT-3 and
nitive decline, with previous reports suggesting shortened NT-4 are elevated in the depressive phase of BD,106
telomere length compared to controls.83-85 More recently, possibly indicating an attempt by the organism to defend
a marker of biological aging based solely on DNA itself against cellular stress. In turn, Barbosa et al.107
methylation levels (‘‘epigenetic age’’ or ‘‘DNA methylation demonstrated decreased NT-3 and NT-4 levels in the
age’’)86 has been used to explore the aging processes in manic phase of BD. Given that neurotrophins are essen-
BD, and the results suggest accelerated epigenetic aging tial for neuronal function and survival, it is assumed
in the blood and brain of BD patients compared to that the viability of nerve cells can be affected by a
controls.71,87 Recent evidence that the epigenetic clock persistent reduction of these molecules in the nervous
can be pharmacologically reversed in humans88 offers system.
an interesting treatment possibility for the modulation of As in clinical studies, preclinical research has demon-
premature aging in BD. strated that amphetamine (AMPH) or ouabain-induced
In addition to DNA methylation, noncoding RNAs have manic behaviors in rats decrease BDNF, NGF, and GDNF
also deserved much attention, including gene expression levels in the brain of animals.95,98 Additionally, decreased
modulators such as microRNAs, long noncoding RNAs, levels of BDNF, NGF, and GDNF followed depressive-like
and others.89 Several alterations in the levels of micro- behaviors in an animal model of depression induced by
RNAs and long noncoding RNAs have been detected in BD maternal deprivation or chronic mild stress.108 A previous
samples, some of which have been validated by indepen- preclinical study suggested that neuroadaptations induced
dent studies.90,91 Recent studies have also suggested by chronic administration of dextroamphetamine (d-AMPH)
that noncoding RNAs may function as clinically relevant might mimic neuroprogression in BD, because the brain is

primed for both the manic and depressive episodes which a further reduction in Na+/K+-ATPase function would
are characteristic of BD. In that study, the authors showed bring the resting potential even closer to the threshold for
that d-AMPH withdrawal induces depressive- and anxious- activation, decreasing the amplitude of the action poten-
like behaviors in rats, as well as a sensitization to manic- tial and resulting in inhibition of neurotransmitter release
like behaviors. In line with this, d-AMPH sensitization (depression).122
decreased the levels of BDNF, NGF, and GDNF and An additional link between mitochondrial dysfunction
increased the levels of NT-3 and NT-4/5 in the brain of and BD is supported by data demonstrating that patients
rats.109 with BD present significantly lower levels of phospho-
Together, these clinical and preclinical studies suggest creatine (PCr) (a high-energy compound) and adenosine
changes in neurotrophic factors as an attractive molecular diphosphate (ADP) and decreased PCr peak area per-
mechanism to explain the decreased cellular plasticity centage, suggesting regional hypometabolism in all three
observed in BD, along with other mechanisms descri- mood states.123 Additionally, the PCr peak area percen-
bed in detail in the next sections. The hypothesis is that tage was observed to be decreased in the left frontal lobe
changes in neuroplasticity, including alterations in neuro- of patients during the depressive state, as well as in the
trophic signaling, could be associated with brain damage, right frontal lobe during manic/euthymic states.124,125
which in turn worsens mood episodes and ultimately Moreover, previous studies have shown that patients
induces cognitive and functioning deficits in patients with BD present lower levels of N-acetyl-aspartate (NAA),
with BD. which is thought to represent a surrogate marker for
impaired mitochondria, along with a negative correlation
Mitochondrial dysfunction and oxidative stress between NAA/creatine + PCr or NAA levels and illness
duration.126-129 Taken together, these studies provide
Mitochondria are organelles that are responsible, both indirect evidence that mitochondrial dysfunction may play
directly and indirectly, for cellular functions such as energy a role in illness progression.20
production; they also function as sources of cellular growth Several clinical and animal studies have reported
substrates and play crucial roles in oxidative/nitrosative alterations in various energetic metabolism components,
stress, cell resilience and cell death.110-112 In the brain, including downregulation of nuclear mRNA molecules and
mitochondria are critical for the modulation of neuronal proteins involved in the Krebs cycle, electron transport
activity, short- and long-term neuronal plasticity, cellular chain (ETC) I-IV complexes, and creatine kinase, as well
resilience, and behavioral adaptations, mainly through as a marked decrease in the activity of ETC complexes
actions on long-term potentiation, the hallmark process and Krebs cycle enzymes.130-143 Together, these studies
of learning and memory.112-115 For more than 50 years, suggest a reduced ability to oxidize NADH and FADH and
multiple studies have highlighted mitochondrial dysfunction transfer electrons to ubiquinone in BD, resulting in reac-
as a common pathway in BD pathophysiology, triggered by tive oxygen species (ROS) production through an increase
mechanisms such as impaired oxidative phosphorylation, in the rate of electron leakage by ETC complexes.
shift to glycolytic production of energy, general decrease in More recent attention has focused on the maintenance
energy, and abnormalities in the morphology and intracel- of a healthy mitochondrial pool, which is critically regu-
lular distribution of mitochondria.116 The ‘‘mitochondrial lated by the dynamics and turnover of the mitochondrial
hypothesis’’ suggests that BD is triggered, at least in part, population. A damaged mitochondrion may segregate its
by mitochondrial dysfunction, which can be intimately damaged components into subcompartments and divide,
linked to a wide range of processes associated with whereas a healthy mitochondrion with a potential heal-
treatment outcomes and disease progression or severity, thier membrane will continue to participate in fusion and
including inflammation, oxidative stress, stress response fission cycles. Depolarized damaged mitochondria are
systems, and accelerated aging. often degraded through mitophagy via the PTEN-induced
A considerable number of studies in the literature has kinase 1 (PINK1)-Parkin pathway.144 Thus, these dyna-
shown an increase in lactate levels and a reduction in mic processes of mitochondrial fusion, fission, transport,
intracellular pH (ipH) in the brain of patients with BD, and turnover enable recruitment of healthy mitochondria
possibly indicating altered mitochondrial function and a to subcellular compartments with high demands for ATP;
glycolytic shift consistent with impaired mitochondrial disruptions in any of these processes will lead to mito-
metabolism in BD.116-120 Glycolysis-only adenosine tri- chondrial pathology, cellular dysfunction, and neurological
phosphate (ATP) production has been shown to be defects.145 Previous research findings into mitochondrial
powerless to maintain normal levels of Na+/K+-ATPase morphology have shown that prefrontal cortex neurons
activity in neurons, inducing a large calcium influx into of the postmortem brain from patients with BD and
neurons, followed by glutamate excitotoxicity and neu- peripheral cells from living BD patients display morpho-
ronal apoptosis, both of which play a central role in logical abnormalities (more mitochondria of smaller size)
neurodegeneration.121 Mallakh et al.122 propose that both and an abnormal pattern of clumping and marginaliza-
manic and depressed states in BD could be caused by tion in the intracellular distribution of mitochondria.146 By
Na+/K+-ATPase dysfunction – a small reduction in Na+/ drawing on the concept of mitochondrial quality control,
K+-ATPase activity in the brain would lead to a hyper- recent studies have demonstrated that patients with BD
excitable state (mania) by bringing the resting potential of present an imbalance in mitochondrial fission and fusion
neurons closer to the threshold for activation and increas- toward fission, followed by a decrease in the levels of
ing the duration of neurotransmitter release; in turn, mitophagy proteins and increase in caspase-3 protein

540 G Scaini et al.
levels in peripheral blood mononuclear cells, suggest- interleukin-1beta (IL-1b), interleukin-6 (IL-6), tumor necro-
ing that, in patients with BD, the number of damaged sis factor (TNF)-alpha, soluble interleukin-2 receptor (sIL-
mitochondria exceeds the capacity of mitophagy, and 2R), and soluble receptor of TNF-type 1 (STNFR1), among
apoptosis becomes the dominant pathway to minimize others, in patients compared to controls.158-164 A recent
tissue damage.147,148 systematic review has suggested an important role for
Moreover, numerous studies have provided evidence acute inflammatory response during mania and depres-
of increased ROS production and oxidative stress in sion, with the elevation in proinflammatory cytokines
patients with BD. Replicated evidence has documented seemingly restored after remission of symptoms.118 In
alterations in multiple aspects of oxidative stress regula- addition, further findings in BD have also described
tion, including the production of ROS and reduced anti- significant negative associations between inflammatory
oxidant capacity. Meta-analyses have shown significantly markers and general cognitive abilities, as well as neuro-
greater levels of lipid peroxidation markers, DNA/RNA anatomical alterations.165-169 However, another systematic
damage, and nitric oxide in BD.149,150 However, mixed review claims that an absolute conclusion cannot be
results regarding two of the primary antioxidant enzymes, reached regarding the presence of neuroinflammation in
glutathione peroxidase (GPx) and superoxide dismutase BD, since the findings are not consistent.170
(SOD), have been reported in BD, followed by a meta- Several different mechanisms have been proposed
analysis that did not reach statistical significance for the to explain the role of immune dysfunction in BD,171
comparison of GPx and SOD activity levels in individuals including changes in blood-brain barrier, cell death-
with BD vs. controls.149 Conversely, a recent study by induced release of damage-associate molecular patterns
Das et al.151 showed that, although glutathione levels did with consequent immune activation, genetic mecha-
not differ in BD and controls, there was a positive, BD- nisms, dysfunction of the gut-brain axis, and a role of the
specific correlation between lactate and glutathione levels, kynurenine pathway. Activation of the kynurenine path-
indicating a physiological association between the antiox- way by cytokines such as interferon-gamma (IFN-g) and
idant system and mitochondrial dysfunction. TNF-a is described as one of several contributors to
Several investigators have reported that excessive psychiatric pathogeneses. Kynurenine metabolites med-
oxidative stress in pathological conditions induces point iate immune-inflammation and neurodegeneration and
mutations and may result in large deletions of mitochon- can lead to neurotoxicity and impaired neurotransmis-
drial DNA (mtDNA) due to restricted DNA repair ability sion. The enzyme indoleamine 2,3-dioxygenase (IDO-1)
and the absence of histones in mitochondria. Regarding converts tryptophan into kynurenine and is activated by
BD, there is an inconsistency in mtDNA copy number inflammatory cytokines. Kynurenine is then metabolized
(mtDNAcn) studies that could be attributed to the diversity into hydroxykynurenine and quinolinic acid in microglia,
in clinical features, tissue types, and ethnicity.71,152-155 A and into kynurenic acid (KYNA) in astrocytes. Hydro-
recent meta-analysis identified no significant differen- xykynurenine and quinolinic acid are N-methyl-D-aspar-
ces in mtDNAcn exhibited by BD patients or controls, tic acid (NDMA) agonists and increase the production
while an Asian-specific meta-analysis for BD-mtDNAcn of free radicals, while KYNA, an N-methyl-D-aspartate
studies revealed significantly lower mtDNAcn in patients (NMDA) receptor antagonist, has neuroprotective effects
with BD, with a low level of heterogeneity.155 Moreover, but also leads to cognitive deficits and psychosis when in
mtDNAcn was inversely correlated with the number of higher levels.172-174
relapses of manic episodes.154 A possible mechanism A previous study showed an imbalance toward the
for the lower levels of mtDNAcn could be related to DNA neurotoxicity path derived from kynurenine metabolism,
polymerase gamma (POLG) dysfunction due to oxida- as evidenced by decreased levels of KYNA, in addition
tive stress. In fact, recent studies have demonstra- to increased hydroxykynurenine/kynurenine ratio in BD
ted that individuals with BD present downregulation compared with healthy controls.175 The higher hydro-
of POLG, the replicative polymerase responsible for xykynurenine levels may correlate to cognitive dysfunc-
maintaining mtDNA, as well as downregulation of the tion not only in the acute phases of BD, but also in
DNA repair enzyme, 8-oxoguanine-DNA glycosylase 1 euthymic periods.27 Recent evidence shows that KYNA
(OGG1).156,157 levels in cerebrospinal fluid represent a biomarker for
The accumulating evidence reviewed above delineates psychotic episodes in BD. This higher risk of developing
multifaceted mitochondrial dysfunction as a pathological psychosis may be explained by enhanced dopaminergic
factor in BD. Moreover, mitochondrial dysfunction, apop- transmission due to increased brain KYNA concentra-
tosis, and non-methylated mtDNA can activate Toll-like tions.176 Conversely, decreased peripheral KYNA and
receptors and lead to spontaneous inflammasome activa- unchanged KYNA levels were observed in the CNS in BD
tion, stimulating cytokine production and inducing rapid patients during the depressive phase.177
activation of the immune system. Abnormalities in kynurenine metabolism resulting
from the inflammatory response displayed in mood dis-
Immune-inflammatory imbalance and kynurenine orders may also contribute to the structural (volume
pathway reduction) and functional alterations observed in the
hippocampus and amygdala.175,178 One possible exp-
Immune dysfunction in BD is supported by pre-clinical lanation for this process is dendritic atrophy in the
and clinical evidence showing elevated levels of pro- context of the neurotoxicity occurring in unmedicated
inflammatory cytokines, including interleukin-4 (IL-4), patients with BD.178

Hypothalamic-pituitary-adrenal axis increased number and size of corticotrophs, leading to the

larger pituitary volume found in neuroimaging studies of
In addition to the genetic component involved in the patients with BD vs. healthy controls.188 Interestingly,
pathogenesis and pathophysiology of BD, it is known that some HPA alterations seem to be a trait predisposing to
nongenetic factors, such as psychosocial stress, can mood disorders – it was demonstrated that first-degree
trigger the development of mood disorders.179 The hypo- relatives of subjects with BD had elevated baseline
thalamic-pituitary-adrenal (HPA) axis is the primary cortisol levels and alterations in the response to the
mediator of the biological response to stress. Abnormal- DEX/CRH test.189-191 Accordingly, a previous study with
ities in this system have been associated with the clinical offspring of parents with BD showed that these at-risk
course of BD180 and may contribute to increased risk of children have epigenetic alterations that can modulate GR
clinical relapse following an intense psychosocially stres- responsiveness and the HPA axis,69 ultimately suggest-
sful event,181 although the underlying mechanisms involved ing a biological mechanism by which the stress axis may
in these associations remain essentially unknown.180 be compromised in BD and in at-risk subjects.
A meta-analysis has demonstrated that BD is related
to a more prominent activity level of the HPA axis, as Circadian rhythm abnormalities
evidenced by increased basal cortisol, postdexametha-
sone (PDEX) cortisol, and adrenocorticotropic hormone Sleep disturbances commonly occur in BD and are part of
(ACTH) levels, along with a higher response to the the diagnostic criteria for BD. Normally, there is reduced
dexamethasone (DEX)/corticotropin releasing hormone sleep during manic episodes, and insomnia or hyper-
(CRH) test.182 The alterations described in HPA axis somnia during depressive episodes.4,192 Dampened and
activity vary according to the clinical phase of BD. shifted circadian rhythms may explain some of the
Although the hyperactive HPA axis seems more promi- sleep disturbances frequently reported by patients with
nent during the manic phase, it may persist during clinical BD.193-195 Indeed, circadian dysregulation is associated
remission because euthymic BD patients also display with BD both during acute episodes and during inter-
higher levels of cortisol.182 The clinical heterogeneity of episode periods, indicating that these disruptions in
the depressive phase may explain the conflicting findings circadian rhythms may represent biological markers of
related to HPA axis activity, with high cortisol levels found the BD.196 Actigraphy studies have demonstrated that
in melancholic depression and normal or low cortisol individuals at risk for BD exhibit a lower relative ampli-
levels associated with atypical depression.183,184 tude of the rest-activity cycle, and more sleep irregularity
Particularly interesting is the study by Fries et al.70 than controls.197 Notably, variability in the sleep-wake cycle
showing that patients with BD, particularly at a late stage has been shown to predict the onset of depressive epi-
of illness, presented increased salivary PDEX cortisol sodes among people with inter-episode BD.198 Similarly,
levels followed by reduced ex vivo glucocorticoid receptor patients with BD have been shown to present lower activity
(GR) responsiveness and increased basal protein levels levels, also in addition to sleeping longer, taking longer to
of FK506-binding protein 51, a cochaperone known to fall asleep, spending more time in bed and awake in the
desensitize GR, in peripheral blood mononuclear cells. middle of the night, and showing a more variable pattern
Moreover, individuals with BD presented increased meth- of sleep-wake cycles. Data from several studies have
ylation at the FK506-binding protein 5 (FKBP5) gene, suggested that patients also exhibit more considerable
suggesting a dysfunctional negative feedback of the HPA intra-daily variability and lower inter-daily stability, as
axis and impaired GR responsiveness due to increased well as relative amplitude of the rest-activity cycle
FKBP51 levels and increased FKBP5 intronic methyla- relative to controls.199
tion. In this same study, the authors suggest that, as BD Additionally, one of the most commonly reported rhythm-
progresses, there is decreased resilience to stress and a related findings in BD is a significantly higher prevalence of
higher risk of new mood episodes, since stress resilience evening chronotypes.200-204 In individuals with BD, even-
and coping mechanisms are primarily mediated by the HPA ingness has also been associated with earlier age of onset,
axis. High levels of PDEX cortisol may also be involved in rapid-cycling course, and other factors such as reduction in
the mechanism of increased late-stage BD recurrence. the peak of the melatonin secretion at night.202 Mondin
Therefore, DEX suppression test results and HPA axis et al.205 showed that patients with BD with evening
hyperactivity may have prognostic value in BD.70 preference had lower levels of IL-6, TNF-a and thiobarbi-
Furthermore, the hyperactive HPA axis correlates with turic acid reactive substance (TBARS), suggesting that
an increased risk of cognitive dysfunction185 and is known chronotype may affect interleukin and oxidative stress
to have neurotoxic effects on the hippocampus that can levels in BD. Furthermore, population-based studies
later predispose to dementia.186 Lee et al.187 described have demonstrated that the eveningness chronotype is
that patients with BD with poorer cognitive performance more common in cyclothymic individuals, especially
had higher levels of serum cortisol, as well as a significant those with at least one prior episode of depression,
correlation between cognitive function after 24 weeks of and some, but not all, temperament studies that are
standard treatment and longitudinal changes in cortisol putatively linked to risk of BD (hyperthymic tempera-
levels, reinforcing the hypothesis that serum cortisol ment) show a higher prevalence of this chronotype in
may be involved in the psychopathological mechanisms at-risk populations.206
of cognitive decline in BD. Moreover, some evidence Moreover, the secretion of melatonin and cortisol also
suggests that an abnormal HPA axis may explain the follows a circadian pattern. Evidence has indicated that

542 G Scaini et al.
people with BD exhibit melatonin secretion abnormalities, Neuroimaging findings in bipolar disorder
suggesting that differences in the amount and timing of
melatonin secretion may reflect different mood states. The first studies using computed tomography (CT) have
During the manic episode, high levels of melatonin were shown structural abnormalities as significantly larger
observed during the day, with an advanced nighttime ventricular-to-brain ratios in groups of individuals with
peak,207 whereas reduced levels and a later onset of BD compared with controls.232 Following the pioneering
melatonin secretion have been reported in bipolar depres- study (among others) of Pearlson & Veroff,232 cumulative
sion compared with unipolar depression, and in euthymic evidence produced by CT and magnetic resonance imag-
phases of BD compared with matched controls.208,209 ing (MRI) have shown changes in neuroanatomic struc-
Similarly, 24-h cortisol secretion is significantly higher in tures associated with BD. In one of the first reviews
patients with BD than in controls, independent of the clinical concerning volumetric structural neuroimaging in BD,
phase (manic, depressive, or euthymic).210 These findings Soares and Mann described a larger third ventricle and a
are consistent with the observation of increased GR mRNA smaller cerebellum, as well as periventricular hyperinten-
in the hippocampus and amygdala in patients with BD sities in BD patients, the latter also found in the elderly
compared with those in controls.211 with unipolar depression.233 More recently, the ENIGMA
In the past few decades, several genetic association Working Group, which includes 28 international groups,
studies have demonstrated a link between multiple showed reduced bilateral cortical thickness in the frontal,
circadian genes and BD, such as CLOCK, ARTNL1, temporal, and parietal regions of patients with BD, espe-
CSNK1e, PER3, NPAS2, NR1D1, TIMELESS, RORA, cially the left rostral middle frontal cortex, left fusiform
RORB, and GSK3b. All had modest associations with gyrus, and left pars opercularis. The authors also found
BD, supporting a polygenic heritability through which an association between the duration of illness with cortical
multiple genes additively contribute to the risk of thickness, and increased cortical thickness with the use
BD.212-220 Although GSK3b is considered a likely can- of Li. A history of psychosis in patients with BD was
didate gene, no association has been reported between associated with reduced surface area in the right caudal
BD and the GSK3b gene polymorphism. However, the anterior cingulate cortex and left inferior temporal gyrus
frequency of a copy number variant (CNV) at the compared with patients without psychosis.234 Regarding
GSK3b locus was higher in individuals with BD than in the volume of brain regions associated with mood regu-
controls.221,222 lation and reward, some studies showed smaller amyg-
In BD, the circadian genes PER3, REV-ERBa, and dala and hippocampus and a larger striatum, although
GSK3b were associated with an early age of disease contrasting findings have also been found.235-238 The
onset, and the CRY2, CLOCK, ARNTL2, TIMELESS, and integration of MRI with machine learning methods to
CSNK1e were related to rapid BD cycling and/or high distinguish between patients with BD and healthy con-
disease recurrence.223-226 These findings are consistent trols, as well as for clinical stratification, was investigated
with the observation that an early age of onset is by Mwangi et al., showing that the algorithm had up
associated with more severe circadian disruptions, such to 70% of accuracy and higher probability scores for those
as eveningness and sleep quality. Thus, specific circadian in the late-stage category (more than 10 total lifetime
genes may be significant in a particular BD subgroup (early manic episodes including hospitalizations).239 This poten-
onset). Furthermore, these findings suggest that variations tial impact of machine learning techniques in the evalua-
in some circadian genes may explain the high sensitivity to tion of individuals with BD was extensively explored in
rhythm changes observed in BD and may be associated a systematic review by Librenza-Garcia et al.240 Of
with disease onset or relapse.196 Additionally, chronotype 51 studies included, 38 applied machine learning to dis-
and genotype association studies in BD showed that the criminate between BD and healthy controls or other psy-
3111T/C CLOCK variant is associated with an extreme chiatric disorders, especially with neuroimaging data.240
night chronotype, and one nonsynonymous PER3 coding For instance, Fung et al.241 investigated psychiatric diag-
SNP and two CSNK1e intronic SNPs were associated with nosis accuracy using a support vector machine (SVM)
the night chronotype in BD patients.212,220 algorithm with brain cortical thickness and surface area
Circadian genes have also been implicated in bipolar- data. The authors found that structural brain differences
like behaviors in animal models. The most notable between individuals with BD and major depressive
example is the behavior of mice with an exon 19 exclusion disorder were able to discriminate these psychiatric
in the CLOCK gene, which represents a valuable model disorders with 74.3% (adequate) accuracy (sensitivity:
of mania.227 These ClockD19 mice display hyperacti- 62.5%; specificity: 84.2%).241 More recently, a Big Data
vity, increased exploratory drive, lowered depression-like Task Force from the International Society for Bipolar
behavior, higher impulsivity, abnormal sleep/wake cycles, Disorders has expanded this literature review and dis-
and increased reward response. ClockD19 mutant mice cussed issues to be addressed in machine learning-based
show a craving for rewarding stimuli similar to patients studies, including the main barriers for applying these
with BD in the manic state.228,229 The manic behavior techniques and strategies to approach them.242
of CLOCK mutant mice can be reversed by treatment with Since human behavior, including cognition, emotion,
Li or by restoring a functional CLOCK gene in the ventral and social interaction, reflects complex neural circuit
tegmental area.230 Another mouse model involving cir- communication,243 the signs and symptoms we observe
cadian genes includes transgenic mice that overexpress in individuals with psychiatric disorders could be under-
GSK3b and show a manic-like phenotype.231 stood as the manifestation of different brain circuitry

dysfunction.244 Diffusion tensor imaging (DTI) is a hypersensitivity to reward-relevant cues is related to hypo/
neuroimaging technique used to evaluate white matter manic symptoms, especially excessive approach motiva-
fiber tract connectivity between different regions, both tion and psychomotor hyperactivation, representing a risk
proximal and distal.245 A review246 of DTI studies in sub- trait for BD.254 Acuff et al.255 compared reward processing
jects with BD showed a consistent decrease in fractional circuitry among offspring of bipolar parents, offspring of
anisotropy (FA) values in patients, especially in the fronto- parents with non-BD disorder, and offspring of healthy
limbic tracts and corpus callosum. As part of the ENIGMA parents during a reward processing task using fMRI. The
network, Favre et al.247 investigated white matter abnorm- results showed that offspring of parents with BD had lower
alities in patients with BD compared to healthy controls. functional connectivity between the right ventral striatum-
The authors found white matter microstructure alterations left caudal anterior cingulate in response to loss; and higher
principally within the cingulum, the main pathway in the functional connectivity between the right pars orbitalis-left
limbic system, and in interhemispheric connectivity by and right orbitofrontal cortex in response to reward,
the corpus callosum.247 Thus, DTI studies have shown indicating potential neural markers for the risk of BD.255
consistent abnormalities in regions associated with emo- Despite the impressive advances in technology and
tional regulation as well as in structures that integrate these interesting neuroimaging findings associated with a psy-
regions interhemispherically. chiatric diagnosis,247 as well as the response to treatment
Foley et al.,248 based on previous studies from the and risk identification,255,256 there is still no direct clinical
literature, have investigated whether fractional anisotropy application of brain imaging at this moment in psychiatry.
in the uncinate fasciculus distinguished participants
with BD-I from those with BD-II and healthy controls. Conclusion, challenges, and perspectives
The results showed significantly decreased FA in the
uncinate fasciculus in patients with BD-I compared with The use of tools and technologies that can positively
both healthy controls and BD-II patients, suggesting a affect mental health parameters using translational
distinction in the pathophysiology of BD subtypes. Mahon approaches still faces several challenges, particularly in
et al.249 used DTI to identify white matter biomarkers of the case of BD. First, there is no biomarker with significant
genetic risk. To achieve their aim, the authors evaluated biological and clinical validation in BD, which complicates
participants with BD, unaffected siblings of individuals diagnosis and hinders the development of new drugs.
with BD, and healthy controls. The results showed that FA Second, the current literature highlights an important
within the right temporal lobe of unaffected siblings was limitation of the existing evidence – most studies are still
significantly different, and intermediate in relation to parti- cross-sectional, and thus capable of identifying associa-
cipants with BD and healthy controls, suggesting a bio- tions but not causal relationships or longitudinal patterns
marker for genetic risk of BD.249 of development. Third, BD involves heterogeneous symp-
Using specific cognitive and emotional tasks, functional tomatology, various comorbidities, and cognitive impair-
MRI (fMRI) methods allow the investigation of neural cir- ment, as well as a wide range of genetic and environmental
cuitry associated with distinct behaviors. Using a cogni- factors. Similarly to other psychiatric disorders, BD is
tive control task, Smucny et al.250 evaluated whether a diagnosed based on purely clinical criteria and history
continuum exists in the underlying neural circuitry across taking, interviewing, and behavioral observation; and
participants with a diagnosis of schizophrenia and BD and overlaps pathophysiologically with numerous other dis-
healthy controls. The authors found a linear trend in the orders.64,257-260 In this context, the translation of biological
task-associated dorsolateral prefrontal cortex (DLPFC) findings in BD to the clinical setting is still highly complex,
and superior parietal cortex (SPC) response among the and there is still a long way between translating these initial
three groups, with participants with schizophrenia show- findings into approved therapies for patients.261
ing more severe dysfunction and those with BD an As discussed in the present article, brain-imaging studies
intermediate pattern. These findings show that, despite have shown evidence of change in regional activity, func-
the different categorical diagnoses, individuals with schizo- tional connectivity, neuronal activity, and bioenergetics
phrenia and BDs may share some neurobiological char- associated with BD, while past research on animals and
acteristics.250 human models have added mechanistic evidence on
Functional neuroimaging studies with BD patients have bioenergetic dysfunction, inflammation, oxidative stress,
found connectivity dysfunctions in neural circuits asso- as well as abnormalities in signaling networks, HPA axis,
ciated with emotion processing, emotion regulation and and circadian rhythm (Figure 2). In addition to its
reward processing.251 Patterns of amygdala activation complexity, brain function is constantly influenced by
and connectivity during emotion processing tasks were environmental exposure, which can be associated not
compared between individuals with BD and unipolar only with the risk of mental illness but also resilience and
depression by Korgaonkar et al., with both groups in protection.262 It is not surprising that all of these changes
remission.252 The findings demonstrated lower connec- are involved in the neurobiology of BD, a disease with a
tivity of the amygdala with the insula and hippocampus complicated clinical course involving manic, depressive,
and of the amygdala with the medial orbitofrontal cortex in mixed, and euthymic episodes.
patients with BD.252 Individuals with BD also presented a In addition, studies providing insights into how parti-
lower modulatory effect of the DLPFC on the amygdala cular brain abnormalities lead to one, not another specific
during emotion regulation tasks compared with healthy clinical presentation, and the interaction between immune
controls.253 In a review, Nusslock & Alloy suggest that and neurochemical alterations and cognition are needed

544 G Scaini et al.
Figure 2 Summary of recent research on neurobiological mechanisms of BD. Multiple biochemical pathways, not all of which
are shown here, interact simultaneously to cause cellular damage. Mitochondrial dysfunction in BD pathophysiology is based
on changes affecting oxidative phosphorylation, energy production, increased formation of ROS, mitochondrial DNA damage,
membrane permeability, Ca+2 imbalance, and impairment in mitochondrial dynamics and mitophagy. These alterations can
lead to increased apoptosis and NLRP3-inflammasome activation. However, this relationship may be bidirectional, wherein
mitochondrial dysfunction can increase inflammatory factors, and inflammation can induce ROS production and mitochondrial
dysfunction. Inflammation, also reported in BD, is responsible for the activation of enzymes indoleamine 2,3-dioxygenase
and kynurenine 3-monooxygenase (KMO), leading to the skewing of the kynurenine metabolic balance toward increased
neurotoxicity. Moreover, inflammatory mediators and stress mechanisms activate the HPA axis resulting in secretion of
corticosteroids from the adrenal cortex. In BD, the negative feedback of cortisol to the hypothalamus and pituitary components
is thought to be impaired, leading to continual activation of the HPA axis and excess cortisol release. Cortisol receptors become
desensitized, leading to increased activity of pro-inflammatory immune mediators and downregulation of neurotrophic factors
such as the brain-derived neurotrophic factor. Besides, corticosteroids are secreted rhythmically, displaying ultradian and
circadian patterns, and CLOCK-related genes directly regulate glucocorticoid receptor expression. Circadian rhythms also play
a role in mitochondrial functioning by regulating biogenesis, fission/fusion, and mitophagy. These alterations could initiate a
vicious cycle where multiple systems and mechanisms exacerbate and accelerate cellular damage, synaptic dysfunction, and
impaired neurogenesis, resulting in progressive structural brain changes and cognitive decline thought to contribute to the
neuroprogression of BD. 3-HK = 3-hydroxykynurenine; ACTH = adrenocorticotropic hormone; BD = bipolar disorder; BDNF =
brain-derived neurotrophic factor; Ca = calcium; CRH = corticotropin releasing hormone; Fis-1 = mitochondrial fission 1 protein;
FKBP51 = FK506-binding protein 51; GR = glucocorticoid receptor; HPA = hypothalamic-pituitary-adrenal; IDO = indoleamine
2,3-dioxygenase; IL = interleukin; KMO = kynurenine 3-monooxygenase; NMDA = N-methyl-D-aspartate; OXPHOS =
mitochondrial oxidative phosphorylation; P = phosphorus; ROS = reactive oxygen species.

for a better understanding of the neurobiology of BD. 12 Kato T. Current understanding of bipolar disorder: toward integra-
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13 Bortolato B, Miskowiak KW, Kohler CA, Vieta E, Carvalho AF.
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ciplinary research on a single cohort of patients will have tematic review of meta-analyses. Neuropsychiatr Dis Treat. 2015;11:
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multimodal and standardized techniques are essential to
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19 Berk M, Berk L, Dodd S, Cotton S, Macneil C, Daglas R, et al. Stage
The Translational Psychiatric Program (USA) is funded by managing bipolar disorder. Bipolar Disord. 2014;16:471-7.
the Department of Psychiatry and Behavioral Sciences, 20 Fries GR, Pfaffenseller B, Stertz L, Paz AV, Dargél AA, Kunz M,
et al. Staging and neuroprogression in bipolar disorder. Curr Psy-
McGovern Medical School, The University of Texas Health chiatry Rep. 2012;14:667-75.
Science Center at Houston (UTHealth). The Laboratory of 21 Berk M, Kapczinski F, Andreazza AC, Dean OM, Giorlando F, Maes
Neurosciences (Brazil) is one of the centers of the Instituto M, et al. Pathways underlying neuroprogression in bipolar disorder:
Nacional de Ciência e Tecnologia de Medicina Molecular focus on inflammation, oxidative stress and neurotrophic factors.
Neurosci Biobehav Rev. 2011;35:804-17.
(INCT-MM) and one of the members of the Center of 22 Gama CS, Kunz M, Magalhaes PV, Kapczinski F. Staging and
Excellence in Applied Neurosciences of Santa Catarina neuroprogression in bipolar disorder: a systematic review of the
(NENASC). This research was supported by grants from literature. Braz J Psychiatry. 2013;35:70-4.
Conselho Nacional de Desenvolvimento Cientı́fico e 23 Schneider MR, DelBello MP, McNamara RK, Strakowski SM, Adler
Tecnológico (CNPq) (SSV and JQ), Fundação de Amparo CM. Neuroprogression in bipolar disorder. Bipolar Disord. 2012;14:
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(FAPESC) (JQ), Instituto Cérebro e Mente (JQ), and Regional cerebral cortical thinning in bipolar disorder. Bipolar
Universidade do Extremo Sul Catarinense (UNESC) (SSV Disord. 2006;8:65-74.
and JQ). SSV and JQ are CNPq Research Fellows. 25 Strakowski SM, DelBello MP, Zimmerman ME, Getz GE, Mills NP,
Ret J, et al. Ventricular and periventricular structural volumes in
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Disclosure 26 El-Badri SM, Ashton CH, Moore PB, Marsh VR, Ferrier IN. Elec-
trophysiological and cognitive function in young euthymic patients
The authors report no conflicts of interest. with bipolar affective disorder. Bipolar Disord. 2001;3:79-87.
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