The Function of TPH2 in Bipolar Disorder and Related Treatment
Mechanisms
Xinyi Kong
1,*,†
,
a
Hanyu Lu
2,*,†
b
and Hanrui Zhu
3,*,† c
1
University of Washington, 1400 NE Campus Parkway, Seattle, WA, 98195-4550, U.S.A.
2
Trinity College, University of Toronto, 27 King's College Cir, Toronto, Ontario, M5S, Canada
3
University of Toronto, 27 King's College Cir, Toronto, Ontario, M5S, Canada
These authors contributed equally
Keywords: Con-Tribute, Poly-Morphisms, Bipolar.
Abstract: Bipolar disorder, known as a mental health condition, that features extreme mood swings, is classified into
three types: Bipolar I, II, and cyclothymic disorder. Bipolar I patients experience at least one manic or mixed
episode, and several depressive episodes. Bipolar II patients experience at least one hypomania or mix
episode, and several depressive episodes. Cyclothymic patients experience relatively mild hypomania and
depressive episodes, but they suffer from a higher number of mixed episodes. The diagnosis of bipolar
disorder is to follow the standard criteria from the DSM-5. However, the determination is relatively subjective.
On the other hand, genetic mutations also con-tribute to the occurrence of bipolar. A variety of gene mutations
or single nucleotide polymorphisms (SNPs) are ex-perimentally shown to be associated with bipolar disorder.
Amongst them, one of the most significant gene poly-morphisms is TPH2 polymorphism. A specific variant
of S41Y functions by disrupting the downstream signalling pathways leading to abnormal levels of serotonin
release. Drug treatment of bipolar primarily includes lithium and second-generation antipsychotics (SGAs),
where lithium mediates bipolar symptoms at psychological, neuronal, and cellular levels. SGAs target both
dopaminergic and serotonergic pathways to relieve these symptoms. However, the advent of other novel
treatment methods challenges traditional treatments. Details of functional pathways are wait-ing to be further
explored in the future. This review provides our current knowledge on the curr ent genetics and treatment of
bipolar.
1 INTRODUCTION
Bipolar disorder is a mood disorder that affects 1% of
the total population (Almeida et al 2009). It was first
identified by the French psychiatrist Jean-Pierre
Falret in 1851. He described this disorder as circular
madness in which patients’ moods change between
depression and mania (Angst 1998). Later in 1921, a
German psychiatrist, Emil Kraepelin, further studied
mental illness and differentiated bipolar disorder
from schizophrenia. He stated that bipolar disorder
belongs to the manic-depressive insanity group and
mentioned the term ''mixed states”, in which mania
and depression occur one after another (Angst,
a
https://orcid.org/0000-0002-4758-3958
b
https://orcid.org/0000-0003-2762-9709
c
https://orcid.org/0000-0003-0462-6433
Sellaro 2000). Eventually, in 1980, bipolar disorder
was formally identified in the third edition of the
Diagnostic and Statistical Manual of Mental
Disorders (DSM-3) (Benazzi 2007). In this book,
standardized diagnostic criteria are described to
distinguish bipolar disorder from other mental
illnesses. In addition, it is the first time that bipolar
disorder is separated into three subtypes. Now this
book has its fifth edition (DSM-5). It specifically
describes the characteristics and diagnostic criteria of
the three types of bipolar disorder, bipolar I disorder
bipolar II disorder, and cyclothymic disorder
(Benazzi 2007).
Bipolar disorder is a mental disorder that reduces
patients’ quality of life and affects their health. It is a
Kong, X., Lu, H. and Zhu, H.
The Function of TPH2 in Bipolar Disorder and Related Treatment Mechanisms.
DOI: 10.5220/0011294900003443
In Proceedings of the 4th International Conference on Biomedical Engineering and Bioinformatics (ICBEB 2022), pages 767-773
ISBN: 978-989-758-595-1
Copyright
c
2022 by SCITEPRESS Science and Technology Publications, Lda. All rights reserved
767
chronic and recurrent mood disorder that could last
lifelong (Carbon, Hsieh, Kane, Correll 2017). The
common onset age is in adolescence or early
adulthood. Patients with it experience different levels
of mania, depression, and mix moods. Bipolar
disorder is hard to treat. Currently, there is no cure for
it. Moreover, it is very challenging for patients to
manage due to the fluctuation of the mood state.
Thus, bipolar patients’ quality of life is affected to a
great extent. A large number of bipolar patients feel
their lives are negatively affected, especially in the
aspect of education, vocation, and work functions as
well as their social relationships (Carkaci-Salli, et al
2014). Their health-related quality of life (HRQOL)
score, the perception of an individual's wellbeing,
physical, psychological, and social functioning is
lower compared to normal people (Escamilla, Zavala
2008). The suicide risk for bipolar patients is 20-30
times higher than the general population (Frye, et al.
2015).
However, we only know little about bipolar
disorder, including its pathology and treatments.
With the development of genetic technology, more
research has been conducted to understand this
disease and its genetic causes. Therefore, in this
review, we present the symptom and diagnosis
methods for three different types of bipolar disorder,
including bipolar I, bipolar II, and cyclothymic
disorder. The mutations that lead to bipolar disorder
are concluded as well. Finally, pre-existing
treatments are described, and emerging future therapy
is proposed. Together, this review provides a
summarization for bipolar disorder. More
importantly, it states the apparent limitations for both
diagnosis and treatments and provides directions for
future research to better understand and treat bipolar
disorder.
2 SYMPTOM
2.1 Bipolar I Disorder
Bipolar I disorder is known as manic-depressive
disorder. Patients with bipolar I disorder are
averagely symptomatically ill for half of the time
after the diagnosis, and the onset age is 23.5 (Geddes,
Miklowitz 2013). Patients experience at least one
manic episode, in which they will suffer from an
unusually elevated mood and energy such as
increased activity and decreased need for sleep. In
addition, it is also possible that patients exhibit
catatonic behaviour and undergo the onset of
postpartum. Except for manic episodes, patients may
experience a major depressive episode (Grande,
Berk, Birmaher, Vieta 2016). The result from the
paper, Lewis et al. report that it is 3 times more
common for bipolar I disorder patients to have
depressive symptoms than manic symptoms (Geddes,
Miklowitz 2013). During a depressive episode,
patients show symptoms such as depressed mood and
loss of pleasure (Hoffman). In addition to separately
manic and depressive symptoms, bipolar I disorder
patients may also suffer from the mixed episode, in
which manic symptoms and depressive symptoms
occur one after another. More than half of the patients
undergo a mania and depression cycle once a year.
Few of them undergo a mood cycle more than 10
times per year (Geddes, Miklowitz 2013).
The symptoms described above could be mild,
server but show no psychotic features, or server and
show psychotic features for bipolar I patients.
Although half of the bipolar I disorder patients show
psychotic symptoms, the lasting time is relatively
short (Grande, Berk, Birmaher, Vieta 2016). Bipolar
I disorder is known for patients to experience manic
and major depressive episodes, but during the ill time,
subsyndromal, minor depressive, and hypomanic are
more common symptoms. The data collected from
146 bipolar I disorder patients indicates that
subsyndromal, minor depression, and hypomania
take up 74.0% of the total ill time. In contrast, mania
and the major depressive episode take up only 12.3%
of the total ill time (Geddes, Miklowitz 2013).
2.2 Bipolar II Disorder
Bipolar II disorder is a relatively mild manic-
depressive disorder in which patients are in a
euthymia state most of the time. The onset age for
bipolar II disorder patients is around 31 years old
(IsHak, Brown, Aye, Kahloon, Mobaraki, Hanna
2012). While they are symptomatically ill, they also
suffer from a mood cycle that undergoes manic and
major depressive episodes (Jann 2014). However,
compared to bipolar I disorder, bipolar II disorder
patients experience less severe mania, called
hypomania (Jauhar, Young 2019). Its symptoms
include increased physical activity, more self-
confidence, and more irritability (Judd, et al. 2002).
The symptoms of hypomania are very similar to
mania, but the mood instability in hypomanic
episodes is not severe enough to cause significant
behavioural impairment (Jauhar, Young 2019).
For bipolar II patients, it is more common to have
depression compared to hypomania. A mixed episode
is relatively rare to occur, and the lasting time is very
short (Grande, Berk, Birmaher, Vieta 2016).
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Although bipolar II disorder is less severe than
bipolar, I type, the patient still shows some level of
cognitive dysfunction even under euthymia state
(IsHak, Brown, Aye, Kahloon, Mobaraki, Hanna
2012).
2.3 Cyclothymic Disorder
Cyclothymic disorder is the mildest disorder
compared to bipolar I and II (Lee, et al 2021). For
cyclothymic patients, the main symptom is mild
hypomania and depression, where patients
experience low and high moods. Both hypomanic and
depressive episodes are not server enough to diagnose
as bipolar disorder. However, the changing of mood
states varies among patients. Patients who normally
undergo depressive episodes may shift to hypomania
for a few days. It is also possible that the mood switch
occurs several times a day.
Except for the typical symptoms, some
cyclothymic patients risk developing comorbid
psychiatric disorders. On average, cyclothymic
patients show a higher number of moods shift despite
the mood circulation styles are different. In addition,
the early onset age, and the late diagnosis due to mild
ill symptoms also contribute as a factor for
comorbidity (Lee, et al 2021).
Table 1. Symptoms of Bipolar disorders.
Category Symptoms
Bipolar I Disorder At least one manic or mixed episode and several depressive episodes.
Bipolar II Disorder
At least one hypomanic (mild mania) episode. Depressive episode is very
common whereas mix episode rarely occurs.
Cyclothymic Disorder
Hypomanic and depressive episode are not server enough to diagnose as
hypomania or depression. Mix episodes occur frequently.
3 DIAGNOSIS
The current diagnosis method is to follow the criteria
from the DSM-5 (Judd, et al. 2002). Patients who
experience at least one manic episode and depression
episodes are identified as bipolar I disorder. Patients
who experience at least one hypomanic episode and
depression episodes are identified as bipolar II
disorder. Patients who experience cycling between
mild hypomania and depression are identified with
the cyclothymic disorder (Lin, et al 2007).
The traditional diagnosis method has been used
since 20 century, but this method is very subjective,
so it is very difficult to correctly diagnose this mental
disorder. As mentioned above, depression is more
common compared to mania and hypomania. The
problem is, mental diseases such as major depressive
disorder and unipolar disorder also display depressive
symptoms (Lin, et al 2007). Therefore, bipolar
disorder is easy to be diagnosed as other mental
disorders. There are total three types of bipolar
disorder. Amongst them, bipolar II disorder is
characterized by the display of hypomania, in which
a full-blown mania is excluded. Thus, without a clear
manic symptom, bipolar II disorder can be
misdiagnosed as a unipolar disorder. The third type,
cyclothymic disorder, is also very challenging for
diagnosis since the symptoms are so mild that the
patients seldom seek for help. Moreover, the
hypomania symptoms usually result in pleasant
feelings, so when they think they are ill, it's normal
when they are depressive. This cause cyclothymic
disorder has a chance to be diagnosed as depression
as well (Lin, et al 2007). The challenges for bipolar
diagnosis mean that more accurate methods should be
provided to avoid misdiagnosis. Neuroimages and
biomarkers are investigated as two novel methods.
Neuroimages of bipolar and unipolar patients are
analysed. The result indicates that compared to the
unipolar patient, depressed bipolar patients show
decreased fractional anisotropy (FA), which plays a
role in mood regulation in the right frontal-temporal
regions. Their white matter that connects key
prefrontal and subcortical neural regions, which plays
a role in emotion processing and the regulation of
neural circuitry, is also different from unipolar
patients (Macritchie, 0 et al 2010). Moreover, during
emotion processing, the amygdala activity, and its
connectivity to the prefrontal cortical show different
patterns between bipolar patients and unipolar
patients (Maina, Bertetto, Boccolini, Salvo, Rosso,
Bogetto 2013). These distinct characteristics between
The Function of TPH2 in Bipolar Disorder and Related Treatment Mechanisms
769
bipolar and unipolar patients can help to differentiate
these two disorders, especially when patients are
under a depressive episode.
In addition to neuroimages, biomarkers are
investigated to use as diagnostic indicators as well.
Plasma proteins analysis between bipolar patients and
healthy individuals reveals that the protein level of
growth differentiation factor 15 (GDF-15),
hemopexin (HPX), hepsin (HPN), matrix
metalloproteinase-7 (MMP-7), retinol-binding
protein 4 (RBP-4), and transthyretin (TTR) are higher
for bipolar I disorder patients compare to bipolar II
disorder patients and healthy individuals (Malhi,
Tanious, Das, Coulston, Berk 2013). Proteins such as
proprotein convertase subtilisin/kexin type 9
(PCSK9), carbonic anhydrase 1 (CA-1), and
peroxiredoxin 2 (PRDX2) are found upregulated in
bipolar II patients compared to healthy individuals
(Mason, Brown, Croarkin, 2016). These proteins are
suggested as potential biomarkers for bipolar disorder
diagnosis.
4 MUTATION
4.1 Genetic Mutation and Its Relation
to Bipolar
Many neurological disorders are considered to be
related to genetic mutations. Many researches have
connected the cause of the bipolar disorder (BD) to
different biological processes. Such mechanisms
include variants like neurotransmitters, receptors,
enzymes, and co-factors. Genetic factors code these
variants, and certain genetic mutations will affect
genetic transcription/translation, protein expression,
neurological signalling cascade, enzyme activity, and
eventually lead to bipolar disorder (Mayo Clinic
Staff). Current drug therapy for most neurological
disorders is non-specific and can only treat certain
common conditions like headache and seizure
(Michalak, Yatham, Kolesar, Lam 2006). To trace the
disease's cause back to its root, treatment targeting the
genetic mutations considered causal for BD should be
most effective and promising. However, it is
important to point out that it is very difficult to
identify certain genetic mutations responsive to
medication and therapy. Therefore, clinical research
in this area is challenging. We will talk about such
potential yet complicated genetic treatment in section
IV.
Studies suggest that a number of genes are
correlated to this disorder. Some of their mutations
are shown to be present in most of the bipolar
patients’ conditions. Dense genetic maps have been
used to identify specific genes and their role in the
neurological pathway, and the knockout effect of
such genes has been studied (Müller-Oerlinghausen,
Berghöfer, Bauer 2002). Numerous candidate genes
have been studied thoroughly, and the following
section talks about one of the most critical genes
involved in BD.
4.2 The Role TPH2 Polymorphism
Plays in Bipolar
The neurotransmitter serotonin (5-
hydroxytryptamine, or 5-HT) is responsible for
modulating appetite, aggression, sleep, and mood. It
has a significant effect on both human peripheral and
central nervous systems. Many neurological
disorders have been associated with dysfunction of
the serotonin signalling cascades and processes.
Tryptophan hydroxylase 2 (TPH2) is the first and
rate-limiting enzyme in the biosynthesis of serotonin.
TPH2 enzyme is expressed abundantly in
serotonergic neurons of the brain. Studies have
shown that TPH2 polymorphism is associated with
many neuropsychiatric disorders, including bipolar
disorder, major depression, schizophrenia, autism,
suicidal behaviour, and aggression (Mayo Clinic
Staff). Over 500 single nucleotide polymorphisms
(SNPs) have been identified in the TPH2 gene, and
about 300 of them are found in humans. Zhang, X. et
al. (Mayo Clinic Staff) summarized 6 coding non-
synonymous SNPs and 3 coding synonymous SNPs.
To determine the biological importance of a specific
SNP and its effect on the serotonergic pathway, the
location of which the genetic variant occurs is critical
(e.g., intron, exon, promoter region, 3’UTR/5’UTR).
Different mutated locations of the TPH2 gene imply
different consequences: dysfunction of gene
transcription/translation, alternative splicing, protein
misfolding, enzyme inactivation, or dysfunction of a
post-translational modification. The functional
consequences are unclear if the mutation occurred in
a noncoding region (e.g., intron/promoter region).
4.3 TPH2 SNP - S41Y
In overview, one specific SNP we will talk about in
this review is tyrosine for serine at position 41 (S41Y)
in the regulatory domain of the enzyme TPH2.
Studies have associated the S41Y SNP with bipolar
disorder and depression in the Han Chinese
population. Most of the bipolar disorder patients at
clinic research express S41Y SNP, which is
ICBEB 2022 - The International Conference on Biomedical Engineering and Bioinformatics
770
evidential for its relevance to bipolar (Phillips,
Kupfer 2013, Pompili, et al 2013).
Carkaci-Salli, N. et al. (Phillips, Kupfer 2013)
expressed TPH2 human protein in bacteria and PC12
cells and discovered that S41Y TPH2 expressed
increased Vmax and in vitro stability decreased by 28
minutes at 37 degrees Celsius. Contradictorily, S41Y
bacteria have increased enzyme activity but
decreased serotonin production, suggesting that
decreased enzyme stability is more critical than
activity in serotonergic biosynthesis. S41Y SNP
decreased cyclic AMP-dependent protein kinase A
(cAMP PKA) phosphorylation by 50 percent
compared to wild type, which leads to the disruption
of post-translational regulation of TPH2, and reduced
serotonin production, which may lead to bipolar
disorder.
We have compared the nucleotide sequence of
TPH2 among humans, mice, zebrafish, and fruit flies,
and the amino acid is not conserved at position 41
among these four species. However, the polar
property is conserved between humans and zebrafish.
Suggesting that zebrafish could be a potential animal
model for studying SNPs at position 41 of TPH2.
5 BIPOLAR TREATMENT
5.1 Treatment Methods
The treatment of the bipolar disorder is diverse,
ranging from drug treatment to clinical therapies.
Primarily, drug treatment is one of the most effective
treatment methods of bipolar disorder because its
targeting often involves neurological pathways
directly responsible for causing bipolar disorder. Two
main types of drug treatment are emphasized:
Lithium treatment and Second-Generation
Antipsychotics (SGAs) (Torrent, et al 2006). Lithium
is considered a gold standard bipolar treatment in the
past century after it was introduced 60 years ago.
Research into its mechanisms is conducted at
multiple levels. Lithium mono therapy is the best
option to relieve acute mania and depression in
bipolar symptoms. Lithium contributes to both pre
and post-synaptic modulations at the neuronal level,
where chronic lithium administration can stabilize
glutamate neurotransmission and increase glutamate
re-uptake to achieve mood stabilization effects. It
also increases the level of GABA in plasma and
downregulates the effects of NMDA receptors as well
(Zhang, Beaulieu, Gainetdinov, Ca-ron 2006).
Neuroimaging techniques are used for bipolar
disorder diagnosis, which can effectively identify the
changes in brain area with lithium use, such as the
increase in the volume of brain grey matter,
hippocampus, left amygdala, and striatum. In
addition, lithium is beneficial to bipolar individuals,
but it can cause harmful side effects on normal
individuals due to its selectivity of action (Zhang,
Beaulieu, Gainetdinov, Ca-ron 2006).
Another important type of drug treatment is
named second-generation antipsychotics, also known
as SGAs. Antipsychotics, known as medications for
treating psychological disorders, are divided into
first-generation antipsychotics (typical) and second-
generation antipsychotics (atypical). The first
generation of antipsychotics functions only in
blocking dopaminergic receptors (D2). However,
SGAs act on blocking both dopaminergic and
serotonergic receptors (5HT2A). Another advantage
of the SGAs is the decreased percentage of causing
moving disorders than first-generation
antipsychotics, and the side effects are milder. For
instance, a meta-analysis from 2017 demonstrated a
significant difference in tardive dyskinesia between
classes (Rajput 1975). A significant feature of bipolar
disorder is the abnormally high level of excitation
caused by excessive dopamine and serotonin
signaling. SGAs, as heterogeneous molecules, can
reduce the high level of excitation by acting on
receptor antagonists of dopaminergic receptors (D2)
and serotonergic receptors (5HT2A), in which they
block the specific functional pathways of
dopaminergic and serotonergic receptors. Although
they have less affinity for the D2 receptor than first-
generation antipsychotics and higher affinity for
5HT2A receptors, these molecules can still block
both pathways. This process leads to a lower level of
dopamine and serotonin transmission, therefore
reducing the abnormal excitation level caused by
bipolar. The approved antipsychotics include
aripiprazole, olanzapine, quetiapine, and ziprasidone,
which all serve as receptor antagonists of D2/5HT2A
or both (Van Meter, Youngstrom, Findling 2012).
5.2 Challenges of Traditional
Treatments
Lithium and second-generation antipsychotics are
both considered traditional treatments for bipolar
disorder. However, these methods also have potential
limitations and challenges. Limitations of lithium
treatment include difficulties in identifying
compensatory responses that are distinct from the
bipolar-caused primary dysfunctions. In addition, the
process of neurotransmission involves many
convoluted mechanisms in multiple different
The Function of TPH2 in Bipolar Disorder and Related Treatment Mechanisms
771
pathways. Under these circumstances, identifying
common targets across different bipolar stages or
phases is very challenging due to the different
personal responses of individual patients and the
various mood states. Also, most of the current
findings of lithium use in bipolar treatments involve
preclinical in vitro or in vitro studies, which use
higher than the therapeutical level of lithium
concentrations (Zhang, Beaulieu, Gainetdinov, Ca-
ron 2006). Therefore, these studies require further
examinations and may not be easily applied for
human studies because different lithium
concentrations may render different neurobiological
effects under various concentrations and doses of
lithium treatment.
Second-generation antipsychotics (SGAs) also
have shortcomings that significantly influence their
functions. Include a variety of adverse or side effects
of using the molecule to treat bipolar disorder. These
side effects include weight gain, abnormal glucose,
cholesterol metabolism, and dysfunction in sexual
behaviours. For instance, the use of antipsychotics in
maintenance treatment in BD from the clinical care of
people presenting with first-episode mania in the first
episode psychosis (FEP) service features the
controversies of SGAs treatment. Treatment with
SGAs, in this case leading to more weight gain and
more severe metabolic dysfunctions. Another
limitation of SGAs is that it only functions well in
bipolar patients with no treatment adherence
problems (Van Meter, Youngstrom, Findling 2012).
5.3 Future Directions
For Lithium treatment, the potential mechanisms
proposed are waiting to be further explored in detail
for understanding the underlying interconnections of
different neurological pathways. Further research
may involve longitudinal studies to determine
whether the underlying mechanisms of
neuroprotective properties and mood stabilization
effects of lithium are mutually intercorrelated. Multi-
modal approaches can also be applied to examine the
part of neuroimaging and genetic studies of bipolar
disorder and the advent of more advanced
technologies.
The use of SGAs treatment for therapeutic
purposes of bipolar disorder is seen as increasingly
important in both the cases of monotherapy and
adjunctive therapy. There are different considerations
of pharmacological properties, efficacy, and
tolerability in bipolar disorder for SGAs use.
Maintenance treatment with SGAs can be used in the
circumstance of patients who have lithium
intolerance or adherence problems in conjunction
with newer digital technologies for early relapse signs
and monitoring individualized health care systems.
Longer-term trials with various compounds and
focusing on treatments acting on differing poles of
illness can be conducted in the future.
6 CONCLUSION
Bipolar disorder is a mental health condition
classified into three types: Bipolar I, II, and
cyclothymic disorder. The diagnosis of bipolar in
current days is by following DSM-5. Novel methods
such as using neuroimaging and biomarker are
proposed. Genetic mutation is one of the causes for
bipolar disorder, in which a specific type of TPH2
gene polymorphism named S41Y plays a role in
affecting TPH2 gene expression and further disrupts
the downstream signalling pathways. To treat this
condition, drug treatments are considered effective
treatment methods. Lithium is one of the treatment
methods targeting glutamate stabilization and
increasing GABA signalling to reduce the excitation
level in bipolar patients. Second-generation
antipsychotics (SGAs) are also able to reduce
excitation by blocking dopaminergic and
serotonergic receptors to prevent further downstream
effects. Bipolar disorder is a mental disorder that can
seriously affect patients’ health. However, currently,
the diagnosis, genetic causes and treatments of
bipolar disorder are not well studied. The diagnosis
of bipolar in current days is by following DSM-5,
which is relatively subjective.
Bipolar treatments in which lithium use is
difficult to target common pathways in different
stages of bipolar disorder. SGAs may render side
effects such as weight gain, abnormal glucose,
cholesterol metabolism, and dysfunction in sexual
behaviours. Moreover, the signalling pathways and
the role of specific genetic factors in gene
polymorphism targeting may also be further
explored. Therefore, more studies are required to
better understand the pathology of bipolar disorder.
In addition, the validation of bipolar neuroimaging
patterns and biomarkers may serve as future
diagnosis method. Novel technologies such as
CRSIPR and other genetic editing tools, are
considered very effective and may be able to cure
bipolar patients by correcting genetic mutations and
applying gene repair mechanisms.
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