The Function of TPH2 in Bipolar Disorder and Related Treatment

Mechanisms

Xinyi Kong

1,*,†

Hanyu Lu

2,*,†

and Hanrui Zhu

3,*,† c

University of Washington, 1400 NE Campus Parkway, Seattle, WA, 98195-4550, U.S.A.

Trinity College, University of Toronto, 27 King's College Cir, Toronto, Ontario, M5S, Canada

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,

https://orcid.org/0000-0002-4758-3958

https://orcid.org/0000-0003-2762-9709

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

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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768

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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772

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