Chapter II.

Rationale / Literature Review

1 in 8 people has some type of mental disorder according to the World Health

Organization (WHO). Sadly, this only seems as if the amount of people with mental disorders is

only increasing It is possible to find the mental disorder before it gets too late due to the work of

biomarkers that Potentially reveal the possibility of a certain individual developing a mental

disorder such as OCD, ADHD, and Bipolar Disorder. Countless theories have been proposed to

understand what is the driving factor for mental diseases such as OCD, ADHD, Bipolar Disorder,

& Schizophrenia. If possible, would research lead to the discovery of a possible biomarker for

said diseases? Several hypotheses have been proposed that claudin-5 is a potential biomarker,

some focusing on testing the amount of claudin-5 in mice and others testing kids and teenagers

that have OCD and test their blood. Some of the literature wants to find a possible method to

regulate amounts of claudin-5 via a possible drug or maybe even update a current drug to

regulate the amount of claudin-5 in humans. Others plan on proving with concrete evidence that

claudin-5 is certainly a biomarker for mental diseases. However, the limitation of all these

studies would be the lack of long-term research. We can only conclude very short-term solutions

for the possible risks claudin-5 might have on the mental health of someone. Besides, accounting

for possible variables such as other possible biomarkers in the body of volunteers, we might even

see some correlation between claudin-5 with other possible biomarkers.

One of the many theories that were presented and studied was analyzing ADHD and how

it's one of the most common neurodevelopmental disorders of childhood. Although ADHD is

quite common, its etiology has yet to be fully explained. Pınar Aydoğan Avşar , Ümit Işık ,

Evrim Aktepe , Faruk Kılıç , Duygu Kumbul Doğuç & Halil İbrahim Büyükbayram (2020)

theorized that . Using a sample size of 80 children/adolescents with ADHD and a control of 40
children/adolescents. They concluded that dysregulation of the blood-brain barrier, especially

abnormalities in claudin-5 function, may be involved in the etiology of ADHD. With the

limitations of sample size and the length of research, they ended up concluding that seemingly

claudin-5 function in the blood-brain barrier plays a driving role in the etiology of ADHD.

A great theory was the possibility that claudin could lead to an ischemic stroke via the

possible upregulation and downregulation of claudin in victims who experienced ischemic

stroke. Jianjun Lva, Wei Hub, Zhi Yang, Tian Lib, Shuai Jiang, Zhiqiang Mae, Fulin China, and

Yang Yang (2017) believed that Claudin-5 is a biomarker for ischemic stroke. (when there is a

lack of oxygen in the blood that causes a stroke due to the brain’s lack of oxygen and nutrients)

They ended up doing a sample test on postmodern subjects who passed due to an ischemic

stroke. They concluded that the upregulation or downregulation of claudin-5 could play a

neuroprotective role in the regulation of BBB in ischemic stroke. However, much of this

evidence is in preclinical testing, and many problems remain unresolved. So more testing and a

longer study would be needed to conclude if this theory holds some amount of value.

A similar type of theory was researched and experimented on with mice however instead

of postmurden victims. Chris Greene, Nicole Hanley, and Matthew Campbell (2019) wanted to

determine the impact of claudin on human neurological abilities and mental health and possibly

discover how claudin impacts humans in different amounts. The researchers decided to

experiment on mice since mice also have a Claudin 5 protein. The only difference is that humans

contain the protein in the 22nd chromosome and the mice contain it in the 16th chromosome.

They would change the regulators that control the amount of claudin-5 in the mice’s body and

then proceed to record the results that it had on the mice. They concluded that Various upstream

signaling components can regulate claudin-5 levels and manipulating these pathways to
modulate claudin-5 expression in response to disease is a viable therapeutic strategy. In addition,

RNAi-mediated suppression of claudin-5 is a well-characterized strategy to temporarily

modulate BBB permeability to low molecular weight therapies in preclinical models of disease

which may be useful for treating various CN-S disorders. Downregulation of claudin-5 is an

early and prominent feature of MS and epilepsy, suggesting that early loss of claudin-5 and

breakdown of paracellular BBB integrity is an important feature of the pathogenesis of these

disorders. Strategies to restore tight junction integrity should be investigated.

This theory that is presented is slightly different from the others before it and it

specifically targets the effect of claudin on children which is an interesting speculation that most

other articles don’t research in specifically children. Ümit Işık, Pınar Aydoğan Avşar, Evrim

Aktepe, Duygu Kumbul Doğuç, Faruk Kılıç & Halil İbrahim Büyükbayram (2020) investigate

that claudin 5 could be a leading factor for OCD in children and investigating how claudin-5

affects children who have unregulated amounts of claudin 5. The testing was done on children

with OCD. They questioned the parents of the children and they tested kids with OCD via SSRI

and antipsychotic combination therapy. They also tested blood levels for claudin in the children.

The resulting dysregulation of the BBB (blood-brain barrier), especially claudin-5, may be

involved in the etiology of OCD. Further detailed and more comprehensive studies designed on a

longitudinal basis are greatly needed to find out exactly whether increased claudin-5 levels are

the cause or consequence of the disease process in OCD.

Lastly, this hypothesis dives into the possible treatment for the biomarker claudin-5 for

schizophrenia. C Greene, J Kealy, MM Humphries, Y Gong, J Hou, N Hudson, LM Cassidy, R

Martiniano, V Shashi, SR Hooper, GA Grant, PF Kenna, K Norris, CK Callaghan, MdN Islam,

SM O’Mara, Z Najda, SG Campbell, JS Pachter, J Thomas10, NM Williams, P Humphries, KC

Murphy and M Campbell (2017) studied how persistent and targeted suppression of claudin-5 at

the BBB in mouse models induces a correlative phenotype of psychosis-like behaviors

suggesting a regulation of BBB integrity and dynamism may be therapeutically relevant for the

treatment of schizophrenia. They would perform a similar study with mice targeting their 16th

chromosome with the final goal being to find out what dose of claudin-5 tends to lead to a

greater percentage of schizophrenia. This study on the other hand involved transferring the cells

of a human kidney and even the production of an Adeno-associated virus to understand the

biological impact claudin-5 has on mice that could transfer to humans. They concluded that at

the anatomical level, the central pathological findings in the brains of schizophrenia patients are

centered on a distinct loss of cortical gray matter, cortical thinning, and reduced numbers of

synaptic structures on cortical pyramidal neurons. There are however no pathognomonic markers

of schizophrenia observable at the histological level post-mortem. Here, we were able to identify

an aberrant pattern of claudin-5 immunoreactivity in 62% of schizophrenia patient brains based

on an analysis of claudin-5 levels.

The possibility that claudin-5 is a biomarker for many different mental health diseases is

not written in stone due to the lack of long-term studies all the studies on claudin-5 are either a

small sample group of people or a short-term study with no true long-term effects that are

concrete. Yet claudin-5 certainly causes some inherent issues when not properly regulated by the

body and possibly leads to the development of mental illnesses. That is the reason with ANOVA

(Analysis of variance) we could Mathematically predict what a long-term effect for claudin-5

would be a using the data from the other articles and plugging said data into the formulas for

ANOVA then creating possible lines of regression and possibly error bars to statistically show
that there would be a significance for claudin-5 being considered a biomarker for many different

kinds of mental illnesses.