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Cover Letter

To: Prof. Kimberly Freeman, COLWRIT 161 class, College Writing Program
From: Cameron Jacobs
Date: 16 October 2023
Subject: Use of biomarkers to identify depression in adolescents

My literature review delves into the complex field of biomarkers and adolescent
depression. As of now, there is little research that has found a causal relationship
between the two. There has been much investigation in adults but in adolescents, it is
still a very understudied area. Due to the lack of research, there are very few universally
accepted claims about the relationship between biomarkers and depression in
adolescents. Furthermore, the current methods in diagnosing depression are based on
qualitative data and don’t allow for the early identification of depression

This literature review is divided into sections, organized thematically. The first section
explores the relationship between inflammatory biomarkers, such as CRP or TNF-α,
and depression . In the following sections, discuss neuroendocrine and neurological
biomarkers that could be used, such as the HPA axis or α-tubulin acetylation. Finally,
the last section discusses a collection of biomarkers that all belong to different systems
of the body but have equally important information that need to be included in this
review.

If I were to submit this review to a journal, I would submit it to the American Journal of
Psychology. This is because my topic is extremely relevant in the psychology field and
that is where many references I reviewed were published. This journal requires the
citation format of APA, which I used in my review. It is a simple format and I had no
issues using it.

Some key terms that would be helpful to know are:

C-reactive protein (CRP): a protein produced by the liver that increases in the blood
when there is inflammation in the body

HPA Axis: neuroendocrine mechanism that mediates the effects of stressors by

regulating numerous physiological processes

Neurotrophins: regulate development, maintenance, and function of vertebrate nervous

systems

Frontolimbic: the front of the limbic system in the brain (controls our behavior and
emotional response)
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The Use of Biomarkers in Identifying Depression in Adolescents:

A Literature Review

Cameron Jacobs

UC Berkeley

Colwrit 161: Writing in the Biological Sciences

Professor Freeman

10-17-2023
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Introduction

There has been growing recognition of the challenges associated with identifying

and diagnosing depression in adolescents. According to the CDC, 1 in 5 (20.9%)

adolescents have experienced a major depressive episode. Furthermore, Adolescents

often struggle to articulate their emotional experiences and societal stigma can

discourage open discussion about mental health. (CDC, 2022). As a result, many youth

often hide their true emotions and refuse to talk about their feelings, making it difficult

for healthcare professionals, parents, and friends to detect the condition early.

Unfortunately, these feelings can often escalate in adolescents and can lead to drastic

outcomes. Suicide is the second leading cause of death for children, adolescents, from

age 15-to-24. (AACAP, n.d.). With this issue plaguing today's adolescents, it is even

more imperative that we identify and treat depression as quickly as possible. However,

the challenges posed in identification and intervention raise concerns about the ability to

effectively and quickly diagnose depression.

Currently, the approach to identifying depression among adolescents is through

​psychological evaluation, where a doctor or mental health professional will ask

questions about thoughts, feelings, behavior, and more. However, one of the major

pitfalls of this is the fact that adolescents are reluctant to discuss mental health issues

that may be plaguing them, possibly due to stigma, fear of judgment, or a lack of

self-awareness. Furthermore, this method doesn’t provide quantifiable information or

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physiological measures based on objective facts: rather it is based on the word of the

patient, making it challenging to provide a clear and objective diagnosis.

Recently, to address these challenges researchers have turned to biomarkers as

a potential solution, aiming to find objective and reliable measures for identifying

depression. In the past, most studies on biomarkers in depression have been performed

on the adult population and not in younger age groups. There is a lack of research into

relevant biomarkers in adolescents which is surprising as a large portion of today’s

teens experience the effects of depression. With a new focus on specific biomarkers in

adolescents, researchers hope to gain a greater understanding of depression as well as

identify biomarkers that can be used to effectively diagnose adolescent depression. As

of now, we are still in the early stages of research and not much has been proven in

adolescent studies.

The goal of this literature review is to explore the current state of research in this

field, shedding light on the most promising biomarkers so far, their reliability, the

implications for clinical practice and identification, as well as what work is needed in the

future to further this concept. This review will cover the current types of biomarkers

explored, from inflammation to neuroendocrine, as well as the relevant information

regarding each one.

Inflammation Biomarkers

An increasingly popular hypothesis surrounding depression is that there is a

positive correlation between inflammation. In many clinical trials, scientists have found

that there seems to be inflammation in many adult patients who experience depression.

One study found that a higher salivary cortisol to C-reactive protein (CRP) ratio was
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associated with more severe anxiety, depression, and sleep disturbance symptoms over

time in healthy adults (Fong et al., 2022). Although this trial only studied adults, in

another study specific to adolescents, the same results were achieved. Multiple

researchers found that a higher morning cortisol to C-reactive protein ratio in

adolescents predicted the development of a first-onset depressive disorder two years

later in these adolescents (Landau et al., 2021, ​Veltman et al., 2018). This finding

suggests that dysregulation between cortisol and CRP systems may serve as an early

predictor of depression in adolescence. Furthermore, the fact that this information was

also found in adult trials implies that there could be considerable benefits in using this

ratio as a biomarker for adolescents, although more research is needed to determine its

use.

In another cross-sectional study, researchers found that suicide attempters had

significantly lower concentrations of neurotrophins and significantly higher

concentrations of inflammatory markers (Priya et al., 2016). The study also observed a

significant negative correlation of neurotrophins with inflammatory markers, stress, and

suicide risk. In a multivariate linear regression model, hs-CRP, pSLE (autoimmune

disease that causes inflammation), and DHUS-R (questionaire regarding peoples

attitudes) emerged as independent predictors of suicide risk. These findings suggest a

potential association between altered levels of neurotrophins and inflammatory markers

and an increased risk of suicide (with a risk of suicide being directly linked to levels of

depression). However, it is important to note this is a cross-sectional study and only

provides a snapshot of the participant's health status at a specific point in time. To make
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a more reputable claim about this possible biomarker, researchers would need to

conduct a longitudinal study following the same principles as its predecessor.

It has also been suggested that, in addition to higher levels of CRP, IL-6 (a protein that

helps regulate immune responses) and TNF-α (an inflammatory cytokine) were

associated with greater depressive symptoms at a later time point, suggesting that

inflammation may contribute to the development of depression (Moriarity et al., 2020).

Furthermore, higher levels of depressive symptoms were linked to greater levels of IL-8

and IL-10 at a later time point, suggesting that depression may also contribute to

inflammation. However, it's worth noting that the observed associations were modest,

and that there may be other factors that contribute to the relationship between

inflammation and depression. Additionally, the study used self-reported depressive

symptoms rather than clinical diagnoses, which may limit the confidence in the findings.

Neurological and Neuroendocrine Biomarkers

There is strong evidence affirming the involvement of dysregulation in the

hypothalamic–pituitary–adrenal (HPA) axis in the onset of depression in adults. Even in

the early 2000s, researchers had strong evidence indicating that the HPA axis activity is

significantly heightened in patients who suffer from depression, compared to healthy

controls (Belvederi Murri et al., 2014). Many have come to the same conclusions over

time and more recently, studies on adolescents have found similar findings. More

recently, it was discovered that variations in the HPA axis could predict the onset of

Major Depressive Disorder (MDD) in a study of adolescent girls (Humphreys et al.,

2019). Particularly, the likelihood of acquiring MDD throughout adolescence and early
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adulthood was associated with the levels of DNA methylation (DNAm) inside particular

CpG sites in genes such as NR3C1, CRH, CRHR1, and CRHR2. Additionally, it is

known that during adolescence, there is a more pronounced response from the

hyperactive HPA-axis compared to adulthood, as well as elevated cortisol levels.

(Zwolińska et al., 2023). In addition, Freimer et al. (2022) found that external stressors,

such as psychosocial stress, can lead to long-term dysregulation of the

hypothalamic-pituitary-adrenal (HPA) axis and affect the development of frontolimbic

circuits, contributing to depression in adolescents. All of this evidence provides a

relatively strong claim that the HPA axis has beneficial use in adolescent depression,

however they also mention that more research will be needed to confirm these findings

in adolescents as not enough scientific exploration has been done up to this point.

In 2020, researchers found that decreased α-tubulin acetylation ( a decrease in a

protein called alpha-tubulin’s chemical modification (acetylation)) in postmortem brain

tissue in individuals with major depressive disorder (MDD), may be linked to the

sequestration of G-αs in lipid rafts (regions in the cell membrane), which is associated

with depression. These findings aligned with previous studies indicating that increased

α-tubulin acetylation causes a response similar to antidepressants by promoting the

translocation of Gαs from lipid rafts (Singh et al., 2020). The findings illuminate a

potential mechanistic link between decreased α-tubulin acetylation, Gαs sequestration

in lipid rafts, and the development of major depressive disorder. The alignment with

previous studies which indicates the antidepressant-like response associated with

increased α-tubulin acetylation provides further support for the use of these molecular

interactions as biomarkers. The only major limitation of this research is that the study
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looked at a wide range of ages and was not specific to adolescents. So, while this

research could be promising, more specific investigation is necessary to prove its

efficacy in adolescents as a biomarker for depression.

Other Biomarkers (Heart and Gut)

Byrne et al. (2010) found that depressed adolescents exhibited higher resting

heart rates compared to non-depressed adolescents of the same demographics. Even

when factors such as sex, depressive severity, illness duration, and medication use

were considered, the elevated heart rate in depressed adolescents persisted.

Furthermore, the study suggested that mechanisms other than autonomic control might

be responsible for this increased heart rate in depression, potentially involving factors

like blood clotting, coronary artery function, and immune system responses, all of which

could contribute to the association between depression and heart disease (Byrne et al.,

2010). The acknowledgment that autonomic control alone may not explain the observed

physiological differences opens avenues for future research to delve into the pathways

linking mental health and cardiovascular function. It should be noted, however, that

participants in the study were adolescents with less severe depression who didn't need

medication, which could affect how broadly we can apply these findings.

Researchers have also begun to explore the relationship between gut health and

mental health. One study was the first to directly investigate gut permeability in

individuals with depression. The results indicated a positive connection between gut

permeability and the severity of certain depressive symptoms, particularly those related

to physical and mental fatigue. Additionally, the study suggests that increased gut
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permeability might partially explain the link between the activity of the sympathetic

nervous system (SNS) and the severity of depressive symptoms (Calarge et al., 2019).

It also hints at the involvement of immune markers in this connection. This suggests that

the combination of gut health and the immune system may play a role in depression.

While the study has limitations, such as a relatively small sample size and a focus on

female adolescents, it opens up potential avenues for future research into the

relationship between gut health, the immune system, and depression as well as the

possibility of using gut health as a treatment target for depression.

Another article explored the relationship between gut microbiota, probiotics, the

HPA axis, and depression. The article found that gut microbiota can lead to

dysregulation of the HPA axis, which in turn can negatively impact the development of

frontolimbic circuits and contribute to the emergence of adolescent-onset clinical

depressive disorders. The article also explored the potential of probiotics as a novel

treatment for depression in adolescents, based on evidence that probiotics can prevent

the development of stress-associated effects in young adults and alleviate depressive

symptoms among clinically depressed adults (Freimer et al., 2022). However, the

authors state that much more research is required to assess the efficacy and safety of

probiotics as a treatment for adolescent depression since probiotics have barely been

researched in adolescent clinical populations. Furthermore, the processes by which

probiotics affect the gut microbiota and the brain are still poorly understood. As a result,

the use of them as treatment for adolescent depression needs far more research before

any claims can be made about their efficacy.

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Discussion

Despite the research being done regarding adolescent depression and

biomarkers, there is still much to be learned about their relationship. This study extends

previous literature knowledge and trials on the associations between a variety of

biomarkers and depressive symptoms in adolescents by summarizing and analyzing the

work of many different research papers. The various studies mentioned in this review

provide helpful insight into the topic but define no clear conclusion on each biomarker.

While research on some biomarkers, such as the CRP to cortisol ratio or dysregulation

in the HPA axis, provide strong evidence of the correlation between them and

depression, others, such as the relationship between gut health and mental health,

need much more exploration. The fundamental fact is that much more research needs

to be directed into these areas of study before any relevant claims can be made about

the correlation between biomarkers and adolescent depression.

Moving forward, research needs to be directed in all areas of this field. First off,

more specific investigation is needed into many of the current studies that have been

completed to verify their validity as much of the current research does not have enough

support. Furthermore, research should be directed into the study of new, undiscovered

biomarkers because as of now, there are only a handful that have been explored.

Finally, all future research must take a longitudinal approach to establish causal

relationships between each biomarker and its relationship to adolescent depression.

This specific field of study on adolescent depression is still a recent development and to

begin making concrete claims, more funding and investigation are necessary.
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In the future, the uses for this research will be immeasurable. In having

biomarkers to identify depression in adolescents, we could diagnose depression far

before the onset of any major symptoms. We could prevent or alleviate many symptoms

in adolescents that often go unnoticed for years. Additionally, rather than the typical

psychological evaluation, we could pair that with a panel in which we have specific

biomarker tests. In doing so, doctors would have both qualitative and quantitative data

to make a proper diagnosis for adolescent patients.

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