Karen Daniela Garay Buenrostro A01372695

Metodología de investigación e innovación

Parcial 1: Monografía Estado del Arte

Transcriptome Signature of the Anxious Distress Specifier for Major Depressive Disorder

Overview of Major Depressive Disorder and the Importance of a Molecular Approach

Major Depressive Disorder (MDD) is a complex and severe psychiatric disorder that
represents a public health concern due to its high prevalence worldwide. Approximately 350
million people are affected by depression, varying in its prevalence between 3% in Japan and
16.9% in the United States of America. Similarly, 8.8% of Mexicans have shown a depressive
disorder throughout their lifetime (Pérez-padilla et al., 2017).

MDD is known to be a heterogeneous disorder with typical symptoms of persistent and

profound depressed mood, anxiety, anhedonia, irritability, fatigue, loss of interest, feelings of
guilt and worthlessness, and suicidal thoughts or attempts. However, these symptoms are
displayed with wide variation in the clinical setting. Additionally, sex differences also account
for its heterogeneity. For example, women are more prone to show comorbid anxiety,
cardiovascular disease, physical pain, and sexual function impairment, whereas men often
exhibit comorbidity with substance abuse, poorer impulse control, increased anger, and
aggressivity (Bittar & Labonté, 2021).

Importantly, the Diagnostic and Statistical Manual of Mental Disorders (DSM-V)

introduced several clinical subtypes of MDD, including the anxious distress specifier.
Zimmerman et al. (2019) showed that these patients had higher levels of anxiety characterized
by increased suicidal ideation and a history of suicide attempts. On the other hand, Fabbri et al.
(2021) classified this subtype as a treatment-resistant depression among the melancholic and
atypical subtypes, encouraging these specific populations for further research
(Zimmerman et al., 2019)
.

The etiology of this disease involves several psychosocial, genetic, and biological factors.
According to Pérez-padilla et al. (2017), it has been estimated that about 200 genes are related
to MDD . Nevertheless, despite years of research in the Biological Psychiatry field, the molecular
pathways underlying the pathology still need further research to integrate a transcriptional
disease signature for depression subtypes. The overall purpose of doing this would be to help
diagnose a patient with potential biomarkers, gain insights into disease mechanisms, and design
novel therapeutic interventions as explained for several diseases such as tuberculosis
(Burel & Peters, 2017)
.

According to Zhang et al. (2021), no macro-neurological features distinguish patients

with psychiatric disorders, which is why a molecular approach is needed. Transcriptomic studies
focus on RNA extraction of a tissue, RNA sequencing and pathway analysis associated with
genes present in the sample. Therefore, transcriptome studies are the closest approach to
Karen Daniela Garay Buenrostro A01372695
Metodología de investigación e innovación
Parcial 1: Monografía Estado del Arte

identifying the molecular phenotype of a particular illness or trait, and by this means, find a
transcriptional signature for depression.

Advances in Transcriptomic Studies for Depression

Literature findings show that subtypes of depression have their own causes and
symptoms, thus explaining the complexity to elucidate a single transcriptional signature.
Nevertheless, studies have demonstrated gene roles and molecular mechanisms using animal
models and postmortem human brain tissues.

Tripathy (2020) emphasizes that animal models remain the best approximation to study
psychiatric disorders since animal behavioral manipulations only model specific aspects of these
disorders. Since stress has a causal role in major psychiatric illnesses like depression and
anxiety, Zhang et al. (2021) explain that stress induction in animals is essential to study the
biological basis of depression at a transcriptome level. Particularly, the study of Scarpa et al.
(2016) compares two brain regions implicated in humans with MDD and three chronic stress
models in mice. Results show an overlap between genes of both species in the medial
prefrontal cortex and nucleus accumbens regions. The authors also suggest the analysis of
larger human cohorts to test whether these transcriptional signatures in mice are associated
with a given symptom cluster or historical features.

Other postmortem studies of MDD have already identified several hundred genes on the
prefrontal context, hippocampus, and nucleus accumbens that point to a GABAergic
interneuron dysfunction that expresses the neuropeptide somatostatin (SST). SST expression is
reduced in the frontal cortex and other regions, and this reduction correlates with symptom
severity (Zhang et al., 2021).

Similarly, the transcriptome signature for MDD has been elucidated from an
endogenous and reactive subtypes perspective. In this study, researchers show transcriptomic
differences between depression in rats with stress exposure (reactive) and congenitally prone
to depression (endogenous). Then, they compared the results with publicly available human
postmortem tissue from the prefrontal cortex (Malki et al., 2014).

Although the most active institutions in the Biological Psychiatry field include Harvard
University, King’s College London, and the University of Toronto, transcriptomic studies in
depression are a more specific topic well-developed in Yale University and the University of
Adelaide as leading research centers. The Transcriptome Signature of Depression is a project
led by Liliana Ciobanu at the University of Adelaide that utilizes blood transcriptomes of older
adults to identify molecular networks involved in geriatric depression. A replication study
named Older Australian Twins Study is currently underway in a sample of 324 subjects of similar
age, gender, and ethnicity; the Project leaders are Perminder Sachdev and Henry Brodaty, and
 Karen Daniela Garay Buenrostro A01372695
Metodología de investigación e innovación
Parcial 1: Monografía Estado del Arte

have been investigating the genetic and environmental contributions to healthy aging since
2007 (Ciobanu et al., 2017).

Finding a Transcriptome Signature for Major Depressive Disorder–Anxious Subtype

Related future depression studies were found in the Grant Listing of the National
Institutes of Health, along with their Grant Numbers. These include: “Unravelling the
mechanisms of Epilepsy-Depression” (K08NS110924-01), “Adolescent markers of Depression
and the Impact of Alcohol” (K23AA026869-01), and “Distributed networks underlying
depression in epilepsy” (K23NS110962-01A1). Although addressing depression, these projects
focus on populations with known neurological comorbidities. On the other hand, although the
Older Australian Twins Study focuses on the transcriptomic signature of depression, they
address a specific type of depression that has an onset of symptoms in the elderly age.

Considering the previously mentioned suggestions of supporting findings with clinical

studies by Malki et al. (2017), Scarpa et al. (2016), and the novelty of the proposal in the
current literature, the present research project will focus on finding a transcriptional signature
for the anxious distress specifier in the major depressive disorder. The research will integrate
both animal models and postmortem human brain samples; the Basolateral amygdala (BLA) will
be the area of interest and will be compared with previous findings in the amygdala by Sibille et
al. ( 2009), and the anxiogenic/pro-depressive effects of this structure reported by Bittar &
Labonté (2021). The same authors remark that a crucial aspect to consider in the future study
will be the type of stress used to induce anxiety-like and depressive-like behaviors (physical or
psychosocial), which appear to trigger distinct changes on neurons and circuits connected to
the BLA. Moreover, it is important to keep in mind their annotations on the male and female
circuits to account for sex differences.

Finally, taking into consideration the previous molecular approaches and the well-
known techniques for transcriptomic studies, it is possible to establish molecular foundations of
anxious-depression subtype in a more precise way, rather than viewing MDD as a complex or
heterogenous stress disease. This will not only be useful for new therapies but will also propel
new studies for the rest of the depression subtypes: melancholic, atypical, hostile, or psychotic.

References

Bittar, T. P., & Labonté, B. (2021). Functional Contribution of the Medial Prefrontal Circuitry in Major
Depressive Disorder and Stress-Induced Depressive-Like Behaviors. Frontiers in Behavioral
Neuroscience, 15(June). https://doi.org/10.3389/fnbeh.2021.699592
 Karen Daniela Garay Buenrostro A01372695
Metodología de investigación e innovación
Parcial 1: Monografía Estado del Arte

Burel, J., & Peters, B. (2017). Discovering transcriptional signatures of disease for diagnosis versus
mechanism. Physiology & Behavior, 176(3), 139–148.
https://doi.org/10.1038/nri.2018.26.Discovering
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Woods, S., Toben, C., Stacey, D., & Baune, B. (2017). Transcriptome Signature of Depression.
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