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INNOSC Theranostics and
Pharmacological Sciences MDD biomarkers: Clinical implications

1. Introduction to save time and money while benefiting both patients and
physicians. Here, we have compiled potential biomarkers
Major depressive disorder (MDD), also known as for MDD authenticated by published literature.
clinical depression, is characterized by a persistent
feeling of sadness and a loss of interest in daily activities, 1.1. Pathophysiology of MDD
significantly impairing social and physical functioning. MDD is believed to arise from complex interactions
It is associated with an increased risk of self-harm and between genetic, environmental, and biological factors.
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substance abuse. It has a remitting and relapsing course The pathophysiology of MDD is multifaceted, involving
and each episode lasts longer than 2 weeks. Due to poor dysregulation in neurotransmitter systems, inflammation,
treatment response, the majority of patients progress and neuroplasticity changes, collectively contributing to
to chronic or treatment-resistant depression (TRD). the manifestation of depressive symptoms. It has been
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Worldwide, approximately 300 million people suffer from reported that genetic predisposition plays a significant
this debilitating disease accounting for 3.4% of the global role in the development of MDD. Family and twin
population, with prevalence rates varying from across studies have consistently shown that MDD is heritable,
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countries. In our part of the world specifically in South with heritability estimates ranging from 30% to 40%.
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Asia, this percentage is relatively low (3.0%) which may Several genetic variants have been implicated in MDD,
be attributed to insufficient reporting, lack of awareness including those affecting the serotonin transporter gene
about mental health disorders, and hesitancy in seeking (5-HTT) and the brain-derived neurotrophic factor
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medical care due to social barriers. According to global (BDNF) gene. Polymorphisms in these genes can influence
health metric data, the years lived with disability due to neurotransmitter function and neuroplasticity, thereby
depressive disorders increased by 47% during the last three increasing the risk of developing MDD. Apart from genetic
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decades for all ages and both sexes and marked MDD variations, environmental stressors are also critical in
as the third leading cause of disability globally. Mental triggering depressive episodes, particularly in individuals
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health disorders impose an alarming burden on national with a genetic predisposition. Adverse life events such as
and international health budgets but even then MDD has childhood trauma, loss of a loved one, or chronic stress can
not received as much research attention as much as other precipitate the onset of MDD. These stressors can activate
diseases, e.g., cardiovascular disease and cerebrovascular the hypothalamic-pituitary-adrenal (HPA) axis, leading to
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accidents. Despite extensive research, scientists could not increased production of cortisol, a stress hormone that has
reveal much about MDD pathophysiology which led to a been associated with depression. Chronic stress can also
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rise in its prevalence and chronicity.
result in epigenetic changes, altering gene expression and
A biomarker is a computable biological measure that further contributing to the risk of MDD. 11
directly correlates with the detection or absence of a specific The monoamine hypothesis of depression posits
disease process, its severity, and/or its risk of evolving. that dysregulation of neurotransmitters, such as
Biomarkers are the essential guide and presently the serotonin, norepinephrine, and dopamine, is central
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keystone of disease management. Biomarkers can serve as to the pathophysiology of MDD. Reduced levels of
trait markers when they define disease pathogenesis or as these neurotransmitters in the synaptic cleft can lead
state markers when they define the clinical progression of to depressive symptoms. Antidepressant medications,
a disease. Due to the lack of differentiating markers that which increase the availability of these neurotransmitters,
distinguish MDD from other disorders of this category, provide indirect support for this hypothesis. 11,12 The single
such as bipolar disorder and generalized anxiety disorder, most potent neurotransmitter of the brain is glutamate
diagnosis often takes months or even years and still relies as it plays a major role in learning, cognition, and mood
on decades-old patient-centered and clinician-centered stabilization by enhancing synaptogenesis and neuronal
assessment interviews. Efficient disease management plasticity. Stress induces neurons to secrete glutamate at
demands biomarkers for screening purposes, prediction, synaptic junctions, which strongly binds to the N-methyl
diagnosis, prognosis, and treatment response. However, D-aspartate receptor (NMDAR), initiating downstream
presently there is no officially approved biomarker for signaling pathways. Blocking NMDAR or reducing
highly prevalent MDD. Recently, various research projects glutamate levels exerts a profound antidepressant effect,
explored valid and reliable biomarkers for predicting and as classically observed with ketamine administration in
diagnosing various forms of MDD, including early-onset patients with suicidal thoughts. 13
MDD, late-onset MDD, and TRD. In parallel, scientists have
probed biomarkers for predicting treatment responses to Inflammation is increasingly recognized as a critical
various antidepressants, aiming to personalized treatment component in the pathophysiology of MDD. Elevated
and prevent TRD. Biomarker discovery has the potential levels of pro-inflammatory cytokines, such as interleukin-6

Volume 8 Issue 2 (2025) 32 doi: 10.36922/itps.4404