Major depressive disorder (MDD): overview and research tools

Explore the heterogeneity of major depressive disorder and find the best tools to study this complex disorder.

Overview

• What is major depressive disorder (MDD)?
• Molecular mechanisms involved in MDD
• Role of biomarkers in MDD
• References

What is major depressive disorder (MDD)?

Major depressive disorder (MDD) is a clinically and biologically heterogeneous disorder, which is thought to originate from the interaction of susceptibility genes and noxious environmental events such as chronic stress. Although MDD is one of the most common debilitating mental disorders, its etiology and pathophysiology remain unclear.

The clinical heterogeneity in MDD together with a lack of knowledge on the pathophysiology hinder the diagnosis and the effective treatment of this disorder. Currently, MDD is diagnosed using a symptom-based approach; there is no non-invasive and quantitative test available¹.

The investigation of mechanisms underlying MDD has been complicated by the following obstacles:

• the lack of a suitable animal model of depression
• the inclusion of a set of biologically and clinically heterogeneous disorders in MDD
• the presence of different subtypes and the continual change of MDD subgrouping
• the high incidence of comorbidities of MDD with other physical or psychiatric disorders
• the lack of specificity and sensitivity rates of a single biomarker¹

Molecular mechanisms underlying MDD

Several possible pathophysiological mechanisms of depression have been suggested, including altered neurotransmission, hypothalamus-pituitary-adrenal (HPA) axis abnormalities involved in chronic stress, inflammation, reduced neuroplasticity, and network dysfunction².

Both glutamatergic and GABAergic neurotransmissions seem to play an important role in the pathogenesis of MDD. Accumulating evidence has demonstrated that the dysfunction of glutamatergic neurotransmission, particularly via N-methyl-d-aspartate (NMDA) receptors, contributes to the neurobiology of MDD. Several studies have revealed an altered expression of NMDA receptor subtypes and impaired NMDA receptor-mediated intracellular signaling pathways in brain circuits of patients with MDD. Furthermore, NMDA receptor antagonists, particularly ketamine, have been shown to exhibit rapid antidepressant effects in treatment-resistant depression in clinical studies³.

Inhibitory neurotransmitter γ-aminobutyric acid (GABA) has also been implicated in the pathophysiology of MDD. Studies have demonstrated a reduction in GABA levels in the brain, decreased expression of GABAergic interneuron markers, and alterations in GABA_A and GABA_B receptor levels in patients with MDD and chronically stressed animals^4,5.

To support your research in MDD, we’ve compiled a list of our best-selling antibodies against key targets in MDD.

Role of biomarkers in MDD

The diagnosis of MDD currently relies on clinical examination and subjective evaluation of depressive symptoms. No approved biomarker is available as part of the diagnostic criteria despite multiple studies that have been carried out to assess various biomarkers for MDD. Identification of biomarkers in MDD could help facilitate the diagnosis of the disorder, choose the optimal treatment, and predict the treatment response as well as the course of the disorder⁶.

Suggested biomarkers for MDD include growth factors, cytokines and other inflammatory markers, oxidative stress markers, endocrine markers, energy balance hormones, genetic and epigenetic features, and neuroimaging⁶.

The most investigated growth factor in MDD is BDNF, which regulates neural plasticity, migration, and survival in the central and peripheral nervous systems. Multiple studies and meta-analyses have consistently reported that plasma and serum BDNF levels are reduced in patients with depression but can be normalized by antidepressant drugs or electroconvulsive therapy⁶.

In the table below, we summarize potential biomarkers for MDD.

BDNF: brain-derived neurotrophic factor, IL: interleukin, TNF: Tumor necrosis factor, MDA: malondialdehyde, HPA: hypothalamus-pituitary-adrenal, DEX/CRH: dexamethasone/corticotropin-releasing hormone.

References:

1. Pitsillou, E. et al. The cellular and molecular basis of major depressive disorder: towards a unified model for understanding clinical depression. Mol Biol Rep. 47, 753-770 (2020).
2. Dean, J., Keshavan, M. The neurobiology of depression: An integrated view. Asian J Psychiatr. 27, 101-111 (2017).
3. Amidfar, M., et al. The role of NMDA receptor in neurobiology and treatment of major depressive disorder: Evidence from translational research. Prog Neuropsychopharmacol Biol Psychiatry. 94, 109668 (2019).
4. Fogaça, M.V., Duman, R.S. Cortical GABAergic Dysfunction in Stress and Depression: New Insights for Therapeutic Interventions. Front Cell Neurosci. 13:87 (2019).
5. Luscher, B., Shen, Q., Sahir, N. The GABAergic deficit hypothesis of major depressive disorder. Mol Psychiatry 16, 383-406 (2011).
6. Hacimusalar, Y., Eşel, E. Suggested Biomarkers for Major Depressive Disorder. Noro Psikiyatr Ars. 55, 280-290 (2018).

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