Markers for Melancholy

Depression involves, in part, dysfunctions in the perception of, response to, and interpretation of emotions. Research is now focusing on biomarkers that are involved in the pathophysiology of depression, which may lead to improved treatments.

Several parts of the brain, including the prefrontal cortex, hippocampus, amygdala, striatum, and insula, work together to regulate emotions, and people with depression exhibit altered structure and function of these areas. Many direct and indirect factors lead to these alterations, including chronic exposure to stress and genetic influences.

For the better part of a century, depression has been approached as a deficiency in specific neurotransmitters in the brain. Pharmacological treatments for depression have relied on increasing the release or blocking the destruction of these neurotransmitters, including dopamine, norepinephrine, and serotonin. Still, these therapies are only able to induce remission in approximately half of patients with depression, leaving many patients suffering and in need of help.

The drive for new treatment options has allowed researchers to focus on neuron density in regions of the brain that are involved in emotions. They have discovered that the body’s response to stress has a significant impact on the generation and destruction of neurons and that inflammatory mediators play a critical role in this response. Scientists and mental health professionals stress that, while these new theories are promising for expanding our understanding of depressive and mood disorders, all of the theories – both new and old – are interconnected and the integration of the theories will provide the most meaningful progress in the treatment of mental health.

We are still a long way away from completely defining the pathophysiology of depression, but screening for compounds or biomarkers that are influential in the disease could assist in the clinical diagnosis of depression and help identify new classes of treatments. Biomarkers like magnesium and proinflammatory cytokines including tumor necrosis factor alpha, interleukin-6, and interleukin-1 beta could reflect biological changes that occur during depression, and compounds such as ketamine and anti-inflammatory agents could moderate the effects of the biological changes.

New treatments that are being considered for depression include reduced response to stress, restoration of the appropriate balance of neurotransmitters, and neuronal generation and regulation in the hippocampus, pituitary gland, and adrenal glands. For example, stress ultimately leads to the release of glucocorticoids in the brain, and suppressing its release or modifying its binding to glucocorticoid receptors in the brain may improve depressive symptoms. Corticotropin-releasing hormone antagonists or dexamethasone are likely candidates for treatment in this case. The removal of part of the adrenal gland has also been proposed. But, a holistic treatment plan that involves cognitive and behavioral stress management techniques is also appropriate.

Changes in treatment for depression are by no means imminent, but the map we are creating of how the mind works will eventually guide the future of mental health care.


Dunjic-Kostic B, Ivkovic M, Radonjic NV, Petronijevic ND, Pantovic M, Damjanovic A, Poznanovic ST, Jovanovic A, Nikolic T, & Jasovic-Gasic M (2013). Melancholic and atypical major depression–connection between cytokines, psychopathology and treatment. Progress in neuro-psychopharmacology & biological psychiatry, 43, 1-6 PMID: 23200828

Hannestad J, DellaGioia N, & Bloch M (2011). The effect of antidepressant medication treatment on serum levels of inflammatory cytokines: a meta-analysis. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 36 (12), 2452-9 PMID: 21796103

Martin C, Tansey KE, Schalkwyk LC, & Powell TR (2014). The inflammatory cytokines: molecular biomarkers for major depressive disorder? Biomarkers in medicine PMID: 24524646

Murck H (2013). Ketamine, magnesium and major depression–from pharmacology to pathophysiology and back. Journal of psychiatric research, 47 (7), 955-65 PMID: 23541145

Rao, M and Alderson, JM. (2014). Dissecting melancholia with evidence-based biomarker tools. Current Psychiatry, 13(2):41-48, 57.

Image via Artaporn Puthikampol / Shutterstock.

Jennifer Gibson, PharmD

Jennifer Gibson, PharmD, is a practicing clinical pharmacist and medical writer/editor with experience in researching and preparing scientific publications, developing public relations materials, creating educational resources and presentations, and editing technical manuscripts. She is the owner of Excalibur Scientific, LLC.
See All Posts By The Author