Evidence-Based Reviews

Dissecting melancholia with evidence-based biomarker tools

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Insight into the neuroanatomical pathophysiology of depression may shed light on the future of managing this disease.



For more than 50 years, depression has been studied, and understood, as a deficiency of specific neurotransmitters in the brain—namely dopamine, norepinephrine, and serotonin. Treatments for depression have been engineered to increase the release, or block the degradation, of these neurotransmitters within the synaptic cleft. Although a large body of evidence supports involvement of dopamine, norepinephrine, and serotonin in the pathophysiology of depression, the observation that pharmacotherapy is able to induce remission only in <50% of patients1 has prompted researchers to look beyond neurotransmitters for an understanding of depressive disorders (Table 1).

Today, theories of depression focus more on differences in neuron density in various regions of the brain; the effect of stress on neurogenesis and neuronal cell apoptosis; alterations in feedback pathways connecting the pre-frontal cortex to the limbic system; and the role of proinflammatory mediators evoked during the stress response (Box,2,3). These theories should not be viewed as separate entities because they are highly interconnected. Integrating them provides for a more expansive understanding of the pathophysiology of depression and biomarkers that are involved (Table 2).

In this article, we:

  • integrate the large body of evidence supporting the contribution of the above variables to the onset and persistence of depression
  • propose a possible risk stratification model
  • explore possibilities for treatment.

The stress response: How does it affect the brain?

Stress initiates a cascade of events in the brain and peripheral systems that enable an organism to cope with, and adapt to, new and challenging situations. That is why physiologic and behavioral responses to stress generally are considered beneficial to survival.

When stress is maintained for a long period, both brain and body are harmed because target cells undergo prolonged exposure to physiologic stress mediators. For example, Woolley and Gould4 exposed rats to varying durations of glucocorticoids and observed that treating animals with corticosterone injection for 21 days induced neuronal atrophy in the hippocampus and prefrontal cortex and increased release of proinflammatory cytokines from astrocytes within the limbic system. Stressful experiences are believed to be closely associated with development of psychological alterations and, thus, neuropsychiatric disorders.5 To go further: Chronic stress is believed to be the leading cause of depression.

When the brain perceives an external threat, the stress response is called into action. The amygdala, part of the primitive limbic system, is the primary area of the brain responsible for triggering the stress response,6 signaling the hypothalamus to release corticotropin-releasing hormone (CRH) to the anterior pituitary gland, which, in turn releases adrenocorticotropic hormone to the adrenal glands (Figure 1).7 The adrenal glands are responsible for releasing glucocorticoids, which, because of their lipophilic nature, can cross the blood-brain barrier and are found in higher levels in the cerebrospinal fluid (CSF) of depressed persons.7

Once in the brain, glucocorticoids can be irreversibly degraded in the cytosol by the enzyme 11-β hydroxysteroid dehydrogenase type 2, a potential target for treating depression, or can bind to the glucocorticoid receptor (GR). Results of a research study of the role of cortisol in suppression of proinflammatory cytokine signaling activity in rainbow trout hepatocytes suggest a negative feedback loop for GR gene regulation during stress.8

Because this auto-regulation is a crucial step in the physiological stress response, the idea of the GR as an important biomarker in depression has gained popularity. In humans, when the GR binds to glucocorticoids that are released from the adrenal cortex during the stress response, the activated GR-cortisol complex represses expression of proinflammatory proteins in astrocytes and microglial cells and in all cells in the periphery before they are transcribed into proteins.9 The GR also has been shown to modulate neurogenesis.8 Repeated stress that persists over a long period leads to GR resistance, thereby reducing inhibition of production of proinflammatory cytokines.

Exposure to stress for >21 days leads to overactivity of the HPA axis and GR resistance,10 which decreases suppression of proinflammatory cytokines. There is evidence that proinflammatory cytokines, tumor necrosis factor-α, and interleukin-6 further induce GR receptor resistance by preventing the cortisol-GR receptor complex from entering cell nuclei and decreasing binding to DNA within the nuclei.11 Dexamethasone, a GR agonist, has been implicated in research studies for potential re-regulation of the HPA axis in depressed persons.12

Nerve cell death in the hippocampus

Studies showing reduced hippocampal volume in unipolar depression and a correlation between the number of episodes and a consequence of untreated depression and studies suggesting that treatment can stop or reduce shrinkage,13 and recent findings of rapid neurogenesis in hippocampi in response to ketamine, brings our focus to hippocampus in depression.


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