Dissecting melancholia with evidence-based biomarker tools

The greatest density of GRs is found in the hippocampus, which is closely associated with the limbic system.⁷ Therefore, the hippocampus is sensitive to increases in glucocorticoids in the brain and plays a crucial role in regulation of the HPA axis.

Evidence shows that in chronic stress exposure (≥21 days), nerve cells in the hippocampus begin to atrophy and can no longer provide negative feedback inhibition to the hypothalamus, causing HPA axis dysregulation and uncontrolled release of glucocorticoids into the bloodstream and CSF.² In patients with Cushing syndrome, who produce abnormally high levels of glucocorticoid, the incidence of depression is as high as 50%.¹⁴ Similarly, patients treated with glucocorticoids such as prednisone often experience psychiatric symptoms, the most common being depression. Gould found that partial adrenalectomy increased hippocampal neurogenesis in rat brains, indicating the beneficial effect of stress hormone antagonism.⁴ CRH antagonists are being looked at as a promising and less invasive treatment option for depression.

Focus has been diverted to the role of the hippocampus in depression because of its ability to regenerate throughout adulthood, leading potentially to a re-regulation of the HPA axis and subsiding of the stress response, which is universally believed to be the primary precipitating factor in depression onset. Rats require 10 to 21 days of rest to recover from the effects of chronic (21 days) administration of glucocorticoids.¹⁵ If this proves to be a directly proportional relationship, then rats would need an estimated 120 days to recover from 6 months of constant glucocorticoid exposure. Considering that the same is true for humans, current depression treatment programs, which average 6 weeks, are not long enough for adequate recovery.

Antidepressants such as selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and tricyclics stimulate neurogenesis in the hippocampus via increases in brain-derived neurotrophic factor (BDNF), suggesting that these neurotransmitters play an important role depression.¹⁶

Repetitive transcranial magnetic stimulation (rTMS), a noninvasive neuromodulation therapy approved to treat major depression, delivers brief magnetic pulses to the limbic structures. Treatment facilitates focal stimulation, rapidly applying electrical charges to the cortical neurons. TMS targets prefrontal circuits of the brain that are underactive during depressive episodes. Recent animal studies have suggested that bromodeoxyuridine (BrdU)-positive cells (newborn cells) are increased significantly in the dentate gyrus, in turn suggesting that hippocampal neurogenesis might be involved in the antidepressant effects of chronic rTMS.¹⁷ Although the underlying therapeutic mechanisms of rTMS treatment of depression remain unclear, it appears that hippocampal neurogenesis might be required to produce the effects of antidepressant treatments, including drugs and electroconvulsive therapy.¹⁷

Selective ‘shunting’ of energy occurs during the stress response

Hormones released from the adrenal glands during stress divert glucose to exercising muscles and the brain’s limbic system, which are involved in the fight-or-flight response.¹⁸ However, metabolic functions and areas of the brain that are not involved in the stress response, such as the cerebral cortex and hippocampus, are deprived of energy as a consequence of this innate selective shunting (Figure 2).¹⁹

Positron-emission tomography (PET) scanning of the resting brain shows that components of the cerebral cortex (prefrontal cortex, hippocampus, striatum) and areas connecting the cerebral cortex to the limbic system exhibit the most energy consumption in the brain during rest (Figure 3).²⁰ PET studies also show that neuronal connections within these energy-demanding areas atrophy more rapidly than in any other area of the brain when their energy supply is reduced or cut off.⁶

When the supply of oxygen and glucose to certain areas of the brain is reduced—such as in traumatic brain injury or stroke—the excitatory neurotransmitter glutamate accumulates in extracellular fluid and causes nerve-cell death.²¹ When a conditioned stimulus is presented during fear acquisition, functional magnetic resonance imaging (fMRI) studies of fear-conditioning have consistently reported, in the prefrontal cortex:

• a decrease in the blood oxygen level-dependent signal, below resting baseline
• a reduction in blood flow (Figure 4).²²

This discovery adds to evidence that demonstrates a decrease in gray-matter density in the frontal lobes as a result of glutaminergic toxicity (Figure 5).

Activation of L-glutamate, believed to play a significant role in depression and other neuropsychiatric disorders, triggers calcium-dependent intracellular responses that “excite cells to death,” so to speak—thereby causing nerve-cell apoptosis and a reduction in synaptic connections between different areas of the brain responsible for learning and memory.²³ Malfunction of these synaptic connections is thought to be partially responsible for depression and other psychiatric disorders.

Excessive activation of N-methyl-d-asparate (NMDA) receptors is thought to be the underlying mechanism that leads to neuronal cell death in glutaminergic toxicity. Therefore, NMDA receptor proteins have become a target in treating neurodegenerative psychiatric illnesses. There is more than one type of NMDA receptor; some of them are excitatory, others are inhibitory. Four compounds have presented as therapeutic candidates for inhibition of NMDA receptor functioning and treatment of depression: those that inhibit glutamate binding, those that block the ion channel, and those that inhibit receptor binding to the terminal regulatory domain.²⁴