DOI: 10.31038/EDMJ.2024811

Major depression is the 2^nd greatest cause of disability worldwide, and the first greatest cause in individuals under 45 years of age. It is a lifetime disorder with multiple depressive episodes interspersed by remissions. Its principal manifestations include anxiety, especially directed at the self, feelings of worthlessness, inability to anticipate or experience pleasure, significant changes in appetite and sleep, hypersecretion of cortisol and norepinephrine [1], and a highly significant increase in the incidences of complex medical illness such as coronary artery disease, stroke [2], diabetes [3], and osteoporosis [4]. Specific central nervous system loci have been connected to these stigmata. There is a. loss of 40% in the volume of the subgenual prefrontal cortex [5,6], making depression a neurodegenerative disease. This site estimates the likelihood of punishment or reward, helps set the tone for the level of self-esteem, ordinarily restrains the amygdala in its generation of fear, accentuates the activity of the nucleus accumbens reward and pleasure center, and restrains the activity of the CRH-cortisol system and the sympathetic nervous system [1]. Its deficits in depression contribute to the majority of its principal clinical manifestations. As noted, these include anxiety and feelings of worthlessness, the decreased activities of the nucleus accumbens and ventral striatal system reward and pleasure centers, as well as hypercortisolism and a hypernoradrenergic state [1].

Hormonal mediators play large roles in these clinical and biochemical manifestations [7]. Corticotropin releasing hormone plays a significant role in the overall biological stigmata of depressive illness. We showed that CRH was hypersecreted in depression [8]. It is predominantly located in the hypothalamus to stimulate the pituitary-adrenal axis and in the amygdala to activate the locus-ceruleus norepinephrine system. It is by itself neurotoxic, and one of its principal effects, the inducement of hypercortisolism also promotes neurodegeneration and maladaptive central nervous system activity. It is also a potent stimulus to inflammation, and its actions include promoting the degranulation of mast cells. Either psychological or emotional stress activates both the hypothalamic and amygdala components of the CRH system [8].

Stress also activates inflammation in the brain and periphery independent of CRH. Circulating inflammatory mediators also damage neural tissue and function and play a significant role in the stigmata of depression [9,10]. In our early evolutionary history, the primary stressors were serious: either competition for territory or competitions for mates. In these instances, even the perception of danger stimulated neuroinflammation, in part, as a premonitory response to support tissue repair in the face of a flight or fight situation.

Norepinephrine excess in depression [11,12] also has deleterious effects. It not only produces anxiety, but also increases heart rate and blood pressure, production of a proinflammatory state (synergistic with CRH) increased coagulation, and insulin resistance.

Insulin in brain derives from the periphery to activate a host of insulin receptors in sites that are involved in depressive pathophysiology. Insulin resistances in the periphery [9] associated with increased plasma insulin levels decrease insulin transport into the CNS by downregulating blood brain barrier insulin receptors. Insulin in brain supports the density of synapses, maintain synaptic itegrity, and synaptic density and integrity decrease when insulin receptors are removed or dysfunctional. Depression is associated with significant synaptic dysfunction in multiple ways [13].

Estrogen in females and androgens in male are often reduced in depression. Estrogen is neuroprotective, anti-inflammatory, reduces anxiety and depression, promote cognition, and modulate synaptic plasticity in rodents. Androgen deficiency is associated with depression which is corrected by restoring androgen levels to normal.

Thyroid hormones are often low in patients with depressive illness [14]. Thyroid hormones suppress the activity of the amygdala and thyroid deficiency is likely to promote anxiety. Adult hypothyroidism is associated with an increase in glucocorticoid actions in the amygdala, which we have shown promotes anxiety, is associated with fear memory enhancement, and deficits in the extinction of fear memories. These deficits are reversed by thyroid hormone replacement.

Concluding Remarks

Endocrine abnormalities contribute to the neurogenerative aspects of depressive illness, to synaptic abnormalities, and can adversely affect sites such as the amygdala and the ventral striatum. CRH, noradrenergic, and glucocorticoid antagonists and anti-inflammatory treatment can all have therapeutic potential for treating depression. Agents that are neuroprotective can also have therapeutic potential in treating depression, and multiple neuroprotective compounds are currently in active trials in antidepressant protocols.

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