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Chapter: Essentials of Psychiatry: Mood Disorders: Depression

Depression: Neurohormonal Theories

The contribution of endocrine system alterations in depression has been examined extensively in biological studies.

Neurohormonal Theories


The contribution of endocrine system alterations in depression has been examined extensively in biological studies. Both hy-pothyroidism and hypercortisolism may result in depression.


Hypothalamic–Pituitary–Thyroid Axis


Hypothalamic–pituitary–thyroid (HPT) axis abnormalities are commonly seen in patients with bipolar disorder. Thyroid hor-mone has been used in antidepressant augmentation as well as in the modulation of rapid cycling bipolar disorder. Neurotrans-mitters regulate hypothalamic functioning and initiate release of thyrotropin-releasing hormone (TRH) into the portal circulation. TRH is transported to the pituitary causing release of thyroid-stimulating hormone (TSH). TSH modulates synthesis and re-lease of T3 and T4.


Thyroid studies in depression are not conclusive. There are more reports of slightly increased peripheral T4 in major de-pression than low T4. Some patients have mild or “sub-clinical” hypothyroidism as reflected in slight TSH abnormalities and as-sociated antithyroid antibodies. The TRH stimulation test has provided suggestive findings: 1) blunted TSH response to TRH occurs in approximately 30% of depressed patients; 2) a possi-ble bipolar/unipolar difference has been reported with bipolar depression showing an augmented TSH response while unipolar depression shows a blunted response; and 3) CSF TRH is found to be raised in some patients with depression, possibly respon-sible for the blunted response of TSH to TRH, and lower levels of circulating T3 and T4. One implication of the suggested bipo-lar–unipolar distinction is that bipolar depressed patients may demonstrate a false hypothyroidism, when their TSH response is consistent with the underlying bipolar disorder. Effective treat-ment of the bipolar disorder may reverse the TSH abnormality.


Hypothalamic–Pituitary–Adrenal Axis


The hypothalamic–pituitary–adrenal axis (HPA) has been the sub-ject of intensive investigation as well. The observation of elevated cortisol secretion from the adrenal glands has been replicated consistently in patients with major depression. Corticotropin-releasing factor (CRF) is the hypothalamic hormone that regu-lates pituitary secretion of corticotropin (ACTH). CRF activity is influenced by multiple neurotransmitters such as 5HT, NE, ACh and GABA. ACTH binds to cells in the adrenal cortex producing release of glucocorticoids, particularly cortisol. Cortisol inhibits secretion of ACTH at the anterior pituitary and CRF at the hy-pothalamus. Measurements of 24-hour urinary cortisol, cortisol in the CSF and cortisol following dexamethasone suppression suggested increased cortisol secretion in MDD. The dexametha-sone suppression test (DST) performed by offering dexametha-sone at 11PM followed by serum cortisol at 8AM, 4PM and 11PM is a neuroendocrine probe that demonstrated adrenocortical hyper-activity in depression. DST nonsuppression normalizes with re-covery from depression. Persistent nonsuppression is associated with early relapse of MDD. Increased CRF secretion may explain the hypercortisolemia and HPA overactivity. Hypercortisolemia is one of the most consistent findings in biological studies of MDD.


Intracellular Abnormalities


A number of intracellular changes, which involve alteratations in cellular second messenger systems and ion channels, are postu-lated to occur in depression. The may involve changes in guanine triphosphate binding proteins, G-proteins on the receptor, cyclic adenosine monophosphate (cAMP) regulation, reduced protein kinase activity and brain derived neurotrophic factor (BDNF). Stress itself has been associated with lowered levels of BDNF, which leaves vulnerable to neurotoxic effects of stress. Antide-pressants as well as ECT increase BDNF and BDNF has been found to increase functioning of serotonin.

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