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Chapter: Essentials of Psychiatry: Psychiatric Pathophysiology: Mood Disorders

Neuropeptides and Hormones

Cortical–Hypothalamic–Pituitary–Adrenal Axis

Neuropeptides and Hormones


Cortical–Hypothalamic–Pituitary–Adrenal Axis


The cortical–hypothalamic–pituitary–adrenal axis has been intensely studied in patients with major depression (Carroll et al., 1968; Sachar et al., 1970; Stokes and Sikes, 1987; Brown et al., 1994; Nemeroff et al., 1997; Thase, 2000). The cortical–hypothalamic– pituitary–adrenal axis hyperactivity in depressed patients can be explained by hypersecretion of CRF and secondary pituitary and adrenal gland hypertrophy, although impaired negative feedback at various CNS sites including hippocampus and the pituitary are also likely to contribute. Downregulation of hippocampal miner-alocorticoid receptors and expression is reported in depressed sui-cides (Lopez et al., 1998). Hyperactivity of the cortical–hypotha-lamic–pituitary–adrenal axis also occurs in patients with bipolar disorder (Kiriike et al., 1988; Stokes and Sikes, 1987). This in-creased cortical–hypothalamic–pituitary–adrenal axis activity has been observed in mixed mood states (Evans and Nemeroff, 1983; Krishnan et al., 1983; Swann et al., 1992), mania (Godwin, 1984), and in depression in rapid-cycling patients (Kennedy et al., 1989). Effect of treatment and recovery from depression are associated with partial reversal of HPA overactivity and may be required for recovery (Garlow et al., 1999; Christensen and Kessing, 2001).


Hypothalamic–Pituitary–Thyroid Axis


About 5 to 10% of people evaluated for depression have previ-ously undetected or subclinical thyroid dysfunction (Thase, 2000). Jackson (1998) suggests that some patients with depres-sion, although generally viewed as chemically euthyroid, have alterations in their thyroid function including slight elevation of the serum thyroxine (T4), blunted thyrotropin (TSH) response to thyrotropin-releasing hormone (TRH) stimulation, and loss of the nocturnal TSH rise. One possible explanation for the blunt-ing of the TSH response to TRH challenge is a downregulation of TRH receptors in the pituitary, in response to the increased levels of TRH secreted into the hypophyseal–portal circulation (Garlow et al., 1999). Elevated CSF concentrations of TRH in depressed patients were reported by Kirkegaard et al. (1979) and Banki et al. (1988), but not by Roy et al. (1994). It has been pro-posed that brain thyroid hormones may play a role in the mecha-nisms of seasonal affective disorder and light therapy (Sher, 2000b, 2001).


Hypothalamic–Growth Hormone Axis


Mood disorders are associated with alterations in the activity of the growth hormone axis (Toivola et al., 1972; Schilkrut et al., 1975; Mendlewicz et al., 1985; Nemeroff et al., 1997; Garlow et al., 1999; Thase, 2000). The most consistent finding in depres-sion is a blunted growth hormone response to clonidine, an alpha-2 receptor agonist (Toivola et al., 1972; Thase, 2000).


Brain Growth Factor


Multiple neurochemical factors, including thyroid hormones, so-matostatin, growth hormone and brain-derived neurotrophic factor (BDNF) may affect brain growth and development (Krawiec et al., 1969; Leroux et al., 1995; Oppenheimer and Schwartz, 1997; Du-man et al., 2000). BDNF, a major neurotrophic factor in the brain, is critical for the survival and guidance of neurons during develop-ment, but is also required for the survival and function of neurons in the adult brain (McAllister et al., 1999; Duman et al., 2000).


Recent studies demonstrate that antidepressant treat-ment upregulates the cyclic adenosine monophosphate (cAMP)  response element-binding protein (CREB) cascade and expres-sion of BDNF (Duman et al., 1999). Upregulation of CREB and BDNF raises the possibility that antidepressant treatment could oppose the cell death pathway. These findings suggest that regu-lation of the cell death pathways could also contribute to the ac-tions of agents used for the treatment of bipolar disorder.


Substance P


Substance P, an undecapeptide, is abundant both in the periph-ery and in the CNS, where it is usually colocalized with one of the classical neurotransmitters, most commonly serotonin (Baby et al., 1999; Argyropoulos and Nutt, 2000; Stout et al., 2001). A role for substance P is proposed in the regulation of pain, asthma, psoriasis, inflammatory bowel disease and, in the CNS, emesis, migraine, schizophrenia, depression and anxiety. Drug develop-ment has focused most intensively on the substance P-preferring receptor, neurokinin-1. Although originally studied as potential analgesic compounds, recent evidence suggests that neurokinin-1 receptor antagonists may possess antidepressant and anxiolytic properties. If confirmed by further controlled clinical studies, this will represent a mechanism of action distinct from all exist-ing antidepressant agents. The existing preclinical and clinical literature is suggestive of, but not conclusive, concerning a role of substance P and neurokinin-1 receptors in the pathophysiology of depression and/or anxiety disorders.

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