■ REVIEW : Corticotropin-releasing Factor, Stress, and Depression

Abstract

Corticotropin-releasing factor (CRF), a 41 amino acid-containing neuropeptide, acts both as a hypothalamic releasing factor, controlling ACTH and corticosteroid secretion, and at extrahypothalamic CNS sites to mod ulate mammalian organisms' responses to stress. In this article, the evidence that CRF-containing neurons within the CNS are hyperactive in patients with depression is reviewed. The evidence, taken together, suggests that during depressive episodes, CRF is hypersecreted, resulting in both pituitary-adrenal axis hyperactivity and certain of the signs and symptoms of depression, including decreased appetite, decreased libido and disturbed sleep. There is also evidence that treatments for depression, including antidepressant medications and electroconvulsive therapy, reduce CRF hypersecretion within the CNS. Finally, evidence suggests that alterations in CRF-containing neurons and receptors are responsible for the widely held ob servation that early untoward life events increase an individual's vulnerability for affective disorders. These findings have a number of implications for treatment of the mood disorders, including the suggestion that the pharmacological manipulation of CRF receptors may provide a novel avenue for the treatment of de pression. NEUROSCIENTIST 3:186-194, 1997

Increased ACTH Concentrations Associated with Cholecystokinin Tetrapeptide-Induced Panic Attacks in Patients with Panic Disorder

“…Moreover, CRH has neurotransmitter-like properties outside the hypothalamus (Hayden-Hixson and Nemeroff 1993). CRH-containing neurons innervate noradrenergic centers in the pons (locus coeruleus) and the central nucleus of the amygdala, areas of recognized importance in anxiety and stress response (Gorman et al 1989;Holsboer et al 1992;Heit et al 1997). Furthermore, preclinical data indicate that CRH may play a role in the anxiogenic (Biro et al 1993) and endocrine (Kamilaris et al 1992) effects of CCK.…”

New directions in the development of antidepressants: the interface of neurobiology and psychiatry

“…It is now well established that CRF orchestrates the central nervous system's control of the behavioural, endocrine, autonomic and immunological response to stress (Owens and Nemeroff, 1991;Heit et al, 1997). CRF-containing cell bodies are distributed heterogenously throughout the brain, with the highest density in the medial parvocellular division of the hypothalamic paraventricular nucleus.…”

The preeminent role of early untoward experience on vulnerability to major psychiatric disorders: the nature-nurture controversy revisited and soon to be resolved

“…6 The biological basis for the increased vulnerability to mood and anxiety disorders appears to be mediated, at least in part, by persistent activation and hyperresponsiveness of the hypothalamic and extrahypothalamic corticotropin-releasing factor (CRF) circuits, as demonstrated in a series of studies by Plotsky, Meaney, and Nemeroff in rats, 7,8 and by our group in collaboration with Coplan, Gorman and Rosenblum in nonhuman primates. 9 Evidence for CRF expression in neurons that do not normally express the peptide has been observed in these animal models of early stress, as well as in postmortem studies of depressed patients.…”

“…The early stress-induced changes in CRF neurons that persist into adulthood have been demonstrated by measurement of increased CSF CRF concentrations, increased CRF mRNA expression, increased CRF concentrations in the median eminence and the hypothalamo-hypophyseal portal system, as well as alterations in CRF receptor density. [7][8][9] Recently we have completed a pilot clinical study, seeking to determine whether women with a history of child abuse with or without current major depression, demonstrate enhanced hyperactivity of the hypothalamic-pituitaryadrenal (HPA) axis in response to a social stressor. In comparison to normal subjects, women with a history of child abuse, exhibited markedly exaggerated ACTH and cortisol responses in this standardized social stress test (the Trier Social Stress Test), as well as an exaggerated heart rate response.…”