Stress Neurobiology and Corticotropin-Releasing Factor

Stress Neurobiology and Corticotropin-Releasing Factor

Sponsored by CME LLC for 1.5 Category 1 credits.

Original release date 09/06. Approved for CME credit through August 2007.

Educational Objectives:
After reading this article, you will be familiar with:
  • The evidence linking hypothalamicpituitary-
    adrenal axis abnormalities and
    psychiatric symptoms.
  • The role of corticotropin-releasing factor
    (CRF) in depressed patients.
  • Extrahypothalamic CRF circuits and their
    impact on depression.

Who will benefit from reading this article?

Psychiatrists, primary care physicians,
neurologists, nurse practitioners, psychiatric
nurses, and other mental health care professionals.
Continuing medical education credit
is available for most specialties. To determine
whether this article meets the CE requirements
for your specialty, please contact your
state licensing board.

Dr Gutman is a resident in the department of psychiatry;
Ms Gutman is an MD, PhD candidate; Dr Owens is associate
professor in the department of psychiatry and behavioral
sciences and associate director of the laboratory
of neuropsychopharmacology; and Dr Nemeroff is
Reunette W. Harris Professor and chair of the department
of psychiatry and behavioral sciences at Emory University
School of Medicine in Atlanta.

Dr Gutman and Ms Gutman report that they are consultants
for WebMD. Dr Owens reports that he has received
research grants from Pfizer, GlaxoSmithKline, Merck, and
Lundbeck. He is a consultant for Bristol-Myers Squibb,
Cielo Institute, Cypress Bioscience, Pfizer, Lundbeck,
Sepracor, and Johnson & Johnson, and he has received
speaker's honoraria from Forest Laboratories, Glaxo-
SmithKline, and Pfizer. Dr Nemeroff reports that he has
received research grants from the American Foundation
for Suicide Prevention (AFSP), AstraZeneca, Bristol-Myers
Squibb, Forest Laboratories, Janssen, National Alliance
for Research on Schizophrenia and Depression, NIMH,
Pfizer, and Wyeth. He is a consultant for Abbott Laboratories,
Acadia Pharmaceuticals, Bristol-Myers Squibb,
Corcept Therapeutics, Cypress Bioscience, Cyberonics,
Eli Lilly, Entrepreneurs Fund, Forest Laboratories, Glaxo-
SmithKline, i3 DLN, Janssen, Lundbeck, Otsuka, Pfizer,
Quintiles, UCB, and Wyeth. He is on the Speakers
Bureau for Abbott Laboratories, GlaxoSmithKline,
Janssen, and Pfizer. In addition, he is a stockholder in
Acadia Pharmaceuticals, Corcept Therapeutics, Cypress
Bioscience, and NovaDel Pharma; and on the Board of
Directors of AFSP, the American Psychiatric Institute for
Research and Education, the George West Mental
Health Foundation, NovaDel Pharma, and the National
Foundation for Mental Health; and he holds equity in
Reevax, BMC-JR LLC, and CeNeRx.

This work was supported in part by MH-58922 (Sylvio
O. Conte Center for the Neuroscience of Mental Disorders)
and MH-42088.

The concept that stressful life events may
render one vulnerable to psychiatric disease
has been a mainstay of the psychiatric literature
for more than a century. This idea was
initiated, in part, by the pioneering work of Sigmund
Freud,who used psychoanalytic methods to explore
the relationship between stressful life events and
psychopathology. These concepts slowly evolved
into more biologically based theories with the early
work of Hans Selye, who studied the relationshipbetween stress, illness, and emotions. The occurrence
of depression, anxiety, and other psychiatric
symptoms in both Cushing and Addison diseases,
which are associated with excessive or markedly
reduced levels of circulating glucocorticoids, respectively,
served as a further impetus for researchers
to scrutinize hypothalamic-pituitary-adrenal (HPA)
axis function in psychiatric disorders.

HPA axis abnormalities
in depression

Evidence linking HPA axis abnormalities and psychiatric
symptoms dates back over 100 years, and
numerous studies have been conducted in this area.
Some of the earliest controlled clinical studies in
psychiatry, dating back to the 1950s, demonstrated
a number of abnormalities in glucocorticoid (ie, cortisol)
function in depressed patients, including elevated
plasma cortisol concentrations,1,2 increased 24-hour
urinary free cortisol concentrations, and increased
levels of cortisol metabolites in urine.3 Elevated cortisol
secretion in depression is among the most reproducible
findings in all of biologic psychiatry.
Structural changes in the components of the HPA
axis have also been documented in depressed
patients, including pituitary gland enlargement
demonstrated by MRI4 and enlargement of the adrenal
glands, presumably due to adrenocorticotropic
hormone (ACTH) hypersecretion in depressed
patients postmortem5,6 and in suicide victims.7 The
adrenal gland enlargement seen in depression has
been confirmed using MRI, and it appears to be
state-dependent,8,9 waxing and waning in parallel
with exacerbation and resolution of depressive
symptoms, respectively.

Corticotropin-releasing factor

Although Saffran and colleagues10 identified a crude
extract that promoted the release of ACTH from the
pituitary in 1955, the ultimate regulator of ACTH
and cortisol release--corticotrophin-releasing factor
(CRF)--was not isolated and chemically characterized
until 1981. Working with extracts derived
from 500,000 sheep hypothalami, Vale and
colleagues11 at the Salk Institute isolated, synthesized,
and elucidated the structure of CRF. This
discovery led to the availability of synthetic CRF,
which allowed for a comprehensive assessment of
the HPA axis. Based on findings from numerous
studies, it is clear that CRF coordinates the endocrine,
immune, autonomic, and behavioral responses of
mammals to stress (Figure).12,13

In the hypothalamus, CRF is synthesized primarily
in the parvocellular neurons of the paraventricular
nucleus (PVN). These PVN CRF neurons receive input from a variety of brain regions, including
the amygdala, the bed nucleus of the stria terminalis,
and the brain stem.14 Hypothalamic CRFcontaining
neurons project to the median eminence.15


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