Stress Neurobiology and Corticotropin-Releasing Factor: Page 4 of 4
Stress Neurobiology and Corticotropin-Releasing Factor: Page 4 of 4
CRF1 receptor antagonists have elicited activity
in animal models of anxiety and depression. CRF
receptor antagonists have been tested in many different
paradigms, including the elevated plus maze,
foot shock, restraint stress, and defensive withdrawal.
Pretreatment with CRF receptor antagonists decreases
measures of anxiety induced by stressors.
There is also some evidence that CRF receptor antagonists
may reduce the effects of drug withdrawal
and stress-induced relapse to drug seeking in
rats.47,72-74 Based on this premise, newly developed
CRF1 receptor antagonists represent a novel putative
class of antidepressants. Such compounds show
activity in nearly every preclinical screening test for
antidepressants and anxiolytics.
Despite the rich preclinical and clinical literature
supporting a potential role for CRF1 receptor
antagonists, there has only been 1 published study
investigating the effects of a CRF1 receptor antagonist
in humans. A small open-label study examining
the effectiveness of R121919, a CRF1 receptor
antagonist, in major depression was completed more
than 5 years ago.75 This study of 20 patients showed
that R121919 (5 to 40 mg/d or 40 to 80 mg/d for
30 days) was well tolerated by patients and did not
significantly affect plasma ACTH or cortisol concentrations
at baseline or following CRF challenge. It
is important that the use of any potential CRF antagonist
not lead to complete HPA axis blockade and
adrenal insufficiency, which can, of course, result
in a severe medical emergency. Hamilton Depression
Rating Scale and Hamilton Anxiety Scale severity
scores were both significantly reduced following
30-day treatment with this drug. Although this small
open-label study does not provide unequivocal
proof, it does provide further evidence that a selec-
tive CRF-receptor antagonist may provide antidepressant
and antianxiety properties in humans.75
Although this drug is no longer in clinical development
because of hepatotoxicity, several novel CRF1
antagonists are currently under investigation.
Conclusions and future directions
Since the discovery of CRF more than 25 years ago,
evidence has accumulated indicating a preeminent
role for this peptide in the pathophysiology of depression
and anxiety. The recent introduction of
small-molecule CRF receptor antagonists as a novel
class of antidepressant and anxiolytic drugs remains
very promising. These compounds block the actions
of exogenous and endogenous CRF in a variety of
in vivo models, supporting a putative role for these
agents in the treatment of stress and/or anxiety and
affective disorders. The promising clinical results
in patients with depression in the completed open
trial of R121919 is of great interest and the results
of further studies are eagerly awaited.
As we await the results of additional clinical trials
examining the efficacy of CRF1 receptor antagonists
in anxiety and mood disorders, it should be
pointed out that these compounds may be beneficial
in a broad array of neuropsychiatric disorders
(including eating disorders, child abuse, and drug
abuse), as well as irritable bowel syndrome and
inflammatory diseases. Whether these drugs will be
effective as monotherapy or whether they represent
an important class of augmenting agents remains to
be determined. Furthermore, the development of
single photon emission CT and positron emission
tomography ligands from these lead compounds for
use in neuroimaging studies are likely to be useful
in furthering our understanding of the pathophysiology
of these mood and anxiety disorders.76,77
Drugs mentioned in this article:
Desipramine (Norpramin, Pertofrane)
Fluoxetine (Prozac, Serafem)
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