Review
The CRF System as a Therapeutic Target for Neuropsychiatric Disorders

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Trends

Data support a role for altered corticotropin-releasing factor (CRF) signaling in several neuropsychiatric disorders.

CRF1 variants interact with a history of trauma, particularly in childhood, to increase the risk of these conditions.

Clinical trials of CRF1 antagonists have had limited success in the treatment of depressive disorders, substance abuse, anxiety disorders, and trauma- and stress-related disorders.

The modest success of clinical trials indicates the need for continued research on CRF system function. Recent studies have unraveled distinctive roles for the CRF1 and CRF2 receptors in balancing CRF's effects in stress and reward circuitry.

The major neuropsychiatric disorders are devastating illnesses that are only modestly responsive to treatment. Improving the treatment of these conditions will require innovative new strategies that depart from previously focused-on pharmacological mechanisms. Considerable preclinical and clinical data indicate corticotropin-releasing factor (CRF) signaling as a target for new psychotropic drug development. Here we review alterations in the CRF system reported in several psychiatric conditions. We also examine the preclinical work that has dissected the distinctive roles of CRF receptors in specific circuits relevant to these disorders. We further describe the clinical trials of CRF1 receptor antagonists that have been conducted. Although these clinical trials have thus far met with limited therapeutic success, the unfolding complexity of the CRF system promises many future directions for studying its role in the etiology and treatment of neuropsychiatric conditions.

Section snippets

The CRF System as a Novel Target for Treating Neuropsychiatric Disorders

Several neuropsychiatric disorders are severe and chronic conditions that are challenging to treat [1]. Most of the medications used to treat these conditions act on monoamine systems, a paradigm of drug action that has not changed in half a century. The less-than-optimal efficacy of these medications suggests the need for innovative new approaches that depart from the conventional drug development approaches [2]. Advances in basic neurobiology indicate CRF signaling as a target for

The CRF System

In 1981 Wylie Vale and colleagues at the Salk Institute in La Jolla, CA first reported the biochemical characterization of CRF [13]. Subsequent studies found CRF mRNA and CRF to be broadly distributed in the central nervous system (CNS) and enriched in the paraventricular nucleus of the hypothalamus (PVN), brain stem, amygdala, hippocampus and, neocortex [4]. On being released from neurons, CRF binds mainly to two seven-transmembrane G protein-coupled receptors with high sequence homology (∼70%

CRF in Psychopathology: From Bench to Bedside

Abnormalities in the CRF system are implicated in a gamut of psychiatric disorders 5, 6, 31, 32. Here we discuss data from patients affected by major categories of mental illness as classified in the most recent version of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) [33]. In parallel, we also examine preclinical studies seeking to dissect the significance of these CRF abnormalities in brain function. We further review the results of clinical trials that have tested CRF1

Concluding Remarks and Future Perspectives

In conclusion, these data strongly support the hypothesis of altered CRF signaling in the etiology of mood disorders, trauma- and stress-related disorders, and substance-related and addictive disorders 34, 51, 52, 57. These data reveal a more complex association between CRF and anxiety disorders, where interactions with other neuromodulatory systems are likely to mediate its role 71, 72.

In agreement with early clinical studies 5, 12, preclinical research suggests that excessive CRF receptor

Acknowledgments

This work was primarily supported by the National Institute of Mental Health (K08 MH 105754-01).

Glossary

Antagonist
a compound that blocks a drug from binding to a receptor.
Basolateral amygdala (BLA)
a division of the amygdala that is commonly involved in the expression of fear and anxiety.
Bed nucleus of stria terminalis (BNST)
a brain structure that is involved in anxiety and reward. It is commonly involved in drug-seeking behavior in rodents.
Behavioral despair
immobile responses that animals make when they are forced to swim in a container from which they cannot escape.
Post-traumatic stress disorder

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