The rationale for corticotropin-releasing hormone receptor (CRH-R) antagonists to treat depression and anxiety
Introduction
For more than 100 years psychopharmacology has been shaped by compounds that have emerged from organic chemistry laboratories and whose systemic effects have then been studied by careful but unsystematic analysis. For example, in 1832 the German chemist Justus von Liebig synthesized chloral hydrate from ethanol and chlorinated lime. A few years later, in Boston, the American physician Charles T. Jackson accidentally observed the sedating effect of ether. This led researchers to test sedating and narcotic effects of other gaseous compounds such as chloroform. The German pharmacologist Oscar Liebreich postulated that chloroform might derive from chloral hydrate by degradation in blood, suggesting that chloral hydrate might be a sedative drug that could be administered orally. The first clinical trials, conducted in the department of psychiatry of the Charité Hospital in Berlin, confirmed the postulated sedative effect, although it turned out that it was not the decomposition of chloral hydrate into chloroform that caused sedation. Similar cases in which potential clinical applications for newly developed chemical compounds were investigated led to the description of clinical indications for barbiturates and phenothiazines. A prominent serendipitous finding, made by the psychiatrist Roland Kuhn in Switzerland in the mid-50s, was for instance the discovery that heterocyclic compounds such as iminodibenzyl derivatives, to which imipramine belongs, have the property to act as antidepressants. All these developments have several characteristics in common: (1) The compounds were synthesized without any anticipation of their clinical utility; (2) their mode of action was unknown and the mechanism thought to be involved in the obvious clinical efficacy often turned out to be wrong; and (3) the clinical efficacy stimulated hypotheses about the causality of the respective disorder. For example, the Australian psychiatrist John Cade believed that lithium salts act through diathesis of uric acid, which produces psychosis. This hypothesis did not stand the test of time. Another pathogenetic hypothesis, departing from the pharmacology of antidepressants, postulated a central deficiency of bioavailable norepinephrine and serotonin. Thus, it was the antidepressants mechanism of action itself that prompted the formulation of the biogenic amine deficiency hypothesis as put forward by Joe Schildkraut in Boston and Alec Coppen in London, and it may be said that no other hypothesis has influenced the development of antidepressants to a similar extent. In this article, depression will serve as an example to illustrate that the classic from bench to bed approach is now becoming more complex, as clinical and preclinical research identify central pathological mechanisms that can provide specific drug targets. One example of such a from bed to bench and back strategy is the close interrelation between the dysregulation of the hypothalamic–pituitary–adrenocortical (HPA) activity in individuals with depression, the progression into depression, the action of current antidepressants, and the development of new drugs targeting HPA regulation.
Section snippets
Clinical evidence for CRH hyperactivity in depression
In response to acute physical or psychological stress, parvocellular neurons of the paraventricular hypothalamus (PVN) produce increased amounts of corticotropin-releasing hormone (CRH), which is released into portal vessels activating secretion of corticotropin (ACTH) from anterior pituitary cells. In turn, ACTH enters the circulation and elicits glucocorticoids from the adrenal gland. This rapid HPA activation can be life-sustaining because of the metabolic effect of elevating blood glucose
Behavioral effects of CRH in animals
Only a few other neuropeptides have been studied more extensively than CRH with regard to their behavioral effects. Several reviews covering this issue have been published (Koob and Bloom, 1985; Dunn and Berridge, 1990; Holsboer et al., 1992; Owens and Nemeroff, 1992), which is why only a brief summary will be given of the main evidence that CRH acts as a mediator of affective symptoms.
Neuroanatomical studies strongly suggest that CRH not only accounts for neuroendocrine adaptations to stress,
Involvement of CRH in central neurotransmitter systems
The high density of CRH-immunoreactive fibers in the LC, which contains almost 50% of the brain norepinephrine (NE) neurons, and the recent evidence for synaptic contacts between CRH terminals and LC dendrites (van Bockstaele et al., 1996) have led to many studies exploring how hormonal, autonomic and behavioral effects of stress are co-ordinated through interactions of CRH with the LC (Valentino et al., 1993). As mentioned earlier, infusion of CRH into the LC of freely moving rats produces an
Causation of increased CRH in depression
Given that excessive CRH accounts for the well-documented HPA hyperdrive and a number of autonomic signs and psychopathological symptoms in individuals with depression, the question of why CRH is not adequately regulated in these patients remains. The best-studied brain regions are the hippocampus and the hypothalamic PVN, where adrenalectomy was repeatedly shown to stimulate CRH biosynthesis and release to an extent similar to that seen in profound stress (Antoni, 1986; Plotsky, 1990; Dallman,
Suppressing the HPA hyperdrive with antidepressants
Serial monitoring of HPA activity and severity of depressive symptoms during treatment with antidepressants revealed that excessive HPA activity gradually decreases and that this effect precedes full clinical recovery, which suggests that normalization of stress hormone regulation is a prerequisite for clinical recovery (Holsboer, 1995a). Such a causal link between neuroendocrine signs and psychopathological symptoms is further supported by two recent observations: (1) patients who do not
CRH receptors
The CRH signal is mediated through functionally and regionally different cell membrane receptors. Up to now, two CRH receptors have been identified, which comprise seven putative transmembrane helices and belong to the family of Gs-protein-coupled receptors (Fig. 12). They are encoded by two distinct genes, both of which have been identified (Chalmers et al., 1996). The CRH1 receptor was identified and cloned from a human ACTH-secreting pituitary adenoma (Chen et al., 1993), mouse pituitary (
Preventing CRH actions by blocking its receptors
Given the evidence that the neuropeptide CRH, when hypersecreted continously in rats, produces numerous behavioral changes resembling the cardinal symptoms of depression and anxiety, the most straightforward therapeutic strategy is a blockade of its action by CRH receptor antagonists. The first CRH receptor antagonist described (Rivier et al., 1984) was the α-helical CRH9–41 peptide, an N-terminus-shortened analog of human/rat CRH. This molecule proved to be a competitive inhibitor of
Mice lacking a functional CRH1 receptor
A further set of experiments suited to complement the studies with antisense probes and antagonists targeted to the CRH1 receptor uses mice with deficient CRH1 receptors due to homologous recombination in embryonic stem cells. By deleting the coding sequences of the transmembrane regions V, VI and VII, including the G-protein coupling domain and the intracellular cytoplasmatic tail (Fig. 12), a research team in Munich, led by Wolfgang Wurst, generated a mouse with a truncated protein instead of
CRH-binding protein
Further fine-tuning of the HPA system is accomplished by the presence of CRH-binding protein (CRH-BP) (Potter et al., 1991). This protein binds CRH with high affinity, and as it is localized in the pituitary, it can diminish the production and release of ACTH. CRH-BP is also broadly distributed in the brain, where it colocalizes in some areas with CRH and its receptors, a finding that supports its role as a modulator of CRH-induced behavioral and autonomic effects. In cases where the CRH/CRH-BP
Psychiatric indications for CRH receptor antagonists
The reason for HPA hyperactivity and, in particular, for enhanced production and release of CRH in depression is not yet known. Genetic and experience-related factors may interact to induce manifold changes in corticosteroid receptor signaling. According to the concept developed by Ronald de Kloet et al., 1998, once the balance of MR- and GR-mediated events is disturbed, an individual loses the ability to maintain homeostasis if challenged, for example, by experiencing an adverse life event.
Unknown BIBs
Liebsch et al., 1998
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