Effects of the high-affinity corticotropin-releasing hormone receptor 1 antagonist R121919 in major depression: the first 20 patients treated

Clinical and preclinical data suggest that unrestrained secretion of cortic octropin-releasing hormone (CRH) in the CNS produces several signs and symp toms of depression and anxiety disorders through continuous activation of C RH1 receptors. This led to the development of drugs that selectively antago nize CRH1 receptors suppressing anxiety-like behavior in rats and also in m onkey models of anxiety. These findings led to a clinical development progr am exploring the antidepressive potential of R121919, a water-soluble pyrro lopyrimidine that binds with high affinity to human CRH1 receptors and is w ell absorbed in humans. This compound was administered to 24 patients with a major depressive episode primarily in order to investigate whether its en docrine mode of action compromises the stress-hormone system or whether oth er safety and tolerability issues exist. The patients were enrolled in two dose-escalation panels: one group (n = 10) where the dose range increased f rom 5-40 mg and another group (n = 10) where the dose escalated from 40 to 80 mg within 30 days each. Four patients dropped out because of withdrawal of consent to participate (three cases) or worsening of depressive symptoma tology in one case. We found that R121919 was safe and well tolerated by th e patients during the observation period. Moreover, the data suggested that CRH1-receptor blockade does not impair the corticotropin and cortisol secr etory activity either at baseline or following an exogenous CRH challenge. We also observed significant reductions in depression and anxiety scores us ing both, patient and clinician ratings. These findings, along with the obs erved worsening of affective symptomatology after drug discontinuation, sug gests that the pharmacological principle of CRH1-receptor antagonism has co nsiderable therapeutic potential in the treatment and the prevention of dis eases where exaggerated central CRH activity is present at baseline or foll owing stress exposure. (C), 2000 Elsevier Science Ltd. All rights reserved.