Clinical and preclinical data suggest that unrestrained secretion of corticoctropin-releasing hormone (CRH) in the CNS produces several signs and symptoms of depression and anxiety disorders through continuous activation of CRH(1) receptors. This led to the development of drugs that selectively antagonize CRH(1) receptors suppressing anxiety-like behavior in rats and also in monkey models of anxiety. These findings led to a clinical development program exploring the antidepressive potential of R121919, a water-soluble pyrrolopyrimidine that binds with high affinity to human CRH(1) receptors and is well absorbed in humans. This compound was administered to 24 patients with a major depressive episode primarily in order to investigate whether its endocrine mode of action compromises the stress-hormone system or whether other safety and tolerability issues exist. The patients were enrolled in two dose-escalation panels: one group (n=10) where the dose range increased from 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 symptomatoloy in one case. We found that R121919 was safe and well tolerated by the patients during the observation period. Moreover, the data suggested that CRH(1)-receptor blockade does not impair the corticotropin and cortisol secretory activity either at baseline or following an exogenous CRH challenge. We also observed significant reductions in depression and anxiety scores using both, patient and clinician ratings. These findings, along with the observed worsening of affective symptomatology after drug discontinuation, suggests that the pharmacological principle of CRH(1)-receptor antagonism has considerable therapeutic potential in the treatment and the prevention of diseases where exaggerated central CRH activity is present at baseline or following stress exposure.