Treatment of depression with the CRH-1-receptor antagonist R121919: endocrine changes and side effects

CRHR1 links peripuberty stress with deficits in social and stress-coping behaviors

“…These data are in good agreement with previous reports showing that enhanced CRH drive is associated with depressive behaviors in both humans (Arato et al, 1989; for a review see Binder and Nemeroff, 2010) and animals (Muller and Wurst, 2004;Kolber et al, 2010); specifically, increasing CRH drive in the central amygdala through lentiviral-induced neuropeptide overexpression was found to enhance floating behaviors in the forced swim test (Keen-Rhinehart et al, 2009). Decreasing CRHR1 levels produces antidepressant-like effects in animals as treatment with CRHR1 antagonists has been reported to do in humans (Zobel et al, 2000;Kunzel et al, 2003). It is worth noting, however, that the behavioral data obtained on the first session of the forced swim test depicted a slightly different picture.…”

“…Although drug treatments tackling CRHR1 have been envisioned as potentially promising anxiolytic and antidepressive drugs (Kunzel et al, 2003;Refojo and Holsboer, 2009), recent evidence in rodents suggests that they could also be effective in modifying not only actual pathological manifestations at adulthood but also the developmental trajectories linking early adversity to adult psychopathology. These rodent studies showed that exposure to stress during the two first postnatal weeks leads to increased central CRH and CRHR1 expression, and altered a number of behaviors in tests of emotion and cognition (Plotsky et al, 2005;Ivy et al, 2010;Wang et al, 2011Wang et al, , 2012.…”

“…Moreover, NBI30775 treatment on its own also led to increased floating behavior in this first session. Studies involving conditional forebrain CRHR1 knockout starting around weaning have reported effects of this manipulation at adulthood (Zobel et al, 2000;Kunzel et al, 2003), however, most studies administering CRHR1 antagonists to control, non-stressed animals during early life only reported mild and non-significant behavioral changes (Fenoglio et al, 2005;Ivy et al, 2010). Our findings, obtained at a slightly different timing of drug administration (i.e., post-puberty or late adolescence instead of pre-weaning regimes given in former studies) hint at the possibility that antagonizing CRHR1 in control individuals during adolescence might affect their developmental trajectory and in turn affect their subsequent emotional behavior.…”

High-Affinity CRF1 Receptor Antagonist NBI-34041: Preclinical and Clinical Data Suggest Safety and Efficacy in Attenuating Elevated Stress Response

“…Even at the highest dose of NBI-34041 the function of the HPA axis remained unimpaired demonstrating that 2 weeks of treatment with NBI-34041 did not affect basal HPA axis function. This is in line with the results of the first clinical trial with NBI 30775, a CRF 1 receptor antagonist and predecessor compound of NBI-34041 (Kunzel et al, 2003;Zobel et al, 2000). Importantly however, the results of the TSST after 9 days of treatment indicated that the hormone response to a public speaking and mental arithmetic stressor was attenuated by the CRF 1 receptor antagonist, as there was a significant dose group effect for the ACTH and cortisol response.…”

“…Since 1991, a large number of small molecule CRF 1 antagonists have been developed (McCarthy et al, 1999;Saunders and Williams, 2003;Zorrilla and Koob, 2004), with a small number entering clinical development. The first description of a clinically active CRF 1 receptor antagonist appeared in the literature a few years ago and demonstrated a pharmacodynamic profile consistent with antidepressant activity (Held et al, 2004;Kunzel et al, 2003Kunzel et al, , 2005Zobel et al, 2000). The development of this compound, however, was discontinued owing to moderate but reversible clinical safety concerns (temporarily elevated liver enzymes).…”