Treatment of depression with the CRH-1-receptor antagonist R121919: endocrine changes and side effects.
A dysregulation of the hypothalamus-pituitary-adrenocortical (HPA) system has been hypothesized to account for a myriad of cardinal symptoms of affective disorders. Specifically, increased CRH signalling via CRH type 1 receptors is thought to be an important factor in the pathogenesis of major depression and anxiety disorders. Consequently, a number of drugs have been developed in order to target the postulated increase in CRH/CRH 1 receptor signalling. One of these compounds, R121919, binds with high affinity to CRH1 receptors antagonising the action of CRH. R121919 was recently tested in an open-label study conceptualized as a safety and tolerability study. As part of this study, a thorough endocrine evaluation and detailed clinical laboratory analysis were assessed several times during 30 days of treatment with two different dose regimens of R121919 (5-40 mg vs. 40-80 mg) in 24 patients with a major depressive episode. During treatment with the experimental drug no serious side effects were noted. In particular, there were no adverse effects or impairment of the hypothalamic-pituitary-gonadal system, the hypothalamic-pituitary-thyroid axis, the renin-angiotensin system, prolactin or vasopressin secretion. Furthermore, no changes in the serum corticotropin and cortisol concentrations and in the responsivity of corticotropin and cortisol following a CRH stimulation test were noted. No effects of R121919 on clinical laboratory parameters including liver enzymes, EEG and ECG were observed. These results encourage the development of other CRH-1-R antagonists as a novel class of antidepressive drugs.
Künzel
Heike E
HE
Max Planck Institute of Psychiatry, Kraepelinstr. 2-10, D-80804, Munich, Germany. kuenzel@mpipsykl.mpg.de
Zobel
Astrid W
AW
Nickel
Thomas
T
Ackl
Nibal
N
Uhr
Manfred
M
Sonntag
Annette
A
Ising
Marcus
M
Holsboer
Florian
F
D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000328:Adult; D000450:Aldosterone / Q000378:metabolism; D000928:Antidepressive Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002940:Circadian Rhythm; D003687:Dehydroepiandrosterone / Q000378:metabolism; D003865:Major Depressive Disorder / Q000188:drug therapy*; D004334:Drug Administration Schedule; D004562:Electrocardiography; D004569:Electroencephalography; D005260:Female; D012739:Gonadal Steroid Hormones / Q000378:metabolism*; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects*; D008297:Male; D008875:Middle Aged; D010913:Pituitary-Adrenal System / Q000187:drug effects*; D011743:Pyrimidines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects; D013963:Thyroid Hormones / Q000378:metabolism; D000099052:CRF Receptor, Type 1
D000928:Antidepressive Agents; D012739:Gonadal Steroid Hormones; D011743:Pyrimidines; C412383:R 121919; D018019:Receptors, Corticotropin-Releasing Hormone; D013963:Thyroid Hormones; D003687:Dehydroepiandrosterone; D000450:Aldosterone; D000099052:CRF Receptor, Type 1; D000324:Adrenocorticotropic Hormone; D006854:Hydrocortisone