Zuranolone GABA(A) receptor positive allosteric modulator Treatment of major depressive disorder Treatment of postpartum depression

摘要

Depression is a psychiatric disorder in which patients tend to experience a constant state of sadness for a period of more than 2 weeks. Patients may also show abnormal behavior, social isolation, loss of appetite, reduced concentration and, in severe cases, suicidal tendencies. The prevalence of major depressive disorders was found to be higher in females at 8.7% as compared to males at 5.3%. Females are also prone to postpartum depression, the prevalence of which ranges from 0.89% to 2.6% per 1,000 births globally. In the last 10 years, no major development has been witnessed in the field of psychiatric medicines used in the treatment of depression, anxiety and other mood disorders. However, in recent years, a new ray of hope seems to be emerging in the form of neuroactive steroids like allopregnanolone acting as positive allosteric modulators (PAMs) of GABA(A) receptors. It has been evident from many studies that GABA(A) receptor plays a decisive role in mood-related disorders and is found to play a crucial role in the pathogenesis of depression, anxiety, mania and other mood disorders. Recent studies suggest that the PAMs acting on GABA(A) receptors may prove to be useful in treating mood-related disorders by amplifying GABAergic signaling throughout the brain. Sage Therapeutics is currently developing one such novel PAM: SAGE-217 (zuranolone). It has been predicted by early clinical development data that a single dose of SAGE-217 will be able to provide relief from symptoms of major depressive disorders as well as postpartum depression. It has thus far shown positive high-end results in phase I and phase II trials. The drug has received fast track and breakthrough therapy status in the United States for the treatment of major depressive disorder, and is now in phase III clinical trials for that indication as well as for postpartum depression. The drug is also in phase II development for insomnia and bipolar depression. This article discusses the mechanism of action, preclinical pharmacology, clinical pharmacokinetics, clinical studies and safety of SAGE-217 for the treatment of the major depressive disorder and postpartum depression.