2018 NEI Congress | Orlando, Florida
November 9, 2018
Keeping up With the Clinical Advances: Depression
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Our understanding of the neurobiology of depression has increased in recent years, there is recognition that the neurobiological substrates of depression may go beyond monoaminergic circuits. At the 2018 NEI Congress, Dr. Stephen Stahl provided an update on novel antidepressant treatments that are recently available or in development, including the mechanisms of action that are thought to underlie their potential antidepressant effects. Novel mechanisms being investigated for the treatment of depression include the endogenous opioids system, the glutamate system, and the GABA system. |
One exciting pathway Dr. Stahl discussed during this presentation was the GABA system.
GABA receptors, when bound by inhibitory neurotransmitters found throughout the brain, act as a brake on nerve activity and calm the brain. When out of balance, this pathway potentially contributes to a number of mood and movement disorders. GABA modulation is being studied as a new possible mechanism of action for treating episodic depression. SAGE-217, a novel, oral neuroactive steroid that, is a positive allosteric modulator of GABA-A receptors, targeting both synaptic and extrasynaptic GABA-A receptors. The GABA system is the major inhibitory signaling pathway of the brain and central nervous system (CNS).
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Benzodiazepine-insensitive GABA-A receptor subtypes (with d-subunits and a4 or a6 subunits) are located extrasynaptically, where they capture not only GABA that diffuses away from the synapse, but also neurosteroids synthesized and released by glia. SAGE-217 is a Positive Allosteric Modulator (PAM) of GABA-A receptors for major depressive disorder (MDD).
Phase II clinical trial was randomized, double blind, placebo controlled clinical trial. The study included 89 subjects with moderate-to-severe MDD; ages 18-65. The onset of action is within 24 hours after first dose. At the end of 14 days patients receiving 30mg of SAGE-217 had a 17.6-point reduction from baseline in HAM-D scale vs. 10.7 point on placebo (p<0.0001). Most common adverse events (AE) were headache, dizziness, nausea, somnolence and AE rates were 53% on SAGE-217 and 46% on placebo. |
References:
Gunduz-Bruce H et al. Biol. Psychiatry. 2018;83:S108-128.
Stahl SM. Stahl's Essential Psychopharmacology. 4th ed. 2013.
Tuem KB, Atey TM. Front Neurol. 2017;8:442.
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