The classic neuropathological hypothesis and treatment basis (e.g., SSRIs, SNRIs, etc) of major depressive disorder has historically centered around monoaminergic dysfunction (e.g., serotonin, norepinephrine, dopamine). More recently, attention is being given to dysfunction in the gamma-aminobutiric acid (GABA) system, with novel treatment developments as a result. GABA, the key inhibitory neurotransmitter in the brain, has a critical role in the optimal functioning of many systems, including central executive, default mode, and salience networks, as well as the hypothalamic-pituitary-adrenal (HPA) axis. Consistently, it has been found that individuals with depression have reduced levels of GABA, altered expression and composition of GABA-A receptors, and lowered levels of GABA-binding neuroactive steroids such as allopregnanolone. The ionotropic, ligand-gated GABA-A receptor is located throughout the brain and has an allosteric binding site (i.e., outside of the ligand-binding site) where neuroactive steroids can bind (Figure). Binding of a neuroactive steroid (NAS) or positive allosteric modulator (PAM) to the GABA-A receptor increases the mean open time and decreases the mean closed time of the GABA chloride channel, even in the absence of abundant levels of GABA thus restoring the critical GABAergic function necessary for healthy brain functioning.
Figure. Neuroactive Steroid (NAS)/Positive Allosteric Modulator (PAM) Actions on GABA-A Receptors
A. In patients with depression, it is hypothesized that there is a paucity of GABA. With low levels of GABA available to bind to the ligand-gated ionotropic GABA-A receptor, the chloride channel does not open and no hyperpolarization and inhibition of the postsynaptic cell occurs. B. Neuroactive steroids (NAS) or positive allosteric modulators (PAMs) bind to the GABA-A receptor at a site that is different from the ligand (GABA) binding site. This binding promotes prolonged opening of the chloride channel, even in the absence of elevated GABA.
There are currently 3 GABA-A PAMS currently being pursued for the treatment of MDD: brexanolone, zuranolone, and PH10. Brexanolone, an intravenous synthetic version of endogenous allopregnanolone is FDA-approved for the treatment of postpartum depression (PPD) and has shown rapid effects (within 60 hours) in ameliorating symptoms of depression. Zuranolone, a more user-friendly, oral, once-daily version of brexanolone, was approved by the U.S. FDA on August 4, 2023 for adults with postpartum depression. Also under investigation is PH10, a synthetic NAS in a nasal spray formulation, that has shown rapid (1 week) improvement in depressive symptoms.
Given that as many as half of patients with depression do not respond to the classic monoaminergic antidepressants (which often do not show any effects for 4-6 weeks), and are left in states of suffering and potential suicide risk, our growing understanding of the role of GABAergic dysfunction and consequent rapid-acting, effective GABAergic treatment developments is a much-needed and potentially life-saving advance.
Reference:
Cutler AC et al. Transl Psychiatry. 2023;13(1):228. Abstract