Extra-synaptic modulation of GABA_A and efficacy in bipolar disorder

Bipolar disorder type I is a severe psychiatric condition that leads to significant morbidity and mortality and whose treatment remains suboptimal. Its pathophysiology involves disturbance in the control of ionic fluxes so that when patients are either manic or depressed, the resting membrane potential of neurons is more depolarized than normal. Available mood stabilizers have a shared mechanism of normalizing ion flux by compensating for ionic abnormalities, and normalizing membrane potential.

Agents that significantly potentiate extrasynaptic GABA_A receptors are expected to be particularly effective in hyperpolarizing resting membrane potential in bipolar patients, thereby normalizing their membrane potential.

New neuroactive steroid-like agents are being tested in humans for depression and insomnia. These agents include brexanolone, ganaxolone, and gaboxadol. Brexanolone has been approved for the treatment of postpartum depression, ganaxolone is being studied for treatment-resistant depression, and gaboxadol development for the treatment of insomnia has been abandoned due to narrow therapeutic index. In addition to the current studies, these agents are expected to have particular efficacy in acute and prophylactic management of bipolar I disorder by hyperpolarizing the resting potential of neurons and antagonizing one of the most reproducible demonstrated biologic abnormalities of this illness.