Neurosteroids for the Treatment of Major Depressive Disorder (MDD) and Chronic Pain (Paper)

Neurosteroids are endogenous steroids within the brain that act as modulators in neurotransmission. Among their targets are the gamma-aminobutyric acid (GABA) receptors, which are responsible for inhibitory signaling in the brain. The interaction between neurosteroids and GABA receptors is complex, influencing mood regulation and pain perception. Endogenous neurosteroids have been used in conditions such as postpartum depression (PPD), where fluctuation in neurosteroid levels contribute to the onset of depressive systems. Conversely, exogenous neurosteroids, such as brexanolone and zuranolone, have emerged as therapeutic agents for PPD. These compounds act as positive allosteric modulators (PAMs) on GABA receptors, enhancing inhibitory neurotransmission and alleviating symptoms of depression. In addition, neurosteroids and GABA receptors can influence chronic pain pathways. There is a shared neurobiological substrate between major depressive disorder (MDD) and chronic pain, involving the dysregulation of GABAergic neurotransmission. Brexanolone and zuranolone offer a dual mechanism of action for treating both MDD and chronic pain. In conclusion, the modulation of neurosteroids and GABA receptors presents a novel therapeutic avenue for addressing the complex process between MDD and chronic pain. Agents like brexanolone and zuranolone offer a targeted approach to alleviate symptoms in both psychiatric and pain management domains.