Understanding the mechanism of action and clinical effects of neuroactive steroids and GABAergic compounds in major depressive disorder

Abstract

The pathophysiology of major depressive disorder (MDD) is thought to result from impaired connectivity between key brain networks. Gamma-aminobutyric acid (GABA) is the key inhibitory neurotransmitter in the brain, working primarily via GABA_A receptors, with an important role in virtually all physiologic functions in the brain. Some neuroactive steroids (NASs) are positive allosteric modulators (PAMs) of GABA_A receptors and potentiate phasic and tonic inhibitory responses via activation of synaptic and extrasynaptic GABA_A receptors, respectively. This review first discusses preclinical and clinical data that support the association of depression with diverse defects in the GABAergic system of neurotransmission. Decreased levels of GABA and NASs have been observed in adults with depression compared with healthy controls, while treatment with antidepressants normalized the altered levels of GABA and NASs. Second, as there has been intense interest in treatment approaches for depression that target dysregulated GABAergic neurotransmission, we discuss NASs approved or currently in clinical development for the treatment of depression. Brexanolone, an intravenous NAS and a GABA_A receptor PAM, is approved by the U.S. Food and Drug Administration for the treatment of postpartum depression (PPD) in patients 15 years and older. Other NASs include zuranolone, an investigational oral GABA_A receptor PAM, and PH10, which acts on nasal chemosensory receptors; clinical data to date have shown improvement in depressive symptoms with these investigational NASs in adults with MDD or PPD. Finally, the review discusses how NAS GABA_A receptor PAMs may potentially address the unmet need for novel and effective treatments with rapid and sustained antidepressant effects in patients with MDD.

Fig. 1. Glutamatergic and GABAergic projection neurons make dense connections between brain regions that participate in mood regulation and reward processing.

Glutamatergic projections illustrated here include those from the frontal cortex to the anterior cingulate cortex (ACC), thalamus (TH), ventral tegmental area (VTA), hippocampus (HPC) and nucleus accumbens (NAc); from hippocampus to hypothalamus (HT), VTA, NAc and PFC; and from amygdala to HT, ACC and NAc. Major GABAergic projections are from HT to the occipital and parietal cortex, HPC to PFC, and from NAc to TH and VTA. Only a subset of known interconnections is shown here. Depression is associated with reduced brain volume and decreased glial cell density in various brain regions, including ACC, PFC, hippocampus, and amygdala. (Figure is reproduced from Sarawagi et al. 2021 [12] according to the terms of the Creative Commons Attribution License [CC BY]).

Fig. 2. In the biosynthesis of NASs, cholesterol is translocated into the inner mitochondrial membrane by the steroidogenic acute regulatory protein.

There it is metabolized by P450scc into pregnenolone, the precursor of all endogenous NASs. Biosynthetic enzymes are denoted in green; neuroactive steroids and substrates are denoted in red. *Allotetrahydrodeoxycorticosterone is also known as tetrahydrodeoxycorticosterone (same Chemical Abstract Services number). Allo-THDOC allotetrahydrodeoxycorticosterone, DHEAS dehydroepiandrosterone sulfate, DHT 5α-dihydrotestosterone, HSD hydroxysteroid dehydrogenase, NAS neuroactive steroid, P450aro cytochrome P450-aromatase, P450c11β cytochrome P450 11β-hydroxylase, P450c17 cytochrome P450 17α-hydroxylase, P450c21 cytochrome P450 21-hydroxylase, P450scc cytochrome P450 side chain cleavage, PREGS pregnenolone sulfate, SULT sulfotransferase.

Fig. 3. The GABAergic and the monoaminergic neurons are interconnected.

Serotonergic neurons originating in the dorsal raphe nucleus and projecting to the prefrontal cortex (PFC) regulate excitability of GABAergic and glutamatergic neurons, which in turn, modulate the excitability of serotonergic neurons in the dorsal raphe nucleus by the GABA-glutamate balance (left). Chronic stress affects local networks regulating activity within the medial PFC (mPFC), leading to changes in local excitatory-inhibitory balance. In a proposed mechanistic model (right), somatostatin-expressing GABAergic neurons provide reduced dendritic inhibition of glutamatergic pyramidal neurons in the infralimbic mPFC under chronic stress, reducing filtering of information flow into the PFC [145]. An altered glutamate and GABA neurotransmission might appear as a disturbance in monoamine signaling. (Part of this figure is adapted from McKlveen et al. 2019 [145], with permission from Elsevier).

Fig. 4. Neuroactive steroid (NAS) positive allosteric modulators (PAMs) of gamma-aminobutyric acid type A (GABA_A) receptors amplify the inhibitory signal of gamma-aminobutyric acid (GABA) in the brain.

NAS GABA_A receptor PAMs, such as allopregnanolone, bind to GABA_A receptors at sites distinctive from those for benzodiazepines (BZDs). NAS GABA_A receptor PAMs bind to both synaptic γ subunit-containing and extrasynaptic δ subunit-containing GABA_A receptors, potentiating phasic and tonic currents, respectively. In contrast, benzodiazepines bind to γ subunit-containing GABA_A receptors only and primarily augment phasic inhibition. Extrasynaptic GABA_A receptors containing δ subunits are insensitive to benzodiazepines [32, 53, 62, 64, 78, 79, 91, 92, 167].