For the last seven decades, clinical practice has focused on developing “me too” antidepressants based on different molecular targets within three major monoamine neurotransmitter systems, serotonin, epinephrine, and dopamine. Despite the differences in types and nature of adverse effects, monoaminergic antidepressants do not differ significantly in their antidepressant efficacy, regardless of the molecular target(s). In addition, these antidepressants have not been adequately effective at managing treatment-resistant depression (TRD). Most importantly, all monoaminergic antidepressants require a period of 4–6 weeks for optimal efficacy. Therefore, a severely depressed patient has to wait for a response during the initial stages of depression when urgent treatment is required to prevent suicidality. Still, there is no guarantee that the first antidepressant will be effective after waiting 4–6 weeks.

The recent paradigm shift from monoamine to glutamatergic and gamma amino butyric acid (GABA)-based hypotheses [1,2] has successfully addressed some unmet needs in treating depression. Although the central role of the most abundant neurotransmitters, glutamate and GABA, in brain function has been known for a long time, it took us several decades to develop antidepressants directly affecting these neurotransmitters. Ketamine is an N-methyl-D-aspartate (NMDA) receptor blocker, indirectly resulting in increased levels of brain-derived neurotrophic factor (BDNF) and rapid onset synaptic neuroplasticity responsible for the quicker onset of antidepressant and antisuicidal effects. Although ketamine was first discovered 60 years ago, it was not until 2000 that the antidepressant effects of ketamine were found serendipitously. However, the rapid onset of ketamine’s antidepressant and antisuicidal effects fueled the formal research that provided strong support for the novel glutamatergic hypothesis of depression [1]. Ketamine has not yet been investigated in preclinical trials but is already used as a 45-minute intravenous infusion to manage acute suicidality in emergency rooms nationwide. Although the rapid antidepressant effects of ketamine could not be translated into the bench-to-bedside transfer of knowledge for the general population, it paved the way for preclinical trials with the intranasal administration of the S-enantiomer of ketamine for its approval to be used in patients with treatment-refractory depression (TRD) [3].

Another exciting development was the FDA approval of brexanolone (a GABA modulator and an analog of allopregnanolone) as the first effective treatment for postpartum depression (PPD), which strongly supports the GABAergic hypothesis [2]. However, brexanolone is an expensive 60-h infusion and, like esketamine, requires registration with the REMS for mandatory monitoring. Although these novel developments are exciting and could be lifesaving, a large number of patients do not have access to these expensive treatments, impairing the transfer of knowledge from the bench to bedside. Therefore, the general population may not benefit from recent psychopharmacological advancements without checks and balances on new drug costs. Nevertheless, mandatory monitoring and the extremely high costs associated with ketamine and esketamine in treating depression have been somewhat addressed after the FDA recently approved another N-methyl-D-aspartate (NMDA) receptor blocker, dextromethorphan, in combination with an older antidepressant, bupropion [4]. Unlike ketamine and esketamine, dextromethorphan–bupropion does not require mandatory registration or monitoring. In addition, dextromethorphan–bupropion is approved for nonrefractory depression, which means that there is a broader clinical application of bench-to-bedside research with dextromethorphan–bupropion than with ketamine or esketamine. These differences could be due to the better tolerability and safety of the dextromethorphan–bupropion combination than that of ketamine or esketamine, with bupropion being already approved as an antidepressant. Along the same lines, zuranolone, an orally administered alternative to the expensive and parenteral brexanolone, is currently in the final stages of development as an antidepressant and potentially as the treatment for PPD [5,6]. Although approval of dextromethorphan–bupropion and future approval of zuranolone may mitigate some of the cost and monitoring barriers, it is still possible that most patients may not benefit from these antidepressants due to a lack of insurance approval. Even in patients who can afford these expensive medications, mental healthcare providers and trainees may be reluctant to change their comfortable prescribing practices to try novel antidepressants unless they are properly educated and trained. In addition, our healthcare systems have not completely recovered from the negative effects of the COVID-19 pandemic, and patients may have become more cautious in trusting and adopting novel strategies [7,8].

Brexanolone is a positive allosteric modulator (PAM) of gamma amino butyric acid-type A (GABA-A) receptors and is the first FDA-approved drug to manage postpartum depression (PPD) [102,103]. Although the neurobiological underpinnings of PPD are highly complex and not fully understood, several studies have reported GABA deficits underlying PPD [104]. Thus, the approval of a GABAergic drug to manage depressive symptoms supports the GABAergic hypothesis of depression [2,105]. However, since brexanolone’s administration takes about 60 h for infusion and is extremely expensive, another oral analog of allopregnanolone, zuranolone, is currently under review for FDA approval to treat MDD and potentially PPD [5]. Like esketamine, a brexanolone prescription also requires risk evaluation and mitigation strategy (REMS) registration to monitor potentially serious adverse effects that could occur with brexanolone infusion [106].

Based on some basic research, brexanolone appears to have multiple effects that may be beneficial for improving PPD. The role of GABA in depression has been supported by the altered composition of GABA-A receptor subunits in depressed patients [2,105]. Brexanolone enhances the inhibitory effects of GABA-A receptors and stabilizes allopregnanolone (a progesterone metabolite) during and after pregnancy by opening chloride channels to hyperpolarize and suppress neural activity in the brain [107,108]. Thus, stimulation of GABA-A receptors results in anxiolytic and antidepressant effects [103,109]. Other GABAergic drugs, such as fengabine, have also been shown to improve depressive symptoms in animal models of depression [110]. In addition, studies have also reported the compromised role of GABA-A receptors in modifying the stress response and reducing depressive symptoms, which may play a part in PPD [110]. GABAergic neurotransmission also controls hippocampal neurogenesis and neural maturation [2], explaining the cognitive and memory deficits observed in depressed patients. In addition, progesterone and its primary metabolite, allopregnanolone, directly regulate the biological mechanisms involved in emotion processing and cognition and the neural reward system involved in depression [111]. Additional studies have associated decreased levels of allopregnanolone with an increased presence of depressive symptoms in pregnant women [112], and increased allopregnanolone levels have been linked to a lower risk of PPD [113].

Preclinical data support brexanolone’s effectiveness by showing that a more significant response and remission rate was seen with brexanolone infusion versus placebo treatment, which was maintained throughout the 30-day follow-up period [114,115]. Notably, only four out of ten study subjects experienced adverse effects in the brexanolone group compared to the eight out of eleven subjects experiencing these in the placebo group. There were no mortalities or serious adverse events in any of the study participants. Common adverse effects included dizziness and sedation. In addition, some patients reported mild to moderate infusion site discomfort, pain, erythema, and an increase in thyroid-stimulating hormone, flushing, and oropharyngeal pain [114,115]. In addition, brexanolone treatment is not recommended for patients with renal dysfunction and should be avoided by patients using benzodiazepines to prevent excessive sedation and respiratory depression [116].

In terms of drug–drug interactions, brexanolone can inhibit CYP2C9, affecting the metabolism of drugs that are substrates for CYP29, such as tolbutamide and S-warfarin [115]. However, unlike the majority of other antidepressants that are primarily metabolized by the phase-I enzymes (i.e., CYP enzymes), brexanolone undergoes phase-II metabolism, including ketoreduction, glucuronidation, and sulfation, and is not likely to be affected by the concurrent use of drugs that inhibit CYP enzymes [114,116,117]. However, drug-induced alterations in the activity of phase II enzymes metabolizing brexanolone may compromise its efficacy and/or tolerability, though pharmacokinetic drug interactions involving brexanolone have not been studied formally. Similar results may be produced by genetic polymorphisms in phase-II enzymes metabolizing brexanolone.