Depression is an increasingly prevalent and debilitating psychiatric disorder with a heterogeneous symptomatic picture and complex neurobiological basis. In the United States, depression is the leading cause of disability and suicide, affecting over 17.3 million adults [1]. Major depressive disorder (MDD) costs Americans approximately $210.5 billion annually, whereas the global economic burden of depression and anxiety is estimated to be one trillion USD annually and rising ^[1][2][1,2]. Approximately one-third of depressed patients fail to remit, even after four adequate therapeutic trials [3]. Diminishing returns demonstrated in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial underscore the need for novel treatment avenues targeting the pathophysiological source of treatment resistance [4]. Disappointingly, no clear consensus exists for the definition of TRD. Lack of response or remission after two adequate trials with standard antidepressant therapies appears to be the modal definition. However, only 17% of studies implement these criteria [5]. Herein, TRD will be defined as such.

Overall, Treatment Resistant Depression (TRD) is associated with several comorbid features, including prolonged mental and physical dysfunction, increased healthcare spending, worse clinical outcomes, and a higher risk of suicide ^{[4][6][7][8][9]}[4,6,7,8,9]. Well-established clinical correlates of TRD include persistent anhedonia and anxiety, the presence of one or more medical and/or psychiatric comorbidities, as well as duration and frequency of depressive episodes [10].

Most of the available FDA-approved pharmacological treatments for MDD target conventional monoamine pathways (i.e., serotonin, dopamine, and norepinephrine), which make up less than ten percent of total central nervous system (CNS) activity [11]. Thus, there is an urgent need for new, improved antidepressant therapies targeting a broader range of neurotransmission. The present study provides an overview of novel, rapid-acting antidepressants with potential efficacy in TRD based on a physiological balance between the brain’s two primary neurotransmitters, glutamate and GABA.

The function of the CNS fundamentally relies on a delicate physiological balance between glutamatergic and GABAergic systems. With more than 90% of CNS neurons acting through these pathways, the excitatory activity must be well-regulated by an inhibitory component [12]. Glutamate hyperactivation associated with impaired GABA inhibition creates detrimental neural physiology, changing gene expression, cellular morphology, and signaling activity. Receptors that are able to receive and process the signals from glutamate or GABA are present on all cells in the brain, including neurons and glia [13]. Abnormalities in volume, activity, and connectivity in cortico-limbic networks have been consistently linked to depressive pathophysiology ^[14][15][14,15]. Glutamatergic and GABAergic dysfunction in the prefrontal cortex (PFC) and anterior cingulate cortex (ACC) has been extensively implicated in both MDD and TRD ^{[16][17][18][19][20][21][22][23][24][25]}[16,17,18,19,20,21,22,23,24,25]. The default mode network (DMN), one of the CNS’s major communication networks has also been implicated in this dynamic. Specifically, cortical GABAergic disinhibition in depressive disorders co-occurs with increases in glutamatergic gene expression in the DMN ^{[24][26][27][28][29][30][31][32]}[24,26,27,28,29,30,31,32].

Glutamate activity plays a key role in learning and memory, synaptic plasticity, and overall behavior [33]. Moreover, glutamatergic transmission appears to be a key mediator of mood, cognition, perception, and emotions associated with TRD [15]. A meta-analysis of 1H-MRS studies demonstrated that decreased Glx levels with absolute values in the prefrontal cortex were correlated with treatment severity (i.e., number of failed antidepressant treatments), indicating that the severity of glutamatergic dysregulation could be related to the severity of illness [34]. Subjects with depression have been shown to display a variety of glutamatergic abnormalities, including reduced glial density, decreased expression of the glutamate reuptake transporters EAAT1 and EAAT2 and decreased enzymatic conversion from glutamate to glutamine [33].

One proposed neurobiological mechanism underlying TRD is related to the toxic effect of extrasynaptic glutamate receptor hyperactivation. As extracellular glutamate release outpaces clearance by glial cells, and the ensuing inflammation and neurodegeneration likely contribute to the acute volume reductions and other cytoarchitectural abnormalities detected in depressed patients’ brains [35]. To counteract these effects, glial cells are responsible for glutamate reuptake and facilitate the glial–astrocytic conversion of glutamate to glutamine, which limits excitotoxicity and provides necessary precursors for GABA synthesis [36]. Glutamine, the most abundant amino acid in the CNS by an order of magnitude, also plays a vital role in cellular buffering, transcription/translation, mitochondrial functioning, and other vital processes [33].

Metabotropic glutamate receptors (mGluRs) are highly expressed in brain regions central to the pathophysiology of TRD. These receptors also influence local GABA and glutamate activity; mGluR₅ interacts with glutamatergic and GABAergic neurons throughout the interconnected circuitry of the PFC, hippocampus, and amygdala. They control processes such as learning, memory acquisition, fear extinction, and synaptic plasticity [37]. In this capacity, learning performance and response depend on the frequency of mGluR₅ expression in the hippocampus ^[38][39][38,39]. The mGluR₅ receptor also mediates stress resilience via post-synaptic mGluR₅ activation on the nucleus accumbens ^[40][41][40,41]. This process may ultimately facilitate hippocampal neurogenesis and normalize hypothalamic–pituitary–adrenal (HPA) axis activity, two processes that have been repeatedly implicated in recovery from depression ^[42][43][42,43].

Ionotropic glutamate receptors also play a vital role in synaptic plasticity [44]. In depressed patients, synaptic plasticity pathways have been shown to be disrupted in the PFC and hippocampi, correlated with α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and NMDA receptor abnormalities ^[45][46][45,46]. The possibility of development of antidepressant medications targeting the NMDA complex was suggested decades ago [47]. Regardless of causal direction, the reciprocal and downstream effects of this dysfunction substantially contribute to neurodegeneration within the PFC and hippocampus. These areas are highly implicated in the adverse cognitive and affective features of depression, especially rumination and anhedonia ^[3][48][3,48].

Brain-derived neurotrophic factor (BDNF) levels, a primary driver of neuroplasticity and glutamate modulation, are reduced in postmortem hippocampal and PFC samples of patients with MDD. It is suggested that alterations in BDNF activity may contribute to the acute regional volumetric decreases associated with MDD/TRD [3]. Moreover, multiple SNPs in BDNF-associated regions have been associated with treatment response to ketamine and selective serotonin reuptake inhibitors (SSRIs) in some patient populations. BDNF knockout mice also show reduced responsiveness to such therapies ^[3][49][3,49]. BDNF and its cellular target (tyrosine kinase receptor B (TrkB)) potently regulate neuronal survival and growth through several downstream effectors: bcl-2, mammalian target of rapamycin (mTOR), glycogen synthase kinase-3B (GSK-3B), and phosphatidylinositol 3-kinase (PI3-kinase)/Akt [50].

Increasing evidence suggests that BDNF-TrkB signaling underlies a substantial portion of both affective pathophysiology and treatment response across therapeutic approaches ^[51][52][51,52]. Importantly, the rate of activity-dependent BDNF release appears to distinguish rapid-acting agents discussed herein from their monoaminergic counterparts, whose delayed treatment response coincides with an indirect increase in BDNF secretion weeks after initiation [53]. It has recently been demonstrated that conventional antidepressants such as fluoxetine and imipramine, as well as the rapid-acting glutamatergic agent ketamine, directly bind to TrkB and allosterically potentiate BDNF signaling ^[52][54][52,54]. This may suggest a final common pathway for many antidepressant modalities—amplification of endogenous glutamate/BDNF signaling via TrkB. Notably, multiple serotonergic hallucinogens have also demonstrated preliminary efficacy in TRD ^[55][56][55,56] and impart downstream glutamatergic effects (as well as robust spinogenesis and dendritogenesis), which are dependent on intact TrkB signaling ^[57][58][57,58]. Lysergic acid diethylamide (LSD) and psilocin have recently been found to directly bind to TrkB with affinities 1000-fold higher than those for conventional antidepressants and ketamine. However, 2R,6R-hydroxynorketamine (R,R-HNK), an active metabolite of ketamine with negligible affinity for NMDA receptors, was found to displace LSD from TrkB at high nanomolar concentrations, suggesting relatively comparable potency [54]. Despite repeated and robust demonstration of antidepressant effects across animal models with R,R-HNK, higher plasma levels appear to confer less improvement in clinical studies of depression and suicidal ideation ^[59][60][59,60]. Surprisingly, in patients with TRD, higher R,R-HNK levels have been shown to correlate with increased encephalographic gamma power—a putative measure of cortical disinhibition/excitation (i.e., decreased activity in GABAergic interneurons and increased activation of fast ionotropic glutamate receptors on pyramidal neurons) [59]. Thus, it remains unclear as to whether the cortical “glutamate surge” and/or resultant TrkB signaling are sine qua non to antidepressant efficacy for this class. The first phase I trial with R,R-HNK is currently underway (NCT04711005), which may hopefully add some clarity. Further caveats to this hypothesis exist as well, and it is important to place any BDNF-related findings within the context of population heterogeneity and neuro-regional specificity ^[50][53][50,53].

Strong evidence supports a key role for GABA in MDD, showing structural and functional GABAergic system deficits throughout the central and peripheral nervous systems [61]. Compared to healthy controls, depressed patients consistently display net reductions in cortical GABA concentrations and neuronal density, as well as decreased enzymatic synthesis in the periphery and cerebrospinal fluid (CSF) ^[61][62][61,62]. In women with TRD/treatment-resistant postpartum depression, depressive severity is linked to GABA concentrations in the DMN ^[26][27][26,27]. In the CNS, reductions in ACC GABA levels appear to correlate with increased anhedonia and treatment resistance ^[19][23][19,23]. In contrast, higher baseline ACC activity is associated with improved outcomes [22]. In TRD specifically, rostral ACC function may mediate the balance between negative rumination and constructive self-evaluation, both facilitated by the DMN ^[17][22][17,22], suggesting that ACC dysfunction plays a role in excessive negative rumination. In both MDD and TRD, region-specific normalization of GABA concentrations in the occipital cortex (OCC), ACC, and DMN have repeatedly been observed in response to all successful antidepressant therapies ^{[19][22][23][63]}[19,22,23,63].

Likewise, reductions in both GABA_A and GABA_B receptor-mediated inhibition in MDD have been demonstrated across genomic [64], postmortem [65], and neuroimaging studies ^[28][48][28,48]. Levinson and colleagues’ transcranial magnetic stimulation (TMS) study demonstrated substantial deficits in GABA_A inhibitory signaling in patients with treatment-resistant depression, but not in those with MDD or euthymic remitters with a history of MDD [28]. These results suggest that neurophysiological deficits of the GABA_B receptor are more broadly related to depressive pathophysiology and symptoms, whereas GABA_A receptor deficits are more selectively associated with illness severity and treatment response [28]. Overall, MDD and TRD seem to be biologically different. GABAergic deficits involve the concomitant presence of neurophysiological, neuroendocrine, cognitive, and behavioral findings ^[32][66][67][32,66,67], which may be reversed with targeted therapeutics.