Major depressive disorder (MDD) is the leading cause of disability worldwide. Despite considerable research, biological mechanisms underlying MDD pathophysiology remain unclear, with significant unmet needs for treatment. Typical antidepressants, including selective serotonin reuptake inhibitors (SSRIs) and serotonin and noradrenaline reuptake inhibitors, increase monoamine concentration in the synaptic cleft, resulting in antidepressant effects (Berton and Nestler, 2006). However, although increased monoamine concentration in the synapse occurs relatively quickly as an acute pharmacological action, recovery from depression takes several weeks to months in clinical practice (Krishnan and Nestler, 2008). Electroconvulsive therapy (ECT) is also an effective treatment for drug-resistant depression, although achieving clinically meaningful or sustained remission with ECT required at least 1 month (Yamasaki et al., 2020). Such substantial time lags are a major concern since patients with depression are at high risk for suicide. Thus, there is an urgent need to develop antidepressants with rapid onset and sustained effectiveness.

Ketamine, a non-competitive glutamate N-methyl-D-aspartate receptor (NMDAR) antagonist, has gained considerable interest in the neuropsychiatric field. A single administration of ketamine elicits rapid and sustained antidepressant effects for 1–2 weeks in both humans and animals (Berman et al., 2000; Zarate et al., 2006; Li et al., 2010; Autry et al., 2011). This discovery offered new insight into the investigation of a whole new class of agents beyond the monoamine system to treat depression (Chaki, 2017). Esketamine, an enantiomer of (R,S)-ketamine, has been approved by the U.S. Food and Drug Administration (USFDA) for treating patients with treatment-resistant depression. Thus, research on pathophysiology and drug discovery for MDD has transitioned from the monoaminergic to the glutamatergic system. Recently, the importance of multiscale neuroscience to study cross-scale interactions at genetic, molecular, cellular, and macroscale levels of brain circuitry, connectivity, and behavior has been emphasized to establish a comprehensive understanding of neuropsychiatric disease (Van Den Heuvel et al., 2019). This mini-review aims to update the current knowledge regarding ketamine effect on the brain, focusing on the glutamatergic signaling pathway from a multiscale perspective at the behavioral, cellular, molecular, and epigenetic levels.

Glutamate is the major excitatory neurotransmitter in the brain, and increasing evidence indicates that dysfunction in glutamatergic signaling contributes to MDD pathophysiology (Popoli et al., 2011; Duman and Aghajanian, 2012; Thompson et al., 2015; Duman et al., 2019; Xia et al., 2021). The glutamatergic system is modulated by both ionotropic [NMDARs, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs), and kainate receptors] and metabotropic glutamate receptors (mGluRs). NMDARs are found throughout the central nervous system and contribute to synaptic calcium (Ca²⁺) influx, which is required for activity-dependent synaptic plasticity (Koester and Sakmann, 1998; Reid et al., 2001; Ngo-Anh et al., 2005; Bloodgood and Sabatini, 2007; Carter et al., 2007). NMDAR function is tightly linked to AMPAR, which gates sodium and mediates fast excitatory transmission. Increased AMPAR density in the postsynaptic membrane causes NMDAR-dependent long-term potentiation (LTP) (Huganir and Nicoll, 2013). AMPARs can also have several direct effects on synaptic transmission (i.e., LTP) and intracellular signals without the proper functioning of NMDARs. This NMDAR-independent and AMPAR-dependent intracellular signaling pathway is also hypothesized to underlie ketamine’s antidepressant actions (Zanos et al., 2016; Duman et al., 2019; Wei et al., 2021).

Ca²⁺ influx into the postsynaptic neuron stimulates a signaling-cascade, such as calcium/calmodulin-dependent kinases [CAMKs; e.g., calcium/calmodulin-dependent kinase II (CaMKIIs), eukaryotic elongation factor 2 (eEF2) kinase]. Brain-derived neurotrophic factor (BDNF) and its receptor, neurotrophic receptor tyrosine kinase 2 (TrkB), also plays a key role in synaptic plasticity (Minichiello, 2009). TrkB activation stimulates phospholipase Cγ1 (PLCγ1), which results in CaMK activation (Minichiello, 2009). Calcium-signaling activation further sends its signal toward downstream epigenetic and transcription modulators, such as MEF2, MeCP2, and HDAC5. These pathways modulate gene expression that affects dendritic growth, synaptic development, and neuronal plasticity (Greer and Greenberg, 2008; Graff and Tsai, 2013; Takemoto-Kimura et al., 2017; Uchida and Shumyatsky, 2018a,b; Figure 1). Taken together, calcium-signaling stimulation through NMDARs and/or AMPARs activates multiple downstream nucleocytoplasmic pathways; it induces activity-dependent epigenetic genetic expression, contributing to depression and antidepressant action.

Chronic stress initiates and exacerbates several psychiatric illnesses. Indeed, adverse stressful environments are associated with the pathophysiology of major psychiatric disorders, including mood and anxiety disorders (Mcewen, 2007; Krishnan and Nestler, 2008; Duman and Aghajanian, 2012). There are several evidences demonstrating alterations in the expression and/or function of glutamatergic signaling and its downstream molecules (e.g., NMDARs, AMPARs, CaMKIIs, MEF2, MeCP2, and HDAC5), which is associated with plasticity and behaviors induced by chronic stress, traditional antidepressant drugs, and/or ketamine (Table 1). Moreover, molecular dysregulation associated with glutamatergic system is visible in postmortem brain tissues of patients with MDD (Table 1). Thus, such clinical and preclinical evidences suggest that calcium-signaling is a downstream target of the glutamatergic system in MDD pathophysiology and antidepressant effects.

Less than one-third of patients with MDD achieve remission using traditional antidepressant pharmacotherapy (Trivedi et al., 2006). Treatment resistance occurs in up to 30% of patients with MDD (Fava, 2003). However, a single subanesthetic dose of ketamine produces a therapeutic response within a few hours that lasts for several days in patients with depression (Berman et al., 2000; Zarate et al., 2006). Intravenous infusion of ketamine results in clinical response and remission in 70 and 30% of treatment-resistant patients with MDD, respectively (Zarate et al., 2006). Additionally, Ketamine reduces suicidal ideation (Krystal et al., 2013). In 2020, esketamine was approved by the USFDA for treating depressive symptoms in adults with MDD having acute suicidal ideation or behavior.

Ketamine elicits robust unwanted side effects, including prepulse-inhibition deficits, cognitive deficits, and schizophrenia-like psychotic symptoms in humans (Lahti et al., 1995; Chan et al., 2013; Giorgetti et al., 2015). Recent preclinical data indicate that ketamine’s enantiomer (R)-ketamine (Hashimoto, 2019; Wei et al., 2021) and its metabolites (2R, 6R)-hydroxynorketamine (HNK) (Zanos et al., 2016) exert antidepressant effects with fewer adverse effects than do ketamine or (S)-ketamine. Since potential mechanisms underlying the rapid antidepressant actions of ketamine and its metabolites have been reviewed elsewhere (Fukumoto et al., 2017; Yang C. et al., 2018; Duman et al., 2019; Krystal et al., 2019; Sial et al., 2020; Highland et al., 2021; Shinohara et al., 2021; Wei et al., 2021; Xia et al., 2021), we review the recent progress in deciphering mechanisms underlying ketamine’s sustained antidepressant effects, with a particular focus on the role of calcium signaling from a multiscale perspective.

This mini-review highlights that the glutamatergic pathway is associated with behavioral, neuroplastic, neurobiological, molecular, and epigenetic effects of ketamine, focusing on Ca²⁺ signaling wherein its dysfunction is involved in depression pathophysiology according to both clinical and animal studies. Such (reverse) translational implications for bridging the research gap between human depression and animal models will provide a better understanding of how ketamine affects and modulates depression pathophysiology and ultimately contribute to the clinical application of ketamine or the development of related compounds for wide range of psychiatric disorders. Glutamatergic transmission and monoaminergic systems induce rapid biological changes that induce fast antidepressant effects. In contrast, ketamine’s sustained antidepressant actions are likely mediated by intracellular Ca²⁺ signaling cascades that affect neurobiological processes, including dendritic spine formation, epigenetic modifications, and long-term synaptic plasticity, and consequently, maintain physiological functioning.

In this mini-review, we particularly focused on the hippocampus and prefrontal cortex, key brain regions associated with MDD pathophysiology and ketamine’s antidepressant effect. However, other brain regions were suggested to also be involved in these processes, such as the lateral habenula. Emerging evidence from preclinical and clinical studies identified an important role of the lateral habenula in depression and ketamine’s antidepressant effect through a glutamatergic pathway (Li et al., 2013; Cui et al., 2018a,b, 2019; Yang et al., 2018; Hu, 2019, Hu et al., 2020). In addition, dynamic molecular changes were observed in the nucleus accumbens of animal models of depression and ketamine-treated animals (Bagot et al., 2017). Thus, future studies are warranted to clarify how ketamine impacts neuronal circuit activity and identify underlying molecular and epigenetic mechanisms.

In summary, ketamine has great potential in the development of groundbreaking neuropsychiatric therapies. Our current understanding of depression pathophysiology and ketamine’s action suggests that diverse drug actions converge around Ca²⁺-signaling-mediated neural plasticity. However, ketamine plays diverse roles in the glutamatergic pathway and other neurotransmitter systems, neurogenesis, inflammation, and even body–brain crosstalk. Furthermore, several studies have suggested the distinct roles of ketamine enantiomers ([S]-ketamine and [R]-ketamine) and their metabolites ([2R,6R]-HNK and [2S,6S]-HNK) in plasticity and behavior (Zanos et al., 2016; Yamaguchi et al., 2018; Hashimoto, 2019; Lumsden et al., 2019; Yokoyama et al., 2020; Highland et al., 2021; Wei et al., 2021). Thus, mechanisms underlying ketamine’s actions remain controversial. Moreover, ketamine effects at the mesoscale of neural architecture and macroscale of neural connectivity, cognition, and behavior are poorly understood. Further investigations at both the multiscale and multisystem levels are necessary to comprehensively understand mechanisms underlying ketamine’s antidepressant effects and develop novel drugs for treating MDD.

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