Major depressive disorder (MDD) is a heterogeneous neuropsychological disorder characterized by a combination of symptoms that negatively impact the productivity and well-being of inflicted patients, including impairments in cognition, emotional regulation, memory, motor function, motivation, and possible suicidal ideation. Approximately 280 million people in the world are affected by this psychiatric disorder, and it is regarded as one of the leading causes of morbidity and disability worldwide [1]. An episode of major depression may occur once in a person’s lifetime, but it is more likely to relapse throughout a person’s life [2]. Although several pharmaceutical strategies have been proven in clinical settings, more than two-thirds of patients with MDD do not achieve stable remission of symptoms, despite currently available medication [3]. Furthermore, the current antidepressant drugs targeting the monoamine systems (norepinephrine, dopamine, and/or serotonin) require a long duration (4–8 weeks) to take effect [4]. The severe adverse effects associated with the pharmacotherapy, including cardiac toxicity, hyperpiesia, sexual dysfunction, body weight gain, and sleep disorders, often hamper patients’ adherence [5,6]. The current pharmacotherapy for MDD remains unsatisfactory, which may be attributed to the lack of understanding of the neurobiological mechanisms underlying this pathological condition.

MDD is a debilitating disorder with multiple potential etiologies, including environmental and genetical influences [7]. Although several hypotheses have been suggested to explain the pathophysiological mechanisms of MDD, the contours of the disorder are still unclear. Among these hypotheses, the dysregulation of neurotransmitters has received the most attention in the neurobiological mechanisms of MDD, i.e., the monoaminergic hypothesis involving serotonin, norepinephrine, and/or dopamine. Clinically, most antidepressants target this system as a therapeutic goal, including tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), serotonin, and norepinephrine reuptake inhibitors (SNRIs), to restore the levels of these monoamines [8].

A growing consensus posits that altered monoaminergic transmission is insufficient to explain the etiology of depressive disorders [9,10,11]. Hypothalamic–pituitary–adrenal (HPA) axis dysregulation has been implicated in the pathogenesis of MDD, as the hyperactivity state of the HPA axis is one of the most consistent findings in the neuroendocrinology of depression [12,13] and as the HPA axis is dysregulated by stress and trauma, both of which are known precipitants of MDD [14]. Furthermore, data from rodents showed that central administration of corticosterone, a stress-related hormone, can produce depression-like behaviors [15]. The plasma levels of corticosterone, a stress hormone, have been widely used as biomarkers of stress [16], depression [17] and anxiety [18] in mice, and such a phenomenon was also observed in humans [19] in the form of plasma cortisol. Chronic stress is reported to induce neuropsychological disorders, including depression and anxiety, via the hyperactivity of the hypothalamic–pituitary–adrenal (HPA) axis [20,21].

In addition to the monoaminergic system, a growing body of evidence has revealed that the glutamatergic system plays a critical role in the pathophysiological mechanisms of MDD [1,22,23]. Several postmortem studies have indicated that glutamate receptor subunits, including the GluR1 subunit and AMPA binding, were reduced in patients with major depression [22,23,24,25]. Beyond the conventional monoaminergic theory, these findings provided an alternative concept in the possible pathological mechanisms of MDD and the different approach in the development of novel antidepressants.

Glutamate is the major excitatory neurotransmitter in the central nervous system. It plays an important role in several physiological functions. A typical glutamate synapse is composed of three distinct cell types: an astrocyte, a presynaptic neuron, and a postsynaptic neuron [26]. In the central nervous system, glutamine synthesis from glutamate and ammonia occurs exclusively in the astrocytes. Then, glutaminase, a precursor for the synthesis of the neurotransmitter glutamate, hydrolyses glutamine to glutamate and ammonia within neurons, completing the glutamate–glutamine cycle in the brain (Figure 1). Glutamate is then packaged into vesicles in the presynaptic neuron by three types of vesicular glutamate transporters (VGLUT1, VGLUT2 and VGLUT3) and released into the synapse from the presynaptic terminals [27], in an activity-dependent manner. The released glutamate in the synaptic cleft can engage both ionotropic and metabotropic glutamate receptors, located in the presynaptic and postsynaptic neurons, as well as on astrocytes [28]. The ionotropic subtypes of glutamate receptors, including the AMPA, N-methyl-D-aspartate (NMDA), and kainate receptors, control fast excitatory neurotransmission, whereas the family of eight metabotropic glutamate receptors (mGluR1-8) are located in presynaptic areas, postsynaptic areas, and extra-synaptically throughout the central nervous system [29]. The concentrations of synaptic glutamate are regulated by glutamate transporters localized in glial cells and neurons due to the fact that there is no process by which glutamate is metabolized in neurons.