International Journal of Neuropsychopharmacology, Volume 22, Issue 2, February 2019, Pages 119–135,


The underlying neurobiological basis of major depressive disorder remains elusive due to the severity, complexity, and heterogeneity of the disorder. While the traditional monoaminergic hypothesis has largely fallen short in its ability to provide a complete picture of major depressive disorder, emerging preclinical and clinical findings suggest that dysfunctional glutamatergic neurotransmission may underlie the pathophysiology of both major depressive disorder and bipolar depression. In particular, recent studies showing that a single intravenous infusion of the glutamatergic modulator ketamine elicits fast-acting, robust, and relatively sustained antidepressant, antisuicidal, and antianhedonic effects in individuals with treatment-resistant depression have prompted tremendous interest in understanding the mechanisms responsible for ketamine’s clinical efficacy. These results, coupled with new evidence of the mechanistic processes underlying ketamine’s effects, have led to inventive ways of investigating, repurposing, and expanding research into novel glutamate-based therapeutic targets with superior antidepressant effects but devoid of dissociative side effects. Ketamine’s targets include noncompetitive N-methyl-D-aspartate receptor inhibition, α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid throughput potentiation coupled with downstream signaling changes, and N-methyl-D-aspartate receptor targets localized on gamma-aminobutyric acid-ergic interneurons. Here, we review ketamine and other potentially novel glutamate-based treatments for treatment-resistant depression, including N-methyl-D-aspartate receptor antagonists, glycine binding site ligands, metabotropic glutamate receptor modulators, and other glutamatergic modulators. Both the putative mechanisms of action of these agents and clinically relevant studies are described.


Major depressive disorder (MDD) is associated with global morbidity leading to costly psychiatric care and significant societal burden, with a commensurate impact on public health (Whiteford et al., 2013). Worldwide, more than 300 million people now live with depression, a staggering increase of over 18% between 2005 and 2015. Workplace costs associated with depression-related disability further add to the global burden of the disease, as do suicide-related expenditures (Greenberg et al., 2015). Indeed, MDD is the leading cause of suicide in the United States.

Standard pharmacological treatments for depression presently revolve around monoaminergic-based targets due to the early serendipitous discovery that drugs inhibiting the reuptake or metabolism of monoaminergic neurotransmitters (serotonin, noradrenaline, dopamine) possess antidepressant effects (Bunney and Davis, 1965; Schildkraut, 1965; Heninger et al., 1996). However, despite their widespread use, the efficacy of these agents is limited by delayed therapeutic onset, low remission rates, and increased treatment refractoriness (Rush et al., 2006; McIntyre et al., 2014). For instance, the large NIMH-funded Sequenced Treatment Alternatives to Relieve Depression study found that only one-third of MDD patients achieved remission after an adequate trial with a traditional antidepressant. Furthermore, even after 2 additional levels of antidepressant switch therapy or augmentation treatment, only two-thirds of patients achieved remission; thus, roughly 35% of patients in the Sequenced Treatment Alternatives to Relieve Depression study were nonremitters, a group described as having treatment-resistant depression (TRD) (Trivedi et al., 2006). Similarly, the remission rate in the recently completed Prolonging Remission in Depressed Elderly study was only 61%, despite the fact that the study used additional effective interventions such as electroconvulsive therapy (Kellner et al., 2016a, b; Rasmussen, 2017).

A large proportion of the global burden of depression described above is attributable to TRD, which accounts for roughly one-third of depressed subjects. While a number of methods for assessing TRD exist (Malhi and Byrow, 2016), it is loosely defined as failure to respond to one or more FDA-approved antidepressant treatments as measured via various criteria, most often the Antidepressant Treatment History Form (Sackeim, 2001); it should be noted that in the context of this paper, TRD refers to treatment resistance to standard antidepressants only. TRD is associated with poorer overall clinical outcomes, significant physical and mental comorbidities, a substantial burden on individuals and their families, high healthcare costs, and marked and protracted functional impairment (Fekadu et al., 2009; Culpepper, 2011). Lack of response to antidepressant therapy in general—and for TRD patients in particular—is also associated with increased suicide risk (Machado-Vieira et al., 2009). Current therapeutics have limited efficacy in treating suicidal ideation, and no FDA-approved medications exist for that purpose (Griffiths et al., 2014). As a result, new trends in polypharmacy for MDD have been conceived in the last few years, particularly for treating chronic and severe forms of TRD, underscoring the critical unmet medical need for new agents with novel mechanisms of action that show rapid antidepressant efficacy (Olin et al., 2012).

In recent years, compelling evidence has accrued in favor of the glutamatergic system as a primary mediator of psychiatric pathology and a target for the therapeutic action of drugs, particularly rapid-acting antidepressants (Sanacora et al., 2008, 2012; Duman and Aghajanian, 2012; Musazzi et al., 2013; Duman et al., 2016; Lener et al., 2017; Murrough et al., 2017a). Although glutamate was not recognized as a neurotransmitter until the 1980s—when monoaminergic pathways had already been mapped in the brain—this excitatory amino acid is the most abundant neurotransmitter in the brain. Early clinical findings suggested that glutamate plasma levels were significantly higher in patients with mood disorders (Altamura et al., 1993; Sanacora et al., 2008). In this context, emerging preclinical and clinical evidence of the impaired relationship between glutamatergic neurotransmission and synaptic plasticity in mood disorders has guided the search for novel pharmacotherapeutic strategies.

Towards this end, the glutamatergic agent ketamine has been intensely investigated over the past 2 decades. Ketamine’s antidepressant effects are hypothesized to be mediated by direct and indirect N-methyl-D-aspartate receptor (NMDAR) inhibition, gamma aminobutyric acid (GABA)-ergic interneuron disinhibition, and conversion to hydroxynorketamine (HNK) metabolites; together, these processes increase presynaptic glutamate release, with the net effect of enhancing glutamatergic throughput at the α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor (AMPAR) relative to the NMDAR (Zanos et al., 2016, 2018a). These presumed mechanisms are not mutually exclusive and may in fact work in a complementary fashion to exert sustained potentiation of excitatory synapses to maintain antidepressant response (Figure 1).

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