Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Drugs. Author manuscript; available in PMC 2012 Sep 12.
Published in final edited form as:
PMCID: PMC3439647

Targeting the Glutamatergic System to Treat Major Depressive Disorder

Rationale and Progress to Date


Major depressive disorder (MDD) is a severe, debilitating medical illness that affects millions of individuals worldwide. The young age of onset and chronicity of the disorder has a significant impact on the long-term disability that affected individuals face. Most existing treatments have focused on the ‘monoamine hypothesis’ for rational design of compounds. However, patients continue to experience low remission rates, residual subsyndromal symptoms, relapses and overall functional impairment.

In this context, growing evidence suggests that the glutamatergic system is uniquely central to the neurobiology and treatment of MDD. Here, we review data supporting the involvement of the glutamatergic system in the pathophysiology of MDD, and discuss the efficacy of glutamatergic agents as novel therapeutics. Preliminary clinical evidence has been promising, particularly with regard to the N-methyl-D-aspartate (NMDA) antagonist ketamine as a ‘proof-of-concept’ agent. The review also highlights potential molecular and inflammatory mechanisms that may contribute to the rapid antidepressant response seen with ketamine.

Because existing pharmacological treatments for MDD are often insufficient for many patients, the next generation of treatments needs to be more effective, rapid acting and better tolerated than currently available medications. There is extant evidence that the glutamatergic system holds considerable promise for developing the next generation of novel and mechanistically distinct agents for the treatment of MDD.

1. Background

Investigation of the mechanisms of action of the earliest effective therapeutic agents for major depressive disorder (MDD) – including monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs) and electroconvulsive therapy (ECT)[1,2] –led researchers to adopt the initial ‘monoamine hypothesis’ of MDD and other affective disorders.[35] Although TCAs became the initial standard treatment for depression, usage was limited by the large number of adverse effects associated with their use and by the danger of overdose rather than by their lack of efficacy.[6] Subsequent drug discovery efforts focused on the rational design of compounds with similar efficacy, but improved tolerability; the most notable example is selective serotonin reuptake inhibitors (SSRIs).[7]

Despite the widespread use of SSRIs, the World Health Organization (WHO) Global Burden of Disease analysis projected that MDD will be the second leading cause of disability worldwide by 2020.[8] Furthermore, marked limitations associated with the use of currently available antidepressants were observed in the 7-year Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial, which encompassed nearly 3000 outpatients aged 18–75 years. The study concluded with the sobering observation that fewer than one-third of patients with MDD achieved remission after a standard antidepressant trial.[9] Additional controversy and debate have surrounded the efficacy of currently available anti-depressants, and a recent meta-analysis suggested a weaker than expected effect compared with placebo.[10] The methodology of these findings has been challenged,[11,12] and another analysis demonstrated that available antidepressants were clinically superior to placebo;[13] nevertheless, the issue of heterogeneity in treatment response remains.

In recent years, a growing body of evidence has implicated the glutamatergic system in the pathogenesis of depression. While much of the early impetus in this area came from preclinical models,[14,15] recent remarkable clinical observations[16,17] – particularly with the N-methyl-D-aspartate (NMDA) antagonist ketamine – have driven increased interest in the aetiological framework and search for potential targets within this complex regulatory system. The fact that so many individuals with MDD continue to struggle in their efforts to find effective treatments underscores the clearly urgent need to develop innovative and mechanistically distinct agents to further reduce the burden of mental illness. This next generation of treatments needs to be more effective, rapid acting and better tolerated than currently available medications.[18] In this context, considerable research suggests that the glutamatergic system may provide key insights into the pathophysiology of MDD, and in the development of novel therapeutics to treat this devastating disorder. Given the scope of this topic, this article focusses primarily on current relevant therapeutics and potential mechanisms underlying ketamine’s rapid antidepressant effect.

2. Rationale for Investigating Glutamate

High concentrations of glutamate were first observed in the brain in the 1930s, suggesting to researchers that this amino acid likely played a neurophysiological role.[19] As a neurotransmitter, glutamate was largely considered nonspecific until experiments in mammalian vertebrates in 1979 used specific agonists and antagonists to identify glutamate receptors in the brain.[20,21] Glutamate is found in substantially higher concentrations than monoamines and in more than 80% of neurons, cementing its role as a major excitatory synaptic neurotransmitter.[22] Accumulating research shows that glutamate plays a key role in regulating neuroplasticity, learning and memory.[23]

Given that glutamate is so widely distributed in the brain, strict regulation is necessary to prevent undue excitotoxicity. This is critical, as glutamate excitotoxicity has been implicated in a number of central nervous system (CNS) disorders, including Alzheimer’s disease, Huntington’s disease and Amyotrophic Lateral Sclerosis (ALS).[2427] The delicate balance of glutamate with the major inhibitory neurotransmitter γ-aminobutyric acid (GABA) is essential for all physiological homeostasis in the CNS.[28] Given the ubiquitous nature of glutamate in the brain, and the fact that it acts on a number of different receptors – including glial cell receptors – it is not surprising that the underlying mechanisms of glutamate signalling are quite complex.

Evidence that glutamate is involved in the pathophysiology of mood disorders is indirect and drawn from imaging and post-mortem studies. Changes in glutamate levels have been noted in plasma,[2931] serum,[32] cerebrospinal fluid (CSF)[33,34] and brain tissue[35] of individuals with mood and psychotic disorders, as well as in suicide victims.[36,37] Most studies reported that serum levels of glutamate in depressed patients were significantly higher than in healthy controls. However, interpreting glutamate levels in plasma, serum and CSF studies is challenging, given confounds such as medication exposure, post-mortem metabolic effects, and the inability to distinguish the source of glutamate (central vs peripheral).[38,39]

In recent years, however, new techniques, such as proton magnetic resonance spectroscopy (1H-MRS), have provided non-invasive in vivo brain imaging methods that can be used to study the mechanism of action of psychotropic drugs. Resonances in the 1H-MR spectrum can be reliably measured for several metabolites with brain concentrations in the millimolar range, including N-acetyl-aspartate (NAA), glutamate, glutamine, the combined measure of glutamate and glutamine (Glx), creatine + phosphocreatine (Cr), choline-related compounds (Cho) and myo-inositol.[40]

In the study of mood disorders, several investigators have focused on measuring Glx and GABA in various and specific brain regions. At its simplest, Glx reflects the total glutamatergic pool available for synaptic/metabolic activity in the form of glutamate or glutamine. One study found decreased Glx levels in the dorsomedial/dorsoanterolateral prefrontal cortex (PFC) of subjects with MDD,[41] echoing findings from prior post-mortem histopathological studies.[36] Elevated levels of glutamate have also been noted in the occipital cortex of MDD patients,[42] and decreased levels in the anterior cingulate cortex (ACC) in individuals with bipolar disorder.[43] A recent review of the MRS literature in mood disorders found reduced Glx levels in the ACC, left dorsolateral PFC (DLPFC), dorsomedial PFC (DMPFC), ventromedial PFC (VMPFC), amygdala and hippocampus of MDD patients.[44] In bipolar disorder, Glx levels were elevated in the grey matter areas of the ACC, medial PFC, DLPFC, parieto-occipital cortex, occipital cortex, insula and hippocampus.[44] However, it is important to consider the methodological heterogeneity across MRS studies; these include, but are not limited to, subject selection, sample size, MRS sequences, field strength and anatomical placement of the voxel of interest.[45] Combining MRS with other imaging techniques – such as functional magnetic resonance imaging (fMRI), positron emission tomography (PET) or magnetoencephalography (MEG) – is already helping investigators integrate data across multiple sources and may ultimately help identify glutamatergic abnormalities that could serve as key biomarkers for diagnosis or antidepressant response.[45]

Lastly, dendritic/structural remodelling in key regions (e.g. PFC, hippocampus, amygdala) of the CNS is thought to play a role in depression and anxiety.[4649] Given that glutamate is necessary for the normal development of dendritic branching,[50] it has been speculated that excessive glutamatergic neurotransmission (via exposure to chronic stress) causes dendritic retraction and loss of spines.[46] Such changes would effectively limit the number of exposed glutamate receptors and as a result, drugs thought to reduce glutamatergic neurotransmission may prevent dendritic retraction and protect brain synapses.[46,51] Interestingly, glutamatergic neurotransmission may further be altered at the genetic level, where genetic variations in key enzymes could influence the presumed in vivo index of glutamatergic neurotransmission.[52]

Taken together, the evidence presented above suggests that the glutamatergic system likely plays a significant role as a ‘primary mediator of psychiatric pathology’.[53] Our increasing knowledge of this system underscores its potential as an alternative or complementary pathway for developing novel treatments for MDD and other mood disorders. Ongoing studies that augment our understanding of the glutamatergic system –and the subsequent application of this information – may ultimately enhance neural plasticity and cellular resilience in patients with mental illness.[54] Table I and table II and the text that follows provide a summary of glutamate targets for drug development and the evidence in support of specific agents.

Table I
Glutamatergic targets for drug development
Table II
Glutamatergic compounds in randomized clinical controlled trialsa

3. The Physiology of Glutamate

Glutamate acts on three key cell compartments: presynaptic neurons, postsynaptic neurons and glia. Often characterized as the ‘tripartite glutamatergic synapse’, this system functions in the uptake, release and inactivation of glutamate via two major subtypes of glutamate receptors in the CNS: ionotropic and metabotropic.[64] In addition, high-affinity excitatory amino acid transporters (EAATs) provide glutamate clearance from extracellular space, and soluble N-ethylmaleimide-sensitive factor attachment receptor (SNARE) complexes are thought to play a role in the structural aspects of synaptic vesicle exocytosis.[65] Lastly, vesicular glutamate transporters (VGLUTs) are responsible for the uptake of glutamate into the synaptic vesicle.[65] Because of limited current therapeutic applications with many of the above targets, most of the following discussion pertains to the ionotropic receptor subtypes: NMDA and α-amino-3-hydroxy-5methyl-4-isoxazole propionic acid (AMPA).

The NMDA receptor channel comprises NR1, NR2 (NR2A–NR2D) and NR3 (NR3A and NR3B) subunits. NMDA receptor antagonists have demonstrated antidepressant-like effects in many animal models of depression, including inescapable stressors, the forced swim test, the tail suspension test, learned helplessness models of depression, and exposure to chronic mild stress procedures.[14,6669] Other studies noted adaptive changes in NMDA receptor expression in response to both TCAs and ECT.[7073]

The AMPA receptor is stimulated by the presence of glutamate and typically produces a fast excitatory synaptic signal. Its activation allows for the inward flow of sodium, causing depolarization of the neuronal membrane. The change in the intracellular charge frees the magnesium cation from the NMDA receptor, allowing the influx of calcium.[74] This channel is composed of four functionally diverse AMPA receptor subunits (GluR1–GluR4), and at mature synapses is co-expressed with NMDA receptors.[7577] The presence of these receptors at synapses is carefully regulated to ensure proper neuronal communication.[78] Consequently, the trafficking of AMPA receptors into and out of synapses is a dynamic process and considered a significant mechanism underlying activity-induced changes in synaptic transmission[79] and plasticity, which are particularly instrumental in learning and memory.[23,76,77]

In animal models, AMPA receptor subunit 1 (GluR-A)-knockout mice (GluR-A−/−) displayed increased learned helplessness, decreased serotonin and noradrenaline (norepinephrine) levels, and disturbed glutamate homeostasis with increased glutamate levels and increased NMDA receptor expression. Bleakman et al.[80] reviewed preclinical models with antidepressant-like behavioural effects and found that AMPA potentiators produced neuronal effects (e.g. brain-derived neurotrophic factor [BDNF] induction) similar to those produced by currently available antidepressants. This is in line with research suggesting that antidepressants exert their effects via a cascade of AMPA-mediated and NMDA-mediated events ultimately promoting synaptic plasticity.[75] In addition, compounds that augment AMPA receptor signalling or decrease NMDA receptor function may have antidepressant effects.[81]

Further evidence of AMPA’s role in mood disorders comes from studies of medications with antidepressant properties that significantly enhance GluR1 and GluR2 expression in a dose-dependent manner in hippocampal neurons.[80] AMPA receptor expression was also recently reported to be increased in post-mortem ACC samples from subjects with MDD.[82] Interestingly, animal models using an AMPA antagonist (NBQX) prior to infusion found that it selectively attenuated ketamine’s antidepressant-like effects.[83] These results suggest that the antidepressant effects of ketamine are in part mediated by AMPA activation[83] and that enhanced AMPA receptor throughput may likely account for the uniquely rapid onset of action of ketamine[84] (ketamine is discussed in greater detail in section 4.1.1 and 4.1.2).

With regard to drug development, several compounds are being developed to allosterically modulate AMPA receptors, including pyrrolidones (piracetam, aniracetam), benzothiazides (cyclothiazide), benzylpiperidines and biarylpropylsulfonamides (for more complete reviews see Bleakman et al.,[80] Alt et al.[85] and O’Neill and Witkin[86]). Accordingly, these compounds do not directly activate AMPA receptors themselves, but slow the rate of receptor desensitization in the presence of an agonist.[87,88] Preclinical research with behavioural despair paradigms found that biarylpropylsulfonamide AMPA receptor potentiators (LY392098 and LY451616) had antidepressant-like effects.[89] In another animal study, CX-516 (Ampalex), an AMPA potentiator, had more rapid antidepressant-like effects (during the first week of treatment) than fluoxetine.[90] More recently, the AMPA receptor potentiator LY451646 was found to mimic the effects of antidepressants in preclinical tests with high predictive validity. Interestingly, this particular compound – along with ketamine – demonstrated that BDNF signalling does not play a role in its antidepressant effects[91] (discussed in greater detail in section 5.1). It is also interesting to note that recent preliminary research was conducted with a rat-human translational pharmacokinetic-pharmacodynamic (PK-PD) model of AMPA receptor modulation, with the goal of predicting human target engagement and informing ideal dose selection in future efficacy clinical trials.[92]

Figure 1 illustrates general glutamatergic neuro-transmission and potential sites for novel drug development. The interested reader is referred to several recent reviews[9395] for more detailed information regarding glutamate metabolism, clearance, cycling and other glutamate receptor functions/applications (e.g. metabotropic receptors).

Fig. 1
Glutamatergic neurotransmission and potential targets for drug development. Tight physiological control is maintained over glutamatergic neurotransmission. Gln is converted to Glu by glutaminase, though it can also be derived from the TCA cycle (not shown). ...

4. Therapeutics

4.1 Ketamine and Other N-Methyl-D-Aspartate (NMDA) Antagonists

4.1.1 Ketamine

Ketamine, a phencyclidine (PCP) derivative, is a noncompetitive, high-affinity NMDA antagonist that prevents excess calcium influx and cellular damage.[96] Its primary mechanism of action is blocking the NMDA receptor at the PCP site within the ionotropic channel. Ketamine also has a high affinity to the NMDA receptor, slower open channel blocking/unblocking kinetics, ‘trapping block versus partial-trapping’ channel closure properties,[97] and different NMDA subunit selectivity than other NMDA antagonists such as memantine, active remacemide, AZD6765.[98101] Several pre-clinical studies found that ketamine demonstrated antidepressant- or anxiolytic-like behaviours in various animal behaviour models of depression (e.g. forced swim test, tail suspension test, etc.).[73,83,102112] An early dose-response preclinical study further demonstrated that low doses of ketamine increased glutamate outflow in the PFC.[113]

In regard to safety, ketamine has been widely used as an anaesthetic agent for children for decades.[114] Literature reviews also note that significant cardiorespiratory adverse events are rare, but dysphoric emergence phenomena (psychotomimetic effects) occur in up to 20% of cases[115,116] in paediatric/adult populations. A single dose of ketamine in rats (up to 20 mg/kg, subcutaneously) did not exert neuronal toxicity.[117]

The first report of ketamine’s potential to alleviate depressive symptoms was a small, randomized, double-blind study demonstrating that a single subanaesthetic (0.5 mg/kg) ketamine infusion improved depressive symptoms within 72 hours in seven patients with treatment-resistant MDD.[16] Subsequently, a larger double-blind, placebo-controlled, crossover study found that a single ketamine infusion (0.5 mg/kg over 40 minutes) had fast and relatively sustained antidepressant effects (lasting 1–2 weeks) in patients with treatment-resistant MDD.[17] In this study, subjects had on average failed six prior antidepressant trials and were medication free at least 2 weeks prior to infusion. Notably, criteria for significant antidepressant response were found in 50% of subjects within 2 hours after ketamine infusion, and 71% within 24 hours. None of the subjects randomized to placebo met response criteria. The magnitude of the effect at this early timepoint was similar to that observed after many weeks of treatment with currently available antidepressants. Adverse effects included perceptual disturbances, confusion, elevations in blood pressure, euphoria, dizziness and increased libido, but most of these peaked within 40 minutes and ceased within 80 minutes post-infusion. In no case did euphoria or derealization/depersonalization persist beyond 80 minutes.[17] This finding of significant antidepressant effects associated with a single ketamine infusion has since been reported in several other studies of individuals with MDD; the magnitude and timeframe of onset and duration of response to ketamine appears remarkably similar across studies.[118121]

Building on this work, the antidepressant effects of ketamine for the treatment of bipolar depression were examined. In the first such study, a single ketamine infusion was found to have rapid anti-depressant effects in 18 patients (maintained on therapeutic levels of lithium or valproate) with treatment-resistant bipolar depression. Within 40 minutes, depressive symptoms significantly improved in subjects receiving ketamine compared with those receiving placebo; the drug difference effect size was largest at day 2. A total of 71% of subjects responded to ketamine and 6% responded to placebo at some point during the trial. Ketamine was generally well tolerated, with the most common adverse effect being dissociative symptoms, which were observed only at the 40-minute point.[55] This study was recently replicated in another double-blind, randomized, crossover, placebo-controlled study.[56] Fifteen subjects with bipolar type I or II depression (also maintained on therapeutic levels of lithium or valproate) received a single intravenous infusion of either ketamine hydrochloride 0.5 mg/kg or placebo on two test days 2 weeks apart. Within 40 minutes, depressive symptoms as well as suicidal ideation significantly improved in subjects receiving ketamine compared with placebo (d = 0.89, 95% CI 0.61, 1.16; and 0.98, 95% CI 0.64, 1.33, respectively); this improvement remained significant through day 3. The most common side effect was again dissociative symptoms, occurring only at the 40-minute timepoint.[56] Notably, this second study was also the first controlled study to show that ketamine had rapid anti-suicidal effects in bipolar depression.

Other studies – albeit uncontrolled – similarly demonstrated that open-label ketamine had significant and rapid anti-suicidal effects in MDD patients. One study of 26 patients with treatment-resistant MDD found significantly reduced Montgomery-Åsberg Depression Rating Scale (MADRS) suicide subscale scores 24 hours after a single ketamine infusion.[122] In another study of 33 subjects with treatment-resistant MDD who received a single ketamine infusion, suicidal ideation scores decreased significantly within 40 minutes, an effect that remained significant for 4 hours post-infusion.[123] One study conducted in a naturalistic setting (e.g. emergency room) showed similar results.[124] Due to the enormous public health implications of these findings, future large-scale prospective studies are warranted.

Although these initial ketamine trials were greeted with considerable enthusiasm, the use of this agent remains highly investigational. Furthermore, due to its associated sedative and psychotomimetic effects, it is unlikely that ketamine will be adopted for widespread clinical use. Despite ketamine’s tolerability and safety profile,[114] long-term safety data are presently also limited, and well designed trials are needed to evaluate effective safety and relapse prevention strategies for the repeated use of ketamine. Additional studies are also needed to assess optimal dosing, alternative delivery routes and the risk of psychosis in patient populations.[125] Thus, considerable research efforts are aimed at developing therapeutic strategies to maintain ketamine’s initial antidepressant effects. Some of the strategies under consideration include the administration of repeated doses of ketamine, or augmentation with other drugs that are better tolerated than ketamine; the latter strategy permits the administration of a single ketamine infusion followed by treatments that do not induce psychotomimetic effects, with the goal of obtaining a rapid and sustained antidepressant effect.

One small study evaluated the therapeutic benefit of repeated ketamine infusions by administering six open-label intravenous ketamine infusions over 12 days in ten medication-free symptomatic patients with treatment-resistant MDD. The study found that ketamine was associated with both an initial and a sustained antidepressant effect. The mean reduction in MADRS scores after the sixth infusion was 85% (SD ± 12%). Post-ketamine, eight of nine patients relapsed, on average 19 days after the sixth infusion (range 6–45 days). One patient remained antidepressant-free with minimal depressive symptoms for over 3 months. Ketamine was fairly well tolerated, with only mild side effects; however, the small sample size and lack of a control group limit the extent to which these findings can be generalized.[120]

4.1.2 Ketamine Augmentation Strategies

A recent pilot randomized, double-blind study (n = 14)[60] evaluated the ability of riluzole – a glutamatergic modulator with antidepressant and synaptic plasticity-enhancing properties[126128] –to prevent post-ketamine relapse (for an in-depth review of riluzole in psychiatric disorders, see Zarate and Manji[129]). The study also investigated whether pretreatment with lamotrigine might attenuate ketamine’s psychotomimetic effects and enhance antidepressant activity. Lamotrigine, a presynaptic glutamate-release inhibitor[130] and anticonvulsant is currently approved by the US FDA for maintenance treatment of bipolar type I disorder and as an antiepileptic for seizure disorders.[131] Trials have demonstrated that lamotrigine has beneficial effects on depressive symptoms in the depressed phase of bipolar disorder[132] and an earlier study demonstrated attenuation of psychotomimetic side effects to ketamine in healthy volunteers.[133] The pilot study by Mathew et al.[60] found that lamotrigine failed to reduce the transient psychotomimetic or dissociative side effects associated with ketamine use, and did not enhance its antidepressant effects. In addition, an interim analysis found no significant differences in post-ketamine time to relapse between the riluzole and placebo groups.

Building on this work, a larger 4-week, double-blind, randomized, placebo-controlled study evaluated riluzole use after a single ketamine infusion. Four to six hours after a single infusion of ketamine 0.5 mg/kg, 42 subjects with treatment-resistant MDD were randomized to double-blind treatment with either riluzole (100–200 mg/day; n = 21) or placebo (n = 21) for 4 weeks. The effect size of improvement with ketamine was initially large and remained moderate throughout the 28-day trial. Overall, 27% of ketamine responders had not relapsed by 4 weeks following a single ketamine infusion, underscoring ketamine’s enduring antidepressant effects in patients with treatment-resistant MDD. The average time to relapse was 13.2 days. However, the difference between the riluzole and the placebo treatment groups was not significant, suggesting that the combination of riluzole with ketamine treatment did not significantly alter the course of antidepressant response to ketamine alone.[61] Taken together, evidence from these two studies[60,61] suggests that riluzole did not maintain ketamine’s antidepressant response. Nevertheless, this does not imply that riluzole lacked significant antidepressant effects; the above studies were conducted in treatment-resistant MDD patients, and it is possible that an antidepressant signal could be detected in less refractory patients.

4.2 NMDA NR2B Antagonists

Non-competitive NMDA receptor antagonists like ketamine and PCP can produce psychotomimetic effects when used acutely. This observation led researchers to investigate whether subtype-selective, rather than pan blockers of the NMDA receptor, could maintain an efficacious profile while minimizing the adverse effects associated with blocking this receptor. In this regard, NR2B receptors are of particular interest. In preclinical models, the NR2B antagonist Ro 25-6981 reversed stress-induced hippocampal long-term potentiation (LTP) [via foot shock stress][134] and had behavioural antidepressant-like effects in the forced swim test.[83] For a detailed review of the properties of NR2B receptors and possible approaches to their use in the development of glutamate-based therapeutics see Loftis and Janowsky[135] and Gogas.[136]

An older clinical trial studying traumatic brain injury first identified an NR2B-selective NMDA antagonist (CP-101,606) that was well tolerated and did not produce psychotropic side effects.[137] In a recent randomized, placebo-controlled, double-blind study, Preskorn et al.[62] evaluated the anti-depressant efficacy of the NR2B subunit-selective NMDA receptor antagonist CP-101,606 in treatment-refractory MDD subjects. Non-responders (n = 30) to a 6-week open-label trial of paroxetine (up to 30 mg/day) and a single intravenous placebo infusion were then randomized to a double-blind single infusion of CP-101,606 or placebo plus continued treatment with paroxetine for up to an additional 4 weeks. Of the patients receiving CP-101,606, 60% responded to the treatment versus 20% for placebo; 78% of treatment responders maintained response status for at least 1 week after infusion. However, the dose was reduced for the rest of the study because several of the research subjects experienced dissociative symptoms. Dosing was clearly an issue in this study, which led the authors to also speculate that lower doses of ketamine that do not cause psychotomimetic states may nevertheless be antidepressive, and that allosteric modulation of the NR2B antagonist “may yield a bona fide greater therapeutic index for CP-101,606 compared with ketamine.”[62]

Subsequently, another small randomized, double-blind, placebo-controlled, crossover pilot study evaluated the potential antidepressant efficacy and tolerability of an oral formulation of the selective NMDA NR2B antagonist MK-0657 in patients with treatment-resistant MDD. MDD subjects underwent a 1-week drug-free period and were subsequently randomized to receive either MK-0657 monotherapy (4–8 mg/day) or placebo for 12 days. Due to recruitment challenges and the discontinuation of the compound’s development by the manufacturer, only five patients completed both periods of the crossover administration of MK-0657 and placebo. Significant antidepressant effects were observed as early as day 5 in patients receiving MK-0657 compared with placebo as assessed by the Hamilton Depression Rating Scale (HAM-D) and Beck Depression Inventory (BDI), the secondary efficacy scales; however, no improvement was noted when symptoms were assessed with the MADRS, the primary efficacy measure.[63] It is interesting to note that differential sensitivity to drug effects between the HAM-D and the MADRS has been well recognized in controlled clinical trials.[138] MK-0657 also significantly increased plasma BDNF levels compared with placebo after 9 days of treatment, demonstrating a biological effect typically observed with most other antidepressants.[139] No serious or dissociative adverse effects were observed in patients receiving this oral formulation of MK-0657. Despite the small sample size, the pilot study suggested that an oral formulation of the NR2B antagonist MK-0657 may have anti-depressant properties in MDD patients without psychotomimetic effects.[63] Further studies with larger sample sizes are necessary to confirm these preliminary findings, and additional studies are necessary to further demonstrate the efficacy and safety of compounds selective for the NR2B receptor.

4.3 Other Non-Competitive NMDA Antagonists: Memantine and Amantadine

Memantine is a low-affinity, non-competitive, open-channel NMDA receptor antagonist.[140144] This drug is FDA approved for the treatment of moderate to severe Alzheimer’s disease,[145,146] with a recent extended-release formulation. In contrast to ketamine, memantine has essentially no psychotomimetic effects at therapeutic doses (5–20 mg/day); a detailed review of the associated preclinical data can be found in Parsons et al.[147]

In 2006, an 8-week, double-blind, placebo-controlled trial (n = 32) of memantine (5–20 mg/day) failed to improve depressive symptoms in patients with MDD.[57] The authors speculated that perhaps compounds such as ketamine – which have a higher affinity for NMDA receptors, stronger open-channel blocking/unblocking kinetics and slower off rates[97] – provide more antidepressant efficacy than lower affinity compounds such as memantine, which are also weaker open channel-blockers with faster off rates.[148] Another recent 8-week, proof-of-concept study (n = 29) similarly failed to show a statistically significant benefit for memantine augmentation (5–20 mg/day) of lamotrigine (stable dose of at least 100 mg/daily for 4 weeks prior to randomization) for patients with bipolar depression. However, memantine had a significant antidepressant effect early during the course of treatment (up to 4 weeks), during its titration. The authors speculated that these effects might be due to a plateau effect from compensatory mechanisms within the glutamate system, or to dose-related effects.[58] Another 12-week, double-blind, placebo-controlled pilot study (n = 35) evaluated memantine (10 mg twice daily) for late-life depression and apathy after a disabling medical event and found that it did not improve affective or functional outcome compared with placebo.[59]

In contrast, a larger Finnish study (n = 80) evaluated alcohol-dependent patients with MDD who were randomized to memantine 20 mg/day or escitalopram 20 mg/day.[149] Memantine has been shown to reduce alcohol cravings in pre-clinical studies,[150153] and alcohol dependence is known to be co-morbid with MDD.[154,155] In the Finnish study, abstinence was not required and both treatments significantly reduced depression and anxiety (primary outcome measures) without significant differences in treatment groups or in cognitive functioning scores.[149] It should be noted that long-term alcohol use increases the number,[156] and alters the function, of glutamate NMDA receptors.[157] Alcohol dependence might therefore be involved in the antidepressant response of NMDA receptor antagonists, given that treatment with glutamate antagonists decreased ethanol seeking and relapse behaviour in rats.[158] Interestingly, a 7-day, placebo-controlled, randomized, single-blind psychopharmacology study (n = 127) that used three different antiglutamatergic strategies (lamotrigine 25 mg 4 times per day, memantine 10 mg 3 times per day or topiramate 25 mg 4 times per day) for ethanol detoxification found that all three significantly improved alcohol withdrawal symptoms and dysphoric mood.[159]

Amantadine, another NMDA receptor antagonist,[160] has been used as an antiviral agent since 1996 against influenza-A viral infections. It should be noted that amantadine appears to act through several pharmacological mechanisms (e.g. serotonergic, dopaminergic, monamine-oxidase, etc.) and has also shown effectiveness in Parkinson’s disease, traumatic head injury and other neurological conditions.[161] Preclinical models have shown synergistic antidepressant-like behavioural effects and influence on immuno-endocrine parameters (e.g. plasma corticosterone levels, interleukin [IL]-10 production) with amantadine combination treatment.[162164] Clinically, interest in its antidepressant qualities were piqued because of its remarkable effect in depressed patients with Borna disease virus (BDV) infection; one study (n = 25) demonstrated a 68% reduction in depressive symptoms in 2.9 weeks (100–300 mg/day).[165,166] Other clinical trials have been quite limited and have primarily used amantadine as an augmentation strategy (up to 300 mg/daily) in treatment-resistant MDD, with some modest effects. Side effects included dry mouth and sedation.[167,168] Larger and better designed studies are needed to evaluate the anti-depressant effects of amantadine.

5. Neurobiology of Ketamine

5.1 Molecular Mechanisms Associated with Ketamine’s Antidepressant Effects

Building on the remarkable clinical observations described above, both preclinical and human studies are exploring the cellular and molecular mechanisms associated with ketamine’s antidepressant actions. In particular, recent well designed experiments[105,108,169] have demonstrated that ketamine rapidly activates the mammalian target of rapamycin (mTOR) pathway, leading to increased synaptic signalling proteins, spine plasticity (maturation/shape formation) in the PFC, and antidepressant-like behaviours in rodents. mTOR is a multi-effector serine/threonine protein kinase involved in translation control and long-lasting synaptic plasticity; dysregulation of its signalling cascade has been hypothesized to be a common pathophysiological feature of neuropsychiatric disorders.[170] Phosphorylation of Akt (or protein kinase B) is thought to more directly activate mTOR. Akt, in turn, is activated by neurotrophic factor signalling cascades, including phosphoinositide-3 kinase (PI3K)-phosphoinositide-dependent kinase 1 (PDK1) and by extracellular signal-regulated protein kinase (ERK) pathways.[170,171]

Specifically, ketamine was found to transiently increase the phosphorylated and activated forms of eukaryotic initiation factor 4E binding protein 1 (4E-BP1), p70S6 kinase (p70S6K) and mTOR.[105] These proteins are all involved in the mTOR-signalling pathway and serve as prominent regulators of protein translation. The same study further demonstrated that inhibition of the kinases Akt and ERK – both of which are ubiquitous mediators of synaptic plasticity – eliminated ketamine’s ability to stimulate the phosphorylation of mTOR, p70S6 kinase and 4E-PB.[105] Interestingly, the mTOR pathway showed specificity, as it was not activated by single or repeated doses of two commonly used antidepressant drugs or by ECT.[105,172] While acute activation of mTOR might be related to the rapid antidepressant effects of ketamine, it should be noted that the extant literature suggests that chronic mTOR activation may lead to deleterious effects, particularly inhibition of autophagy (the ability of a cell to manage build-up of aggregate proteins and toxic substances), ultimately leading to reduced cellular resilience.[173,174]

Beurel et al.[175] recently showed that GSK-3 inhibition also contributed to the rapid anti-depressant-like effects of ketamine in a model of learned helplessness and knock-in preclinical models. Considerable previous evidence implicates deficient GSK-3 serine-phosphorylation in vulnerability to mood-related behavioural disturbances.[176179] Consequently, modulating GSK-3 by serine-phosphorylation has been suggested as an important mechanism for mood regulation.[180] Beurel et al.[175] showed that GSK-3 inhibition was evident in the hippocampus and the PFC 30 and 60 minutes after ketamine infusion, echoing prior studies of the antidepressant effects of ketamine.[105] Other studies have noted the potential involvement of Akt,[171] which is activated by ketamine[105] and known to regulate GSK-3.[181] These findings may encourage the application of specific GSK-3 inhibitors or small molecular compounds to this site for rapid antidepressant effects.[175] Nevertheless, GSK-3 inhibition may have limitations because of its involvement in diverse pathways that contain multiple substrates, which may lead to side effects or toxicity.[182]

Another recent study demonstrated that the antidepressant effects of ketamine were associated with the rapid synthesis of BDNF in the hippocampus of mice. The results demonstrated that ketamine blockade of NMDA receptors at rest deactivated eukaryotic elongation factor 2 (eEF2) kinase (a key mediator of ribosomal translocation) resulting in reduced eEF2 phosphorylation and increased BDNF translation.[169] More importantly, eEF2 inhibitors in the study exerted antidepressant-like effects in the forced swim test after 30 minutes, a timescale comparable to that of ketamine. No such response was observed in the BDNF knockout mice, which suggests that BDNF expression following eEF2 inhibition is required to produce an antidepressant-like response. Interestingly, the study was not able to detect ketamine-induced mTOR signalling, or rapamycin (an mTOR inhibitor) blockade of the behavioural actions of ketamine.[169] Some reasons explaining the lack of ketamine-induced mTOR signalling[169] compared with earlier findings[105] include differences in measurement (homogenates of hippocampus vs synaptosome-enriched fractions of PFC), earlier time of analysis (30 minutes after ketamine infusion) and systemic administration of an mTOR inhibitor versus intra-cerebroventricular (ICV) administration.[171] Given that the prior mTOR study[105] examined molecular effects 2 hours after drug treatment and behavioural effects 24 hours after drug treatment,[105] Autry et al.[169] concluded that the role of mTOR in the antidepressant effects of ketamine may be one of maintenance rather than rapid induction.

Another study demonstrated that knock-in mice with the (BDNF) Val66Met polymorphism – particularly those expressing the BDNF Met allele –had loss of synaptogenic and antidepressant actions in pyramidal cells in the PFC with low-dose ketamine.[108] The Val66Met single nucleotide polymorphism (SNP) is found in approximately 20–30% of humans[183] and results in decreased trafficking into the regulated secretion pathway and impaired activity-dependent release of BDNF.[184] The BDNFMet allele has also been linked with select learning and memory impairments[185] as well as vulnerability to psychiatric disorders.[186191]

Despite the work described above, and an earlier finding demonstrating that acute administration of ketamine increases BDNF levels in rodent models,[104] the role of BDNF expression and ketamine is decidedly mixed. For example, other studies using repeated daily dosing of ketamine found no alterations in hippocampal BDNF levels.[103,107] Clinically, one recent study (responders vs non-responders) found that ketamine’s rapid initial antidepressant effects were not mediated by peripheral measures of BDNF,[192] while another study evaluating chronic ketamine drug users showed elevated levels of peripheral BDNF;[193] however, it should be noted that in the latter study, most of the ketamine users were also polydrug users. Also, as discussed earlier, studies conducted with both ketamine and the AMPA receptor potentiator LY 451646 demonstrated that BDNF signalling or TrkB phosphorylation did not play a role in its antidepressant effects.[91] These findings[91] are not consistent with the hypothesis that BDNF, via TrkB (tyrosine kinase), activates the mTOR pathway.[194196]

Lastly, a recent study[197] (n = 62) demonstrated that patients carrying a BDNF Met substitution (Val/Met and Met/Met) had an attenuated anti-depressant response to ketamine infusion compared with Val/Val patients. The study specifically examined whether the rs6265 (Val66Met SNP) was associated with response to ketamine in patients experiencing a major depressive episode. Results showed a 24% (SD ± 31) improvement for Met carriers versus 41% (SD ± 24) for Val carriers from baseline HAM-D score to 210/230 minutes post-infusion. While limitations of the results include the inability to correct for population stratification and the small sample size, this study builds on prior preclinical data,[108] with Liu et al.[198] showing that homozygous Val/Val mice exhibited a stronger neural response (prefrontal cortex synaptogenesis) and antidepressant effect to ketamine on the basis of this single polymorphism.

It is also interesting to note that – although data are mixed – three studies[89,105,169] reported that the molecular and behavioural effects of ketamine were blocked by an AMPA receptor antagonist.[199] A recent human study corroborates the importance of enhanced non-NMDA receptor-mediated synaptic potentiation as central to the mechanism of action of ketamine as demonstrated by MEG.[200] These findings highlight the significance of AMPA receptor signalling for enhancement of synaptic plasticity,[54,79] where novel classes of AMPA potentiators (allosteric modulation) may play a key role in future treatments.[201] Finally, continued and improved understanding of the complex regulatory mTOR translational system and its role in synaptogenesis may continue to elucidate the underlying mechanisms of future rapid-acting and efficacious antidepressant treatments.

5.2 The Role of Inflammation and Ketamine

Given that MDD is a heterogeneous condition with differing underlying aetiologies, the disorder has also been associated with chronic, low-grade inflammation and cell-mediated immune (CMI) activation (the part of the immune system that involves interactions between different immune cells).[202206] Paralleling the above research are continued findings of reduced neurogenesis, increased neurodegeneration and the overall neuro-progressive nature of MDD that is likely enhanced by these inflammatory processes.[207210] These effects appear to be in part mediated by increased levels of interferon (IFN)-γ, IL-2 and pro-inflammatory cytokines (e.g. IL-1, IL-6 and tumour necrosis factor [TNF]-α),[211] as well as newer pathways, such as the activation of indoleamine 2,3-dioxygenase (IDO), which can indirectly lower brain concentrations of tryptophan and serotonin[212] and elevate the production of detrimental tryptophan catabolites, such as kynurenine and quinolinic acid (a strong agonist of the glutamatergic NMDA receptor).[213] Given the broad scope of research in this field, the interested reader is referred to several reviews detailing the mechanistic explanations of cell-mediated activation, inflammation, immune-mediated alteration of serotonin and glutamate, and other neuroprogressive processes in MDD.[211,214,215]

Subanaesthetic doses of ketamine dose-dependently suppressed TNFα and IL-6 in in vivo pre-clinical models.[216218] Another study found that ketamine had hepatoprotective effects, mediated at least in part via reduced COX-2 and inducible nitric oxide synthase (iNOS) protein – both are regulated by changes in nuclear factor kappa B (NFκB) binding activity.[219] Recent data again demonstrated that ketamine inhibited transcription factor NFκB and activator protein (AP)-1, which regulate production of proinflammatory mediators.[220] These relationships are significant as prior evidence has shown that TNFα and signalling pathways that modulate NFκB activity play prominent roles in the regulation of hippocampal synaptic plasticity.[221] NFκB signalling has been implicated in regulation of neurogenesis, particularly axon initiation, elongation, guidance and branching, dendrite arbor size and complexity, and dendritic spine density in adults.[222,223]

Clinically, a single low dose of ketamine 0.25 mg/kg significantly suppressed intraoperative and postoperative increases in serum IL-6 in a randomized, double-blind study of patients undergoing coronary artery bypass surgery (CABG) with cardiopulmonary bypass. The authors note that prolonged increases in circulating IL-6 are associated with morbidity and mortality after cardiac operation and that during the first 7 days after surgery, serum IL-6 levels in the ketamine group were significantly lower than those in the control group (p < 0.05).[224] Another randomized, double-blind, placebo-controlled study (n = 50) assessing the anti-inflammatory effects of ketamine 0.5 mg/kg in cardiac surgical patients demonstrated decreased levels of increases in C-reactive protein (CRP), IL-6 and IL-10 from intensive care unit admission to post-operative day 1.[225] However, the literature is mixed, as other studies have documented no changes in inflammatory markers in surgical settings with low-dose ketamine.[225,226] No clinical inflammatory data are currently available in trials evaluating MDD. However, continued research in this area promises to expand our understanding of ketamine’s role in mediating neuroplasticity and its anti-depressant effect.

6. Conclusion

MDD is a severe medical illness that affects the lives and functioning of millions of individuals worldwide. Considerable evidence now suggests that cellular resilience and neuroplasticity contribute to the expression of affective illness.[227] This in turn provides a plausible role for implicating glutamatergic system dysregulation in the pathophysiology of mood disorders like MDD. The evidence reviewed here supports the notion that MDD is associated with abnormal functioning of the glutamatergic neurotransmitter system and continued collaboration between preclinical and clinical researchers will clarify the magnitude and extent of these abnormalities.

Given the mismatch between our ever-expanding knowledge of the glutamatergic system and the slow pace of therapeutic development, there is a clear need for improved compounds and pre-clinical models to treat MDD. For an excellent discussion of the barriers to clinical translation using glutamatergic targets and future drug development, see Javitt et al.[228] In addition, continuing proof-of-concept studies should be encouraged to identify relevant therapeutic targets. More notably for MDD, ketamine may well be the prototype for the next generation of rapid-acting novel antidepressants. In the setting of declining pharmaceutical industry involvement and the increasing cost of clinical studies, traditional clinical development should also look at implementing more adaptive design tools to maximize the use of knowledge accumulated via preclinical studies.[229] The development of innovative, safe and effective agents for the treatment of MDD will have an important impact not only on public health worldwide, but for the many individual patients and their families who struggle with this debilitating illness.


The authors gratefully acknowledge the support of the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH; Bethesda, MD, USA), and thank the 7SE Research Unit of the NIMH-NIH for their support.

Role of funding source: This review was supported by the IRP-NIMH-NIH. The NIMH had no further role in the writing of this review, or in the decision to submit the paper for publication.


Financial disclosures: The authors gratefully acknowledge the support of the IRP-NIMH-NIH, and the NARSAD Independent Investigator Award and Brain and Behavior Foundation Bipolar Research Award (Dr Zarate). Dr Mathews and Ioline Henter have no conflict of interest to disclose, financial or otherwise. Dr Zarate is listed as a co-inventor on a patent application for the use of ketamine and its metabolites in major depression. Dr Zarate has assigned his rights in the patent to the US Government but will share a percentage of any royalties that may be received by the Government.


1. Cole JO. Therapeutic efficacy of antidepressant drugs: a review. JAMA. 1964;190:448–55. [PubMed]
2. Davis JM. Efficacy of tranquilizing and antidepressant drugs. Arch Gen Psychiatry. 1965;13 (6):552–72. [PubMed]
3. Jensen K. Depressions in patients treated with reserpine for arterial hypertension. Acta Psychiatr Neurol Scand. 1959;34 (2):195–204. [PubMed]
4. Bunney WE, Jr, Davis JM. Norepinephrine in depressive reactions: a review. Arch Gen Psychiatry. 1965;13 (6):483–94. [PubMed]
5. Schildkraut JJ. The catecholamine hypothesis of affective disorders: a review of supporting evidence. Am J Psychiatry. 1965;122 (5):509–22. [PubMed]
6. Connolly KR, Thase ME. If at first you don’t succeed: a review of the evidence for antidepressant augmentation, combination and switching strategies. Drugs. 2011;71 (1):43–64. [PubMed]
7. Schechter LE, Ring RH, Beyer CE, et al. Innovative approaches for the development of antidepressant drugs: current and future strategies. NeuroRx. 2005;2 (4):590–611. [PMC free article] [PubMed]
8. Murray CJ, Lopez AD. Evidence-based health policy: lessons from the Global Burden of Disease Study. Science. 1996;274 (5288):740–3. [PubMed]
9. Trivedi MH, Rush AJ, Wisniewski SR, et al. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry. 2006;163 (1):28–40. [PubMed]
10. Kirsch I, Deacon BJ, Huedo-Medina TB, et al. Initial severity and antidepressant benefits: a meta-analysis of data submitted to the Food and Drug Administration. PLoS Med. 2008;5 (2):e45. [PMC free article] [PubMed]
11. Horder J, Matthews P, Waldmann R. Placebo, prozac and PLoS: significant lessons for psychopharmacology. J Psychopharmacol. 2011;25 (10):1277–88. [PubMed]
12. Fountoulakis KN, Möller HJ. Efficacy of antidepressants: a re-analysis and re-interpretation of the Kirsch data. Int J Neuropsychopharmacol. 2011;14 (3):405–12. [PubMed]
13. Gueorguieva R, Mallinckrodt C, Krystal JH. Trajectories of depression severity in clinical trials of duloxetine: insights into antidepressant and placebo responses. Arch Gen Psychiatry. 2011;68 (12):1227–37. [PMC free article] [PubMed]
14. Trullas R, Skolnick P. Functional antagonists at the NMDA receptor complex exhibit antidepressant actions. Eur J Pharmacol. 1990;185 (1):1–10. [PubMed]
15. Skolnick P, Layer RT, Popik P, et al. Adaptation of N-methyl-D-aspartate (NMDA) receptors following antidepressant treatment: implications for the pharmacotherapy of depression. Pharmacopsychiatry. 1996;29 (1):23–6. [PubMed]
16. Berman RM, Cappiello A, Anand A, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000;47 (4):351–4. [PubMed]
17. Zarate CA, Jr, Singh JB, Carlson PJ, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006;63 (8):856–64. [PubMed]
18. Machado-Vieira R, Salvadore G, Luckenbaugh DA, et al. Rapid onset of antidepressant action: a new paradigm in the research and treatment of major depressive disorder. J Clin Psychiatry. 2008;69 (6):946–58. [PMC free article] [PubMed]
19. Watkins JC, Jane DE. The glutamate story. Br J Pharmacol. 2006;147 (Suppl 1):S100–8. [PMC free article] [PubMed]
20. Evans RH, Francis AA, Hunt K, et al. Antagonism of excitatory amino acid-induced responses and of synaptic excitation in the isolated spinal cord of the frog. Br J Pharmacol. 1979;67 (4):591–603. [PMC free article] [PubMed]
21. Verkhratsky A, Kirchhoff F. Glutamate-mediated neuronalglial transmission. J Anat. 2007;210 (6):651–60. [PMC free article] [PubMed]
22. Mathew SJ, Keegan K, Smith L. Glutamate modulators as novel interventions for mood disorders. Rev Bras Psiquiatr. 2005;27 (3):243–8. [PubMed]
23. Malenka RC, Nicoll RA. Long-term potentiation: a decade of progress? Science. 1999;285 (5435):1870–4. [PubMed]
24. Parsons CG, Danysz W, Quack G. Glutamate in CNS disorders as a target for drug development: an update. Drug News Perspect. 1998;11 (9):523–9. [PubMed]
25. Francis PT. Glutamatergic systems in Alzheimer’s disease. Int J Geriatr Psychiatry. 2003;18 (Suppl 1):S15–21. [PubMed]
26. Cortese BM, Phan KL. The role of glutamate in anxiety and related disorders. CNS Spectr. 2005;10 (10):820–30. [PubMed]
27. Fan MM, Raymond LA. N-methyl-D-aspartate (NMDA) receptor function and excitotoxicity in Huntington’s disease. Prog Neurobiol. 2007;81 (5–6):272–93. [PubMed]
28. Schoepp DD. Unveiling the functions of presynaptic metabotropic glutamate receptors in the central nervous system. J Pharmacol Exp Ther. 2001;299 (1):12–20. [PubMed]
29. Kim JS, Schmid-Burgk W, Claus D, et al. Increased serum glutamate in depressed patients. Arch Psychiatr Nervenkr. 1982;232 (4):299–304. [PubMed]
30. Altamura CA, Mauri MC, Ferrara A, et al. Plasma and platelet excitatory amino acids in psychiatric disorders. Am J Psychiatry. 1993;150 (11):1731–3. [PubMed]
31. Altamura CA, Mauri MC, Ferrara A, et al. Plasma and platelet amino acid concentrations in patients affected by major depression and under fluvoxamine treatment. Neuropsychobiology. 1998;37 (3):124–9. [PubMed]
32. Mitani H, Shirayama Y, Yamada T, et al. Correlation between plasma levels of glutamate, alanine and serine with severity of depression. Prog Neuropsychopharmacol Biol Psychiatry. 2006;30 (6):1155–8. [PubMed]
33. Levine J, Panchalingam K, Rapoport A, et al. Increased cerebrospinal fluid glutamine levels in depressed patients. Biol Psychiatry. 2000;47 (7):586–93. [PubMed]
34. Frye MA, Tsai GE, Huggins T, et al. Low cerebrospinal fluid glutamate and glycine in refractory affective disorder [published erratum appears in Biol Psychiatry 2007; 61 (10): 1221] Biol Psychiatry. 2007;61 (2):162–6. [PubMed]
35. Francis PT, Poynton A, Lowe SL, et al. Brain amino acid concentrations and Ca2+-dependent release in intractable depression assessed antemortem. Brain Res. 1989;494 (2):315–24. [PubMed]
36. Nowak G, Ordway GA, Paul IA. Alterations in the N-methyl-D-aspartate (NMDA) receptor complex in the frontal cortex of suicide victims. Brain Res. 1995;675 (1–2):157–64. [PubMed]
37. Holemans S, De Paermentier F, Horton RW, et al. NMDA glutamatergic receptors, labelled with [3H]MK-801, in brain samples from drug-free depressed suicides. Brain Res. 1993;616 (1–2):138–43. [PubMed]
38. Altamura C, Maes M, Dai J, et al. Plasma concentrations of excitatory amino acids, serine, glycine, taurine and histidine in major depression. Eur Neuropsychopharmacol. 1995;5 (Suppl):71–5. [PubMed]
39. Maes M, Verkerk R, Vandoolaeghe E, et al. Serum levels of excitatory amino acids, serine, glycine, histidine, threonine, taurine, alanine and arginine in treatment-resistant depression: modulation by treatment with antidepressants and prediction of clinical responsivity. Acta Psychiatr Scand. 1998;97 (4):302–8. [PubMed]
40. Frye MA, Watzl J, Banakar S, et al. Increased anterior cingulate/medial prefrontal cortical glutamate and creatine in bipolar depression. Neuropsychopharmacology. 2007;32 (12):2490–9. [PubMed]
41. Hasler G, van der Veen JW, et al. Reduced prefrontal glutamate/glutamine and gamma-aminobutyric acid levels in major depression determined using proton magnetic resonance spectroscopy. Arch Gen Psychiatry. 2007;64 (2):193–200. [PubMed]
42. Sanacora G, Gueorguieva R, Epperson CN, et al. Subtype-specific alterations of gamma-aminobutyric acid and glutamate in patients with major depression. Arch Gen Psychiatry. 2004;61 (7):705–13. [PubMed]
43. Yildiz-Yesiloglu A, Ankerst DP. Neurochemical alterations of the brain in bipolar disorder and their implications for pathophysiology: a systematic review of the in vivo proton magnetic resonance spectroscopy findings. Prog Neuropsychopharmacol Biol Psychiatry. 2006;30 (6):969–95. [PubMed]
44. Yuksel C, Ongur D. Magnetic resonance spectroscopy studies of glutamate-related abnormalities in mood disorders. Biol Psychiatry. 2010;68 (9):785–94. [PMC free article] [PubMed]
45. Salvadore G, Zarate CA., Jr Magnetic resonance spectroscopy studies of the glutamatergic system in mood disorders: a pathway to diagnosis, novel therapeutics, and personalized medicine? Biol Psychiatry. 2010 Nov 1;68(9):780–2. [PMC free article] [PubMed]
46. Gorman JM, Docherty JP. A hypothesized role for dendritic remodeling in the etiology of mood and anxiety disorders. J Neuropsychiatry Clin Neurosci. 2010;22 (3):256–64. [PubMed]
47. Holmes A, Wellman CL. Stress-induced prefrontal reorganization and executive dysfunction in rodents. Neurosci Biobehav Rev. 2009;33 (6):773–83. [PMC free article] [PubMed]
48. McEwen BS. Stress, sex, and neural adaptation to a changing environment: mechanisms of neuronal remodeling. Ann N Y Acad Sci. 2010;1204 (Suppl):E38–59. [PMC free article] [PubMed]
49. Pittenger C, Duman RS. Stress, depression, and neuro-plasticity: a convergence of mechanisms. Neuropsychopharmacology. 2008;33 (1):88–109. [PubMed]
50. Lee LJ, Lo FS, Erzurumlu RS. NMDA receptor-dependent regulation of axonal and dendritic branching. J Neurosci. 2005;25 (9):2304–11. [PMC free article] [PubMed]
51. Bessa JM, Ferreira D, Melo I, et al. The mood-improving actions of antidepressants do not depend on neurogenesis but are associated with neuronal remodeling. Mol Psychiatry. 2009;14(8):764–73. 739. [PubMed]
52. Ongur D, Haddad S, Prescot AP, et al. Relationship between genetic variation in the glutaminase gene GLS1 and brain glutamine/glutamate ratio measured in vivo. Biol Psychiatry. 2011;70 (2):169–74. [PMC free article] [PubMed]
53. Sanacora G, Treccani G, Popoli M. Towards a glutamate hypothesis of depression: an emerging frontier of neuropsychopharmacology for mood disorders. Neuropharmacology. 2012;62 (1):63–77. [PMC free article] [PubMed]
54. Manji HK, Quiroz JA, Sporn J, et al. Enhancing neuronal plasticity and cellular resilience to develop novel, improved therapeutics for difficult-to-treat depression. Biol Psychiatry. 2003;53 (8):707–42. [PubMed]
55. Diazgranados N, Ibrahim L, Brutsche NE, et al. A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression. Arch Gen Psychiatry. 2010;67 (8):793–802. [PMC free article] [PubMed]
56. Zarate CA, Jr, Brutsche NE, Ibrahim L, et al. Replication of ketamine’s antidepressant efficacy in bipolar depression: a randomized controlled add-on trial. Biol Psychiatry. 2012;71 (11):939–46. [PMC free article] [PubMed]
57. Zarate CA, Jr, Singh JB, Quiroz JA, et al. A double-blind, placebo-controlled study of memantine in the treatment of major depression. Am J Psychiatry. 2006;163 (1):153–5. [PubMed]
58. Anand A, Gunn AD, Barkay G, et al. Early antidepressant effect of memantine during augmentation of lamotrigine inadequate response in bipolar depression: a double-blind, randomized, placebo-controlled trial. Bipolar Disord. 2012;14 (1):64–70. [PubMed]
59. Lenze EJ, Skidmore ER, Begley AE, et al. Memantine for late-life depression and apathy after a disabling medical event: a 12-week, double-blind placebo-controlled pilot study. Int J Geriatr Psychiatry. Epub 2011 Dec 16. [PMC free article] [PubMed]
60. Mathew SJ, Murrough JW, aan het Rot M, et al. Riluzole for relapse prevention following intravenous ketamine in treatment-resistant depression: a pilot randomized, placebo-controlled continuation trial. Int J Neuropsychopharmacol. 2010;13 (1):71–82. [PMC free article] [PubMed]
61. Ibrahim L, Diazgranados N, Franco-Chaves J, et al. Course of improvement in depressive symptoms to a single intravenous infusion of ketamine vs. add-on riluzole: results from a four-week, double-blind, placebo-controlled study. Neuropsychopharmacology. 2012 May;37(6):1526–33. [PMC free article] [PubMed]
62. Preskorn SH, Baker B, Kolluri S, et al. An innovative design to establish proof of concept of the antidepressant effects of the NR2B subunit selective N-methyl-D-aspartate antagonist, CP-101,606, in patients with treatment-refractory major depressive disorder. J Clin Psychopharmacol. 2008;28 (6):631–7. [PubMed]
63. Ibrahim L, DiazGranados N, Jolkovsky L, et al. A randomized, placebo-controlled, crossover pilot trial of the oral selective NR2B antagonist MK-0657 in patients with treatment-resistant major depressive disorder. Neuropsychopharmacology. 2012 May;37(6):1526–33. [PMC free article] [PubMed]
64. Machado-Vieira R, Manji HK, Zarate CA. The role of the tripartite glutamatergic synapse in the pathophysiology and therapeutics of mood disorders. Neuroscientist. 2009;15 (5):525–39. [PMC free article] [PubMed]
65. Lesch KP, Schmitt A. Antidepressants and gene expression profiling: how to SNARE novel drug targets. Pharmacogenomics J. 2002;2 (6):346–8. [PubMed]
66. Meloni D, Gambarana C, De Montis MG, et al. Dizocilpine antagonizes the effect of chronic imipramine on learned helplessness in rats. Pharmacol Biochem Behav. 1993;46 (2):423–6. [PubMed]
67. Papp M, Moryl E. Antidepressant activity of non-competitive and competitive NMDA receptor antagonists in a chronic mild stress model of depression. Eur J Pharmacol. 1994;263 (1–2):1–7. [PubMed]
68. Layer RT, Popik P, Olds T, et al. Antidepressant-like actions of the polyamine site NMDA antagonist, eliprodil (SL-82. 0715) Pharmacol Biochem Behav. 1995;52 (3):621–7. [PubMed]
69. Przegaliński E, Tatarczyńska E, Dereń-Wesolek A, et al. Antidepressant-like effects of a partial agonist at strychnine-insensitive glycine receptors and a competitive NMDA receptor antagonist. Neuropharmacology. 1997;36 (1):31–7. [PubMed]
70. Nowak G, Trullas R, Layer RT, et al. Adaptive changes in the N-methyl-D-aspartate receptor complex after chronic treatment with imipramine and 1-aminocyclopropane-carboxylic acid. J Pharmacol Exp Ther. 1993;265 (3):1380–6. [PubMed]
71. Paul IA, Layer RT, Skolnick P, et al. Adaptation of the NMDA receptor in rat cortex following chronic electro-convulsive shock or imipramine. Eur J Pharmacol. 1993;247 (3):305–11. [PubMed]
72. Paul IA, Nowak G, Layer RT, et al. Adaptation of the N-methyl-D-aspartate receptor complex following chronic antidepressant treatments. J Pharmacol Exp Ther. 1994;269 (1):95–102. [PubMed]
73. Chaturvedi HK, Chandra D, Bapna JS. Interaction between N-methyl-D-aspartate receptor antagonists and imipramine in shock-induced depression. Indian J Exp Biol. 1999;37 (10):952–8. [PubMed]
74. Machado-Vieira R, Salvadore G, Ibrahim LA, et al. Targeting glutamatergic signaling for the development of novel therapeutics for mood disorders. Curr Pharm Des. 2009;15 (14):1595–611. [PMC free article] [PubMed]
75. Sanacora G, Zarate CA, Krystal JH, et al. Targeting the glutamatergic system to develop novel, improved therapeutics for mood disorders. Nat Rev Drug Discov. 2008;7 (5):426–37. [PMC free article] [PubMed]
76. Malinow R, Malenka RC. AMPA receptor trafficking and synaptic plasticity. Annu Rev Neurosci. 2002;25:103–26. [PubMed]
77. Zhu JJ, Qin Y, Zhao M, et al. Ras and Rap control AMPA receptor trafficking during synaptic plasticity. Cell. 2002;110 (4):443–55. [PubMed]
78. Esteban JA. AMPA receptor trafficking: a road map for synaptic plasticity. Mol Interv. 2003;3 (7):375–85. [PubMed]
79. Anggono V, Huganir RL. Regulation of AMPA receptor trafficking and synaptic plasticity. Curr Opin Neurobiol. Epub 2012 Jan 2. [PMC free article] [PubMed]
80. Bleakman D, Alt A, Witkin JM. AMPA receptors in the therapeutic management of depression. CNS Neurol Disord Drug Targets. 2007;6 (2):117–26. [PubMed]
81. Chourbaji S, Vogt MA, Fumagalli F, et al. AMPA receptor subunit 1 (GluR-A) knockout mice model the glutamate hypothesis of depression. FASEB J. 2008;22 (9):3129–34. [PubMed]
82. Gibbons AS, Brooks L, Scarr E, et al. AMPA receptor expression is increased post-mortem samples of the anterior cingulate from subjects with major depressive disorder. J Affect Disord. 2012 Feb;136(3):1232–7. [PMC free article] [PubMed]
83. Maeng S, Zarate CA, Jr, Du J, et al. Cellular mechanisms underlying the antidepressant effects of ketamine: role of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors. Biol Psychiatry. 2008;63 (4):349–52. [PubMed]
84. Zarate C, Jr, Machado-Vieira R, Henter I, et al. Glutamatergic modulators: the future of treating mood disorders? Harv Rev Psychiatry. 2010;18 (5):293–303. [PMC free article] [PubMed]
85. Alt A, Nisenbaum ES, Bleakman D, et al. A role for AMPA receptors in mood disorders. Biochem Pharmacol. 2006;71 (9):1273–88. [PubMed]
86. O’Neill MJ, Witkin JM. AMPA receptor potentiators: application for depression and Parkinson’s disease. Curr Drug Targets. 2007;8 (5):603–20. [PubMed]
87. Bleakman D, Lodge D. Neuropharmacology of AMPA and kainate receptors. Neuropharmacology. 1998;37 (10–11):1187–204. [PubMed]
88. Borges K, Dingledine R. AMPA receptors: molecular and functional diversity. Prog Brain Res. 1998;116:153–70. [PubMed]
89. Li X, Tizzano JP, Griffey K, et al. Antidepressant-like actions of an AMPA receptor potentiator (LY392098) Neuropharmacology. 2001;40 (8):1028–33. [PubMed]
90. Knapp RJ, Goldenberg R, Shuck C, et al. Antidepressant activity of memory-enhancing drugs in the reduction of submissive behavior model. Eur J Pharmacol. 2002;440 (1):27–35. [PubMed]
91. Lindholm JS, Autio H, Vesa L, et al. The antidepressant-like effects of glutamatergic drugs ketamine and AMPA receptor potentiator LY 451646 are preserved in bdnf/heterozygous null mice. Neuropharmacology. 2012;62 (1):391–7. [PubMed]
92. Bursi R, Erdemli G, Campbell R, et al. Translational PK-PD modelling of molecular target modulation for the AMPA receptor positive allosteric modulator Org 26576. Psychopharmacology (Berl) 2011;218 (4):713–24. [PubMed]
93. Niciu MJ, Kelmendi B, Sanacora G. Overview of glutamatergic neurotransmission in the nervous system. Pharmacol Biochem Behav. 2012;100 (4):656–64. [PMC free article] [PubMed]
94. Szewczyk B, Palucha-Poniewiera A, Poleszak E, et al. Investigational NMDA receptor modulators for depression. Expert Opin Investig Drugs. 2012;21 (1):91–102. [PubMed]
95. Krystal JH, Mathew SJ, D’Souza DC, et al. Potential psychiatric applications of metabotropic glutamate receptor agonists and antagonists. CNS Drugs. 2010;24 (8):669–93. [PubMed]
96. Harrison NL, Simmonds MA. Quantitative studies on some antagonists of N-methyl D-aspartate in slices of rat cerebral cortex. Br J Pharmacol. 1985;84 (2):381–91. [PMC free article] [PubMed]
97. Bolshakov KV, Gmiro VE, Tikhonov DB, et al. Determinants of trapping block of N-methyl-d-aspartate receptor channels. J Neurochem. 2003;87 (1):56–65. [PubMed]
98. Narita M, Yoshizawa K, Nomura M, et al. Role of the NMDA receptor subunit in the expression of the discriminative stimulus effect induced by ketamine. Eur J Pharmacol. 2001;423 (1):41–6. [PubMed]
99. De Vry J, Jentzsch KR. Role of the NMDA receptor NR2B subunit in the discriminative stimulus effects of ketamine. Behav Pharmacol. 2003;14 (3):229–35. [PubMed]
100. Maler JM, Esselmann H, Wiltfang J, et al. Memantine inhibits ethanol-induced NMDA receptor up-regulation in rat hippocampal neurons. Brain Res. 2005;1052 (2):156–62. [PubMed]
101. Maeng S, Zarate CA., Jr The role of glutamate in mood disorders: results from the ketamine in major depression study and the presumed cellular mechanism underlying its antidepressant effects. Curr Psychiatry Rep. 2007;9 (6):467–74. [PubMed]
102. Engin E, Treit D, Dickson CT. Anxiolytic- and antidepressant-like properties of ketamine in behavioral and neurophysiological animal models. Neuroscience. 2009;161 (2):359–69. [PubMed]
103. Garcia LS, Comim CM, Valvassori SS, et al. Chronic administration of ketamine elicits antidepressant-like effects in rats without affecting hippocampal brain-derived neurotrophic factor protein levels. Basic Clin Pharmacol Toxicol. 2008;103 (6):502–6. [PubMed]
104. Garcia LS, Comim CM, Valvassori SS, et al. Acute administration of ketamine induces antidepressant-like effects in the forced swimming test and increases BDNF levels in the rat hippocampus. Prog Neuropsychopharmacol Biol Psychiatry. 2008;32 (1):140–4. [PubMed]
105. Li N, Lee B, Liu RJ, et al. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science. 2010;329 (5994):959–64. [PMC free article] [PubMed]
106. Yilmaz A, Schulz D, Aksoy A, et al. Prolonged effect of an anesthetic dose of ketamine on behavioral despair. Pharmacol Biochem Behav. 2002;71 (1–2):341–4. [PubMed]
107. Garcia LS, Comim CM, Valvassori SS, et al. Ketamine treatment reverses behavioral and physiological alterations induced by chronic mild stress in rats. Prog Neuropsychopharmacol Biol Psychiatry. 2009;33 (3):450–5. [PubMed]
108. Li N, Liu RJ, Dwyer JM, et al. Glutamate N-methyl-D-aspartate receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure. Biol Psychiatry. 2011;69 (8):754–61. [PMC free article] [PubMed]
109. da Silva FC, do Carmo de Oliveira Cito M, da Silva MI, et al. Behavioral alterations and pro-oxidant effect of a single ketamine administration to mice. Brain Res Bull. 2010;83 (1–2):9–15. [PubMed]
110. Rosa AO, Lin J, Calixto JB, et al. Involvement of NMDA receptors and L-arginine-nitric oxide pathway in the antidepressant-like effects of zinc in mice. Behav Brain Res. 2003;144 (1–2):87–93. [PubMed]
111. Kos T, Popik P, Pietraszek M, et al. Effect of 5-HT3 receptor antagonist MDL 72222 on behaviors induced by ketamine in rats and mice. Eur Neuropsychopharmacol. 2006;16 (4):297–310. [PubMed]
112. Chindo BA, Adzu B, Yahaya TA, et al. Ketamine-enhanced immobility in forced swim test: a possible animal model for negative symptoms of schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2012;26:26. [PubMed]
113. Moghaddam B, Adams B, Verma A, et al. Activation of glutamatergic neurotransmission by ketamine: a novel step in the pathway from NMDA receptor blockade to dopaminergic and cognitive disruptions associated with the prefrontal cortex. J Neurosci. 1997;17 (8):2921–7. [PubMed]
114. Green SM, Rothrock SG, Lynch EL, et al. Intramuscular ketamine for pediatric sedation in the emergency department: safety profile in 1022 cases. Ann Emerg Med. 1998;31 (6):688–97. [PubMed]
115. Howes MC. Ketamine for paediatric sedation/analgesia in the emergency department. Emerg Med J. 2004;21 (3):275–80. [PMC free article] [PubMed]
116. Strayer RJ, Nelson LS. Adverse events associated with ketamine for procedural sedation in adults. Am J Emerg Med. 2008;26 (9):985–1028. [PubMed]
117. Jevtovic-Todorovic V, Wozniak DF, Benshoff ND, et al. A comparative evaluation of the neurotoxic properties of ketamine and nitrous oxide. Brain Res. 2001;895 (1–2):264–7. [PubMed]
118. Valentine GW, Mason GF, Gomez R, et al. The antidepressant effect of ketamine is not associated with changes in occipital amino acid neurotransmitter content as measured by [(1)H]-MRS. Psychiatry Res. 2011;191 (2):122–7. [PMC free article] [PubMed]
119. Bunney BG, Bunney WE. Rapid-acting antidepressant strategies: mechanisms of action. Int J Neuropsychopharmacol. 2011;7:1–19. [PubMed]
120. aan het Rot M, Collins KA, Murrough JW, et al. Safety and efficacy of repeated-dose intravenous ketamine for treatment-resistant depression. Biol Psychiatry. 2010;67 (2):139–45. [PubMed]
121. Phelps LE, Brutsche N, Moral JR, et al. Family history of alcohol dependence and initial antidepressant response to an N-methyl-D-aspartate antagonist. Biol Psychiatry. 2009;65 (2):181–4. [PMC free article] [PubMed]
122. Price RB, Nock MK, Charney DS, et al. Effects of intravenous ketamine on explicit and implicit measures of suicidality in treatment-resistant depression. Biol Psychiatry. 2009;66 (5):522–6. [PMC free article] [PubMed]
123. DiazGranados N, Ibrahim LA, Brutsche NE, et al. Rapid resolution of suicidal ideation after a single infusion of an N-methyl-D-aspartate antagonist in patients with treatment-resistant major depressive disorder. J Clin Psychiatry. 2010;71 (12):1605–11. [PMC free article] [PubMed]
124. Larkin GL, Beautrais AL. A preliminary naturalistic study of low-dose ketamine for depression and suicide ideation in the emergency department. Int J Neuropsychopharmacol. 2011;14 (8):1127–31. [PubMed]
125. Mathew SJ, Shah A, Lapidus K, et al. Ketamine for treatment-resistant unipolar depression: current evidence. CNS Drugs. 2012;26 (3):189–204. [PMC free article] [PubMed]
126. Doble A. The pharmacology and mechanism of action of riluzole. Neurology. 1996;47 (6 Suppl 4):S233–41. [PubMed]
127. Du J, Suzuki K, Wei Y, et al. The anticonvulsants lamotrigine, riluzole, and valproate differentially regulate AMPA receptor membrane localization: relationship to clinical effects in mood disorders. Neuropsychopharmacology. 2007;32 (4):793–802. [PubMed]
128. Mizuta I, Ohta M, Ohta K, et al. Riluzole stimulates nerve growth factor, brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor synthesis in cultured mouse astrocytes. Neurosci Lett. 2001;310 (2–3):117–20. [PubMed]
129. Zarate CA, Manji HK. Riluzole in psychiatry: a systematic review of the literature. Expert Opin Drug Metab Toxicol. 2008;4 (9):1223–34. [PMC free article] [PubMed]
130. Papazisis G, et al. Neuroprotection by lamotrigine in a rat model of neonatal hypoxic-ischaemic encephalopathy. Int J Neuropsychopharmacol. 2008;11 (3):321–9. [PubMed]
131. Goodnick PJ. Bipolar depression: a review of randomised clinical trials. Expert Opin Pharmacother. 2007;8 (1):13–21. [PubMed]
132. Geddes JR, Calabrese JR, Goodwin GM. Lamotrigine for treatment of bipolar depression: independent meta-analysis and meta-regression of individual patient data from five randomised trials. Br J Psychiatry. 2009;194 (1):4–9. [PubMed]
133. Anand A, Charney DS, Oren DA, et al. Attenuation of the neuropsychiatric effects of ketamine with lamotrigine: support for hyperglutamatergic effects of N-methyl-D-aspartate receptor antagonists. Arch Gen Psychiatry. 2000;57 (3):270–6. [PubMed]
134. Wang M, Yang Y, Dong Z, et al. NR2B-containing N-methyl-D-aspartate subtype glutamate receptors regulate the acute stress effect on hippocampal long-term potentiation/long-term depression in vivo. Neuroreport. 2006;17 (12):1343–6. [PubMed]
135. Loftis JM, Janowsky A. The N-methyl-D-aspartate receptor subunit NR2B: localization, functional properties, regulation, and clinical implications. Pharmacol Ther. 2003;97 (1):55–85. [PubMed]
136. Gogas KR. Glutamate-based therapeutic approaches: NR2B receptor antagonists. Curr Opin Pharmacol. 2006;6 (1):68–74. [PubMed]
137. Merchant RE, Bullock MR, Carmack CA, et al. A double-blind, placebo-controlled study of the safety, tolerability and pharmacokinetics of CP-101,606 in patients with a mild or moderate traumatic brain injury. Ann N Y Acad Sci. 1999;890:42–50. [PubMed]
138. Faries D, Herrera J, Rayamajhi J, et al. The responsiveness of the Hamilton Depression Rating Scale. J Psychiatr Res. 2000;34 (1):3–10. [PubMed]
139. Kemp AH, Gordon E, Rush AJ, et al. Improving the prediction of treatment response in depression: integration of clinical, cognitive, psychophysiological, neuroimaging, and genetic measures. CNS Spectr. 2008;13(12):1066–86. quiz 1087–8. [PubMed]
140. Kornhuber J, Weller M, Schoppmeyer K, et al. Amantadine and memantine are NMDA receptor antagonists with neuroprotective properties. J Neural Transm Suppl. 1994;43:91–104. [PubMed]
141. Bormann J. Memantine is a potent blocker of N-methyl-D-aspartate (NMDA) receptor channels. Eur J Pharmacol. 1989;166 (3):591–2. [PubMed]
142. Kornhuber J, Bormann J, Retz W, et al. Memantine displaces [3H]MK-801 at therapeutic concentrations in postmortem human frontal cortex. Eur J Pharmacol. 1989;166 (3):589–90. [PubMed]
143. Kornhuber J, Bormann J, Hübers M, et al. Effects of the 1-amino-adamantanes at the MK-801-binding site of the NMDA-receptor-gated ion channel: a human postmortem brain study. Eur J Pharmacol. 1991;206 (4):297–300. [PubMed]
144. Kornhuber J, Weller M. Psychotogenicity and N-methyl-D-aspartate receptor antagonism: implications for neuroprotective pharmacotherapy. Biol Psychiatry. 1997;41 (2):135–44. [PubMed]
145. Muller WE, Mutschler E, Riederer P. Noncompetitive NMDA receptor antagonists with fast open-channel blocking kinetics and strong voltage-dependency as potential therapeutic agents for Alzheimer’s dementia. Pharmacopsychiatry. 1995;28 (4):113–24. [PubMed]
146. Lo D, Grossberg GT. Use of memantine for the treatment of dementia. Expert Rev Neurother. 2011;11 (10):1359–70. [PubMed]
147. Parsons CG, Danysz W, Quack G. Memantine is a clinically well tolerated N-methyl-D-aspartate (NMDA) receptor antagonist: a review of preclinical data. Neuropharmacology. 1999;38 (6):735–67. [PubMed]
148. Tsai GE. Searching for rational anti N-methyl-D-aspartate treatment for depression. Arch Gen Psychiatry. 2007;64(9):1099–100. author reply 1100–1. [PubMed]
149. Muhonen LH, Lönnqvist J, Juva K, et al. Double-blind, randomized comparison of memantine and escitalopram for the treatment of major depressive disorder comorbid with alcohol dependence. J Clin Psychiatry. 2008;69 (3):392–9. [PubMed]
150. Holter SM, Danysz W, Spanagel R. Evidence for alcohol anti-craving properties of memantine. Eur J Pharmacol. 1996;314 (3):R1–2. [PubMed]
151. Bachteler D, Economidou D, Danysz W, et al. The effects of acamprosate and neramexane on cue-induced reinstatement of ethanol-seeking behavior in rat. Neuropsychopharmacology. 2005;30 (6):1104–10. [PubMed]
152. Piasecki J, Koros E, Dyr W, et al. Ethanol-reinforced behaviour in the rat: effects of uncompetitive NMDA receptor antagonist, memantine. Eur J Pharmacol. 1998;354 (2–3):135–43. [PubMed]
153. Escher T, Call SB, Blaha CD, et al. Behavioral effects of aminoadamantane class NMDA receptor antagonists on schedule-induced alcohol and self-administration of water in mice. Psychopharmacology (Berl) 2006;187 (4):424–34. [PubMed]
154. Boden JM, Fergusson DM. Alcohol and depression. Addiction. 2011;106 (5):906–14. [PubMed]
155. Conner KR, Pinquart M, Gamble SA. Meta-analysis of depression and substance use among individuals with alcohol use disorders. J Subst Abuse Treat. 2009;37 (2):127–37. [PubMed]
156. Nagy J. Renaissance of NMDA receptor antagonists: do they have a role in the pharmacotherapy for alcoholism? IDrugs. 2004;7 (4):339–50. [PubMed]
157. Petrakis IL, Limoncelli D, Gueorguieve R, et al. Altered NMDA glutamate receptor antagonist response in individuals with a family vulnerability to alcoholism. Am J Psychiatry. 2004;161 (10):1776–82. [PubMed]
158. Bäckström P, Bachteler D, Koch S, et al. mGluR5 antagonist MPEP reduces ethanol-seeking and relapse behavior. Neuropsychopharmacology. 2004;29 (5):921–8. [PubMed]
159. Krupitsky EM, Rudenko AA, Burakov AM, et al. Anti-glutamatergic strategies for ethanol detoxification: comparison with placebo and diazepam. Alcohol Clin Exp Res. 2007;31 (4):604–11. [PubMed]
160. Rogóz Z, Skuza G, Maj J, et al. Synergistic effect of uncompetitive NMDA receptor antagonists and antidepressant drugs in the forced swimming test in rats. Neuropharmacology. 2002;42 (8):1024–30. [PubMed]
161. Huber TJ, Dietrich DE, Emrich HM. Possible use of amantadine in depression. Pharmacopsychiatry. 1999;32 (2):47–55. [PubMed]
162. Rogóz Z, Kubera M, Rogóz K, et al. Effect of co-administration of fluoxetine and amantadine on immunoendocrine parameters in rats subjected to a forced swimming test. Pharmacol Rep. 2009;61 (6):1050–60. [PubMed]
163. Kubera M, Basta-Kairn A, Budziszewska B, et al. Effect of amantadine and imipramine on immunological parameters of rats subjected to a forced swimming test. Int J Neuropsychopharmacol. 2006;9 (3):297–305. [PubMed]
164. Maj J, Rogoz Z. Synergistic effect of amantadine and imipramine in the forced swimming test. Pol J Pharmacol. 2000;52 (2):111–4. [PubMed]
165. Dietrich DE, Bode L, Spannhuth CW, et al. Amantadine in depressive patients with Borna disease virus (BDV) infection: an open trial. Bipolar Disord. 2000;2 (1):65–70. [PubMed]
166. Ferszt R, Kühl KP, Bode L, et al. Amantadine revisited: an open trial of amantadinesulfate treatment in chronically depressed patients with Borna disease virus infection. Pharmacopsychiatry. 1999;32 (4):142–7. [PubMed]
167. Stryjer R, Strous RD, Shaked G, et al. Amantadine as augmentation therapy in the management of treatment-resistant depression. Int Clin Psychopharmacol. 2003;18 (2):93–6. [PubMed]
168. Rogóz Z, Skuza G, Daniel WA, et al. Amantadine as an additive treatment in patients suffering from drug-resistant unipolar depression. Pharmacol Rep. 2007;59 (6):778–84. [PubMed]
169. Autry AE, Adachi M, Nosyreva E, et al. NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. Nature. 2011;475 (7354):91–5. [PMC free article] [PubMed]
170. Hoeffer CA, Klann E. mTOR signaling: at the crossroads of plasticity, memory and disease. Trends Neurosci. 2010;33 (2):67–75. [PMC free article] [PubMed]
171. Duman RS, Li N, Liu RJ, et al. Signaling pathways underlying the rapid antidepressant actions of ketamine. Neuropharmacology. 2012;62 (1):35–41. [PMC free article] [PubMed]
172. Cryan JF, O’Leary OF. Neuroscience: a glutamate pathway to faster-acting antidepressants? Science. 2010;329 (5994):913–4. [PubMed]
173. Ravikumar B, Rubinsztein DC. Can autophagy protect against neurodegeneration caused by aggregate-prone proteins? Neuroreport. 2004;15 (16):2443–5. [PubMed]
174. Pickford F, Masliah E, Brtischgi M, et al. The autophagy-related protein beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid beta accumulation in mice. J Clin Invest. 2008;118 (6):2190–9. [PMC free article] [PubMed]
175. Beurel E, Song L, Jope RS. Inhibition of glycogen synthase kinase-3 is necessary for the rapid antidepressant effect of ketamine in mice. Mol Psychiatry. 2011;16 (11):1068–70. [PMC free article] [PubMed]
176. Kaidanovich-Beilin O, Milman A, Weizman A, et al. Rapid antidepressive-like activity of specific glycogen synthase kinase-3 inhibitor and its effect on beta-catenin in mouse hippocampus. Biol Psychiatry. 2004;55 (8):781–4. [PubMed]
177. O’Brien WT, Harper AD, Jové F, et al. Glycogen synthase kinase-3beta haploinsufficiency mimics the behavioral and molecular effects of lithium. J Neurosci. 2004;24 (30):6791–8. [PubMed]
178. Beaulieu JM, Sotnikova TD, Yao WD, et al. Lithium antagonizes dopamine-dependent behaviors mediated by an AKT/glycogen synthase kinase 3 signaling cascade. Proc Natl Acad Sci U S A. 2004;101 (14):5099–104. [PMC free article] [PubMed]
179. Gould TD, Chen G, Manji HK. In vivo evidence in the brain for lithium inhibition of glycogen synthase kinase-3. Neuropsychopharmacology. 2004;29 (1):32–8. [PubMed]
180. Polter A, Beurel E, Yang S, et al. Deficiency in the inhibitory serine-phosphorylation of glycogen synthase kinase-3 increases sensitivity to mood disturbances. Neuropsychopharmacology. 2010;35 (8):1761–74. [PMC free article] [PubMed]
181. Jope RS, Johnson GV. The glamour and gloom of glycogen synthase kinase-3. Trends Biochem Sci. 2004;29 (2):95–102. [PubMed]
182. Rayasam GV, Tulasi VK, Sodhi R, et al. Glycogen synthase kinase 3: more than a namesake. Br J Pharmacol. 2009;156 (6):885–98. [PMC free article] [PubMed]
183. Shimizu E, Hashimoto K, Iyo M. Ethnic difference of the BDNF 196G/A (val66met) polymorphism frequencies: the possibility to explain ethnic mental traits. Am J Med Genet B Neuropsychiatr Genet. 2004;126B (1):122–3. [PubMed]
184. Casey BJ, Glatt CE, Tottenham N, et al. Brain-derived neurotrophic factor as a model system for examining gene by environment interactions across development. Neuroscience. 2009;164 (1):108–20. [PMC free article] [PubMed]
185. Egan MF, Kojima M, Callicott JH, et al. The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell. 2003;112 (2):257–69. [PubMed]
186. Neves-Pereira M, Mundo E, Muglia P, et al. The brain-derived neurotrophic factor gene confers susceptibility to bipolar disorder: evidence from a family-based association study. Am J Hum Genet. 2002;71 (3):651–5. [PMC free article] [PubMed]
187. Sklar P, Gabriel SB, McInnis MG, et al. Family-based association study of 76 candidate genes in bipolar disorder: BDNF is a potential risk locus. Brain-derived neutrophic factor. Mol Psychiatry. 2002;7 (6):579–93. [PubMed]
188. Sen S, Nesse RM, Stoltenberg SF, et al. A BDNF coding variant is associated with the NEO personality inventory domain neuroticism, a risk factor for depression. Neuropsychopharmacology. 2003;28 (2):397–401. [PubMed]
189. Ribasés M, Gratacós M, Fernández-Aranda F, et al. Association of BDNF with anorexia, bulimia and age of onset of weight loss in six European populations. Hum Mol Genet. 2004;13 (12):1205–12. [PubMed]
190. Sun M, Liu L, Yang Y, et al. Association study of brain-derived neurotrophic factor Val66Met polymorphism and clinical characteristics of first episode schizophrenia [in Chinese] Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2012;29 (2):155–8. [PubMed]
191. Autry AE, Monteggia LM. Brain-derived neurotrophic factor and neuropsychiatric disorders. Pharmacol Rev. 2012;64 (2):238–58. [PMC free article] [PubMed]
192. Machado-Vieira R, Yuan P, Brutsche N, et al. Brain-derived neurotrophic factor and initial antidepressant response to an N-methyl-D-aspartate antagonist. J Clin Psychiatry. 2009;70 (12):1662–6. [PMC free article] [PubMed]
193. Ricci V, Martinotti G, Gelfo F, et al. Chronic ketamine use increases serum levels of brain-derived neurotrophic factor. Psychopharmacology (Berl) 2011;215 (1):143–8. [PubMed]
194. Inamura N, Nawa H, Takei N. Enhancement of translation elongation in neurons by brain-derived neurotrophic factor: implications for mammalian target of rapamycin signaling. J Neurochem. 2005;95 (5):1438–45. [PubMed]
195. Slipczuk L, Bekinschtein P, Katche C, et al. BDNF activates mTOR to regulate GluR1 expression required for memory formation. PLoS ONE. 2009;4 (6):e6007. [PMC free article] [PubMed]
196. Takei N, Inamura N, Kawamura M, et al. Brain-derived neurotrophic factor induces mammalian target of rapamycin-dependent local activation of translation machinery and protein synthesis in neuronal dendrites. J Neurosci. 2004;24 (44):9760–9. [PubMed]
197. Laje G, Lally N, Mathews D, et al. Brain-derived neurotrophic factor Val66Met polymorphism and antidepressant efficacy of ketamine in depressed patients. Biol Psychiatry. In press. [PMC free article] [PubMed]
198. Liu RJ, Lee FS, Li XY, et al. Brain-derived neurotrophic factor Val66Met allele impairs basal and ketamine-stimulated synaptogenesis in prefrontal cortex. Biol Psychiatry. 2012;71 (11):996–1005. [PMC free article] [PubMed]
199. Murrough JW. Ketamine as a novel antidepressant: from synapse to behavior. Clin Pharmacol Ther. 2012;91 (2):303–9. [PMC free article] [PubMed]
200. Cornwell BR, Salvadore G, Furey M, et al. Synaptic potentiation is critical for rapid antidepressant response to ketamine in treatment-resistant major depression. Biol Psychiatry. Epub 2012 Apr 20. [PMC free article] [PubMed]
201. Li X, Witkin JM, Need AB, et al. Enhancement of antidepressant potency by a potentiator of AMPA receptors. Cell Mol Neurobiol. 2003;23 (3):419–30. [PubMed]
202. Maes M, Bosmans E, Suy E, et al. Immune disturbances during major depression: upregulated expression of interleukin-2 receptors. Neuropsychobiology. 1990;24 (3):115–20. [PubMed]
203. Maes M, Bosmans E, Suy E, et al. Depression-related disturbances in mitogen-induced lymphocyte responses and interleukin-1 beta and soluble interleukin-2 receptor production. Acta Psychiatr Scand. 1991;84 (4):379–86. [PubMed]
204. Maes M, Lambrechts J, Bosmans E, et al. Evidence for a systemic immune activation during depression: results of leukocyte enumeration by flow cytometry in conjunction with monoclonal antibody staining. Psychol Med. 1992;22 (1):45–53. [PubMed]
205. Bufalino C, Hepgul N, Aguglia E, et al. The role of immune genes in the association between depression and inflammation: a review of recent clinical studies. Brain Behav Immun. Epub 2012 May 8. [PubMed]
206. Eyre H, Baune BT. Neuroplastic changes in depression: a role for the immune system. Psychoneuroendocrinology. Epub 2012 Apr 21. [PubMed]
207. Duman RS, Monteggia LM. A neurotrophic model for stress-related mood disorders. Biol Psychiatry. 2006;59 (12):1116–27. [PubMed]
208. Catena-Dell’Osso M, Bellantuono C, Consoli G, et al. Inflammatory and neurodegenerative pathways in depression: a new avenue for antidepressant development? Curr Med Chem. 2011;18 (2):245–55. [PubMed]
209. Gardner A, Boles RG. Beyond the serotonin hypothesis: mitochondria, inflammation and neurodegeneration in major depression and affective spectrum disorders. Prog Neuropsychopharmacol Biol Psychiatry. 2011;35 (3):730–43. [PubMed]
210. Maes M, et al. The inflammatory & neurodegenerative (I&ND) hypothesis of depression: leads for future research and new drug developments in depression. Metab Brain Dis. 2009;24 (1):27–53. [PubMed]
211. Leonard B, Maes M. Mechanistic explanations how cell-mediated immune activation, inflammation and oxidative and nitrosative stress pathways and their sequels and concomitants play a role in the pathophysiology of unipolar depression. Neurosci Biobehav Rev. 2012;36 (2):764–85. [PubMed]
212. Moir AT, Eccleston D. The effects of precursor loading in the cerebral metabolism of 5-hydroxyindoles. J Neurochem. 1968;15 (10):1093–108. [PubMed]
213. Maes M, Leonard BE, Myint AM, et al. The new ‘5-HT’ hypothesis of depression: cell-mediated immune activation induces indoleamine 2,3-dioxygenase, which leads to lower plasma tryptophan and an increased synthesis of detrimental tryptophan catabolites (TRYCATs), both of which contribute to the onset of depression. Prog Neuropsychopharmacol Biol Psychiatry. 2011;35 (3):702–21. [PubMed]
214. Muller N, Schwarz MJ. The immune-mediated alteration of serotonin and glutamate: towards an integrated view of depression. Mol Psychiatry. 2007;12 (11):988–1000. [PubMed]
215. Moylan S, Maes M, Wray NR, et al. The neuroprogressive nature of major depressive disorder: pathways to disease evolution and resistance, and therapeutic implications. Mol Psychiatry. Epub 2012 Apr 24. [PubMed]
216. Koga K, Ogata M, Takenaka I, et al. Ketamine suppresses tumor necrosis factor-alpha activity and mortality in carrageenan-sensitized endotoxin shock model. Circ Shock. 1994;44 (3):160–8. [PubMed]
217. Taniguchi T, Shibata K, Yamamoto K. Ketamine inhibits endotoxin-induced shock in rats. Anesthesiology. 2001;95 (4):928–32. [PubMed]
218. Taniguchi T, Takemoto Y, Kanakura H, et al. The dose-related effects of ketamine on mortality and cytokine responses to endotoxin-induced shock in rats. Anesth Analg. 2003;97 (6):1769–72. [PubMed]
219. Suliburk JW, Helmer KS, Gonzalez EA, et al. Ketamine attenuates liver injury attributed to endotoxemia: role of cyclooxygenase-2. Surgery. 2005;138 (2):134–40. [PubMed]
220. Welters ID, Hafer G, Menzebach A, et al. Ketamine inhibits transcription factors activator protein 1 and nuclear factor-kappaB, interleukin-8 production, as well as CD11b and CD16 expression: studies in human leukocytes and leukocytic cell lines. Anesth Analg. 2010;110 (3):934–41. [PubMed]
221. Albensi BC, Mattson MP. Evidence for the involvement of TNF and NF-kappaB in hippocampal synaptic plasticity. Synapse. 2000;35 (2):151–9. [PubMed]
222. Gutierrez H, Davies AM. Regulation of neural process growth, elaboration and structural plasticity by NF-kappaB. Trends Neurosci. 2011;34 (6):316–25. [PMC free article] [PubMed]
223. Vallabhapurapu S, Karin M. Regulation and function of NF-kappaB transcription factors in the immune system. Annu Rev Immunol. 2009;27:693–733. [PubMed]
224. Roytblat L, Talmor D, Rachinsky M, et al. Ketamine attenuates the interleukin-6 response after cardiopulmonary bypass. Anesth Analg. 1998;87 (2):266–71. [PubMed]
225. Bartoc C, Frumento RJ, Jalbout M, et al. A randomized, double-blind, placebo-controlled study assessing the anti-inflammatory effects of ketamine in cardiac surgical patients. J Cardiothorac Vasc Anesth. 2006;20 (2):217–22. [PubMed]
226. Cho JE, Shim JK, Choi YS, et al. Effect of low-dose ketamine on inflammatory response in off-pump coronary artery bypass graft surgery. Br J Anaesth. 2009;102 (1):23–8. [PubMed]
227. Carlson PJ, Singh JB, Zarate CA, Jr, et al. Neural circuitry and neuroplasticity in mood disorders: insights for novel therapeutic targets. NeuroRx. 2006;3 (1):22–41. [PMC free article] [PubMed]
228. Javitt DC, Schoepp D, Kalivas PW, et al. Translating glutamate: from pathophysiology to treatment. Sci Transl Med. 2011;3(102):102mr2. [PMC free article] [PubMed]
229. Orloff J, Douglas F, Pinheiro J, et al. The future of drug development: advancing clinical trial design. Nat Rev Drug Discov. 2009;8 (12):949–57. [PubMed]
PubReader format: click here to try


Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


  • Compound
    PubChem Compound links
  • MedGen
    Related information in MedGen
  • PubMed
    PubMed citations for these articles
  • Substance
    PubChem Substance links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...