Clinical Use Of Ketamine Research Articles

Resolvin E1 as a potential lead for the treatment of depression

Typical monoamine-based antidepressants have significant limitations, including a time lag for therapeutic response and low efficacy (more than one-third of depressed patients fail to respond to multiple antidepressant medications and are considered treatment-resistant). Conversely, ketamine, an N-methyl-D-aspartate receptor antagonist, exhibits rapid and sustained antidepressant actions in patients with treatment-resistant depression. However, clinical use of ketamine is limited due to its serious side effects. Thus, there is a significant need to develop novel ketamine-like antidepressants with fewer side effects. We previously demonstrated that intracerebroventricular infusion of resolvins (RvD1, RvD2, RvE1, RvE2, and RvE3), specialized pro-resolving lipid mediators derived from docosahexaenoic and eicosapentaenoic acids, produce antidepressant-like effects in mouse models of depression. Among resolvins, RvE1 produces the most potent antidepressant-like effects likely via ChemR23 in several mouse models of depression. Local infusion of RvE1 into the medial prefrontal cortex (mPFC) or dorsal hippocampal dentate gyrus (DG) also produces antidepressant-like effects, suggesting that these brain regions are sites of action of RvE1. Additionally, intranasal (i.n.) administration of RvE1 produces antidepressant-like effects through mechanisms similar to ketamine: activity-dependent release of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF), and subsequent mechanistic target of rapamycin complex 1 (mTORC1) activation in the mPFC play a crucial role in the rapid and sustained antidepressant-like actions of i.n. RvE1. Moreover, the antidepressant-like effects of i.n. RvE1 require BDNF and VEGF release, but not mTORC1 activation, in the dorsal DG. These findings suggest that RvE1 can be a promising lead for a novel rapid-acting antidepressant.

Is there evidence for using ketamine among individuals with dementia?

The aim of this short narrative review was to evaluate the existing literature regarding the clinical use of ketamine among individuals with dementia, especially those with behavioral disturbances. PubMed, Cochrane, and Ovid (Embase, APA PsycINFO, and MEDLINE) databases were searched for abstracts using the search terms "ketamine" AND "dementia." Only articles describing the use of ketamine in individuals with dementia were included. Articles that did not include individuals with dementia, did not use ketamine, were published in a non-English language, primarily described animal studies, or were reviews were excluded. Three case reports met the inclusion criteria. One described the use of subcutaneous ketamine for depression, one described the use of intramuscular ketamine for acute agitation, and one described the use of S-ketamine as anesthesia during electroconvulsive therapy for depression and catatonia. No significant adverse effects were reported in any of the cases. Although the use of ketamine in the treatment of depression and agitation associated with dementia has potential, the current evidence remains limited. High-quality prospective studies are needed to confirm the observations of these case reports before ketamine can be used to treat behavioral disturbances in individuals with dementia.

Ketamine for mood disorders, anxiety, and suicidality in children and adolescents: a systematic review.

Mood disorders, anxiety, and suicidality in youth are increasing and rapid-acting treatments are urgently needed. One potential is ketamine or its enantiomer esketamine, which was FDA approved in 2019 to treat major depressive disorder with suicidality in adults. This systematic review evaluated the evidence for the clinical use of ketamine to treat mood disorders, anxiety, and suicidality in youth. The PRISMA guidelines were used, and a protocol registered prospectively ( https://osf.io/9ucsg/ ). The literature search included Pubmed/MEDLINE, Ovid/MEDLINE, Scopus, CINAHL, PsychInfo, and Google Scholar. Trial registries and preprint servers were searched, and authors contacted for clarification. Studies reported on the clinical use of ketamine to treat anxiety, depression, bipolar disorder, or suicidality in youth ≤19years old and assessed symptoms before and after ketamine use. Study screening and data extraction were conducted independently by 2-4 authors. Safety, tolerability, and efficacy data were collected. The Cochrane Risk of Bias guidelines assessed the quality of the evidence. Twenty-two published reports based on 16 studies were identified: 7 case studies, 6 observational studies, 3 randomized trials, and 6 secondary data analyses. Studies reported immediate improvements in depression, anxiety, and suicidality. Improvements were maintained for weeks-months following treatment. Ketamine was well-tolerated with the most common side effects being dizziness, nausea, and mild dissociation. Transient hemodynamic changes were reported, all of which resolved quickly and did not require medical intervention. Initial evidence suggests ketamine is safe and may be effective for mood disorders, anxiety, and suicidality in youth. Further randomized trials are warranted.

Use of ketamine for treatment resistant depression: updated review of literature and practical applications to a community ketamine program in Edmonton, Alberta, Canada.

Though intravenous (IV) ketamine and intranasal (IN) esketamine are noted to be efficacious for treatment-resistant depression (TRD), access to each of these treatments within healthcare systems is limited due to cost, availability, and/or monitoring requirements. IV ketamine has been offered at two public hospital sites in Edmonton, Canada since 2015. Since then, demand for maintenance ketamine treatments has grown. This has required creative solutions for safe, accessible, evidence-based patient care. Aims of this paper are twofold. First, we will provide a synthesis of current knowledge with regards to the clinical use of ketamine for TRD. Consideration will be given regarding; off-label racemic ketamine uses versus FDA-approved intranasal esketamine, populations treated, inclusion/exclusion criteria, dosing, assessing clinical response, concomitant medications, and tolerability/safety. Second, this paper will describe our experience as a community case study in applying evidence-based treatment. We will describe application of the literature review to our clinical programming, and in particular focus on cost-effective maintenance treatments, long-term safety concerns, routes of ketamine administration other than via intravenous, and cautious prescribing of ketamine outside of clinically monitored settings. We conducted a literature review of the on the use of ketamine for TRD up to June 30, 2023. Key findings are reviewed, and we describe their application to our ketamine program. Evidence for the use of ketamine in resistant depression has grown in recent years, with evolving data to support and direct its clinical use. There is an increasing body of evidence to guide judicious use of ketamine in various clinical circumstances, for a population of patients with a high burden of suffering and morbidity. While large-scale, randomized controlled trials, comparative studies, and longer-term treatment outcomes is lacking, this community case study illustrates that currently available evidence can be applied to real-world clinical settings with complex patients. As cost is often a significant barrier to accessing initial and/or maintenance IV or esketamine treatments, public ketamine programs may incorporate SL or IN ketamine to support a sustainable and accessible treatment model. Three of such models are described.

Narrative Review: Low-Dose Ketamine for Pain Management.

Pain is the leading cause of medical consultations and occurs in 50-70% of emergency department visits. To date, several drugs have been used to manage pain. The clinical use of ketamine began in the 1960s and it immediately emerged as a manageable and safe drug for sedation and anesthesia. The analgesic properties of this drug were first reported shortly after its use; however, its psychomimetic effects have limited its use in emergency departments. Owing to the misuse and abuse of opioids in some countries worldwide, ketamine has become a versatile tool for sedation and analgesia. In this narrative review, ketamine's role as an analgesic is discussed, with both known and new applications in various contexts (acute, chronic, and neuropathic pain), along with its strengths and weaknesses, especially in terms of psychomimetic, cardiovascular, and hepatic effects. Moreover, new scientific evidence has been reviewed on the use of additional drugs with ketamine, such as magnesium infusion for improving analgesia and clonidine for treating psychomimetic symptoms. Finally, this narrative review was refined by the experience of the Pain Group of the Italian Society of Emergency Medicine (SIMEU) in treating acute and chronic pain with acute manifestations in Italian Emergency Departments.

Clinical use of ketamine in psychiatric disorders

Clinical use of ketamine in psychiatric disorders has been highlighted in the past twenty years. Ketamine, an antagonist of the N-methyl-D-aspartate receptor, has been widely studied in clinical studies mostly regarding depression disorder. Here, we performed an electronic search in major indexing databases and reviewed 83 randomized controlled trials (RCTs) of ketamine in different psychiatric disorders including major depressive disorder, treatment-resistant depression, post-partum depression, bipolar depression, post-traumatic stress disorder, obsessive compulsive disorder, generalized anxiety disorder, social anxiety disorder and autism spectrum disorder. The results also included recent reports on the use of esketamine in major depressive disorder in addition to studies related to the anti-depressant effect of ketamine in suicidal ideation and in combination with electroconvulsive therapy. There has been some concerns and limitations regarding the use of ketamine in most of the studies ketamine was used as add-on therapy; optimum dosage, profile of cognitive effect and side effects are yet to be determined. Moreover, large-scale RCTs and data concerning acute depression are still lacking. Altogether, prescription of ketamine for depression disorder is increasing in the light of available clinical findings, yet more trials are needed to evaluate the efficacy, safety and tolerability of ketamine and esketamine in the treatment of other psychiatric disorders.

The Ketamine Side Effect Tool (KSET): A comprehensive measurement-based safety tool for ketamine treatment in psychiatry

ObjectivesOn a background of the rapidly expanding clinical use of ketamine and esketamine for treatment of depression and other conditions, we examined safety monitoring, seeking to identify knowledge gaps relevant to clinical practice. MethodsAn international group of psychiatrists discussed the issue of safety of ketamine and esketamine and came to a consensus on key safety gaps. ResultsThere is no standard safety monitoring for off-label generic ketamine. For intranasal esketamine, each jurisdiction providing regulatory approval may specify monitoring. Treatment is often provided beyond the period for which safety has been demonstrated, with no agreed framework for monitoring of longer term side effects for either generic ketamine or intranasal esketamine. LimitationsThe KSET has established face and content validity, however it has not been validated against other measures of safety. ConclusionsWe recommend the Ketamine Side Effect Tool (KSET) as a comprehensive safety monitoring tool for acute and longer term side effects.

The multiple faces of ketamine in anaesthesia and analgesia.

ObjectiveKetamine is an anaesthetic agent with a unique dissociative profile and pharmacological effects ranging from the induction and maintenance of anaesthesia to analgesia and sedation, depending on the dose. This article provides information for the clinical use of ketamine in anaesthesia, in both conventional and special circumstances.MethodsThis is a non-systematic review of the literature, through a PubMed search up to February 2021.ResultsWith a favourable pharmacokinetic profile, ketamine is used in hospital and prehospital settings for emergency situations. It is suitable for patients with many heart conditions and, unlike other anaesthetics, its potential for cardiorespiratory depression is low. Furthermore, it may be used when venous access is difficult as it may be administered through various routes. Ketamine is the anaesthetic of choice for patients with bronchospasm thanks to its bronchodilatory and anti-inflammatory properties.ConclusionWith a favourable pharmacokinetic profile, ketamine is used in hospital and prehospital settings for emergency situations and is suitable for patients with many cardiac and respiratory conditions.

Ketamine treatment for depression: qualitative study exploring patient views.

Ketamine is a new and promising treatment for depression but comes with challenges to implement because of its potential for abuse. We sought the views of patients to inform policy and practical decisions about the clinical use of ketamine before large-scale roll-out is considered. This qualitative study used three focus groups and three validation sessions from 14 patients with prior diagnoses of depression but no experience of ketamine treatment. Focus groups explored their views about clinical use of ketamine and the best way for ketamine to be administered and monitored. The qualitative data were analysed by three service-user researchers using thematic analysis. Five themes were generated: changing public perceptions, risks, monitoring, privacy and data protection, and practical aspects. Participants were conscious of the stigma attached to ketamine as a street drug and wanted better public education, and evidence on the safety of ketamine after long-term use. They felt that monitoring was required to provide evidence for ketamine's safe use and administration, but there were concerns about the misuse of this information. Practical aspects included discussions about treatment duration, administration and accessibility (for example who would receive it, under what criteria and how). Patients are enthusiastic about ketamine treatment but need more information before national roll-out. The wider societal impact of ketamine treatment also needs to be considered and patients need to be part of any future roll-out to ensure its success.

Chronic administration of ketamine induces cognitive deterioration by restraining synaptic signaling

The discovery of the rapid antidepressant effects of ketamine has arguably been the most important advance in depression treatment. Recently, it was reported that repeated long-term ketamine administration is effective in preventing relapse of depression, which may broaden the clinical use of ketamine. However, long-term treatment with ketamine produces cognitive impairments, and the underlying molecular mechanisms for these impairments are largely unknown. Here, we found that chronic in vivo exposure to ketamine for 28 days led to decreased expression of the glutamate receptor subunits GluA1, GluA2, GluN2A, and GluN2B; decreased expression of the synaptic proteins Syn and PSD-95; decreased dendrite spine density; impairments in long-term potentiation (LTP) and synaptic transmission in the hippocampal CA1 area; and deterioration of learning and memory in mice. Furthermore, the reduced glutamate receptor subunit and synaptic protein expression and the LTP deficits were still observed on day 28 after the last injection of ketamine. We found that the expression and phosphorylation of CaMKIIβ, ERK1/2, CREB, and NF-κB were inhibited by ketamine. The reductions in glutamate receptor subunit expression and dendritic spine density and the deficits in LTP, synaptic transmission, and cognition were alleviated by overexpression of CaMKIIβ. Our study indicates that inhibition of CaMKIIβ-ERK1/2-CREB/NF-κB signaling may mediate chronic ketamine use-associated cognitive impairments by restraining synaptic signaling. Hypofunction of the glutamatergic system might be the underlying mechanism accounting for chronic ketamine use-associated cognitive impairments. Our findings may suggest possible strategies to alleviate ketamine use-associated cognitive deficits and broaden the clinical use of ketamine in depression treatment.

Resolvins as novel targets for rapid-acting antidepressants

Conventional monoaminergic antidepressants have significant limitations, including delayed onset of therapeutic response and relatively low efficacy. Recent studies reveal that the NMDA receptor antagonist ketamine produces rapid and sustained antidepressant effects in treatment-resistant depressed patients. Despite the unique antidepressant efficacy, clinical use of ketamine as an antidepressant is limited due to its serious drawbacks, such as abuse potential and psychotomimetic/dissociative effects. The molecular and neuronal mechanisms underlying the antidepressant actions of ketamine have been intensively studied to pave the way for the development of novel, rapid and more efficacious antidepressants with fewer side effects than ketamine. Preclinical studies demonstrate that ketamine produces antidepressant effects through rapid release and/or expression of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF), and stimulation of mechanistic target of rapamycin complex 1 (mTORC1) signaling in the medial prefrontal cortex and hippocampus. We have recently found that resolvins (RvD1, RvD2, RvE1, RvE2 and RvE3), bioactive metabolites derived from docosahexaenoic acid and eicosapentaenoic acid, produce antidepressant effects, and that the antidepressant effects of RvD1, RvD2 and RvE1 require mTORC1 activation. These findings suggest that resolvins could be promising targets for the development of novel rapid antidepressants with fewer side effects than ketamine because they are endogenous lipid mediators that play an important role in homeostasis.

Resolvins as novel targets for rapid-acting antidepressants

Conventional monoaminergic antidepressants have significant limitations, including delayed onset of therapeutic response and relatively low efficacy. Recent studies reveal that the NMDA receptor antagonist ketamine produces rapid and sustained antidepressant effects in treatment-resistant depressed patients. Despite the unique antidepressant efficacy, clinical use of ketamine as an antidepressant is limited due to its serious drawbacks, such as abuse potential and psychotomimetic/dissociative effects. The molecular and neuronal mechanisms underlying the antidepressant actions of ketamine have been intensively studied to pave the way for the development of novel, rapid and more efficacious antidepressants with fewer side effects than ketamine. Preclinical studies demonstrate that ketamine produces antidepressant effects through rapid release and/or expression of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF), and stimulation of mechanistic target of rapamycin complex 1 (mTORC1) signaling in the medial prefrontal cortex and hippocampus. We have recently found that resolvins (RvD1, RvD2, RvE1, RvE2 and RvE3), bioactive metabolites derived from docosahexaenoic acid and eicosapentaenoic acid, produce antidepressant effects, and that the antidepressant effects of RvD1, RvD2 and RvE1 require mTORC1 activation. These findings suggest that resolvins could be promising targets for the development of novel rapid antidepressants with fewer side effects than ketamine because they are endogenous lipid mediators that play an important role in homeostasis.

Ketamine and depression: a narrative review.

Depression is the third leading cause of disability in the world. Depressive symptoms may be reduced within several weeks after the start of conventional antidepressants, but treatment resistance concerns one-third of patients who fail to achieve recovery. Over the last 20 years, ketamine, an antagonist of the N-methyl-D-aspartate receptor, has been described to have antidepressant properties. A literature review was conducted through an exhaustive electronic search. It was restricted to Cochrane reviews, meta-analyses, and randomized controlled trials (RCTs) of ketamine for major depressive disorder and/or bipolar disorder. This review included two Cochrane reviews, 14 meta-analyses and 15 trials. Ketamine was studied versus placebo, versus other comparators and as an anesthetic adjuvant before electroconvulsive therapy. In 14 publications, ketamine provided a rapid antidepressant effect with a maximum efficacy reached at 24 hrs. Its effect lasted for 1–2 weeks after infusion, but a longer-term effect is little reported. Ketamine does not seem to improve depressive symptoms at the end of electroconvulsive sessions. Safety and tolerability profiles with ketamine at low single dose are generally good in depressed patients. However, there is a lack of data concerning ketamine with repeated administration at higher doses. The clinical use of ketamine is increasing. Intranasal (S)-ketamine has recently been approved for depression by the Food and Drug Administration. It could be a promising treatment in depressed patients with suicidal ideation. Collectively, the level of proof of efficacy remains low and more RCTs are needed to explore efficacy and safety issues of ketamine in depression.

Exploring patients' and carers' views about the clinical use of ketamine to inform policy and practical decisions: mixed-methods study.

Only one-third of patients with major depressive disorder achieve remission. One new and promising treatment, ketamine, may prove challenging to implement because of its abuse potential. Although clinicians' views have been sought, we need patients' views before large scale roll-out is considered. To explore patients' and carers' views to inform policy and practical decisions about the clinical use of ketamine. We carried out a mixed-methods study using data from 44 participants in 21 focus groups in three sessions and an online survey with patients, carers and advocates during a consultation day. Focus groups explored participant's views about ketamine as a form of treatment and the best way for ketamine to be prescribed and monitored. The qualitative data were analysed by two patient-researchers using an exploratory framework analysis and was supplemented by a survey. The ten themes generated were monitoring, information, effect on daily life, side-effects, recreational use, effectiveness, appropriate support, cost, stigma and therapy. Participants wanted better evidence on the safety of ketamine after long-term use and felt that monitoring was required. Collecting this information would provide evidence for ketamine's safe use and administration. There were, however, concerns about the misuse of this information. Practical issues of access were important: repeated travelling to clinics and a lack of sufficiently informed medical staff were key barriers. Clinicians have some similar and some different views to those of patients, carers and advocates, which need to be considered in any future roll-out of ketamine. R.M. has had UK National Institute for Health Research grant funding to study ketamine, is participating in trials of esketamine, runs a clinic that provides ketamine treatment, and has consulted for Johnson & Johnson and Eleusis.

Effects of Perinatal Exposure to Ketamine on the Developing Brain.

Initially used as an analgesic and anesthetic, ketamine has unfortunately been abused as a popular recreational party drug due to its psychotropic effects. Over the last decade, ketamine has also emerged as an effective rapid-onset anti-depressant. The increasingly widespread use and misuse of the drug in infants and pregnant women has posed a concern about the neurotoxicity of ketamine to the immature brains of developing fetuses and children. In this review, we summarize recent research findings on major possible mechanisms of perinatal ketamine-induced neurotoxicity. We also briefly summarize the neuroprotective effects of ketamine in the presence of noxious stimuli. Future actions include implementation of more drug abuse education and prevention campaigns to raise the public’s awareness of the harmful effects of ketamine abuse; further investigations to justify the clinical use of ketamine as analgesic, anesthetic and anti-depressant; and further studies to develop alternatives to ketamine or treatments that can alleviate the detrimental effects of ketamine use, especially in infants and pregnant women.

Ketamine’s Antidepressant Effect May Depend on Opioid System

Ketamine’s Antidepressant Effect May Depend on Opioid System

Antidepressant Efficacy and Tolerability of Ketamine and Esketamine: A Critical Review.

Ketamine and its enantiomer S-ketamine (esketamine) are promising candidates to produce a rapid-onset antidepressant effect in treatment-resistant depression. Ketamine causes continued blockade of the glutamate N-methyl-D-aspartate (NMDA) receptor, though this might not primarily mediate the antidepressant effect. Alternative hypotheses include selectivity for the NMDA receptor subtype containing the NMDA receptor subunit 2B (NR2B), inhibition of the phosphorylation of the eukaryotic elongation factor 2 (eEF2) kinase, increased expression of brain-derived neurotrophic factor (BDNF) and tropomyosin receptor kinase B (TrKB), and activation of the mammalian target of rapamycin (mTOR) signaling pathway, alongside other independent actions attributed to the ketamine metabolism to R-hydroxynorketamine (R-HNK). The enantiomer S-ketamine (esketamine) displays approximately fourfold greater affinity for the glutamate NMDA receptor in vitro than R-ketamine. Proof-of-concept single-dose and repeat-dose studies with intravenous ketamine show a significant antidepressant and probably antisuicidal effect in the short term, with response rates over 60% as early as 4.5h after a single dose, with a sustained effect after 24h, and over 40% after 7days. This response can be further sustained over several weeks with repeated doses (two to three doses per week). Tolerability seems acceptable in the short term, with transient elevation of blood pressure and mild and transient dissociative and psychotomimetic effects. Intranasal esketamine has shown a comparable antidepressant effect, which has resulted in the US FDA granting the drug a "breakthrough therapy" designation, and theoretically it may offer an improved tolerability profile. However, major concerns remain regarding an effective protocol to maintain the clinical antidepressant effect of ketamine seen with acute administration and the safety of ketamine and esketamine in the long term, specifically related to potential neurocognitive and urologic toxicity, together with the potential induction of substance use disorders. Ketamine and esketamine are not currently approved treatments for depression, but the clinical use of ketamine is increasing in a variety of practice settings internationally.

187. Ketamine Metabolism to Hydroxynorketamines: Relevance to Fast Antidepressant Action

The widespread clinical use of ketamine as an antidepressant is limited due to its abuse liability and capacity to produce dissociative effects. Ketamine’s mechanism of antidepressant action has been hypothesized to be due to NMDAR inhibition; however, other NMDAR antagonists do not manifest the full antidepressant actions of ketamine. Ketamine is rapidly and stereospecifically metabolized to norketamine, dehydronorketamine, hydroxyketamine and the hydroxynorketamines (HNKs).

Analysis of print news media framing of ketamine treatment in the United States and Canada from 2000 to 2015.

ObjectivesThere are multifaceted views on the use of ketamine, a potentially addictive substance, to treat mental health problems. The past 15 years have seen growing media coverage of ketamine for medical and other purposes. This study examined the print news media coverage of medical and other uses of ketamine in North America to determine orientations and trends over time.MethodsPrint newspaper coverage of ketamine from 2000 to 2015 was reviewed, resulting in 43 print news articles from 28 North American newspapers. A 55-item structured coding instrument was applied to assess news reports of ketamine. Items captured negative and positive aspects, therapeutic use of ketamine, and adverse side effects. Chi-squares tested for changes in trends over time.ResultsIn the 15-year reviewed period, the three most frequent themes related to ketamine were: abuse (68.2%), legal status (34.1%), and clinical use in anesthesia (31.8%). There was significant change in trends during two periods (2000–2007 and 2008–2015). In 2008–2015, print news media articles were significantly more likely to encourage clinical use of ketamine to treat depression (p = 0.002), to treat treatment resistant depression (p = 0.043), and to claim that ketamine is more effective than conventional antidepressants (p = 0.043).ConclusionsOur review found consistent positive changes in the portrayals of ketamine by the print news media as a therapeutic antidepressant that mirror the recent scientific publications. These changes in news media reporting might influence the popularity of ketamine use to treat clinical depression. Guidance is required for journalists on objective reporting of medical research findings, including limitations of current research evidence and potential risks of ketamine.

Modulation of the activity of N-methyl-d-aspartate receptors as a novel treatment option for depression: current clinical evidence and therapeutic potential of rapastinel (GLYX-13).

Classical monoaminergic antidepressants show several disadvantages, such as protracted onset of therapeutic action. Conversely, the fast and sustained antidepressant effect of the N-methyl-d-aspartate receptor (NMDAR) antagonist ketamine raises vast interest in understanding the role of the glutamate system in mood disorders. Indeed, numerous data support the existence of glutamatergic dysfunction in major depressive disorder (MDD). Drawback to this short-latency therapy is its side effect profile, especially the psychotomimetic action, which seriously hampers the common and widespread clinical use of ketamine. Therefore, there is a substantial need for alternative glutamatergic antidepressants with milder side effects. In this article, we review evidence that implicates NMDARs in the prospective treatment of MDD with focus on rapastinel (formerly known as GLYX-13), a novel synthetic NMDAR modulator with fast antidepressant effect, which acts by enhancing NMDAR function as opposed to blocking it. We summarize and discuss current clinical and animal studies regarding the therapeutic potential of rapastinel not only in MDD but also in other psychiatric disorders, such as obsessive–compulsive disorder and posttraumatic stress disorder. Additionally, we discuss current data concerning the molecular mechanisms underlying the antidepressant effect of rapastinel, highlighting common aspects as well as differences to ketamine. In 2016, rapastinel received the Breakthrough Therapy designation for the treatment of MDD from the US Food and Drug Administration, representing one of the most promising alternative antidepressants under current investigation.