Glutamatergic Antidepressants Research Articles

Ketamine for Depression: Advances in Clinical Treatment, Rapid Antidepressant Mechanisms of Action, and a Contrast with Serotonergic Psychedelics.

The approval of ketamine for treatment-resistant depression has created a model for a novel class of rapid-acting glutamatergic antidepressants. Recent research into other novel rapid-acting antidepressants - most notably serotonergic psychedelics (SPs) - has also proven promising. Presently, the mechanisms of action of these substances are under investigation to improve these novel treatments, which also exhibit considerable side effects such as dissociation. This chapter lays out the historical development of ketamine as an antidepressant, outlines its efficacy and safety profile, reviews the evidence for ketamine's molecular mechanism of action, and compares it to the proposed mechanism of SPs. The evidence suggests that although ketamine and SPs act on distinct primary targets, both may lead to rapid restoration of synaptic deficits and downstream network reconfiguration. In both classes of drugs, a glutamate surge activates α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) throughput and increases in brain-derived neurotrophic factor (BDNF) levels. Taken together, these novel antidepressant mechanisms may serve as a framework to explain the rapid and sustained antidepressant effects of ketamine and may be crucial for developing new rapid-acting antidepressants with an improved side effect profile.

Rapastinel alleviates the neurotoxic effect induced by NMDA receptor blockade in the early postnatal mouse brain.

Rapastinel is a novel psychoactive substance that acts as an N-methyl-D-aspartate-receptor (NMDAR) agonist and triggers antidepressant- and antipsychotic-like effects in animal models. However, it is unknown if rapastinel possesses a better side-effect profile than fast-acting glutamatergic antidepressants, like ketamine, which trigger neurotoxicity in the perinatal rodent cortex and protracted schizophrenia-like alterations. Here we found a remarkable neuroprotective effect of rapastinel against apoptosis induced by the NMDAR antagonist MK-801 in comparison to that elicited by clozapine and the mGlu2/3 agonist LY354740. These results suggest the potential therapeutic/prophylactic effect of rapastinel in ameliorating deleterious effects induced by NMDAR blockade during neurodevelopment.

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.

The frontal cortex as a network hub controlling mood and cognition: Probing its neurochemical substrates for improved therapy of psychiatric and neurological disorders.

The highly-interconnected and neurochemically-rich frontal cortex plays a crucial role in the regulation of mood and cognition, domains disrupted in depression and other central nervous system disorders, and it is an important site of action for their therapeutic control. For improving our understanding of the function and dysfunction of the frontal cortex, and for identifying improved treatments, quantification of extracellular pools of neuromodulators by microdialysis in freely-moving rodents has proven indispensable. This approach has revealed a complex mesh of autoreceptor and heteroceptor interactions amongst monoaminergic pathways, and led from selective 5-HT reuptake inhibitors to novel classes of multi-target drugs for treating depression like the mixed α2-adrenoceptor/5-HT reuptake inhibitor, S35966, and the clinically-launched vortioxetine and vilazodone. Moreover, integration of non-monoaminergic actions resulted in the discovery and development of the innovative melatonin receptor agonist/5-HT2C receptor antagonist, Agomelatine. Melatonin levels, like those of corticosterone and the "social hormone", oxytocin, can now be quantified by microdialysis over the full 24 h daily cycle. Further, the introduction of procedures for measuring extracellular histamine and acetylcholine has provided insights into strategies for improving cognition by, for example, blockade of 5-HT6 and/or dopamine D3 receptors. The challenge of concurrently determining extracellular levels of GABA, glutamate, d-serine, glycine, kynurenate and other amino acids, and of clarifying their interactions with monoamines, has also been resolved. This has proven important for characterizing the actions of glycine reuptake inhibitors that indirectly augment transmission at N-methyl-d-aspartate receptors, and of "glutamatergic antidepressants" like ketamine, mGluR5 antagonists and positive modulators of AMPA receptors (including S47445). Most recently, quantification of the neurotoxic proteins Aβ42 and Tau has extended microdialysis studies to the pathogenesis of neurodegenerative disorders, and another frontier currently being broached is microRNAs. The present article discusses the above themes, focusses on recent advances, highlights opportunities for clinical "translation", and suggests avenues for further progress.

Is there a future for other glutamate receptor modulators in the pharmacotherapy of mood disorders?

There is increasing evidence that some glutamatergic drugs could have antidepressant effects. Ketamine as a promising prototype for novel glutamatergic antidepressants has a much faster onset of action and is...

Ketamine and other N-methyl-D-aspartate receptor antagonists in the treatment of depression: a perspective review.

Current pharmacotherapies for major depressive disorder (MDD) and bipolar depression (BDep) have a distinct lag of onset that can generate great distress and impairment in patients. Furthermore, as demonstrated by several real-world effectiveness trials, their efficacy is limited. All approved antidepressant medications for MDD primarily act through monoaminergic mechanisms, agonists or antagonists with varying affinities for serotonin, norepinephrine and dopamine. The glutamate system has received much attention in recent years as an avenue for developing novel therapeutics. A single subanesthetic dose infusion of the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist ketamine has been shown to have rapid and potent antidepressant effects in treatment-resistant MDD and BDep. In a reverse translational framework, ketamine's clinical efficacy has inspired many preclinical studies to explore glutamatergic mechanisms of antidepressant action. These studies have revealed enhanced synaptic plasticity/synaptogenesis via numerous molecular and cellular mechanisms: release of local translational inhibition of brain-derived neurotrophic factor and secretion from dendritic spines, mammalian target of rapamycin activation and glycogen synthase kinase-3 inhibition. Current efforts are focused on extending ketamine's antidepressant efficacy, uncovering the neurobiological mechanisms responsible for ketamine's antidepressant activity in biologically enriched subgroups, and identifying treatment response biomarkers to personalize antidepressant selection. Other NMDA receptor antagonists have been studied both preclinically and clinically, which have revealed relatively modest antidepressant effects compared with ketamine but potentially other favorable characteristics, for example, decreased dissociative or psychotomimetic effects; therefore, there is great interest in developing novel glutamatergic antidepressants with greater target specificity and/or decreased adverse effects.

Reversal of Non-Suppression of Cortisol Levels in a Patient With Refractory Depression Receiving Ketamine

Back to table of contents Previous article Next article Communications and UpdatesFull AccessReversal of Non-Suppression of Cortisol Levels in a Patient With Refractory Depression Receiving KetamineRobert Ostroff, M.D. Jay S. Kothari, M.D.Robert OstroffSearch for more papers by this author, M.D. Jay S. KothariSearch for more papers by this author, M.D.Published Online:1 Jan 2015https://doi.org/10.1176/appi.ajp.2014.14060776AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: Research has shown that the hypothalamic-pituitary-adrenal (HPA) axis is involved in the mediation of stress and depression (1). The dexamethasone suppression test (DST) consists of the administration of 1 mg of dexamethasone at 11:00 p.m. and measurement of cortisol at 8:00 a.m. and 4:00 p.m. the following day. Sixty percent of depressed patients do not show the anticipated suppression of cortisol. A positive dexamethasone suppression test is a cortisol level >5 mcg/dl at 8:00 a.m. or 4:00 p.m. (2).Ketamine, administered intravenously, has been found to provide immediate but short-term relief of the depressed state (3–5). We decided to test the hypothesis that reversal of depression would reverse nonsuppression of cortisol levels in a consenting male patient with refractory depression.“Mr. J,” a 46-year-old man with treatment-resistant depression, was hospitalized following a serious suicide attempt. He had failed trials of selective serotonin reuptake inhibitors, tricyclic antidepressants, antipsychotics, lithium, lamotrigine, riluzole, and ECT. In preparation for a trial of tranylcypromine, we discontinued the patient’s current medications and initiated intravenous ketamine infusions at 0.5 mg/kg over the course of 40 minutes each. Prior to the patient’s first ketamine infusion, his DST showed nonsuppression, with an 8:00 a.m. cortisol level of 1.7 mcg/ml and a 4:00 p.m. cortisol level of 7.4mcg/ml. After three alternate-day infusions of ketamine, his mood improved dramatically, with a 50% reduction in his Hamilton Depression Rating Scale score. Repeat DST showed suppression with 8:00 a.m. and 4:00 p.m. cortisol levels of 1.1 and 1.0, respectively (normalized). One week after discontinuation of ketamine, the patient’s symptoms returned. Prior to starting the monoamine oxidase inhibitor, and upon re-emergence of symptoms, his cortisol levels were once again nonsuppressed, with levels of 7.7 mcg/ml and 14.5 mcg/ml, respectively.HPA axis dysregulation occurs frequently with depression and with states of stress. To our knowledge, this is the first report demonstrating the use of DST during a ketamine infusion trial to track the changes in the regulation of this axis. The rapid changes in DST from nonsuppression to suppression to nonsuppression mirror the changes in the patient’s state of depressive symptoms. The role of ketamine in the HPA axis in depressed patients needs to be better elucidated and may help us understand the pathophysiology of the depressed state.From the Department of Psychiatry, Yale University, New Haven, Conn.The authors report no financial relationships with commercial interests.References1 Gragnoli C: Hypothesis of the neuroendocrine cortisol pathway gene role in the comorbidity of depression, type 2 diabetes, and metabolic syndrome. Appl Clin Genet 2014; 7:43–53Crossref, Medline, Google Scholar2 Nuller IuL, Ostroumova MN: [Disruption of the homeostatic regulation of adrenal function in endogenous depression]. Zh Nevropatol Psikhiatr Im S S Korsakova 1978; 78:381–385 [Russian]Medline, Google Scholar3 Naughton M, Clarke G, O’Leary OF, et al.: A review of ketamine in affective disorders: current evidence of clinical efficacy, limitations of use and pre-clinical evidence on proposed mechanisms of action. J Affect Disord 2014; 156:24–35Crossref, Medline, Google Scholar4 Krystal JH, Sanacora G, Duman RS: Rapid-acting glutamatergic antidepressants: the path to ketamine and beyond. Biol Psychiatry 2013; 73:1133–1141Crossref, Medline, Google Scholar5 Salvadore G, Singh JB: Ketamine as a fast acting antidepressant: current knowledge and open questions. CNS Neurosci Ther 2013; 19:428–436Crossref, Medline, Google Scholar FiguresReferencesCited byDetailsCited ByStress, mental disorder and ketamine as a novel, rapid acting treatmentEuropean Neuropsychopharmacology, Vol. 65Effects of stress on endophenotypes of suicide across species: A role for ketamine in risk mitigationNeurobiology of Stress, Vol. 18 Volume 172Issue 1 January 01, 2015Pages 95-96 Metrics PDF download History Accepted 1 September 2014 Published online 1 January 2015 Published in print 1 January 2015

Rapid-onset antidepressant efficacy of glutamatergic system modulators: the neural plasticity hypothesis of depression.

Depression is a devastating psychiatric disorder widely attributed to deficient monoaminergic signaling in the central nervous system. However, most clinical antidepressants enhance monoaminergic neurotransmission with little delay but require 4-8 weeks to reach therapeutic efficacy, a paradox suggesting that the monoaminergic hypothesis of depression is an oversimplification. In contrast to the antidepressants targeting the monoaminergic system, a single dose of the N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine produces rapid (within 2 h) and sustained (over 7 days) antidepressant efficacy in treatment-resistant patients. Glutamatergic transmission mediated by NMDARs is critical for experience-dependent synaptic plasticity and learning, processes that can be modified indirectly by the monoaminergic system. To better understand the mechanisms of action of the new antidepressants like ketamine, we review and compare the monoaminergic and glutamatergic antidepressants, with emphasis on neural plasticity. The pathogenesis of depression may involve maladaptive neural plasticity in glutamatergic circuits that may serve as a new class of targets to produce rapid antidepressant effects.

Glutamate and its receptors in the pathophysiology and treatment of major depressive disorder

Monoaminergic neurotransmitter (serotonin, norepinephrine and dopamine) mechanisms of disease dominated the research landscape in the pathophysiology and treatment of major depressive disorder (MDD) for more than 50 years and still dominate available treatment options. However, the sum of all brain neurons that use monoamines as their primary neurotransmitter is <20%. In addition, most patients treated with monoaminergic antidepressants are left with significant residual symptoms and psychosocial disability not to mention side effects, e.g., sexual dysfunction. In the past several decades, there has been greater focus on the major excitatory neurotransmitter in the human brain, glutamate, in the pathophysiology and treatment of MDD. Although several preclinical and human magnetic resonance spectroscopy studies had already implicated glutamatergic abnormalities in the human brain, it was rocketed by the discovery that the N-methyl-D-aspartate receptor antagonist ketamine has rapid and potent antidepressant effects in even the most treatment-resistant MDD patients, including those who failed to respond to electroconvulsive therapy and who have active suicidal ideation. In this review, we will first provide a brief introduction to glutamate and its receptors in the mammalian brain. We will then review the clinical evidence for glutamatergic dysfunction in MDD, the discovery and progress-to-date with ketamine as a rapidly acting antidepressant, and other glutamate receptor modulators (including proprietary medications) for treatment-resistant depression. We will finally conclude by offering potential future directions necessary to realize the enormous therapeutic promise of glutamatergic antidepressants.

Treatment of Resistant Depression in Patients with Cancer with Low Doses of Ketamine and Desipramine

Journal of Palliative MedicineVol. 13, No. 3 Letters to the EditorTreatment of Resistant Depression in Patients with Cancer with Low Doses of Ketamine and DesipramineDuraiyah Thangathurai, Jay Roby, and Peter RoffeyDuraiyah ThangathuraiSearch for more papers by this author, Jay RobySearch for more papers by this author, and Peter RoffeySearch for more papers by this authorPublished Online:23 Feb 2010https://doi.org/10.1089/jpm.2009.0312AboutSectionsView articleView Full TextPDF/EPUB ToolsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail View article"Treatment of Resistant Depression in Patients with Cancer with Low Doses of Ketamine and Desipramine." , 13(3), p. 235FiguresReferencesRelatedDetailsCited BySingle Subcutaneous Ketamine Dose Followed by Oral Ketamine for Depression Symptoms in Hospice Patients: A Case Series13 April 2021 | Journal of Pain & Palliative Care Pharmacotherapy, Vol. 35, No. 2Substance Use Disorders in Pregnancy and Lactation26 May 2021The Efficacy of Ketamine in the Palliative Care Setting: A Comprehensive Review of the Literature Nathaniel Goldman, Michael Frankenthaler, and Lidia Klepacz3 September 2019 | Journal of Palliative Medicine, Vol. 22, No. 9Psychiatric, behavioral, and cognitive disorders in patients with extracranial cancers23 July 2018 | CNS Spectrums, Vol. 23, No. 6A research study review of effectiveness of treatments for psychiatric conditions common to end-stage cancer patients: needs assessment for future research and an impassioned plea3 April 2018 | BMC Psychiatry, Vol. 18, No. 1Benzodiazepine use, misuse, and abuse: A reviewMental Health Clinician, Vol. 6, No. 3Dopamine D2/D3 but not dopamine D1 receptors are involved in the rapid antidepressant-like effects of ketamine in the forced swim testBehavioural Brain Research, Vol. 279The activation of adenosine monophosphate-activated protein kinase in rat hippocampus contributes to the rapid antidepressant effect of ketamineBehavioural Brain Research, Vol. 253Daily Oral Ketamine for the Treatment of Depression and Anxiety in Patients Receiving Hospice Care: A 28-Day Open-Label Proof-of-Concept Trial Scott A. Irwin, Alana Iglewicz, Richard A. Nelesen, Jessica Y. Lo, Connie H. Carr, Sheilani D. Romero, and Linda S. Lloyd22 July 2013 | Journal of Palliative Medicine, Vol. 16, No. 8Rapid-Acting Glutamatergic Antidepressants: The Path to Ketamine and BeyondBiological Psychiatry, Vol. 73, No. 12Glutamatergic antidepressants27 June 2012Be Prudent of Ketamine in Treating Resistant Depression in Patients with Cancer Chun Yang, Zhi-qiang Zhou, and Jian-jun Yang19 May 2011 | Journal of Palliative Medicine, Vol. 14, No. 5 Volume 13Issue 3Mar 2010 InformationCopyright 2010, Mary Ann Liebert, Inc.To cite this article:Duraiyah Thangathurai, Jay Roby, and Peter Roffey.Treatment of Resistant Depression in Patients with Cancer with Low Doses of Ketamine and Desipramine.Journal of Palliative Medicine.Mar 2010.235-235.http://doi.org/10.1089/jpm.2009.0312Published in Volume: 13 Issue 3: February 23, 2010PDF download

Toluene has antidepressant-like actions in two animal models used for the screening of antidepressant drugs

Many abused solvents share a profile of effects with classical antidepressants. For example, toluene, which is a representative and widely abused solvent, has been reported to increase both serotonin and noradrenaline levels in several brain areas after an acute exposure and to act as a noncompetitive antagonist of the glutamatergic N-methyl-D-aspartic acid (NMDA) receptor subtype. Therefore, it is possible that toluene could possess antidepressant-like actions. To provide an initial screening of toluene's antidepressant-like actions in the forced swimming test (FST) and the tail suspension test (TST) in mice and to analyze its possible mechanism of action. Two series of experiments were performed. In the first one, male animals were exposed to toluene (0, 500, 1,000, 2,000, or 4,000 ppm) in a static exposure chamber for 30 min, and immediately after, evaluated for antidepressant-like effects. The results were compared with those obtained from mice treated with the serotonergic antidepressant clomipramine (CMI), the noradrenergic antidepressant desipramine (DMI), and the glutamatergic antidepressants, ketamine and MK-801. In the second part, we analyzed the effect of a combined administration of a subeffective concentration of toluene with a suboptimal dose of the various antidepressants acting at different neurotransmitter systems. Toluene produced a concentration-dependent antidepressant-like action in the FST and TST and facilitated both MK-801 and ketamine antidepressant-like effects, but not those of DMI or CMI. Toluene has antidepressant-like effects that are synergized with NMDA receptor antagonists.