Carta Acesso aberto Revisado por pares

d -Cycloserine, an NMDA Glutamate Receptor Glycine Site Partial Agonist, Induces Acute Increases in Brain Glutamate Plus Glutamine and GABA Comparable to Ketamine

2016; American Psychiatric Association; Volume: 173; Issue: 12 Linguagem: Inglês

10.1176/appi.ajp.2016.16060735

ISSN

1535-7228

Autores

Joshua T. Kantrowitz, Matthew S. Milak, Xiangling Mao, Dikoma C. Shungu, J. John Mann,

Tópico(s)

Neuroscience and Neuropharmacology Research

Resumo

Back to table of contents Previous article Next article Letters to the EditorFull Accessd-Cycloserine, an NMDA Glutamate Receptor Glycine Site Partial Agonist, Induces Acute Increases in Brain Glutamate Plus Glutamine and GABA Comparable to KetamineJoshua T. Kantrowitz, M.D., Matthew S. Milak, M.D., Xiangling Mao, M.S., Dikoma C. Shungu, Ph.D., J. John Mann, M.D.Joshua T. Kantrowitz, M.D., Matthew S. Milak, M.D., Xiangling Mao, M.S., Dikoma C. Shungu, Ph.D., J. John Mann, M.D.Published Online:1 Dec 2016https://doi.org/10.1176/appi.ajp.2016.16060735AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: Ketamine, an N-methyl-d-aspartate glutamate receptor (NMDAR) antagonist, is effective acutely for major depression (1), but development of alternative NMDAR antagonists is limited by incomplete understanding of mechanism and optimal dosage. Based on preclinical and clinical studies (1, 2), we hypothesize that NMDAR antagonism will produce an acute increase in GABA and glutamate plus glutamine (Glx) as an early event in antidepressant action. Using proton magnetic resonance spectroscopy (1H MRS), we found acute ketamine treatment in depressed patients produced rapid, transient elevations (approximately 40%) of both Glx and GABA levels in the medial prefrontal cortex (1), suggesting that this is an initial step in the antidepressant action cascade for NMDAR antagonists. We used the same methods (1) to assess the effects of high-dose d-cycloserine (1000 mg), an NMDAR glycine site partial agonist, on brain GABA and Glx in healthy subjects. Compared with ketamine, d-cycloserine has a slower (onset within 2–4 weeks) but comparable antidepressant effect (3). d-cycloserine has a dose-dependent biphasic effect on the NMDAR, potentiating function at low dosages ( 500 mg (4).After baseline 1H MRS scans, six healthy subjects (age=33 years, SD=4 years; four males and two females) were administered 1000 mg of oral d-cycloserine, followed by serial 1H MRS scans for up to 90 minutes to measure Glx and GABA levels. Areas under the curve computed using the trapezoidal rule yielded large effect sizes for both Glx (69%, SD=48%, d=1.44) and GABA (39%, SD=31%, d=1.26) without inducing overt psychosis (Figure 1, next page). There was an overall main effect on Glx (F5,22.8=2.9, p=0.034), with an initial peak at approximately 35 minutes postdose (increase of 23%, SD=5%) and a second peak 75–90 minutes postdose (increase of 20%, SD=7%). For GABA, there was a comparable, trend-level main effect (F5,23.3=2.5, p=0.058; increase of 16%, SD=5%).FIGURE 1. Sample In Vivo Human Brain GABA and Glutamate Plus Glutamine (Glx) Spectra, and Percentage Change of Concentrations Measured by Proton Magnetic Resonance Spectroscopy (1H MRS)aa Panel A illustrates medial prefrontal cortex GABA and Glx detection with the J-editing 1H MRS technique. Traces in (a) and (b) represent single-voxel subspectra of the J-editing method acquired in 15 minutes, respectively, with the editing pulses off and on, and 580 total interleaved averages. The spectrum in (c) is the difference between spectra in (a) and (b) and shows the edited brain GABA and Glx resonances. Model fitting of the experimental spectrum in (c) was used to obtain the peak GABA and Glx areas as shown in the spectrum in (d). The spectrum in (e) shows the residual of the difference between spectra in (c) and (d). Panel B shows the percentage change of 1H MRS-measured GABA-water and Glx-water concentrations in healthy controls in the medial prefrontal cortex following d-cycloserine. Frame duration was 13 minutes and 20 seconds. Significant group increases, denoted by ** for p<0.01 and by * for p<0.05, relative to predrug baseline levels for Glx were observed. No clinically significant side effects, change in vital signs, or behavioral symptoms as measured by the Positive and Negative Syndrome Scale were observed. Error bars denote standard deviation from the mean. The overall significance on the mixed model was p=0.03.d-cycloserine increased both neurotransmitter levels comparably to ketamine, and this may be the initial step in the antidepressant cascade of NMDAR antagonism. Future studies should examine the relationship of these neurotransmitters to the degree of the antidepressant effect of d-cycloserine. Targeting the NMDAR and AMPA receptors may have specific advantages in treatment-resistant depression. The more rapid clinical improvement seen with ketamine may be due to other pharmacological effects that distinguish it from d-cycloserine, and these need to be identified to facilitate development of more rapidly acting antidepressants.From the Departments of Psychiatry and of Radiology, College of Physicians and Surgeons, Columbia University, New York; the Nathan Kline Institute for Psychiatric Research, Orangeburg, N.Y.; and the Department of Radiology, Weill Medical College, Cornell University, New York.Supported by the 2015 Irving Institute Imaging Pilot Award to Dr. Kantrowitz.Dr. Kantrowitz has received consulting payments within the last 24 months from Vindico Medical Education, the Annenberg Center for Health Sciences at Eisenhower, Health Advances, Strategic Edge Communications, Transperfect, Havas Life, and Cowen and Company; he has conducted clinical research supported by NIMH, the Stanley Foundation, Forum, Sunovion, Lundbeck, Alkermes, Pfizer, and Lilly; and he owns a small number of shares of common stock in GlaxoSmithKline. Dr. Mann receives royalties for commercial use of the Columbia-Suicide Severity Rating Scale from the Research Foundation for Mental Hygiene. All other authors report no financial relationships with commercial interests.References1 Milak MS, Proper CJ, Mulhern ST, et al.: A pilot in vivo proton magnetic resonance spectroscopy study of amino acid neurotransmitter response to ketamine treatment of major depressive disorder. Mol Psychiatry 2015; 21:320–327Crossref, Medline, Google Scholar2 Ren Z, Pribiag H, Jefferson SJ, et al.: Bidirectional homeostatic regulation of a depression-related brain state by gamma-aminobutyric acidergic deficits and ketamine treatment. Biol Psychiatry 2016; 80:457–468Crossref, Medline, Google Scholar3 Kantrowitz JT, Halberstam B, Gangwisch J: Single-dose ketamine followed by daily d-cycloserine in treatment-resistant bipolar depression. J Clin Psychiatry 2015; 76:737–738Crossref, Medline, Google Scholar4 Emmett MR, Mick SJ, Cler JA, et al.: Actions of d-cycloserine at the N-methyl-d-aspartate-associated glycine receptor site in vivo. Neuropharmacology 1991; 30:1167–1171Crossref, Medline, Google Scholar FiguresReferencesCited byDetailsCited byKetamine decreases neuronally released glutamate via retrograde stimulation of presynaptic adenosine A1 receptors11 August 2021 | Molecular Psychiatry, Vol. 26, No. 12Ventromedial prefrontal cortex/anterior cingulate cortex Glx, glutamate, and GABA levels in medication-free major depressive disorder5 August 2021 | Translational Psychiatry, Vol. 11, No. 1D-Serine: A Cross Species Review of Safety10 August 2021 | Frontiers in Psychiatry, Vol. 12Relationship of Brain Glutamate Response to D-Cycloserine and Lurasidone to Antidepressant Response in Bipolar Depression: A Pilot Study2 June 2021 | Frontiers in Psychiatry, Vol. 12Novel Glutamatergic Modulators for the Treatment of Mood Disorders: Current Status26 April 2021 | CNS Drugs, Vol. 35, No. 5Steroid hormone secretion after stimulation of mineralocorticoid and NMDA receptors and cardiovascular risk in patients with depression20 April 2020 | Translational Psychiatry, Vol. 10, No. 1The potential of 1H-MRS in CNS drug development5 September 2019 | Psychopharmacology, Vol. 43Progress in Neuro-Psychopharmacology and Biological Psychiatry, Vol. 90Schizophrenia Research, Vol. 207CNS Drugs, Vol. 31, No. 5Effect of a Novel NMDA Receptor Modulator, Rapastinel (Formerly GLYX-13), in OCD: Proof of ConceptCarolyn I. Rodriguez, M.D., Ph.D., Jordana Zwerling, M.A., Eyal Kalanthroff, Ph.D., Hanyang Shen, M.P.H., M.Sc., Maria Filippou, M.D., M.B.S., Booil Jo, Ph.D., Helen Blair Simpson, M.D., Ph.D., Ronald M. Burch, M.D., Ph.D., Joseph R. Moskal, Ph.D.1 December 2016 | American Journal of Psychiatry, Vol. 173, No. 12 Volume 173Issue 12 December 01, 2016Pages 1241-1242 Metrics KeywordsAntidepressantsBiological MarkersResearch Design And MethodsPDF download History Accepted 1 August 2016 Published online 1 December 2016 Published in print 1 December 2016

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