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Letters to the Editor

Dr Kantrowitz and Colleagues Reply

See letter by Kim et al and letter by Kantrowitz et al

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Dr Kantrowitz and Colleagues Reply

To the Editor: In their letter, Kim et al accentuate our findings1 that d-cycloserine (DCS) may have antidepressant properties. Kim et al suggest that intermittent treatment with lower-dose DCS (100-125 mg) may be helpful in a population with mild depression secondary to obsessive-compulsive disorder. As the authors state, the baseline levels of depression were mild, but the level of improvement was of a large effect size.

Kim et al suggest that the potential antidepressant properties of both DCS and rapastinel (formerly GLYX-13) are due to agonism at N-methyl-d-aspartate-type glutamate receptor glycine-site (NMDAR-GS).

DCS is not a full agonist at the NMDAR-GS; however, it is a partial agonist. The authors are correct that in lower doses (< 100 mg), DCS primarily potentiates NMDAR-GS function and has been shown to be partially effective in treatment of schizophrenia2 and anxiety disorders.3 Similar to other partial agonists at this receptor, DCS has a dose-dependent, biphasic effect, acting as an agonist at low doses but functioning as a net NMDAR antagonist4,5 at higher doses (> 500 mg).6-8

Clinical data strongly support the concept that an antagonist-level dose is required for antidepressant action, as efficacy is consistently shown at ~1,000 mg,1,9,10 but not at lower doses (250 mg).11 Moreover, rapastinel, which the authors reference in support of the NMDAR-GS agonist theory, is also a partial agonist with a similar biphasic agonist/antagonist effect. Similar to the majority of clinical studies with DCS, antidepressant efficacy is shown only at antagonist doses.12,13

In support of Kim et al, d-serine, a full agonist14 at the NMDAR-GS, may have antidepressant properties when used acutely.15 We also note that the author’s strategy of intermittent dosing may produce different pharmacodynamics than daily dosing.16 We agree with the authors that further study of dosing strategies is needed.


1. Kantrowitz JT, Halberstam B, Gangwisch J. Single-dose ketamine followed by daily d-cycloserine in treatment-resistant bipolar depression. J Clin Psychiatry. 2015;76(6):737-738. PubMed doi:10.4088/JCP.14l09527

2. Goff DC, Cather C, Gottlieb JD, et al. Once-weekly d-cycloserine effects on negative symptoms and cognition in schizophrenia: an exploratory study. Schizophr Res. 2008;106(2-3):320-327. PubMed doi:10.1016/j.schres.2008.08.012

3. Norberg MM, Krystal JH, Tolin DF. A meta-analysis of d-cycloserine and the facilitation of fear extinction and exposure therapy. Biol Psychiatry. 2008;63(12):1118-1126. PubMed doi:10.1016/j.biopsych.2008.01.012

4. van Berckel BN, Lipsch C, Timp S, et al. Behavioral and neuroendocrine effects of the partial NMDA agonist d-cycloserine in healthy subjects. Neuropsychopharmacology. 1997;16(5):317-324. PubMed doi:10.1016/S0893-133X(96)00196-0

5. van Berckel BN, Lipsch C, Gispen-de Wied C, et al. The partial NMDA agonist d-cycloserine stimulates LH secretion in healthy volunteers. Psychopharmacology (Berl). 1998;138(2):190-197. PubMed doi:10.1007/s002130050662

6. 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(11):1167-1171. PubMed doi:10.1016/0028-3908(91)90161-4

7. Hood WF, Compton RP, Monahan JB. D-cycloserine: a ligand for the N-methyl-d-aspartate coupled glycine receptor has partial agonist characteristics. Neurosci Lett. 1989;98(1):91-95. PubMed doi:10.1016/0304-3940(89)90379-0

8. Watson GB, Bolanowski MA, Baganoff MP, et al. D-cycloserine acts as a partial agonist at the glycine modulatory site of the NMDA receptor expressed in Xenopus oocytes. Brain Res. 1990;510(1):158-160. PubMed doi:10.1016/0006-8993(90)90745-W

9. Crane GE. Cyloserine as an antidepressant agent. Am J Psychiatry. 1959;115(11):1025-1026. PubMed doi:10.1176/ajp.115.11.1025

10. Heresco-Levy U, Gelfin G, Bloch B, et al. A randomized add-on trial of high-dose d-cycloserine for treatment-resistant depression. Int J Neuropsychopharmacol. 2013;16(3):501-506. PubMed doi:10.1017/S1461145712000910

11. Heresco-Levy U, Javitt DC, Gelfin Y, et al. Controlled trial of d-cycloserine adjuvant therapy for treatment-resistant major depressive disorder. J Affect Disord. 2006;93(1-3):239-243. PubMed doi:10.1016/j.jad.2006.03.004

12. Burgdorf J, Zhang XL, Nicholson KL, et al. GLYX-13, a NMDA receptor glycine-site functional partial agonist, induces antidepressant-like effects without ketamine-like side effects. Neuropsychopharmacology. 2013;38(5):729-742. PubMed doi:10.1038/npp.2012.246

13. Preskorn S, Macaluso M, Mehra DO, et al; GLYX-13 Clinical Study Group. Randomized proof of concept trial of GLYX-13, an N-methyl-d-aspartate receptor glycine site partial agonist, in major depressive disorder nonresponsive to a previous antidepressant agent. J Psychiatr Pract. 2015;21(2):140-149. PubMed doi:10.1097/01.pra.0000462606.17725.93

14. Kantrowitz J, Javitt DC. Glutamatergic transmission in schizophrenia: from basic research to clinical practice. Curr Opin Psychiatry. 2012;25(2):96-102. PubMed

15. Malkesman O, Austin DR, Tragon T, et al. Acute d-serine treatment produces antidepressant-like effects in rodents. Int J Neuropsychopharmacol. 2012;15(8):1135-1148. PubMed doi:10.1017/S1461145711001386

16. Javitt DC. Harnessing N-methyl-d-aspartate receptors for new treatment development in psychiatry: positive lessons from negative studies. Am J Psychiatry. 2013;170(7):699-702. PubMed doi:10.1176/appi.ajp.2013.13040503

Joshua T. Kantrowitz, MDa,b

Batsheva Halberstam, PhDa

James Gangwisch, PhDa

aPsychiatry, Columbia University, New York, New York

bSchizophrenia Research Center, Nathan Kline Institute, Orangeburg, New York

Potential conflicts of interest: None.

Funding/support: None.

J Clin Psychiatry 2016;77(8):e1008

© Copyright 2016 Physicians Postgraduate Press, Inc.

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