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The clinical antidepressant effect of exogenous agmatine is not reversed by parachlorophenylalanine: a pilot study

Published online by Cambridge University Press:  26 February 2013

Baron Shopsin
Baron Shopsin*
Affiliation:
Former Chief, Unit for The Study and Treatment of Affective, Disorders, & Lithium Clinic, Neuropsychopharmacology Research Section, Department of Psychiatry, NYU Medical Center, and Associate Professor of Psychiatry, NYU School of Medicine, USA
*
Baron Shopsin, MD,PO Box 2054, Ponte Vedra Beach, Florida 32004, USA. E‐mail: [email protected]
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Abstract

Objectives

To examine and record the clinical antidepressant effect of exogenous agmatine, an amino acid derived central glutamaergic modulator in endogenously depressed subjects. It was also the author's intention to examine the effects of parachlorophenylalanine (PCPA) in therapeutic responders to determine if serotonergic mechanisms mediate agmatine's antidepressant effect.

Methodology

Exogenous agmatine was ingested in doses of 2‐3mg/day by depressed subjects with Major Depresssive Disorder (MDD), clinically assessed using the 21 item Hamilton Rating Scale for Depression (HAM‐D), the Clinical Global Impression (CGI) and the Brief Psychiatric Rating Scale (BPRS). Antidepressant responders volunteered to concommittantly ingest parachlorophenylalanine (PCPA) at starting doses of 250mg/day, and increased until depressive relapse, mitigating side effects, or a maximum dosage of 1250mg/day.

Results

Three depressed subjects showing total illness remission with exogenous agmatine did not relapse after concomitantly adding PCPA. Effective in relieving both psychomotor agitation and retardation, the antidepressant effect was free of physical or behavioural side effects: gastrointestinal discomfort and loose stools in one subject resolved spontaneously within days. All three subjects refused to risk depressive relapse by temporarily stopping agmatine after PCPA was stopped.

Conclusion

The antidepressant effect of exogenous agmatine was documented in a small number of MDD subjects, and was not reversed/modified by PCPA confirming findings in animals that therapeutic response is not mediated by serotonergic mechanisms. A NAMDA (N‐methyl‐D‐aspartate) receptor antagonist, agmatine's recognized function in brain as inhibitory modulator of excitatory glutamatergic transmission suggests a pivotal role for brain glutamate, contributing to the ripening glutamatergic basis of depression, and a rational basis for future antidepressant pharmacotherapy.

Keywords

agmatineantidepressantastrocyteglutamatergicN-methyl-D-aspartateparachlorophenylalanineSerotonergic
Type
Original Articles
Information
Acta Neuropsychiatrica , Volume 25 , Issue 2 , April 2013 , pp. 113 - 118
Copyright
Copyright © Scandinavian College of Neuropsychopharmacology 2013

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Footnotes

He remains clinically active and maintains a private practice.

[Correction added on 2 August 2012, after first online publication: The affiliation was updated to indicate that the author is the former chief of the stated affiliation and an associate professor of psychiatry who currently remains clinically active with a private practice.]

References

1Sastre, M, Regunathan, S, Galea, E, Reis, DJ. Agmatinase activity in rat brain: a metabolic pathway for the degradation of agmatine. J Neurochem 1996;67:1761–1765. Epub 1996/10/01.Google Scholar
2Regunathan, S, Feinstein, DL, Raasch, W, Reis, DJ. Agmatine (decarboxylated arginine) is synthesized and stored in astrocytes. Neuroreport 1995;6:1897–1900. Epub 1995/10/02.Google Scholar
3Yang, XC, Reis, DJ. Agmatine selectively blocks the N‐methyl‐D‐aspartate subclass of glutamate receptor channels in rat hippocampal neurons. J Pharmacol Exp Ther 1999;288:544–549. Epub 1999/01/26.Google Scholar
4Wang, WP, Iyo, AH, Miguel‐Hidalgo, J, Regunathan, S, Zhu, MY. Agmatine protects against cell damage induced by NMDA and glutamate in cultured hippocampal neurons. Brain Res 2006;1084:210–216. Epub 2006/03/21.Google Scholar
5Feng, Y, LeBlanc, MH, Regunathan, S. Agmatine reduces extracellular glutamate during pentylenetetrazole‐induced seizures in rat brain: a potential mechanism for the anticonvulsive effects. Neurosci Lett 2005;390:129–133. Epub 2005/08/30.Google Scholar
6Wegener, G, Mathé, AA. Nitric oxide signaling in depression and antidepressant action. Neurobiology of depression. CRC Press, Taylor & Francis Publishing Group, London, UK 2011:341–370.Google Scholar
7Abe, K, Abe, Y, Saito, H. Agmatine suppresses nitric oxide production in microglia. Brain Res 2000;872:141–148. Epub 2000/08/05.Google Scholar
8Qiu, WW, Zheng, RY. Neuroprotective effects of receptor imidazoline 2 and its endogenous ligand agmatine. Neurosci Bull 2006;22:187–191. Epub 2007/08/21.Google Scholar
9Ahn, SK, Hong, S, Park, YM, Lee, WT, Park, KA, Lee, JE. Effects of agmatine on hypoxic microglia and activity of nitric oxide synthase. Brain Res 2011;1373:48–54. Epub 2010/12/15.Google Scholar
10Gorbatyuk, OS, Milner, TA, Wang, G, Regunathan, S, Reis, DJ. Localization of agmatine in vasopressin and oxytocin neurons of the rat hypothalamic paraventricular and supraoptic nuclei. Exp Neurol 2001;171:235–245. Epub 2001/09/28.Google Scholar
11Shopsin, B, Friedman, E, Gershon, S. Parachlorophenylalanine reversal of tranylcypromine effects in depressed patients. Arch Gen Psychiatry 1976;33:811–819.Google Scholar
12Krass, M, Wegener, G, Vasar, E, Volke, V. Antidepressant‐like effect of agmatine is not mediated by serotonin. Behav Brain Res 2008;188:324–328. Epub 2008/01/08.Google Scholar
13Shutoh, F, Hamada, S, Shibata, M et al. Long term depletion of serotonin leads to selective changes in glutamate receptor subunits. Neurosci Res 2000;38:365–371. Epub 2001/02/13.Google Scholar
14Sierralta, F, Pinardi, G, Miranda, HF. Effect of p‐chlorophenylalanine and alpha‐methyltyrosine on the antinociceptive effect of antidepressant drugs. Pharmacol Toxicol 1995;77:276–280. Epub 1995/10/01.Google Scholar
15Diazgranados, 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;71:1605–1611. Epub 2010/08/03.Google Scholar
16Zarate, 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;63:856–864.Google Scholar
17Ibrahim, L, Diazgranados, N, Franco‐Chaves, J, Kronstein, P et al. Course of Improvement in Depressive Symptoms to a Single Intravenous Infusion of Ketamine vs Add‐on Riluzole: results from a 4‐Week, Double‐Blind, Placebo‐Controlled Study. Neuropsychopharmacology 2012;37:1526–1533.Google Scholar
18Zarate, CA, Manji, HK. Riluzole in psychiatry: a systematic review of the literature. Expert Opin Drug Metab Toxicol 2008;4:1223–1234. Epub 2008/08/30.Google Scholar
19Zarate, CA Jr, Payne, JL, Quiroz, J et al. An open‐label trial of riluzole in patients with treatment‐resistant major depression. Am J Psychiatry 2004;161:171–174. Epub 2004/01/02.Google Scholar