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  • The International Journal of Neuropsychopharmacology, Volume 16, Issue 3
  • April 2013, pp. 501-506

A randomized add-on trial of high-dose d-cycloserine for treatment-resistant depression

  • Uriel Heresco-Levy (a1) (a2), Genia Gelfin (a1) (a2), Boaz Bloch (a3) (a4), Raz Levin (a1), Shani Edelman (a1), Daniel C. Javitt (a5) and Ilana Kremer (a3) (a4)
  • DOI:
  • Published online: 17 September 2012

Antagonism of N-methyl-d-aspartate glutamatergic receptors (NMDAR) may represent an effective antidepressant mechanism. d-cycloserine (DCS) is a partial agonist at the NMDAR-associated glycine modulatory site that at high doses acts as a functional NMDAR antagonist. Twenty-six treatment-resistant major depressive disorder patients participated in a double blind, placebo-controlled, 6-wk parallel group trial with a gradually titrated high dose (1000 mg/d) of DCS added to their antidepressant medication. DCS treatment was well tolerated, had no psychotomimetic effects and led to improvement in depression symptoms as measured by Hamilton Depression Rating Scale (HAMD; p = 0.005) and Beck Depression Inventory (p = 0.046). Of the 13 subjects treated with DCS, 54% had a ⩾50% HAMD score reduction vs. 15% of the 13 patients randomized to placebo (p = 0.039). A significant (p = 0.043) treatment× pre-treatment glycine serum levels interaction was registered. These findings indicate that NMDAR glycine site antagonism may be a cost-effective target for development of mechanistically novel antidepressants. Larger-sized DCS trials are warranted.

Corresponding author
Address for correspondence: U. Heresco-Levy, MD, Psychiatry Department, Hadassah Medical School, Hebrew University, Ezrath Nashim-Herzog Memorial Hospital, P.O. Box 3900, Jerusalem, 91035, Israel. Tel.: 972 2 531 6906 Fax: 972 2 653 6075 Email:
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The International Journal of Neuropsychopharmacology
  • ISSN: 1461-1457
  • EISSN: 1469-5111
  • URL: /core/journals/the-international-journal-of-neuropsychopharmacology
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