The International Journal of Neuropsychopharmacology

Rapid Communication

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

Uriel Heresco-Levya1a2 c1, Genia Gelfina1a2, Boaz Blocha3a4, Raz Levina1, Shani Edelmana1, Daniel C. Javitta5 and Ilana Kremera3a4

a1 Psychiatry Department, Ezrath-Nashim Herzog Memorial Hospital, Jerusalem, Israel

a2 Psychiatry Department, Hadassah Medical School, Hebrew University, Jerusalem, Israel

a3 Psychiatry Department, Haemek Medical Center, Afula, Israel

a4 Psychiatry Department, B. Rappaport Faculty of Medicine, Technion, Haifa, Israel

a5 Psychiatry Department, Columbia University, New York, USA


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.

(Received May 15 2012)

(Reviewed July 10 2012)

(Revised July 17 2012)

(Accepted July 19 2012)

(Online publication September 17 2012)

Key words

  • d-cycloserine;
  • depression;
  • NMDAR;
  • treatment


c1 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:


  Clinical Trial Registration: clinical identifier: NCT00408031.