title: A randomized add-on trial of high-dose D-cycloserine for treatment-resistant depression.
abstract: 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.
authors.affiliation: Psychiatry Department, Ezrath-Nashim Herzog Memorial Hospital, Jerusalem, Israel. heresco@md.huji.ac.il
authors.forename: Uriel
authors.initials: U
authors.lastname: Heresco-Levy
authors.forename: Genia
authors.initials: G
authors.lastname: Gelfin
authors.forename: Boaz
authors.initials: B
authors.lastname: Bloch
authors.forename: Raz
authors.initials: R
authors.lastname: Levin
authors.forename: Shani
authors.initials: S
authors.lastname: Edelman
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Javitt
authors.forename: Ilana
authors.initials: I
authors.lastname: Kremer
mesh_terms: D000328:Adult; D000368:Aged; D000928:Antidepressive Agents / Q000008:administration & dosage*; D003523:Cycloserine / Q000008:administration & dosage*; D003865:Major Depressive Disorder / Q000188:drug therapy* / Q000453:epidemiology / Q000523:psychology*; D004311:Double-Blind Method; D004351:Drug Resistance / Q000187:drug effects / Q000502:physiology; D004359:Drug Therapy, Combination; D006801:Humans; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome
chemical_list: D000928:Antidepressive Agents; D003523:Cycloserine