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.

This study provisionally identifies a common genetic polymorphism, 5-HTTLPR, that modestly (effect size=7%) contributed to greater shyness scores in a nonclinical group of second-grade students. These first findings may be relevant to previous reports that have shown an association between the 5-HTTLPR long form and obsessive-compulsive disorder and autism.

There was a highly significant association between SERT and the categorical definition of smoking, irrespective of dependence level, suggesting that this gene influences the initiation of smoking. Mediation analysis failed to substantiate the hypothesis that novelty seeking partially mediates the effect of SERT on smoking. SERT appears to independently contribute to novelty seeking and smoking.

Dysfunction of glutamatergic neurotransmission may be relevant to the pathogenesis of post-traumatic stress disorder (PTSD). Preclinical and clinical evidence suggests that PTSD symptoms could be alleviated following enhancement of neurotransmission mediated at the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors. Eleven patients with chronic PTSD participated in a double-blind, placebo-controlled, cross-over trial with 50 mg/d D-cycloserine which acts as a partial agonist at the glycine regulatory site on the NMDA receptor. D-cycloserine treatment resulted in significant improvements in numbing, avoidance, and anxiety symptoms; however, similar effects were also observed during placebo treatment. In addition, D-cycloserine treatment resulted in a significant (p=0.03), reduction in the perseverative error scores as measured by the Wisconsin Card Sorting Test. This pilot study is the first to assess the efficacy of a NMDA receptor modulator for PTSD treatment and its results warrant further, larger-scale investigation.