 There is an extensive literature on the effects of NMDA enhancing agents on positive, negative, and depressive symptoms and on neurocognitive function see Tsai Lin, 2010; Lin et al. 2011 for reviews. Although many studies have reported positive results in at least one symptom domain Heresco-Levy et al. 1996, 1999, 2004; Tsai et al. 1998, 1999, 2004, 2006; Javitt et al. 2001; Goff et al. 1996; Lane et al. 2008, the results of other studies have been negative or ambiguous Goff et al. 1999; Evins et al. 2000; Duncan et al. 2004; van Berckel et al. 1999. Factors likely to contribute to this variability include: mechanism of action of the agent, compliance, concurrent treatment with first- vs second generation antipsychotic drugs, baseline glycine blood levels, presenceabsence of kynurenine pathway metabolic abnormalities Wonodi et al. 2010; Erhardt et al. 2007 and individual differences in brain glycine uptake and metabolism Kaufman et al. 2009; Buchanan et al. 2007. Genetic variants that impact the synthesis and breakdown of glycine, glutamate, or other modulators of NMDA receptor function are also likely to have significant effects. Although glycine augmentation has shown variable efficacy in patients unselected for having a mutation that would be expected to lower brain glycine levels, the GLDC triplication in the two carriers in this study would be expected to result in unusually low brain glycine levels, supporting its therapeutic potential as an augmentation strategy. 