COMMENTARY Glycine Transporter-I Inhibitors: A New Class of Antidepressant? Sanjay J. Mathew T he number of neuropharmacologic mechanisms and mole- cular targets affecting glutamate metabolism that are under investigation as antidepressants has proliferated. Bolstered by the unexpected success of subanesthetic dose ketamine, a glutamate N-methyl-D-aspartate receptor (NMDAR) antagonist, as a rapid treatment for pharmacotherapy-resistant major depressive disorder (MDD) (1), a major drug discovery pathway converges on NMDAR modulators that may be devoid of ketamine’s psychoto- mimetic side effects. Examples of next-generation ketamine-like agents include esketamine, the S-enantiomer of racemic ketamine (available as an anesthetic in several European Union countries); AZD6765, a “low-trapping” channel blocker; and selective NMDAR subtype 2B antagonists. A complementary pharmacologic strat- egy capitalizes on the essential role of alpha-amino-3-hydroxy- 5-mehtyl-4-isoxazolpropionic acid receptor (AMPAR) activation in the rapid and sustained antidepressant effects of ketamine, although clinical development of AMPAR potentiators or AMPA- kines has been challenging. Beyond ionotropic receptor (NMDA, AMPA/kainate) targets, metabotropic glutamate receptors and astroglial glutamate transporters are the initial molecular targets of several antidepressants in development. Another leading drug discovery pathway focuses on com- pounds that directly or indirectly affect the glycine-B (Gly-B) allosteric modulatory site of the NMDAR. Glycine-site modulators of the NMDAR (such as D-cycloserine [DCS] and GLYX-13) and glycine transporter-1 (GlyT-1) inhibitors (such as sarcosine [N-methylglycine] the subject of the report by Huang et al. in this issue of Biological Psychiatry) (2) are predicated on the hypothesis that potentiation of NMDAR function also represents a viable antidepressant strategy. Glycine Site of NMDAR and Depression Glycine, an inhibitory amino acid neurotransmitter, and D-serine are endogenous ligands at the Gly-B site on the NMDAR, and, along with glutamate, coactivate the receptor. The glycine modulatory site affects NMDAR channel open time and the rate of NMDAR desensitization in the presence of the agonist glutamate but, in contrast to ketamine, does not directly induce channel opening (3). There is emerging evidence for dysregulation in glycine metabolism in depressed individuals and in those with poor responses to selective serotonin reuptake inhibitors (4). The glycine site of NMDAR is certainly not a new target for depression: as early as the 1950s, DCS (recognized now to act as a partial glycine site NMDAR agonist) was associated with rapid antide- pressant benefit. The antidepressant efficacy of DCS in a sample of treatment-resistant patients was recently confirmed in an adjunctive placebo-controlled trial using a high dose (5) in which DCS effectively functions as an NMDAR antagonist. Interestingly, patients with high plasma levels of glycine (greater than healthy volunteers) were especially responsive to DCS. Translational Study of Sarcosine as an Antidepressant Huang et al. (2) examines sarcosine in several preclinical models and in a proof-of-concept trial in patients with major depressive disorder. Sarcosine is a naturally occurring GlyT-1 inhibitor, the effect of which is to enhance NMDAR activity by raising synaptic glycine levels via inhibition of its reuptake from the synaptic cleft. Sarcosine was initially shown by this same group to have efficacy for negative symptoms in schizophrenia when used as an add-on treatment to antipsychotic medication (6). The results of subsequent monotherapy and adjunctive studies of sarcosine in chronic and acutely decompensated patients with schizophrenia have been mixed (3). In the preclinical experiments, sarcosine displayed antidepressant-like properties in several animal behavioral mod- els. The studies included typical acute behavioral screens for antidepressants (forced swim test, tail suspension test) and anxiolytics (elevated plus maze). Of greater translational rele- vance, sarcosine was also examined in models of depression that require chronic dose administration (chronic unpredictable stress/ anhedonia test). Chronic administration of sarcosine reversed the chronic unpredictable stress-induced behavioral deficits in both the sucrose preference test and novelty suppressed feeding test. Overall, the preclinical profile of sarcosine was generally consis- tent with that of a conventional antidepressant medication. The proof-of-concept clinical trial in 40 patients with MDD was a 6-week, randomized, double-blind flexible dose study to test the hypothesis that sarcosine would induce a “more rapid and robust response” than citalopram (used as a positive control). Patients were predominately Taiwanese men in their mid-30s, primarily antidepressant treatment–naive, had been off antide- pressants for at least 3 months, and had moderate-to-severe depressive symptoms at baseline. Efficacy and safety were assessed in 2-week intervals. Sarcosine was significantly more effective than citalopram across multiple dimensions of the primary rating scale (the 17-item Hamilton Rating Scale for Depression) at all assessments. After 2 weeks, sarcosine was superior to citalopram by approxi- mately 5 points on the Hamilton Rating Scale for Depression, accounting for the majority of overall improvement at study end point. By Week 4, 40% of sarcosine-treated patients met remission criteria, and by Week 6, 65% of patients were in remission. Benefits were observed in core depressive symptoms and did not solely reflect improvements in associated sleep or anxiety symptoms. Similar to previous findings in schizophrenia, sarco- sine’s adverse event profile was mild, and there were no reported dissociative or psychotomimetic side effects. Despite these highly favorable results, several caveats should be noted, the most important of which is the absence of a placebo From the Mental Health Care Line, Michael E. DeBakey VA Medical Center, and Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, Texas. Address correspondence to Sanjay J. Mathew, M.D., Michael E. Debakey VA Medical Center & Baylor College of Medicine, 2002 Holcombe Boulevard, Houston, Texas 77030; E-mail: sjmathew@bcm.edu. Received Aug 23, 2013; accepted Aug 26, 2013. 0006-3223/$36.00 BIOL PSYCHIATRY 2013;74:710–711 http://dx.doi.org/10.1016/j.biopsych.2013.08.019 Published by Elsevier Inc on behalf of Society of Biological Psychiatry