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Glycine Transporter-I Inhibitors: A New Class of Antidepressant?
COMMENTARY
Glycine Transporter-I Inhibitors: A New Class of Antidepressant? Sanjay J. Mathew
T
he number of neuropharmacologic mechanisms and molecular 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 psychotomimetic 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 strategy capitalizes on the essential role of alpha-amino-3-hydroxy5-mehtyl-4-isoxazolpropionic acid receptor (AMPAR) activation in the rapid and sustained antidepressant effects of ketamine, although clinical development of AMPAR potentiators or AMPAkines 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 compounds 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 antidepressant benefit. The antidepressant efficacy of DCS in a sample of treatment-resistant patients was recently confirmed in an 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: [email protected]. Received Aug 23, 2013; accepted Aug 26, 2013.
0006-3223/$36.00 http://dx.doi.org/10.1016/j.biopsych.2013.08.019
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 models. The studies included typical acute behavioral screens for antidepressants (forced swim test, tail suspension test) and anxiolytics (elevated plus maze). Of greater translational relevance, 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 consistent 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 antidepressants 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 approximately 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, sarcosine’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
BIOL PSYCHIATRY 2013;74:710–711 Published by Elsevier Inc on behalf of Society of Biological Psychiatry
Commentary control group. The statistical superiority of sarcosine over citalopram would be obscured if the study population showed placebo responsiveness within the usual range observed in modern clinical trials of MDD. Second, the citalopram group had lower than expected response (20%) and remission (5%) rates, and an unusually high dropout rate. These findings could be attributed to an unconventional twice-per-day dosing regimen and the low mean dose of citalopram (27 mg). Especially problematic was a 40% dropout between Weeks 2 and 4 in the citalopram group, compared with only 5% in the sarcosine group. Third, because the initial postrandomization evaluation was only conducted after 2 weeks of treatment, it is not possible to evaluate early onset (i.e., within the first 72 hours) of mood and behavioral effects. This study raises questions regarding dose-response and target engagement. Sarcosine dosing in the clinical trial was flexible, from 500 mg to 1500 mg per day, with a mean dose of 900 mg (SD ¼ 502 mg), which is difficult to reconcile with the dose used in the preclinical chronic experiments (560 mg/kg per day for 21 days). It is unclear whether sarcosine at the 500-mg dose (the dose achieved by Week 2) meaningfully affects brain glycine metabolism because no information was available on glycine levels in cerebrospinal fluid or plasma. Inasmuch as sarcosine and GlyT-1 inhibitors may be associated with an inverted U-shaped dose-response curve due to NMDAR internalization and decreased NMDAR activity at high doses (3), future studies require careful attention to dose and evidence of target engagement. High-affinity GlyT-1 inhibitors reliably are associated with changes in cerebrospinal fluid and brain dialysate glycine levels; glycine measurement in the context of early trials should help characterize pharmacokinetic-pharmacodynamic relationships. Isolation of the glycine resonance by proton spectroscopy is technically challenging because of overlap by stronger resonances and the relatively low brain concentration. However, recent work in human brain has used Gly-optimized in vivo proton spectroscopy at high field strengths (7T), supporting this technique for quantification of regional brain glycine (7). Can we reconcile GlyT-1 inhibition with the antidepressant efficacy of NMDAR antagonist therapies, the common antidepressant effects of which seem “discordant and counterintuitive?” This study does not directly address mechanism, but possibilities may include the following: 1) common mechanisms at non-NMDAR ionotropic AMPAR; 2) common changes in the balance between extrasynaptic NMDARs (in which excessive stimulation is linked with cell death) and synaptic NMDARs (in which stimulation is associated with neuroprotective enhancement), whereby NMDAR agonists act at the synapse and antagonists act extrasynaptically; and 3) induction of synaptogenesis and activation of the mammalian target of rapamycin signaling pathway, which requires activity-dependent release of brain-derived neurotrophic factor (8). Examination of sarcosine’s acute and chronic behavioral effects relative to ketamine and similar agents are essential future studies.
Conclusions Are these data sufficiently compelling to initiate larger investigations of sarcosine and, more generally, GlyT-1 inhibitors? Although the clinical study appears promising, this was a small pilot trial. The ongoing Phase III program of the high-affinity GlyT1 inhibitor RG1678 in schizophrenia will be informative because these trials represent the largest and most comprehensive evaluation of this mechanism in a psychiatric illness. A key unresolved issue for any future program in depression is
BIOL PSYCHIATRY 2013;74:710–711 711 identifying the optimal stage of illness a GlyT-1 inhibitor would be most beneficial. Although ketamine and similar agents have been studied primarily in chronic and treatment-resistant individuals, there is no scientific rationale to restrict the testing of GlyT-1 inhibitors to difficult-to-treat patients if the safety profile is acceptable. Indeed, recent pilot studies of glycine in individuals with risk syndrome for psychosis showed feasibility of NMDA agonist approaches in high-risk individuals (9). Finally, the inherent complexity of the NMDAR must be acknowledged in formulating a rationale drug discovery strategy. In addition to mechanisms described earlier, NMDAR are modulated by glutathione, binding to a redox site, as well as zinc and polyamines (3). We recently reported lowered cortical levels of glutathione in patients with MDD compared with healthy control subjects, suggesting dysregulation in oxidative stress biology in subgroups of depressed individuals (10). How similar depressed patients would respond to a GlyT-1 inhibitor is an interesting unanswered question. Dr. Mathew receives support from the National Institutes of Health/National Institute of Mental Health Grant Nos. RO1MH081870 and R01MH085054, an National Alliance for Research on Schizophrenia and Depression Independent Investigator Award, and the Brown Foundation, Inc. This work was supported with resources and the use of facilities at the Michael E. DeBakey VA Medical Center, Houston, Texas. Funding support was also provided by the Brain & Behavior Research Foundation. The author thanks A. Foulkes for assistance in the preparation of the manuscript. Dr. Mathew has been named as an inventor on a pending use patent of ketamine for the treatment of depression. Dr. Mathew has relinquished his claim to any royalties and will not benefit financially if ketamine is approved for this use. Dr. Mathew has received consulting fees or research support from Allergan, AstraZeneca, Bristol-Myers Squibb, Cephalon, Inc., Corcept, Johnson & Johnson, Naurex, Noven, Roche, and Takeda. 1. aan het Rot M, Zarate CA Jr, Charney DS, Mathew SJ (2012): Ketamine for depression: Where do we go from here? Biol Psychiatry 72:537–547. 2. Huang C-C, Wei I-H, Huang C-L, Chen K-T, Tsai M-H, Tsai P, et al. (2012): Inhibition of glycine transporter-1 as a novel mechanism for the treatment of depression. Biol Psychiatry 74:734–741. 3. Javitt DC (2012): Glycine transport inhibitors in the treatment of schizophrenia. Handb Exp Pharmacol 213:367–399. 4. Ji Y, Hebbring S, Zhu H, Jenkins GD (2011): Glycine and a glycine dehydrogenase (GLDC) SNP as citalopram/escitalopram response biomarkers in depression: Pharmacometabolomics-informed pharmacogenomics. Clin Pharmacol Ther 89:97–104. 5. Heresco-Levy U, Gelfin G, Bloch B, Levin R, Edelman S, Javitt DC, Kremer I (2013): A randomized add-on trial of high dose D-cycloserine for treatment-resistant depression. Int J Neuropsychopharmacol 16:501–506. 6. Tsai G, Lane HY, Yang P, Chong MY, Lange N (2004): Glycine transporter 1 inhibitor, N-methylglycine (sarcosine) added to antipsychotics for the treatment of schizophrenia. Biol Psychiatry 55: 452–456. 7. Banerjee A, Ganji S, Hulsey K, Dimitrov I, Maher E, Ghose S, et al. (2012): Measurement of glycine in gray and white matter in the human brain in vivo by H-MRS at 7.0 T. Magn Reson Med 68:325–331. 8. Duman RS, Aghajanian GK (2012): Synaptic dysfunction in depression: Potential therapeutic targets. Science 338:68–72. 9. Woods SW, Walsh BC, Hawkins KA, Miller TJ, Saksa JR, D’Souza DC, et al. (2013): Glycine treatment of the risk syndrome for psychosis: Report of two pilot studies. Eur Neuropsychopharmacol 23:931–940. 10. Shungu DC, Weiduschat N, Murrough JW, Mao X, Pillemer S, Dyke JP, et al. (2012): Increased ventricular lactate in chronic fatigue syndrome. III. Relationships to cortical glutathione and clinical symptoms implicate oxidative stress in disorder pathophysiology. NMR Biomed 25: 1073–1087.
www.sobp.org/journal
Glycine Transporter-I Inhibitors: A New Class of Antidepressant? Sanjay J. Mathew
T
he number of neuropharmacologic mechanisms and molecular 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 psychotomimetic 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 strategy capitalizes on the essential role of alpha-amino-3-hydroxy5-mehtyl-4-isoxazolpropionic acid receptor (AMPAR) activation in the rapid and sustained antidepressant effects of ketamine, although clinical development of AMPAR potentiators or AMPAkines 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 compounds 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 antidepressant benefit. The antidepressant efficacy of DCS in a sample of treatment-resistant patients was recently confirmed in an 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: [email protected]. Received Aug 23, 2013; accepted Aug 26, 2013.
0006-3223/$36.00 http://dx.doi.org/10.1016/j.biopsych.2013.08.019
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 models. The studies included typical acute behavioral screens for antidepressants (forced swim test, tail suspension test) and anxiolytics (elevated plus maze). Of greater translational relevance, 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 consistent 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 antidepressants 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 approximately 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, sarcosine’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
BIOL PSYCHIATRY 2013;74:710–711 Published by Elsevier Inc on behalf of Society of Biological Psychiatry
Commentary control group. The statistical superiority of sarcosine over citalopram would be obscured if the study population showed placebo responsiveness within the usual range observed in modern clinical trials of MDD. Second, the citalopram group had lower than expected response (20%) and remission (5%) rates, and an unusually high dropout rate. These findings could be attributed to an unconventional twice-per-day dosing regimen and the low mean dose of citalopram (27 mg). Especially problematic was a 40% dropout between Weeks 2 and 4 in the citalopram group, compared with only 5% in the sarcosine group. Third, because the initial postrandomization evaluation was only conducted after 2 weeks of treatment, it is not possible to evaluate early onset (i.e., within the first 72 hours) of mood and behavioral effects. This study raises questions regarding dose-response and target engagement. Sarcosine dosing in the clinical trial was flexible, from 500 mg to 1500 mg per day, with a mean dose of 900 mg (SD ¼ 502 mg), which is difficult to reconcile with the dose used in the preclinical chronic experiments (560 mg/kg per day for 21 days). It is unclear whether sarcosine at the 500-mg dose (the dose achieved by Week 2) meaningfully affects brain glycine metabolism because no information was available on glycine levels in cerebrospinal fluid or plasma. Inasmuch as sarcosine and GlyT-1 inhibitors may be associated with an inverted U-shaped dose-response curve due to NMDAR internalization and decreased NMDAR activity at high doses (3), future studies require careful attention to dose and evidence of target engagement. High-affinity GlyT-1 inhibitors reliably are associated with changes in cerebrospinal fluid and brain dialysate glycine levels; glycine measurement in the context of early trials should help characterize pharmacokinetic-pharmacodynamic relationships. Isolation of the glycine resonance by proton spectroscopy is technically challenging because of overlap by stronger resonances and the relatively low brain concentration. However, recent work in human brain has used Gly-optimized in vivo proton spectroscopy at high field strengths (7T), supporting this technique for quantification of regional brain glycine (7). Can we reconcile GlyT-1 inhibition with the antidepressant efficacy of NMDAR antagonist therapies, the common antidepressant effects of which seem “discordant and counterintuitive?” This study does not directly address mechanism, but possibilities may include the following: 1) common mechanisms at non-NMDAR ionotropic AMPAR; 2) common changes in the balance between extrasynaptic NMDARs (in which excessive stimulation is linked with cell death) and synaptic NMDARs (in which stimulation is associated with neuroprotective enhancement), whereby NMDAR agonists act at the synapse and antagonists act extrasynaptically; and 3) induction of synaptogenesis and activation of the mammalian target of rapamycin signaling pathway, which requires activity-dependent release of brain-derived neurotrophic factor (8). Examination of sarcosine’s acute and chronic behavioral effects relative to ketamine and similar agents are essential future studies.
Conclusions Are these data sufficiently compelling to initiate larger investigations of sarcosine and, more generally, GlyT-1 inhibitors? Although the clinical study appears promising, this was a small pilot trial. The ongoing Phase III program of the high-affinity GlyT1 inhibitor RG1678 in schizophrenia will be informative because these trials represent the largest and most comprehensive evaluation of this mechanism in a psychiatric illness. A key unresolved issue for any future program in depression is
BIOL PSYCHIATRY 2013;74:710–711 711 identifying the optimal stage of illness a GlyT-1 inhibitor would be most beneficial. Although ketamine and similar agents have been studied primarily in chronic and treatment-resistant individuals, there is no scientific rationale to restrict the testing of GlyT-1 inhibitors to difficult-to-treat patients if the safety profile is acceptable. Indeed, recent pilot studies of glycine in individuals with risk syndrome for psychosis showed feasibility of NMDA agonist approaches in high-risk individuals (9). Finally, the inherent complexity of the NMDAR must be acknowledged in formulating a rationale drug discovery strategy. In addition to mechanisms described earlier, NMDAR are modulated by glutathione, binding to a redox site, as well as zinc and polyamines (3). We recently reported lowered cortical levels of glutathione in patients with MDD compared with healthy control subjects, suggesting dysregulation in oxidative stress biology in subgroups of depressed individuals (10). How similar depressed patients would respond to a GlyT-1 inhibitor is an interesting unanswered question. Dr. Mathew receives support from the National Institutes of Health/National Institute of Mental Health Grant Nos. RO1MH081870 and R01MH085054, an National Alliance for Research on Schizophrenia and Depression Independent Investigator Award, and the Brown Foundation, Inc. This work was supported with resources and the use of facilities at the Michael E. DeBakey VA Medical Center, Houston, Texas. Funding support was also provided by the Brain & Behavior Research Foundation. The author thanks A. Foulkes for assistance in the preparation of the manuscript. Dr. Mathew has been named as an inventor on a pending use patent of ketamine for the treatment of depression. Dr. Mathew has relinquished his claim to any royalties and will not benefit financially if ketamine is approved for this use. Dr. Mathew has received consulting fees or research support from Allergan, AstraZeneca, Bristol-Myers Squibb, Cephalon, Inc., Corcept, Johnson & Johnson, Naurex, Noven, Roche, and Takeda. 1. aan het Rot M, Zarate CA Jr, Charney DS, Mathew SJ (2012): Ketamine for depression: Where do we go from here? Biol Psychiatry 72:537–547. 2. Huang C-C, Wei I-H, Huang C-L, Chen K-T, Tsai M-H, Tsai P, et al. (2012): Inhibition of glycine transporter-1 as a novel mechanism for the treatment of depression. Biol Psychiatry 74:734–741. 3. Javitt DC (2012): Glycine transport inhibitors in the treatment of schizophrenia. Handb Exp Pharmacol 213:367–399. 4. Ji Y, Hebbring S, Zhu H, Jenkins GD (2011): Glycine and a glycine dehydrogenase (GLDC) SNP as citalopram/escitalopram response biomarkers in depression: Pharmacometabolomics-informed pharmacogenomics. Clin Pharmacol Ther 89:97–104. 5. Heresco-Levy U, Gelfin G, Bloch B, Levin R, Edelman S, Javitt DC, Kremer I (2013): A randomized add-on trial of high dose D-cycloserine for treatment-resistant depression. Int J Neuropsychopharmacol 16:501–506. 6. Tsai G, Lane HY, Yang P, Chong MY, Lange N (2004): Glycine transporter 1 inhibitor, N-methylglycine (sarcosine) added to antipsychotics for the treatment of schizophrenia. Biol Psychiatry 55: 452–456. 7. Banerjee A, Ganji S, Hulsey K, Dimitrov I, Maher E, Ghose S, et al. (2012): Measurement of glycine in gray and white matter in the human brain in vivo by H-MRS at 7.0 T. Magn Reson Med 68:325–331. 8. Duman RS, Aghajanian GK (2012): Synaptic dysfunction in depression: Potential therapeutic targets. Science 338:68–72. 9. Woods SW, Walsh BC, Hawkins KA, Miller TJ, Saksa JR, D’Souza DC, et al. (2013): Glycine treatment of the risk syndrome for psychosis: Report of two pilot studies. Eur Neuropsychopharmacol 23:931–940. 10. Shungu DC, Weiduschat N, Murrough JW, Mao X, Pillemer S, Dyke JP, et al. (2012): Increased ventricular lactate in chronic fatigue syndrome. III. Relationships to cortical glutathione and clinical symptoms implicate oxidative stress in disorder pathophysiology. NMR Biomed 25: 1073–1087.
www.sobp.org/journal