Inhibition of Glycine Transporter-I as a Novel Mechanism for the Treatment of Depression


      Antidepressants, aiming at monoaminergic neurotransmission, exhibit delayed onset of action, limited efficacy, and poor compliance. Glutamatergic neurotransmission is involved in depression. However, it is unclear whether enhancement of the N-methyl-D-aspartate (NMDA) subtype glutamate receptor can be a treatment for depression.


      We studied sarcosine, a glycine transporter-I inhibitor that potentiates NMDA function, in animal models and in depressed patients. We investigated its effects in forced swim test, tail suspension test, elevated plus maze test, novelty-suppressed feeding test, and chronic unpredictable stress test in rats and conducted a 6-week randomized, double-blinded, citalopram-controlled trial in 40 patients with major depressive disorder. Clinical efficacy and side effects were assessed biweekly, with the main outcomes of Hamilton Depression Rating Scale, Global Assessment of Function, and remission rate. The time course of response and dropout rates was also compared.


      Sarcosine decreased immobility in the forced swim test and tail suspension test, reduced the latency to feed in the novelty-suppressed feeding test, and reversed behavioral deficits caused by chronic unpredictable stress test, which are characteristics for an antidepressant. In the clinical study, sarcosine substantially improved scores of Hamilton Depression Rating Scale, Clinical Global Impression, and Global Assessment of Function more than citalopram treatment. Sarcosine-treated patients were much more likely and quicker to remit and less likely to drop out. Sarcosine was well tolerated without significant side effects.


      Our preliminary findings suggest that enhancing NMDA function can improve depression-like behaviors in rodent models and in human depression. Establishment of glycine transporter-I inhibition as a novel treatment for depression waits for confirmation by further proof-of-principle studies.

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        • Kessler R.C.
        • McGonagle K.A.
        • Zhao S.
        • Nelson C.B.
        • Hughes M.
        • Eshleman S.
        • et al.
        Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States. Results from the National Comorbidity Survey.
        Arch Gen Psychiatry. 1994; 51: 8-19
        • American Psychiatric Association
        Diagnostic and Statistical Manual of Mental Disorders. 4th ed. American Psychiatric Association, Washington, DC1994 (1994)
        • Keller M.B.
        • Lavori P.W.
        • Muller T.I.
        • Endicott J.
        • Coryell W.
        • Hirschfeld R.M.
        • et al.
        Time to recovery, chronicity, and levels of psychopathology in major depression: A 5-year prospective follow-up of 431 subjects.
        Arch Gen Psychiatry. 1992; 49: 809-816
        • Crane G.E.
        Cycloserine as an antidepressant agent.
        Am J Psychiatry. 1959; 115: 1025-1026
        • Epstein I.G.
        • Nair K.G.S.
        • Boy L.G.
        The treatment of human tuberculosis with cycloserine.
        Prog Rep Dis Chest. 1955; 29: 241-257
        • Heresco-Levy U.
        • Javitt D.C.
        • Ermilov M.
        • Mordel C.
        • Silipo G.
        • Lichtenstein M.
        Efficacy of high-dose glycine in the treatment of enduring negative symptoms of schizophrenia.
        Arch Gen Psychiatry. 1999; 56: 29-36
        • Tsai G.E.
        • Lane H.Y.
        • Yang P.
        • Chong M.Y.
        • Lange N.
        Glycine transporter I inhibitor, N-methylglycine (sarcosine), added to antipsychotics for the treatment of schizophrenia.
        Biol Psychiatry. 2004; 55: 452-456
        • Lane H.Y.
        • Chang Y.C.
        • Liu Y.C.
        • Chiu C.C.
        • Tsai G.E.
        Sarcosine or D-serine add-on treatment for acute exacerbation of schizophrenia: a randomized, double-blind, placebo-controlled study.
        Arch Gen Psychiatry. 2005; 62: 1196-1204
        • Tsai G.E.
        • Lin P.Y.
        Strategies to enhance N-methyl-D-aspartate receptor-mediated neurotransmission in schizophrenia, a critical review and meta-analysis.
        Curr Pharm Des. 2010; 16: 522-537
        • Depoortère R.
        • Dargazanli G.
        • Estenne-Bouhtou G.
        • Coste A.
        • Lanneau C.
        • Desvignes C.
        • et al.
        Neurochemical, electrophysiological and pharmacological profiles of the selective inhibitor of the glycine transporter-1 SSR504734, a potential new type of antipsychotic.
        Neuropsychopharmacology. 2005; 30: 1963-1985
        • Malkesman O.
        • Austin D.R.
        • Tragon T.
        • Wang G.
        • Rompala G.
        • Hamidi A.B.
        • et al.
        Acute d-serine treatment produces antidepressant-like effects in rodents.
        Int J Neuropsychopharmacol. 2011; 12: 1-14
        • Beneyto M.
        • Meador-Woodruff J.H.
        Lamina-specific abnormalities of NMDA receptor-associated postsynaptic protein transcripts in the prefrontal cortex in schizophrenia and bipolar disorder.
        Neuropsychopharmacology. 2008; 33: 2175-2186
        • Nowak G.
        • Ordway G.A.
        • Paul I.A.
        Alterations in the N-methyl-D-aspartate (NMDA) receptor complex in the frontal cortex of suicide victims.
        Brain Res. 1995; 675: 157-164
        • Kugaya A.
        • Sanacora G.
        Beyond monoamines: glutamatergic function in mood disorders.
        CNS Spectr. 2005; 10: 808-819
        • Zarate Jr, C.A.
        • Singh J.B.
        • Carlson P.J.
        • Brutsche N.E.
        • Ameli R.
        • Luckenbaugh D.A.
        • et al.
        A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression.
        Arch Gen Psychiatry. 2006; 63: 856-864
        • Diazgranados N.
        • Ibrahim L.
        • Brutsche N.E.
        • Newberg A.
        • Kronstein P.
        • Khalife S.
        • et al.
        A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression.
        Arch Gen Psychiatry. 2010; 67: 793-802
        • American Psychiatric Association
        Structured Clinical Interview for DSM-IV. American Psychiatric Press, Washington, DC1994
        • Hamilton M.
        A rating scale for depression.
        J Neurol Neurosurg Psychiatry. 1960; 23: 56-62
        • Lane H.Y.
        • Huang C.L.
        • Wu P.L.
        • Liu Y.C.
        • Chang Y.C.
        • Lin P.Y.
        • et al.
        Glycine transporter I inhibitor, N-methylglycine (sarcosine), added to clozapine for the treatment of schizophrenia.
        Biol Psychiatry. 2006; 60: 645-649
        • Lane H.Y.
        • Liu Y.C.
        • Huang C.L.
        • Chang Y.C.
        • Liau C.H.
        • Perng C.H.
        • et al.
        Sarcosine (N-methylglycine) treatment for acute schizophrenia: A randomized, double-blind study.
        Biol Psychiatry. 2008; 63: 9-12
        • Lane H.Y.
        • Lin C.H.
        • Huang Y.J.
        • Liao C.H.
        • Chang Y.C.
        • Tsai G.E.
        A randomized, double-blind, placebo-controlled comparison study of sarcosine (N-methylglycine) and D-serine add-on treatment for schizophrenia.
        Int J Neuropsychopharmacol. 2010; 13: 451-460
        • Frank E.
        • Prien R.F.
        • Jarrett R.B.
        • Keller M.B.
        • Kupfer D.J.
        • Lavori P.W.
        • et al.
        Conceptualization and rationale for consensus definitions of terms in major depressive disorder: Remission, recovery, relapse, and recurrence.
        Arch Gen Psychiatry. 1991; 48: 851-855
        • Guy W.
        ECDEU Assessment Manual for Psychopharmacology.
        National Institute of Mental Health, Rockville, MD1976
        • Trivedi M.H.
        • Morris D.W.
        • Grannemann B.D.
        • Mahadi S.
        Symptom clusters as predictors of late response to antidepressant treatment.
        J Clin Psychiatry. 2005; 66: 1064-1070
        • Lingjaerde O.
        • Ahlfors U.G.
        • Bech P.
        • Dencker S.J.
        • Elgen K.
        The UKU Side Effect Rating Scale: A new comprehensive rating scale for psychotropic drugs and cross-sectional study of side effects in neuroleptic-treated patients.
        Acta Psychiatr Scand. 1987; 334: 1-100
        • Rodgers R.J.
        • Johnson N.
        Factor analysis of spatiotemporal and ethological measures in the murine elevated plus-maze test of anxiety.
        Pharmacol Biochem Behav. 1995; 52: 297-303
        • Calabrese J.R.
        • Suppes T.
        • Bowden C.L.
        • Sachs G.S.
        • Swann A.C.
        • McElroy S.L.
        • et al.
        A double-blind, placebo-controlled, prophylaxis study of lamotrigine in rapid-cycling bipolar disorder.
        J Clin Psychiatry. 2000; 61: 841-850
        • Hu F.B.
        • Goldberg J.
        • Hedeker D.
        • Flay B.R.
        • Pentz M.A.
        Comparison of population-averaged and subject-specific approaches for analyzing repeated binary outcomes.
        Am J Epidemiol. 1998; 147: 694-703
        • Porsolt R.D.
        • Anton G.
        • Blavet N.
        • Jalfre M.
        Behavioural despair in rats: A new model sensitive to antidepressant treatments.
        Eur J Pharmacol. 1978; 47: 379-391
        • Chen L.
        • Muhlhauser M.
        • Yang C.R.
        Glycine tranporter-1 blockade potentiates NMDA-mediated responses in rat prefrontal cortical neurons in vitro and in vivo.
        J Neurophysiol. 2003; 89: 691-703
        • Varty G.B.
        • Morgan C.A.
        • Cohen-Williams M.E.
        • Coffin V.L.
        • Carey G.J.
        The gerbil elevated plus-maze, I: Behavioral characterization and pharmacological validation.
        Neuropsychopharmacology. 2002; 27: 357-370
        • Cryan J.F.
        • Markou A.
        • Lucki I.
        Assessing antidepressant activity in rodents: Recent developments and future needs.
        Trends Pharmacol Sci. 2002; 23: 238-245
        • Maeng S.
        • Zarate Jr, C.A.
        • Du J.
        • Schloesser R.J.
        • McCammon J.
        • Chen G.
        • et al.
        Cellular mechanisms underlying the antidepressant effects of ketamine: Role of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors.
        Biol Psychiatry. 2008; 63: 349-352
        • Zarate Jr, C.
        • Machado-Vieira R.
        • Henter I.
        • Ibrahim L.
        • Diazgranados N.
        • Salvadore G.
        Glutamatergic modulators: the future of treating mood disorders?.
        Harv Rev Psychiatry. 2010; 18: 293-303
        • Breedlove S.M.
        • Watson N.V.
        • Rosenzweig M.R.
        Learning and memory.
        In: Biological Psychology: An Introduction to Behavioral, Cognitive, and Clinical Neuroscience. 6th ed. Sinauer Associates, Inc., Sunderland, MA2010 (536–539)
        • Hardingham G.E.
        • Bading H.
        Synaptic versus extrasynaptic NMDA receptor signalling: Implications for neurodegenerative disorders.
        Nat Rev Neurosci. 2010; 11: 682-696
        • Sreekumar A.
        • Poisson L.M.
        • Rajendiran T.M.
        • Khan A.P.
        • Cao Q.
        • Yu J.
        • et al.
        Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression.
        Nature. 2009; 457: 910-914
        • Jentzmik F.
        • Stephan C.
        • Miller K.
        • Schrader M.
        • Erbersdobler A.
        • Kristiansen G.
        • et al.
        Sarcosine in urine after digital rectal examination fails as a marker in prostate cancer detection and identification of aggressive tumours.
        Eur Urol. 2010; 58: 12-18
        • Struys E.A.
        • Heijboer A.C.
        • van Moorselaar J.
        • Jakobs C.
        • Blankenstein M.A.
        Serum sarcosine is not a marker for prostate cancer.
        Ann Clin Biochem. 2010; 47: 282
        • Pavlou M.
        • Diamandis E.P.
        The search for new prostate cancer biomarkers continues.
        Clin Chem. 2009; 55: 1277-1279
        • Tsai G.
        • Yang P.
        • Chung L.
        • Lange N.
        • Coyle J.T.
        D-serine added to antipsychotic for the treatment of schizophrenia.
        Biol Psychiatry. 1998; 44: 1081-1089
        • Tsai G.
        • Yang P.
        • Chang Y.
        • Chong M.
        D-alanine added to antipsychotics for the treatment of schizophrenia.
        Biol Psychiatry. 2006; 59: 230-234
        • Rutherford B.R.
        • Sneed J.R.
        • Roose S.P.
        Does differential drop-out explain the influence of study design on antidepressant response? A meta-analysis.
        J Affect Disord. 2012; 140: 57-65
        • Stahl S.M.
        Placebo-controlled comparison of the selective serotonin reuptake inhibitors citalopram and sertraline.
        Biol Psychiatry. 2000; 48: 894-901
        • Cipriani A.
        • Furukawa T.A.
        • Salanti G.
        • Geddes J.R.
        • Higgins J.P.
        • Churchill R.
        • et al.
        Comparative efficacy and acceptability of 12 new-generation antidepressants: A multiple-treatments meta-analysis.
        Lancet. 2009; 373: 746-758
        • Yu B.N.
        • Chen G.L.
        • He N.
        • Ouyang D.S.
        • Chen X.P.
        • Liu Z.Q.
        • et al.
        Pharmacokinetics of citalopram in relation to genetic polymorphism of CYP2C19.
        Drug Metab Dispos. 2003; 31: 1255-1259
        • Hsu J.W.
        • Su T.P.
        • Huang C.Y.
        • Chen Y.S.
        • Chou Y.H.
        Fast onset of antidepressant effects of citalopram compared with sertraline in drug-naïve first-episode major depressive disorder in a Chinese population: A 6-week double-blind, randomized comparative study.
        J Clin Psychopharmacol. 2010; 31: 577-581
        • Lin C.H.
        • Lin S.H.
        • Jang F.L.
        Adjunctive low-dose aripiprazole with standard-dose sertraline in treating fresh major depressive disorder: A randomized, double-blind, controlled study.
        J Clin Psychopharmacol. 2011; 31: 563-568
        • Hohmann A.A.
        Gender bias in psychotropic drug prescribing in primary care.
        Med Care. 1989; 27: 478-490
        • Salvadore G.
        • Cornwell B.R.
        • Colon-Rosario V.
        • Coppola R.
        • Grillon C.
        • Zarate Jr, C.A.
        • et al.
        Increased anterior cingulate cortical activity in response to fearful faces: A neurophysiological biomarker that predicts rapid antidepressant response to ketamine.
        Biol Psychiatry. 2009; 65: 289-295
        • Kundermann B.
        • Hemmeter-Spernal J.
        • Strate P.
        • Gebhardt S.
        • Huber M.T.
        • Krieg J.C.
        • et al.
        Pain sensitivity in major depression and its relationship to central serotoninergic function as reflected by the neuroendocrine response to clomipramine.
        J Psychiatr Res. 2009; 43: 1253-1261

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      • Glycine Transporter-I Inhibitors: A New Class of Antidepressant?
        Biological PsychiatryVol. 74Issue 10
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          The 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.
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