title: Inhibition of glycine transporter-I as a novel mechanism for the treatment of depression.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Psychiatry, China Medical University Hospital, Taichung, Taiwan; Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan.
authors.forename: Chih-Chia
authors.initials: CC
authors.lastname: Huang
authors.forename: I-Hua
authors.initials: IH
authors.lastname: Wei
authors.forename: Chieh-Liang
authors.initials: CL
authors.lastname: Huang
authors.forename: Kuang-Ti
authors.initials: KT
authors.lastname: Chen
authors.forename: Mang-Hung
authors.initials: MH
authors.lastname: Tsai
authors.forename: Priscilla
authors.initials: P
authors.lastname: Tsai
authors.forename: Rene
authors.initials: R
authors.lastname: Tun
authors.forename: Kuo-Hao
authors.initials: KH
authors.lastname: Huang
authors.forename: Yue-Cune
authors.initials: YC
authors.lastname: Chang
authors.forename: Hsien-Yuan
authors.initials: HY
authors.lastname: Lane
authors.forename: Guochuan Emil
authors.initials: GE
authors.lastname: Tsai
mesh_terms: D000328:Adult; D000818:Animals; D000928:Antidepressive Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D018687:Antidepressive Agents, Second-Generation / Q000008:administration & dosage / Q000494:pharmacology; D015283:Citalopram / Q000008:administration & dosage / Q000494:pharmacology; D003863:Depression / Q000188:drug therapy; D003865:Major Depressive Disorder / Q000188:drug therapy*; D004195:Disease Models, Animal; D004311:Double-Blind Method; D005260:Female; D050487:Glycine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D012521:Sarcosine / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000928:Antidepressive Agents; D018687:Antidepressive Agents, Second-Generation; D050487:Glycine Plasma Membrane Transport Proteins; D015283:Citalopram; D012521:Sarcosine
keywords: Anxiety; N-methyl-D-aspartate; elevated plus maze; forced swimming test; glutamate; sarcosine