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

      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.

      Key Words

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      Linked Article

      • 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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