A Multicenter, Add-On Randomized Controlled Trial of Low-Dose<scp>d</scp>-Serine for Negative and Cognitive Symptoms of Schizophrenia

Weiser, Mark; Heresco-Levy, Uriel; Davidson, Michael; Javitt, Daniel C.; Werbeloff, Nomi; Gershon, Ari A.; Abramovich, Y.; Amital, Daniela; Doron, Adiel; Konas, Shai; Levkovitz, Yehiel; Liba, David; Teitelbaum, Alexander; Mashiach, Mordechai; Zimmerman, Yosef

doi:10.4088/jcp.11m07031

Cited by 91 publications

(63 citation statements)

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“…10,11 However, other studies have not reported significant changes in negative symptoms between glycine, d-serine or d-cycloserine and placebo, and thus were not able to replicate these findings. 12,13 A reason for these inconsistent results may be the considerable hetero geneity among patients with schizophrenia.…”

Section: J Psychiatry Neurosci 2017;42(4)mentioning

confidence: 99%

Glutamatergic deficit and schizophrenia-like negative symptoms: new evidence from ketamine-induced mismatch negativity alterations in healthy male humans

Thiebes

Leicht

Ćurić

et al. 2017

JPN

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Section: J Psychiatry Neurosci 2017;42(4)mentioning

confidence: 99%

Glutamatergic deficit and schizophrenia-like negative symptoms: new evidence from ketamine-induced mismatch negativity alterations in healthy male humans

Thiebes

Leicht

Ćurić

et al. 2017

JPN

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“…The use of D-serine to potentiate NMDA receptormediated neurotransmission has been particularly attractive because it is a more potent allosteric activator than glycine (Mothet et al, 2000), it is more permeable than glycine to the blood-brain barrier (Oldendorf, 1971) and it is not known to affect other neurotransmitter systems. There have been several small clinical studies ranging from 20 to 195 patients where D-serine has been tested in combination with other antipsychotics for the treatment of schizophrenia (Heresco-Levy et al, 2005;Kantrowitz et al, 2010;Lane et al, 2005Lane et al, , 2010Tsai et al, 1998Tsai et al, , 1999Weiser et al, 2012). Patients who have received D-serine have shown improvement in some clinical studies (Heresco-Levy et al, 2005;Kantrowitz et al, 2010;Tsai et al, 1998), whereas in others there was no effect (Lane et al, 2005(Lane et al, , 2010Tsai et al, 1999;Weiser et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

“…There have been several small clinical studies ranging from 20 to 195 patients where D-serine has been tested in combination with other antipsychotics for the treatment of schizophrenia (Heresco-Levy et al, 2005;Kantrowitz et al, 2010;Lane et al, 2005Lane et al, , 2010Tsai et al, 1998Tsai et al, , 1999Weiser et al, 2012). Patients who have received D-serine have shown improvement in some clinical studies (Heresco-Levy et al, 2005;Kantrowitz et al, 2010;Tsai et al, 1998), whereas in others there was no effect (Lane et al, 2005(Lane et al, , 2010Tsai et al, 1999;Weiser et al, 2012). Only one study examined D-serine dose response (30-120 mg/kg/day) and the most improvement was seen at doses ⩾ 60 mg/kg/day (Kantrowitz et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

D-Amino-Acid Oxidase Inhibition Increases D-Serine Plasma Levels in Mouse But not in Monkey or Dog

Rojas

Alt

Ator³

et al. 2015

Neuropsychopharmacol

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D-serine has been shown to improve positive, negative, and cognitive symptoms when used as add-on therapy for the treatment of schizophrenia. However, D-serine has to be administered at high doses to observe clinical effects. This is thought to be due to D-serine undergoing oxidation by D-amino-acid oxidase (DAAO) before it reaches the brain. Consequently, co-administration of D-serine with a DAAO inhibitor could be a way to lower the D-serine dose required to treat schizophrenia. Early studies in rodents to evaluate this hypothesis showed that concomitant administration of structurally distinct DAAO inhibitors with D-serine enhanced plasma and brain D-serine levels in rodents compared with administration of D-serine alone. In the present work we used three potent DAAO inhibitors and confirmed previous results in mice. In a follow-up effort, we evaluated plasma D-serine levels in monkeys after oral administration of D-serine in the presence or absence of these DAAO inhibitors. Even though the compounds reached steady state plasma concentrations exceeding their K i values by 460-fold, plasma D-serine levels remained the same as those in the absence of DAAO inhibitors. Similar results were obtained with dogs. In summary, in contrast to rodents, DAAO inhibition in monkeys and dogs did not influence the exposure to exogenously administered D-serine. Results could be due to differences in D-serine metabolism and/or clearance mechanisms and suggest that the role of DAAO in the metabolism of D-serine is different across species. These data provide caution regarding the utility of DAAO inhibition for patients with schizophrenia.

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“…It has been reported that Zn serves as an endogenous neuromodulator of several important transmitters (19) and this role can be used for explaining its mechanism of action in the improvement of schizophrenia. There is growing the body of evidence implicating glutamatergic system in the pathophysiology of schizophrenia (4,17,18,38). Along with the studies reporting the efficacy of NMDA receptor allosteric agonists at the glycinB site in schizophrenia (4) some scientists have hypothesized the possible efficacy of NMDA antagonists in this disorder (4,39).…”

Section: Discussionmentioning

confidence: 99%

Efficacy of Zinc Sulfate as an Add-on Therapy to Risperidone versus Risperidone Alone in Patients With Schizophrenia: A Double-Blind Randomized Placebo-Controlled Trial

Mortazavi

Farzin

Zarhghami

et al. 2015

Iran J Psychiatry Behav Sci

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Background: Zinc can modulate fast-excitatory transmission, facilitate the release of amino butyric acid and potentiate nicotinic acetylcholine receptors. There are also emerging evidences discussing the implication of these neurotransmitters in pathophysiology of schizophrenia. Objectives: The purpose of this study was to evaluate the efficacy of Zn sulfate as an add-on therapy in the treatment of schizophrenia in a 6-week, double-blind and placebo-controlled trial. Patients and Methods: Eligible participants were 30 inpatients with schizophrenia according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria. Patients were randomly allocated into two equal groups; one group of patients received risperidone 6 mg/day plus capsules of Zn sulfate (each containing 50 mg elemental Zn) three times a day and another group received risperidone 6 mg/day plus placebo. The Positive and Negative Syndrome Scale (PANSS) was applied to assess the psychotic symptoms and aggression risk at baseline, week 2, 4, and 6 of the study. Results:The results of this study showed that both protocols significantly decreased the scores on all subscales of the PANSS and supplemental aggression risk subscale as well as PANSS total score over the study. However, this improvement was significantly higher in Zn sulfate receiving group compared to the placebo group. No major clinical side-effects were detected. Conclusions: It may be concluded that Zn is an effective adjuvant agent in the management of patients with schizophrenia.

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A Multicenter, Add-On Randomized Controlled Trial of Low-Dosed-Serine for Negative and Cognitive Symptoms of Schizophrenia

Abstract: ClinicalTrials.gov identifier: NCT00138775.

Cited by 91 publications

References 0 publications

Glutamatergic deficit and schizophrenia-like negative symptoms: new evidence from ketamine-induced mismatch negativity alterations in healthy male humans

Glutamatergic deficit and schizophrenia-like negative symptoms: new evidence from ketamine-induced mismatch negativity alterations in healthy male humans

D-Amino-Acid Oxidase Inhibition Increases D-Serine Plasma Levels in Mouse But not in Monkey or Dog

Efficacy of Zinc Sulfate as an Add-on Therapy to Risperidone versus Risperidone Alone in Patients With Schizophrenia: A Double-Blind Randomized Placebo-Controlled Trial

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