Placebo-Controlled Trial of <scp>d</scp>-Cycloserine Added to Conventional Neuroleptics, Olanzapine, or Risperidone in Schizophrenia

Heresco-Levy, Uriel; Ermilov, Marina; Shimoni, Jonathan; Shapira, Baruch; Silipo, Gail; Javitt, Daniel C.

doi:10.1176/appi.ajp.159.3.480

Cited by 160 publications

(64 citation statements)

References 11 publications

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“…Beneficial effects on negative symptoms were obtained in four trials (6,33,34,47), while four other studies (12,31,32,37) did not find a significant change. Two studies (36,46) with doses of 100 and 250 mg/day showed worsening of negative symptoms.…”

Section: D-cycloserine Added To Conventional Antipsychoticsmentioning

confidence: 78%

“…Ten trials evaluated the addition of D-cycloserine to typical antipsychotics (6,12,(31)(32)(33)(34)36,37,46,47). Seven of them (6,12,31-34,47) did not find any significant change in positive symptoms and two (with higher dosages, namely 100 and 250 mg/day) reported worsening of positive symptoms (36,46).…”

Section: D-cycloserine Added To Conventional Antipsychoticsmentioning

confidence: 99%

“…Four trials evaluated the effect of D-cycloserine added to second-generation antipsychotics (6,31,33,50) and none of them detected any significant change in positive symptoms. Three studies (6,33,50) demonstrated a decrease of negative symptoms at the dose of 50 mg/day.…”

Section: D-cycloserine Added To Second-generation Antipsychoticsmentioning

confidence: 99%

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Glutamate-N-methyl-D-aspartate receptor modulation and minocycline for the treatment of patients with schizophrenia: an update

Chaves

Marque

Trzesniak

et al. 2009

Braz J Med Biol Res

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Section: D-cycloserine Added To Conventional Antipsychoticsmentioning

confidence: 78%

Section: D-cycloserine Added To Conventional Antipsychoticsmentioning

confidence: 99%

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Glutamate-N-methyl-D-aspartate receptor modulation and minocycline for the treatment of patients with schizophrenia: an update

Chaves

Marque

Trzesniak

et al. 2009

Braz J Med Biol Res

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“…One study reported increased expression of G72 in prefrontal cortex [134]. The impressive replications of the association of G72 with the risk for schizophrenia is all the more intriguing, given recently replicated findings that (i) D-serine reduces negative symptoms, improves cognition and reduces positive symptoms in patients with chronic schizophrenia who are receiving concurrent typical antipsychotic medications [135,136] and (ii) that serum and cerebrospinal fluid levels of D-serine are reduced in schizophrenic subjects [40,131].…”

Section: Box 1 Schizophrenia Risk Genes That Affect Transmission At mentioning

confidence: 99%

Circuit-based framework for understanding neurotransmitter and risk gene interactions in schizophrenia

Lisman

Coyle

Green

et al. 2008

Trends in Neurosciences

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Many risk genes interact synergistically to produce schizophrenia and many neurotransmitter interactions have been implicated. We have developed a circuit-based framework for understanding gene and neurotransmitter interactions. NMDAR hypofunction has been implicated in schizophrenia because NMDAR antagonists reproduce symptoms of the disease. One action of antagonists is to reduce the excitation of fast-spiking interneurons, resulting in disinhibition of pyramidal cells. Overactive pyramidal cells, notably those in the hippocampus, can drive a hyperdopaminergic state that produces psychosis. Additional aspects of interneuron function can be understood in this framework, as follows. (i) In animal models, NMDAR antagonists reduce parvalbumin and GAD67, as found in schizophrenia. These changes produce further disinhibition and can be viewed as the aberrant response of a homeostatic system having a faulty activity sensor (the NMDAR). (ii) Disinhibition decreases the power of gamma oscillation and might thereby produce negative and cognitive symptoms. (iii) Nicotine enhances the output of interneurons, and might thereby contribute to its therapeutic effect in schizophrenia.

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“…Nevertheless, it has been observed clinically that these agents (glycine and D-serine) are effective in treatment of schizophrenia when combined with typical or newer atypical antipsychotics, 29 but may be less effective in the presence of clozapine. 30,31 Further, the partial antagonist D-cycloserine significantly improves symptoms of schizophrenia when combined with either typical 32,33 or newer atypical 34,35 antipsychotics, but paradoxically worsens symptoms when combined with clozapine. 36 …”

mentioning

confidence: 99%

Inhibition of System A-mediated glycine transport in cortical synaptosomes by therapeutic concentrations of clozapine: implications for mechanisms of action

et al. 2004

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Clozapine is an atypical antipsychotic with particular efficacy in schizophrenia, possibly related to potentiation of brain N-methyl-D-aspartate receptor (NMDAR) -mediated neurotransmission. NMDARs are regulated in vivo by glycine, which is regulated in turn by glycine transporters. The present study investigates transport processes regulating glycine uptake into rat brain synaptosomes, along with effects of clozapine on synaptosomal glycine transport. Amino-acid uptake of amino acids was assessed in rat brain P2 synaptosomal preparations using a radiotransport assay. Synaptosomal glycine transport was inhibited by a series of amino acids and by the selective System A antagonist MeAIB (2-methylaminoisobutyric acid). Clozapine inhibited transport of both glycine and MeAIB, but not other amino acids, at concentrations associated with preferential clinical response (0.5-1 lg/ml). By contrast, other antipsychotics studied were ineffective. The novel glycine transport inhibitor Further, in meta-analytic studies, clozapine effect sizes are approximately double those of other agents. 4,5 Several theories have been proposed to account for the unique clinical effects of clozapine. These include preferential binding to serotonin (5-HT2A) receptors, 6 D4 selectivity, 7 or weak binding to D2 receptors with fast dissociation kinetics.8 However, these theories propose to account only for the decreased risk of extrapyramidal side effects associated with clozapine and other atypical antipsychotics, not for its preferential efficacy. Other newer atypicals, including risperidone and olanzapine, each share at least some of the above properties with clozapine. While these agents, like clozapine, have reduced risk of EPS, they do not appear to share clozapine's differential therapeutic efficacy, particularly against negative symptoms. Clozapine treatment typically produces trough plasma levels in the range of 0.2-1.2 mg/ml during therapeutic treatment, 9 with preferential response to clozapine being associated with plasma concentrations of approximately 0.5 mg/ml or greater in both cross-sectional 10 and longitudinal 11 studies. Two active metabolites of clozapine, desmethyl clozapine and clozapine-N-oxide, have also been described and

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Placebo-Controlled Trial of d-Cycloserine Added to Conventional Neuroleptics, Olanzapine, or Risperidone in Schizophrenia

Abstract: These data support the efficacy of the addition of 50 mg/day of D-cycloserine to treatment with conventional neuroleptics and suggest that therapeutic benefits may also be attained when D-cycloserine is added to olanzapine or risperidone.

Cited by 160 publications

References 11 publications

Glutamate-N-methyl-D-aspartate receptor modulation and minocycline for the treatment of patients with schizophrenia: an update

Glutamate-N-methyl-D-aspartate receptor modulation and minocycline for the treatment of patients with schizophrenia: an update

Circuit-based framework for understanding neurotransmitter and risk gene interactions in schizophrenia

Inhibition of System A-mediated glycine transport in cortical synaptosomes by therapeutic concentrations of clozapine: implications for mechanisms of action

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