D-Alanine Added to Antipsychotics for the Treatment of Schizophrenia

Department of Psychiatry, Harbor-UCLA Medical Center, Torrance, California 90509, USA.
Biological Psychiatry (Impact Factor: 10.26). 03/2006; 59(3):230-4. DOI: 10.1016/j.biopsych.2005.06.032
Source: PubMed


Hypofunction of the N-methyl-d-aspartate (NMDA) subtype glutamate receptor had been implicated in the pathophysiology of schizophrenia. Treatment with D-serine, glycine, endogenous full agonists of the glycine site of the NMDA receptor (NMDA-glycine site), D-cycloserine, a partial agonist, or sarcosine, a glycine transporter-1 inhibitor, improves the symptoms of schizophrenia. D-alanine is another endogenous agonist of the NMDA-glycine site that might have beneficial effects on schizophrenia.
Thirty-two schizophrenic patients enrolled in a 6-week double-blind, placebo-controlled trial of D-alanine (100 mg/kg/day), which was added to their stable antipsychotic regimens. Measures of clinical efficacy and side effects were determined every other week.
Patint who received D-alanine treatment revealed significant reductions in their Clinical Global Impression Scale and Positive and Negative Syndrome Scale (PANSS) total scores. The Scale for the Assessment of Negative Symptoms and PANSS subscores of positive and cognitive symptoms were improved. D-alanine was well tolerated, and no significant side effect was noted.
The significant improvement with the D-alanine further supports the hypothesis of hypofunction of NMDA neurotransmission in schizophrenia and strengthens the proof of the principle that NMDA-enhancing treatment is a promising approach for the pharmacotherapy of schizophrenia.

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    • "Particular importance is attributed to hypofunction of ionotropic NMDA (N-methyl-D aspartate ) receptor located on inhibitory GABAergic interneurons, morphologically and functionally closely related to glutamatergic neurons (Olney et al., 1999, Carlsson et al., 2000, Murray et al., 2014). NMDA receptor modulators, such as co-agonists (glycine or substances having similar properties, such as D-serine, D-cycloserine and D-alanine) or the glycine transporter inhibitors GlyT-1 (sarcosine, bitopertin, Org 25935), were tested to increase treatment efficacy of schizophrenia glycine (Heresco-Levy et al., 2004, Diaz et al., 2005, Buchanan et al., 2007a), D-serine (Lane et al., 2005, Weiser et al., 2012), D-cycloserine (Goff et al., 2008, Cain et al., 2014), alanine (Tsai et al., 2006), sarcosine (Lane et al., 2010, Amiaz et al., 2015), bitopertin (Bugarski-Kirola et al., 2014), Org 25935 (Schoemaker et al., 2014). The results of these studies, although inconclusive, most indicate beneficial effects of augmentation of antipsychotic therapy, also in the negative and cognitive symptomatology (Buchanan et al., 2007b, Singh and Singh, 2011, Umbricht et al., 2014). "
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    ABSTRACT: This study was undertaken with the purpose to determine if there are changes in metabolic parameters during 6-month add-on treatment with sarcosine in patients with schizophrenia. This was a randomized double blind, placebo-controlled and parallel group study. Eligible participants were randomly assigned to receive 2 g of sarcosine (n=30) or placebo (n=29). Sarcosine was administered as supplementation to the ongoing antipsychotic treatment. Augmentation with sarcosine had no effect on any of the analyzed cardiometabolic parameters. Also, augmentation with sarcosine had no effect on any of the analyzed body composition parameters. This is the first randomized placebo-controlled study to examine the metabolic safety of sarcosine in patients with schizophrenia. Clinically, this observation is of high importance considering how prevalent are metabolic abnormalities in patients with schizophrenia.
    No preview · Article · Sep 2015 · Psychiatry Research
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    • "While dopamine agonists produce positive symptoms , NMDA antagonism also mimics some of the negative symptoms and cognitive deficits. Conversely, upregulation of NMDA function by modulation of the NMDA coagonist glycine (Thomson, 1989) has proven effective clinically in the treatment of individuals with schizophrenia (Krystal et al., 1994; Goff et al., 1999; Heresco-Levy et al., 1999, 2002; Tsai et al., 2006). Thus, regulation of NMDA function may be a critical component of future pharmacological therapies of schizophrenia (Krystal et al., 2009). "
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    ABSTRACT: Genetic variants in DTNBP1 encoding the protein dysbindin-1 have often been associated with schizophrenia and with the cognitive deficits prominent in that disorder. Because impaired function of the hippocampus is thought to play a role in these memory deficits and because NMDAR-dependent synaptic plasticity in this region is a proposed biological substrate for some hippocampal-dependent memory functions in schizophrenia, we hypothesized that reduced dysbindin-1 expression would lead to impairments in NMDAR-dependent synaptic plasticity and in contextual fear conditioning. Acute slices from male mice carrying 0, 1, or 2 null mutant alleles of the Dtnbp1 gene were prepared, and field recordings from the CA1 striatum radiatum were obtained before and after tetanization of Schaffer collaterals of CA3 pyramidal cells. Mice homozygous for the null mutation in Dtnbp1 exhibited significantly reduced NMDAR-dependent synaptic potentiation compared to wild type mice, an effect that could be rescued by bath application of the NMDA receptor coagonist glycine (10 μM). Behavioral testing in adult mice revealed deficits in hippocampal memory processes. Homozygous null mice exhibited lower conditional freezing, without a change in the response to shock itself, indicative of a learning and memory deficit. Taken together, these results indicate that a loss of dysbindin-1 impairs hippocampal plasticity which may, in part, explain the role dysbindin-1 plays in the cognitive impairments of schizophrenia. © 2013 Wiley Periodicals, Inc.
    Full-text · Article · Feb 2014 · Hippocampus
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    • "Clinical trials using glycine as an adjunctive treatment to typical or newer atypical non-clozapine antipsychotics have reported significant improvements in symptoms, with particular efficacy in improving functioning in the cognitive and negative domains [161] [162] [163] [164] [165] [166] [167]. D-serine and D-alanine are also full NMDAR glycine-site agonists, and, like glycine, improved symptoms in patients stabilized on non-clozapine antipsychotics [168] [169] [170]. "
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    ABSTRACT: Over the last 50 years, evidence for central involvement of glutamatergic neurotransmission in the pathophysiology of schizophrenia has accumulated. Recent advances in neuroimaging technology now allow several components of glutamatergic neurotransmission to be assessed in the living human brain. Positron emission tomography (PET) or single photon emission tomography (SPET) in combination with select radiotracers allows visualization of glutamatergic receptors in vivo, and magnetic resonance (MR) - based techniques allow mapping of the effects of glutamatergic agents on regional brain activation, and the measurement of regional glutamate concentrations. These imaging studies have provided evidence for regional glutamatergic abnormalities in psychosis, and are beginning to describe both the evolution of these abnormalities over the course of the illness and their response to therapeutic intervention. In parallel, advances in small animal imaging and the development of animal models have provided a platform to explore the neuropathological consequences of glutamatergic abnormality, and the potential antipsychotic efficacy of novel compounds. The molecular diversity of the glutamatergic system has driven the design of several compounds targeting aspects of glutamatergic transmission, and clinical trials have yielded encouraging results. Here, we review the contribution of imaging studies to date in understanding glutamatergic abnormalities in psychosis, and discuss the potential of new glutamatergic compounds for treatment of the disorder.
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