Article

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: 10.25). 03/2006; 59(3):230-4. DOI: 10.1016/j.biopsych.2005.06.032
Source: PubMed

ABSTRACT 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.

0 Followers
 · 
123 Views
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    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.
    Hippocampus 02/2014; 24(2):204-13. DOI:10.1002/hipo.22215 · 4.30 Impact Factor
  • Source
    • "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]. "
    [Show abstract] [Hide abstract]
    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.
    Current pharmaceutical biotechnology 01/2012; 13(8):1500-12. DOI:10.2174/138920112800784961 · 2.51 Impact Factor
  • Source
    • "In particular, strategies that target glutamatergic neurotransmission have been showing promising results. These include the supplementation of D-serine, D-cycloserine, D-alanine, or glycine, as well as the modulation of their transporters (Kantrowitz et al., 2010, Cascella et al., 1994, Heresco-Levy et al., 2004, Heresco-Levy and Javitt, 2004, Javitt, 2004, Heresco-Levy et al., 2005, Lane et al., 2005, Lane et al., 2006, Tsai et al., 2006, Javitt, 2008). Although it is not clear from our current data whether L-serine is simply utilized to synthesize D-serine, they suggest the potential of L-serine supplementation for the treatment of patients with schizophrenia. "
    [Show abstract] [Hide abstract]
    ABSTRACT: l-Serine is required for the synthesis of glycine and d-serine, both of which are NMDA receptor co-agonists. Although roles for d-serine and glycine have been suggested in schizophrenia, little is known about the role of the l-serine synthesizing cascade in schizophrenia or related psychiatric conditions. Here we report a patient with schizophrenia carrying a balanced chromosomal translocation with the breakpoints localized to 3q13.12 and 9q21.2. We examined this proband and her son with schizotypal personality disorder for chromosomal abnormalities, molecular expression profiles, and serum amino acids. Marked decrease of l-serine and glutamate was observed in the sera of the patient and her son, compared with those in normal controls. Interestingly, expression of PSAT1 gene, which is located next to the breakpoint and encodes one of the enzymes in the l-serine synthesizing cascade, was reduced in both patient and her son. Direct effect of impaired PSAT1 gene expression on decreased serum l-serine level was strongly implicated by rat astrocyte experiments. In summary, we propose an idea that PSAT1 may be implicated in altered serine metabolism and schizophrenia spectrum conditions.
    Neuroscience Research 10/2010; 69(2):154-60. DOI:10.1016/j.neures.2010.10.003 · 2.15 Impact Factor
Show more