Glutamate receptor modulators

What are glutamate modulators? 

Antipsychotic medications predominantly target the dopamine neurotransmitter system, with some efficacy for alleviating the positive symptoms of schizophrenia. However, the persistence of negative and cognitive symptoms suggests that other mechanisms are also likely to be involved. The glutamate hypothesis of schizophrenia proposes that reduction of glutamatergic N-methyl-D-aspartate (NMDA) receptor function represents a primary neuropathology in schizophrenia. Therefore, glutamate receptor modulators have been suggested as an adjunctive therapy to standard antipsychotic treatments, when individuals have sub-optimal responses to treatment. The glutamate receptor modulators that have been trialed in schizophrenia are predominantly amino acids, and act on several different aspects of the glutamatergic neurotransmission system. Agents include glycine, D-serine, D-cycloserine, D-alanine, CX516, sarcosine, N-acetyl cysteine, and memantine. These agents have been studied for efficacy in improving symptom severity and cognitive function.

What is the evidence for glutamate modulators?

High quality evidence suggests a medium-sized effect of adjunctive glycine, D-cycloserine, D–serine or CX516 for improving overall and negative symptoms, but no benefit for cognitive function. D-serine is most effective for overall symptoms when added to non-clozapine antipsychotics, and CX516 when added to clozapine. For adjunctive minocycline, there is moderate quality evidence for improving overall and negative symptoms. For adjunctive glycine, there is moderate to low quality evidence of a medium-sized benefit for improved positive and depressive symptoms. For adjunctive D-serine, there is moderate to low quality evidence for a small benefit for improving total psychopathology, negative, cognitive and depressive symptoms. For adjunctive sarcosine, there is moderate to low quality evidence for small to medium improvements in total symptoms, general psychopathology, and negative symptoms. For memantine, there is moderate to low quality evidence a large effect for improving negative symptoms. There is limited (low quality) evidence for the use of D-alanine or N-acetyl cysteine for improving outcomes in schizophrenia. For people with insufficient response to clozapine, moderate quality evidence suggests no improvements with glycine, lamotrigine or topiramate augmentation and low quality evidence is unable to determine any benefits of CX516, D-cycloserine, D-serine or sarcosine augmentation for these patients.

March 2019

Last updated at: 11:51 pm, 20th March 2019
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