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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?

Moderate to high quality evidence shows small improvements in negative, positive and total symptoms with adjunctive NMDA modulators compared to adjunctive placebo. For negative symptoms, adjunctive D-serine, N-acetyl-cysteine, and D-alanine were most effective. For positive symptoms, NMDA receptor modulators add-on to non-clozapine antipsychotics were most effective. For total symptoms, adjunctive D-serine, glycine, N-acetyl-cysteine, sarcosine, and D-alanine were most effective.

Moderate quality evidence finds medium to large improvements in negative symptoms with adjunctive memantine compared to placebo, with no significant effects on positive, overall or depressive symptoms, and no differences in adverse effects. Adjunctive memantine may also improve cognitive symptoms. Moderate to low quality evidence finds a small benefit of adjunctive minocycline for overall and negative symptoms, but not for positive or depressive symptoms.

September 2019

Last updated at: 12:33 am, 25th September 2019
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