The glutamatergic model of schizophrenia followed from the observation that blockade of N-methyl-D-aspartate (NMDA) receptor-gated channels by phencyclidine or ketamine produces symptoms characteristic of schizophrenia.3 Subsequently, convergent support came from animal models, ketamine provocation studies in humans, genetic studies, and postmortem studies. The drugs that were available to test the hypothesis were limited by poor brain penetrance (glycine, D-serine, and D-alanine) or by partial activity (D-cycloserine and sarcosine) and as a group produced mixed results with a tendency for positive effects in early, smaller trials and negative results in later, larger trials.4"6 This lack of consistency may reflect the inherent limitations of these early agents, inadequate dosing, or methodological problems associated with large-scale replication trials such as high placebo response rates, participant heterogeneity, or lack of precision in measures of negative symptoms. The unreliability of clinical trials has also plagued the development of the other leading glutamatergic candidate, LY2140023 monohydrate, anmGlu2/3 agonist that demonstrated significant efficacy in a first trial but was not effective in a subsequent trial in which placebo response was much greater. In addition, unlike first-generation antipsychotics, second-generation antipsychotics may enhance NMDA receptor signaling-positive results with the glycine site agonists came mostly from early studies in which they were combined with first-generation antipsychotics. In short, results have been promising but inconsistent with agents acting at the glycine modulatory site of the NMDA receptor, but a more rigorous test of this approach awaited the arrival of a more suitable compound such as bitopertin.
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