Consistent with its

action as a partial agonist, an initial dose-finding study with D-cycloserine added on to conventional neuroleptics reported a U-shaped doseresponse curve with an intermediate dose that improved negative as well as cognitive symptoms.78 Given that the GMS is not saturated in vivo, one might speculate that a partial agonist would augment the activity of the NMDA receptor up to a point and then actually begin to compete with the endogenous agonist. Furthermore, this point of inflection Inhibitors,research,lifescience,medical in the nature of the D-cylcoserine effect may vary depending on the individual patient’s level of GMS saturation. D-cylcoserine may in any case be an impractical approach for prolonged treatment, as NMDA receptor desensitization has been observed with chronic administration.79 The apparent lack of consistent success of D-cycloserine use in schizophrenia Inhibitors,research,lifescience,medical stands in contrast to the positive results observed with it in extinction therapy for specific phobias. The extinction of a conditioned fear memory is an NMDA-dependent process,80 which can be enhanced by positive modulation of the GMS.81,82 D-cycloserine has been effective in treating acrophobia in combination of a virtual reality-based cognitive behavioral therapy83,84 Thus, a key difference between the

successful application of Inhibitors,research,lifescience,medical D-cycloserine in anxiety disorders and the unsuccessful Inhibitors,research,lifescience,medical application in schizophrenia may be that the

in the former it is used acutely or subchronically as an adjunct to concomitant activation of specific brain circuitry related to specific fear or phobia. Cediranib D-serine itself is a potential therapy, as it has been shown in rodents to be relatively efficient at crossing the blood-brain barrier upon peripheral administration compared to glycine,85 and can persist in cortex thereafter.86 In contrast to other GMS agonists, there is direct indication that D-serine is affected in schizophrenia, as it is decreased in CSF69 and serum from patients.68 The significant effects of D-serine on total psychopathology, Inhibitors,research,lifescience,medical negative symptoms, and cognitive symptoms found found in the Tsai and Lin74 meta-analysis are based only on small trials that tested it as an add-on therapy to typical or atypical antipsychotics. In the case of D-serine as well as other agents, testing in conjunction with typical or atypical antipsychotics may occlude potential effects on positive symptoms, which are relatively well controlled with available antipsychotics. Large Phase II trials of D-serine in schizophrenia and schizophrenia prodrome are currently underway, both as an add-on to antipsychotics and as a monotherapy. An intriguing pattern in the literature on GMS agonists, corroborated by the meta-analysis, is that they are ineffective when combined with clozapine as opposed to other antipsychotics.