One curious feature of the study was that the group of patients on placebo showed no improvement during the trial duration, whereas it is usual for improvement in symptomatology to be seen in patients in clinical trials on both placebo and active drug. A subsequent phase II trial of LY2140023 was reported by Lilly to be ‘inconclusive’ due to a large placebo response, with neither LY2140023 nor olanzapine showing a significant improvement over placebo. They also reported that Inhibitors,research,lifescience,medical convulsions

occurred in 3 out of the 669 patients recruited [Kinon et al. 2010]. The study has not been published in full, and it is not clear whether Lilly plan to pursue further trials using this prodrug. It has been suggested that mGlu2/3 agonists may work primarily through dopaminergic mechanisms [Seeman and Guan, 2009]. However, recent work reveals that the efficacy of mGlu2/3 agonists to block the effects of amphetamine, ketamine and PCP are lost in mGlu2/3 knockout mice [Fell et al. 2009]. Inhibitors,research,lifescience,medical It is possible that mGlu2/3 agonists may have downstream effects reducing D2High expression [Seeman et al. 2009]. Further studies of LY404039, LY2140023 and related compounds are

awaited. Topiramate, an antiepileptic Inhibitors,research,lifescience,medical drug with AMPA antagonist properties has been found to be effective as an adjunctive therapy in treatment-resistant patients with schizophrenia [Tiihonen et al. 2005], and to reduce the effects of MK-801 in rats [Deutsch

et al. 2002], although it is possible that these effects of topiramate may occur through enhancement of Inhibitors,research,lifescience,medical GABA MAPK inhibitor transmission, as AMPA antagonism Inhibitors,research,lifescience,medical only occurs at higher concentrations [Gibbs et al. 2000]. Other mechanisms The antibiotic minocycline has, somewhat unexpectedly, been shown to inhibit the effects of NMDA receptor antagonism by MK-801 on rats [Levkovitz et al. 2007; Zhang et al. 2007], and to reverse PCP-induced cognitive deficits [Fujita et al. 2008]. A double-blind, randomized controlled trial of minocycline as add-on treatment in patients with early phase schizophrenia (within the first 5 years of diagnosis) revealed a significant effect on negative and cognitive symptoms [Levkovitz et al. 2010]. Although the exact mechanism of action for minocycline in below schizophrenia has still to be ascertained, it is possible that its effect arises through the inhibition of glutamate excitotoxicity (mediated via nitric oxide) by blocking p38 MAP kinase and c-jun N-terminal kinase (mitogen-activated protein kinases responsive to stress stimuli that regulate cellular functions including neurodegeneration, apoptosis, cell differentiation and proliferation) [Pi et al. 2004; Wilkins et al. 2004].