Targeting glutamate to treat schizophrenia lesson

Authors: Katherine Beck Daniel C Javitt Oliver D Howes

Publish Date: 2016/05/23

Volume: 233, Issue: 13, Pages: 2425-2428

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Abstract

On the face of it the treatment of schizophrenia offers lots of choice there are more than 30 antipsychotic drugs licensed for firstline treatment However as they all essentially use the same common mechanism of action D2 antagonism from a mechanistic perspective there is little choice Howes and Kapur 2009 This is a problem because one third of patients do not respond to standard medications Beck et al 2014 and the drugs have limited efficacy for negative and cognitive symptoms This is not surprising as both treatment resistance and negative and cognitive symptoms seem to involve other neurotransmitter systems Mouchlianitis et al 2015 Therefore there is a need to develop novel treatments targeting other neurotransmittersEmerging evidence suggests a key role for glutamate dysfunction in the pathophysiology of schizophrenia—in particular NmethylDaspartatereceptor NMDAR hypofunction Javitt and Zukin 1991 Coyle 1996 NMDAR antagonists are able to mimic the full range of symptoms seen in schizophrenia Krystal et al 1994 and genetic post mortem and animal studies lend further support to the NMDAR hypothesis This has led to a drive to develop drugs targeting the NMDAR One approach has been to target the NMDAR’s glycine binding site Glycine is required to bind at the same time as glutamate to allow the activation of the NMDAR Kleckner and Dingledine 1988 Increasing glycine occupancy has the potential to increase NMDAR neurotransmission Danysz and Parsons 1998Early clinical trials conducted at single sites found that glycine administered in combination with antipsychotics could reduce negative and cognitive symptoms when compared with antipsychotics alone Javitt et al 1994 HerescoLevy et al 1996 1999 2004 However a multicentre study did not show separation from placebo Buchanan et al 2007 Furthermore glycine does not easily cross the blood–brain barrier necessitating high doses affecting its tolerability Alternative approaches to increasing brain glycine have been sought Of particular interest is the glycine transporter 1 GlyT1 which is postulated to be a key regular of synaptic glycine Supplisson and Bergman 1997A number of GlyT1 inhibitors have been synthesised and trialled However only the HoffmannLa Roche compound bitopertin has reached phase III clinical trials Singer et al 2015 Bitopertin is a selective and potent glycine reuptake inhibitor GRI A phase II proof of concept study of patients with schizophrenia with predominant negative symptoms found that bitopertin at doses of 10 and 30 mg daily moderately reduced negative symptoms Umbricht et al 2014 However this was not significant in the intentiontotreat analysisA clinical trial programme called “SearchLyte” was instigated It consisted of six phase III studies Three of these targeted the drug’s ability to treat patients with persistent negative symptoms The other three studies were designed to determine the drug’s ability to reduce positive symptoms in patients who had not responded to the antipsychotic drugs currently available Two of the trials were discontinued after a futility analysis Singer et al 2015 The remaining trials did not meet their primary endpoints with the exception of the NightLyte study This included patients with a suboptimal response to previous antipsychotics and found that the addition of bitopertin 10 mg significantly improved the Positive and Negative Syndrome Scale PANSS positive factor scoreWhilst the phase III trials focussed on the adjunctive use of bitopertin Roche also completed a phase II/III monotherapy trial BugarskiKirola et al 2014 This included patients with an acute exacerbation of illness and comparisons with both a placebo and an active control group using olanzapine It found a trend for improvement in the total PANSS which was the study’s primary endpoint for both bitopertin 30 mg and olanzapine However this did not significantly differ from placebo for either drug As a result it was considered a failed study Nevertheless bitopertin showed a significant improvement in the PANSS positive subscale score and an increase in readiness for hospital discharge compared to placebo Unfortunately bitopertin is no longer being developed for use as an antipsychoticSimilar problems occurred in the development of mGluR2/3 agonists which act by inhibiting glutamate release Li et al 2015 Despite a promising proof of concept study finding improved positive and negative symptoms after treatment with LY2140023 compared with placebo Patil et al 2007 later trials were unsuccessful One followup multicentre phase II trial was inconclusive with a high placebo response rate Kinon et al 2011 and another phase II openlabel study found LY2140023 was inferior to a comparison atypical antipsychotic Li et al 2015 In August 2012 Eli Lilly announced their decision to stop phase III trials as one of the trials closest to completion failed to meet its primary endpoint Li et al 2015The first possibility of course is that CNS levels of the drugs were inadequate and/or variable between patients and in the case of bitopertin levels of glycine consequently inadequate for therapeutic effects In this issue of Psychopharmacology Hofmann et al 2016 measure plasma and CNS levels of bitopertin and another glycine transporter inhibitor RG7118 They find that bitopertin and RG7118 both exhibit a dosedependent linear relationship between plasma and cerebrospinal fluid glycine concentrations in healthy controls This study confirms bitopertin’s ability to enter the CNS and increase glycine levels Moreover the variability between subjects is relatively low at least for the 30 and 60mg doses As there is no reason to think that patients with schizophrenia will be different in this respect the Hofmann et al 2016 findings seem to rule out failure of bitopertin to reliably enter the CNS and increase glycine levels as an explanation for the inconsistent findings

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