A phase II/III trial of bitopertin monotherapy compared with placebo in patients with an acute exacerbation of schizophrenia – Results from the CandleLyte study

Bugarski‐Kirola, Dragana; Wang, A.; Abi‐Saab, Danielle; Blättler, Thomas

doi:10.1016/j.euroneuro.2014.03.007

Cited by 83 publications

(44 citation statements)

References 38 publications

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“…Research from different disciplines such as basic science, epidemiology and clinical studies demonstrates that the main component of oestrogen, oestradiol, has a protective effect in schizophrenia reducing the severity of symptoms, with oestrogen receptors being a potential therapeutic target van Goethem et al, 2015). Gonadal steroids play an important role in cognitive processing and sex differences in cognitive function are found in both animal and human studies (Bugarski-Kirola et al, 2014). It is now well established that cognitive deficits in schizophrenia are an unmet clinical need and that any effects to improve cognition by existing antipsychotic drug therapy or by psychological therapies are small and generally not clinically meaningful ( and Edgar et al, 2014;Huang et al, 2014c; see recent metanalyses of cognitive remediation by Parrott et al, 2014).…”

Section: Sex Matters! In 2011 Kulkarni and Neill Edited A Volume Of Cmentioning

confidence: 97%

A systematic review comparing sex differences in cognitive function in schizophrenia and in rodent models for schizophrenia, implications for improved therapeutic strategies

Léger

Neill

2016

Neuroscience & Biobehavioral Reviews

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Section: Sex Matters! In 2011 Kulkarni and Neill Edited A Volume Of Cmentioning

confidence: 97%

A systematic review comparing sex differences in cognitive function in schizophrenia and in rodent models for schizophrenia, implications for improved therapeutic strategies

Léger

Neill

2016

Neuroscience & Biobehavioral Reviews

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“…However, sarcosine-derived GlyT1 inhibitors produce undesirable side effects, such as hypoactivity and ataxia, and have therefore prompted the development of non-sarcosine-based GlyT1inhibitors. Unfortunately, the noncompetitive GlyT-1 antagonist, bitopertin, which significantly reduced negative symptoms in a Phase-II trial in schizophrenia, failed to reach its endpoints to improve negative symptoms in multicenter Phase II/III trials (Bugarski-Kirola, Wang, Abi-Saab, & Blattler, 2014). One reason for the poor clinical outcomes with this class of drugs could be that inhibiting GlyT1 augments NMDAR function primarily at extra-synaptic receptors as suggested by recent electrophysiological studies (Li et al, 2013; Papouin et al, 2012), thereby undercutting therapeutic effects.…”

Section: Augmenting Nmda Receptor Function To Treat Schizophreniamentioning

confidence: 99%

The NMDA Receptor and Schizophrenia

Balu

2016

Advances in Pharmacology

242

114

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Schizophrenia is a severe mental illness that affects almost 1% of the population worldwide. Even though the etiology of schizophrenia is uncertain, it is believed to be a neurodevelopmental disorder that results from a combination of environmental insults and genetic vulnerabilities. Over the past 20 years, there has been a confluence of evidence from many research disciplines pointing to alterations in excitatory signaling, particularly involving hypofunction of the N-methyl-D-aspartate receptor (NMDAR), as a key contributor to the schizophrenia disease process. This review describes the structure-function relationship of the NMDAR channel and how the glycine modulatory site (GMS) acts as an important regulator of its activity. In addition, this review highlights the genetic, pharmacologic, and biochemical evidence supporting the hypothesis that NMDAR hypofunction contributes to the pathophysiology of schizophrenia. Finally, this chapter highlights some of the most recent and promising pharmacological strategies that are designed to either, directly or indirectly, augment NMDAR function in an effort to treat the cognitive and negative symptoms of schizophrenia that are not helped by currently available medications.

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“…For example, there are recently published studies in which quetiapine [Cutler et al 2010] and olanzapine [Bugarski-Kirola et al 2014;Kinon et al 2011], administered at therapeutic doses, did not separate from placebo on standard efficacy measures.…”

Section: Discussionmentioning

confidence: 99%

A 6-week, double-blind, placebo- and haloperidol-controlled, phase II study of lurasidone in patients with acute schizophrenia

Potkin

Kimura

Guarino

2015

Therapeutic Advances in Psychopharmacology

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Objective: The objective of this study was to evaluate the short-term efficacy and safety of the atypical antipsychotic agent lurasidone in the treatment of schizophrenia. Methods: In this phase II, randomized, double-blind, placebo-controlled study, hospitalized adult patients diagnosed with schizophrenia and experiencing an acute exacerbation of psychotic symptoms were randomly assigned to 6 weeks of fixed-dose lurasidone 20 mg/day ( n = 71), lurasidone 40 mg/day ( n = 67), lurasidone 80 mg/day ( n = 71), haloperidol 10 mg/day ( n = 72, included to test for assay sensitivity), or placebo ( n = 72). Efficacy was assessed using the brief psychiatric rating scale, positive and negative syndrome scale, and clinical global impression-severity. Safety assessments included incidence of adverse events and clinical laboratory measures. Results: Numerical improvement was observed from baseline to week 6 (last observation carried forward) on all efficacy measures in all treatment groups; however, no statistically significant differences were noted between any lurasidone group and placebo, or between haloperidol and placebo. The most common adverse events in lurasidone-treated patients, with an incidence of at least 10% (dose groups combined) and greater than placebo, were sedation (15.3%), dyspepsia (13.4%), nausea (13.4%), akathisia (12.4%), and vomiting (10.5%); for haloperidol, the most common adverse events (incidence ⩾ 10% and greater than placebo) were extrapyramidal disorder (20.8%), sedation (19.4%), akathisia (19.4%), dystonia (15.3%), insomnia (13.9%), and somnolence (12.5%). Lurasidone was associated with minimal changes in weight, metabolic parameters, and prolactin levels. Conclusions: None of the lurasidone groups separated from placebo in this clinical study of patients with acute schizophrenia. In addition, haloperidol, which was included for assay sensitivity, did not separate from placebo, resulting in a failed study. Possible reasons for the lack of assay sensitivity in this study include the use of multiple active treatment arms and the relatively large placebo response. Consistent with other studies, lurasidone was generally safe and well tolerated, with minimal effects on weight or metabolic parameters.

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A phase II/III trial of bitopertin monotherapy compared with placebo in patients with an acute exacerbation of schizophrenia – Results from the CandleLyte study

Cited by 83 publications

References 38 publications

A systematic review comparing sex differences in cognitive function in schizophrenia and in rodent models for schizophrenia, implications for improved therapeutic strategies

A systematic review comparing sex differences in cognitive function in schizophrenia and in rodent models for schizophrenia, implications for improved therapeutic strategies

The NMDA Receptor and Schizophrenia

A 6-week, double-blind, placebo- and haloperidol-controlled, phase II study of lurasidone in patients with acute schizophrenia

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