Efficacy and safety of the glycine transporter type-1 inhibitor AMG 747 for the treatment of negative symptoms associated with schizophrenia

Dunayevich, Eduardo; Boyer, Robert; Chen, Chao-Yin; Yang, Jun Mo; Nilsen, Jon; Dietrich, Julie; Sun, Hong; Marder, Stephen R.

doi:10.1016/j.schres.2016.10.027

Cited by 29 publications

(17 citation statements)

References 29 publications

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“…The small magnitude change observed with bitopertin is consistent with small magnitude improvements that have been observed with high affinity GlyT1 inhibitors such as such as AMG-747 33 or Org25935 34 . Given our small sample, a potential small effect size change on both symptoms and biomarkers cannot be excluded.…”

Section: Discussionsupporting

confidence: 79%

Neurophysiological Effects of Bitopertin in Schizophrenia

Kantrowitz¹,

Nolan²,

Epstein³

et al. 2017

J Clin Psychopharmacol

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Purpose/Background Deficits in N-methyl-D-aspartate receptor (NMDAR) function contribute to symptoms and cognitive dysfunction in schizophrenia, and are associated with impaired generation of event-related potential (ERP) measures including auditory mismatch negativity (MMN). Parallel studies of the NMDAR agonist D-serine have suggested that sensitivity of these measures to glutamate-based interventions is related to symptomatic and cognitive response. Bitopertin is a selective inhibitor of glycine transport. This study investigates effects of bitopertin on NMDAR-related ERP deficits in schizophrenia. Methods/Procedures Schizophrenia/schizoaffective disorder patients were treated with bitopertin (10 mg, n=29), in a double-blind, parallel group investigation. Auditory MMN served as primary outcome measures. Secondary measures included clinical symptoms and neurocognitive performance. Findings/Results No significant changes were seen with bitopertin for neurophysiological, clinical or neurocognitive assessments. Implications/Conclusions These findings represent the first assessment of the effect of bitopertin on neurophysiological biomarkers. Bitopertin did not significantly affect either symptoms or NMDAR-related biomarkers at the dose tested (10 mg). MMN showed high test-retest reliability, supporting their use as a target engagement measures.

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Section: Discussionsupporting

confidence: 79%

Neurophysiological Effects of Bitopertin in Schizophrenia

Kantrowitz¹,

Nolan²,

Epstein³

et al. 2017

J Clin Psychopharmacol

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“…We analyzed a total of 18 independent DBRCTs (12 academic and 6 industry-funded) from 17 publications, 5,6,8,[29][30][31][32][33][34][35][36][37][38][39][40][41][42] comprising 998 patients with stable SSD and predominant/prominent negative symptoms. The studies assessed the effect of 13 active drugs vs placebo on negative symptoms as primary outcome.…”

Section: Resultsmentioning

confidence: 99%

“…3 Despite the clinical relevance of negative symptoms, many pharmacological treatments so far have shown only statistically significant but not clinically meaningful efficacy in improving this symptomatology relative to placebo. 4 Further, except for some studies with positive results in phase 2, 5,6 most studies investigating new treatment targets, such as glutamatergic compounds, have shown no consistent evidence of negative symptom improvement, 7 especially in patients with predominant or prominent negative symptoms of schizophrenia. 8 Both predominant and prominent negative symptoms constructs identify people with schizophrenia with disabling negative symptoms.…”

Section: Introductionmentioning

confidence: 99%

Predictors of Placebo Response in Pharmacological Clinical Trials of Negative Symptoms in Schizophrenia: A Meta-regression Analysis

Fraguas

Díaz‐Caneja

Pina‐Camacho

et al. 2018

Schizophrenia Bulletin

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We conducted a meta-regression analysis of all double-blind, randomized, placebo-controlled clinical trials (DBRCTs) reporting effects of drug and placebo on negative symptoms in people with stable schizophrenia and predominant or prominent negative symptoms to assess predictors of placebo response in these individuals. We used Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines for systematic reviews and meta-analyses to conduct a systematic literature search to identify DBRCTs assessing treatment efficacy on negative symptoms, as primary outcome, in patients with stable schizophrenia and predominant or prominent negative symptoms. We used Cohen's d, with 95% CIs, as the effect size measure for placebo response, based on negative symptom change scores from baseline to endpoint (range 4 to 24 wk) in the placebo-treated group. We included 18 DBRCTs from 17 publications, assessing the effect of 13 drugs vs placebo on negative symptoms and comprising 998 patients, in the meta-regression analyses. Overall, drugs showed greater efficacy than placebo in reducing negative symptoms, with small effect size (Cohen's d: 0.208, P = .020). Placebo response was significant (P < .001) and clinically relevant (Cohen's d: 2.909), but there was significant heterogeneity and high risk of publication bias. Multivariable meta-regression analyses showed that larger numbers of arms in the trial, larger numbers of study sites and industry sponsorship were significant moderators of placebo response in this population. Our results suggest that some clinical trial design and operational factors affect the level of placebo response in such studies, thus highlighting the need for designs better suited to assess these outcomes.

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“…The involvement of glutamatergic mechanism in SZ has been hypothesized for many years. SZ-relative abnormalities have been well documented in mice with mutations in postsynaptic components of glutamatergic transmission, such as NMDAR [ 35 , 36 ], glycine transporter [ 37 ], and metabotropic glutamate receptor [ 38 ]. The hypofunction of postsynaptic NMDAR on inhibitory neurons that leads to disinhibition of glutamate transmission and glutamate excitotoxicity has formed the bedrock of the glutamate hypothesis of SZ.…”

Section: Discussionmentioning

confidence: 99%

Brain-Specific SNAP-25 Deletion Leads to Elevated Extracellular Glutamate Level and Schizophrenia-Like Behavior in Mice

et al. 2017

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Several studies have associated reduced expression of synaptosomal-associated protein of 25 kDa (SNAP-25) with schizophrenia, yet little is known about its role in the illness. In this paper, a forebrain glutamatergic neuron-specific SNAP-25 knockout mouse model was constructed and studied to explore the possible pathogenetic role of SNAP-25 in schizophrenia. We showed that SNAP-25 conditional knockout (cKO) mice exhibited typical schizophrenia-like phenotype. A significantly elevated extracellular glutamate level was detected in the cerebral cortex of the mouse model. Compared with Ctrls, SNAP-25 was dramatically reduced by about 60% both in cytoplasm and in membrane fractions of cerebral cortex of cKOs, while the other two core members of SNARE complex: Syntaxin-1 (increased ~80%) and Vamp2 (increased ~96%) were significantly increased in cell membrane part. Riluzole, a glutamate release inhibitor, significantly attenuated the locomotor hyperactivity deficits in cKO mice. Our findings provide in vivo functional evidence showing a critical role of SNAP-25 dysfunction on synaptic transmission, which contributes to the developmental of schizophrenia. It is suggested that a SNAP-25 cKO mouse, a valuable model for schizophrenia, could address questions regarding presynaptic alterations that contribute to the etiopathophysiology of SZ and help to consummate the pre- and postsynaptic glutamatergic pathogenesis of the illness.

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Efficacy and safety of the glycine transporter type-1 inhibitor AMG 747 for the treatment of negative symptoms associated with schizophrenia

Cited by 29 publications

References 29 publications

Neurophysiological Effects of Bitopertin in Schizophrenia

Neurophysiological Effects of Bitopertin in Schizophrenia

Predictors of Placebo Response in Pharmacological Clinical Trials of Negative Symptoms in Schizophrenia: A Meta-regression Analysis

Brain-Specific SNAP-25 Deletion Leads to Elevated Extracellular Glutamate Level and Schizophrenia-Like Behavior in Mice

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