When the drugs don't work: the potential of glutamatergic antipsychotics in schizophrenia

Papanastasiou, Evangelos; Stone, James; Shergill, Sukhwinder S.

doi:10.1192/bjp.bp.112.110999

Cited by 23 publications

(18 citation statements)

References 15 publications

(25 reference statements)

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“…More specifically, variations in corticostriatal association are seen in relation to treatment response in line with recent related findings (Sarpal et al, 2015); and striatonigral dysconnection is identified as a distinct feature of treatment-resistant illness. There is increasing interest in examining glutamatergic treatment options in schizophrenia (Papanastasiou et al, 2013) and elevated glutamate function has been observed in association with treatment resistance (Demjaha et al, 2014). Given recent accounts that the N-methyl-D-aspartate receptor antagonist, ketamine-which disinhibits glutamatergic stimulation of non-NMDA receptors (Moghaddam et al, 1997)-modulates functional connectivity of ventral striatum (Dandash et al, 2014), striatonigral disconnection is a viable mechanism for targeted treatment of refractory schizophrenia.…”

Section: Discussionmentioning

confidence: 99%

Dysfunctional Striatal Systems in Treatment-Resistant Schizophrenia

White

Wigton

Joyce³

et al. 2015

Neuropsychopharmacol

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The prevalence of treatment-resistant schizophrenia points to a discrete illness subtype, but to date its pathophysiologic characteristics are undetermined. Information transfer from ventral to dorsal striatum depends on both striato-cortico-striatal and striato-nigro-striatal subcircuits, yet although the functional integrity of the former appears to track improvement of positive symptoms of schizophrenia, the latter have received little experimental attention in relation to the illness. Here, in a sample of individuals with schizophrenia stratified by treatment resistance and matched controls, functional pathways involving four foci along the striatal axis were assessed to test the hypothesis that treatment-resistant and non-refractory patients would exhibit contrasting patterns of resting striatal connectivity. Compared with non-refractory patients, treatment-resistant individuals exhibited reduced connectivity between ventral striatum and substantia nigra. Furthermore, disturbance to corticostriatal connectivity was more pervasive in treatment-resistant individuals. The occurrence of a more distributed pattern of abnormality may contribute to the failure of medication to treat symptoms in these individuals. This work strongly supports the notion of pathophysiologic divergence between individuals with schizophrenia classified by treatmentresistance criteria.

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Section: Discussionmentioning

confidence: 99%

Dysfunctional Striatal Systems in Treatment-Resistant Schizophrenia

White

Wigton

Joyce³

et al. 2015

Neuropsychopharmacol

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“…Further, based on our present understanding, D 2 blockade forms the foundation of AP efficacy, at least in those who respond to currently available agents [116]. Although efforts continue to develop APs that effect their response through non-D 2 mechanisms [51,117], there are as of yet no such options. This is not to say we have not made gains.…”

Section: Expert Opinionmentioning

confidence: 97%

Emerging drugs for antipsychotic-induced tardive dyskinesia: investigational drugs in Phase II and Phase III clinical trials

Lockwood

Remington

2015

Expert Opinion on Emerging Drugs

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“…Innovative antipsychotic substances with novel mechanisms address the brain's glutamate system [111,112]. Among them, glycine-uptake inhibitors, NMDA receptor coagonists and agonists at the metabotropic glutamate receptors (mGlu) have been focused on [19].…”

Section: Agonists At the Metabotropic Glutamate Receptorsmentioning

confidence: 99%

Glutamatergic agents for schizophrenia: current evidence and perspectives

Zink

Correll

2015

Expert Review of Clinical Pharmacology

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Suboptimal outcomes in schizophrenia are a consequence of lacking insight into the etiology, biomarkers and treatment-relevant subgroups, the therapeutic restriction to dopaminergic-modulating antipsychotics that fail to significantly improve negative and cognitive symptoms, non-adherence, and, in the case of treatment-resistance, the underutilization of clozapine. Evidence suggests additional, extra-dopaminergic abnormalities in amino acid neurotransmission, particularly the glutamatergic system. Antidopaminergic antipsychotics modulate this system on several levels, as do mood stabilizers, including lamotrigine, topiramate and pregabaline. Recently, agonists at metabotropic glutamate receptors and glycine uptake inhibitors failed in large placebo-controlled trials for schizophrenia. Problems to overcome for successfully leveraging glutamatergic agents for schizophrenia are patient selection, focus on positive symptoms and late disease stages, and dose-response relationships. Because glutamate guides processes of brain development and maturation, clinical research should focus on the at-risk mental state or first-episode psychosis, address cognition and negative symptoms and use monotherapy designs in parallel to augmentation strategies.

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When the drugs don't work: the potential of glutamatergic antipsychotics in schizophrenia

Cited by 23 publications

References 15 publications

Dysfunctional Striatal Systems in Treatment-Resistant Schizophrenia

Dysfunctional Striatal Systems in Treatment-Resistant Schizophrenia

Emerging drugs for antipsychotic-induced tardive dyskinesia: investigational drugs in Phase II and Phase III clinical trials

Glutamatergic agents for schizophrenia: current evidence and perspectives

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