Altered glutamatergic response and functional connectivity in treatment resistant schizophrenia: the effect of riluzole and therapeutic implications

Toby Pillinger,Pamela Hathway,Maria Rogdaki,Oliver D Howes,Alice Egerton,Robert A Mccutcheon

doi:10.1007/s00213-019-5188-5

Toby Pillinger, Pamela Hathway + Show 4 more

Open Access

https://doi.org/10.1007/s00213-019-5188-5

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Abstract

RationaleAnterior cingulate cortex (ACC) glutamatergic abnormalities are reported in treatment-resistant schizophrenia (TRS) and implicated in functional dysconnectivity and psychopathology. Preclinical evidence indicates riluzole reduces synaptic glutamate. However, it is unknown whether riluzole can modulate glutamate metabolite levels and associated functional connectivity in TRS.ObjectivesTo examine the relationship between glutamatergic function and cortical connectivity and determine if riluzole can modulate glutamate metabolite levels and cortical functional connectivity in TRS.MethodsNineteen TRS patients and 18 healthy volunteers (HV) underwent magnetic resonance imaging consisting of MR spectroscopy measuring ACC glutamate plus glutamine (Glx), fMRI measuring resting ACC-functional connectivity, and arterial spin labelling measuring regional cerebral blood flow (rCBF), and clinical measures. They then received 50 mg riluzole twice daily for 2 days when imaging was repeated.ResultsBaseline (pre-riluzole) Glx levels were correlated directly with negative symptom severity (r = 0.49; p = 0.03) and inversely with verbal learning in TRS (r = − 0.63; p = 0.002), but not HV (r = − 0.24; p = 0.41). Connectivity between the ACC and anterior prefrontal cortex (aPFC) was correlated with verbal learning in TRS (r = 0.49; p = 0.04), but not HV (r = 0.28; p = 0.33). There was a significant group × time interaction effect on Glx levels (p < 0.05) and on ACC connectivity to the aPFC (p < 0.05, FWE-corrected). Riluzole decreased Glx and increased ACC-aPFC connectivity in TRS relative to HV. Change in Glx correlated inversely with change in ACC-aPFC connectivity in TRS (r = − 0.52; p = 0.02) but not HV (r = 0.01; p = 0.98). Riluzole did not alter rCBF (p > 0.05), indicating absence of a non-specific blood flow effect.ConclusionResults indicate glutamatergic function and cortical connectivity are linked to symptoms and cognitive measures and that it is possible to pharmacologically modulate them in TRS.

Highlights

Schizophrenia has a worldwide lifetime prevalence of approximately 1% (McGrath et al 2008)
Metaanalysis of in vivo magnetic resonance spectroscopy (MRS) studies has shown an elevation in glutamate plus glutamine (Glx) across several brain regions in schizophrenia (Merritt et al 2016), with some, not all, studies observing that the magnitude of regional glutamate alterations correlates with the severity of negative and cognitive symptoms (Merritt et al 2013)
Treatment-resistant schizophrenia was defined as presence of at least one positive and one negative symptom rated as ≥ 4 on the Positive and Negative Syndrome Scale (PANSS) (Kay et al 1987), indicative of at least moderate severity, and a score of < 60 on the Global Assessment of Functioning scale (GAF) (APA 2013) indicative of at least moderate functional impairment, despite 2 trials of an antipsychotic

Summary

Introduction

Schizophrenia has a worldwide lifetime prevalence of approximately 1% (McGrath et al 2008). Approximately two-thirds of patients with schizophrenia show a suboptimal symptomatic response to standard antipsychotic administration, which all target dopamine D2 receptors (Howes et al 2017; Meltzer 1997). The N-methyl-D-aspartate receptor (NMDAR) hypofunction model of schizophrenia proposes that dysfunction of NMDARs on parvalbumin-containing γaminobutyric acid–ergic interneurons results in disinhibition of excitatory pyramidal cells leading to an increase in glutamatergic activity (Lisman et al 2008; Olney and Farber 1995; Stone et al 2007). Administration of the NMDAR antagonist ketamine increases glutamatergic metabolites in the frontal cortex (Moghaddam et al 1997; Stone et al 2012); induces mental experiences characteristic of positive, negative, and cognitive symptoms of schizophrenia in healthy volunteers; and exacerbates psychotic symptoms in patients with schizophrenia (Cheng et al 2018; Javitt and Zukin 1991). Metaanalysis of in vivo magnetic resonance spectroscopy (MRS) studies has shown an elevation in glutamate plus glutamine (Glx) across several brain regions in schizophrenia (Merritt et al 2016), with some, not all, studies observing that the magnitude of regional glutamate alterations correlates with the severity of negative and cognitive symptoms (Merritt et al 2013)

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