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

Abstract

Rationale Anterior 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. Objectives To examine the relationship between glutamatergic function and cortical connectivity and determine if riluzole can modulate glutamate metabolite levels and cortical functional connectivity in TRS. Methods Nineteen 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. Results Baseline (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. Conclusion Results indicate glutamatergic function and cortical connectivity are linked to symptoms and cognitive measures and that it is possible to pharmacologically modulate them in TRS. Electronic supplementary material The online version of this article (10.1007/s00213-019-5188-5) contains supplementary material, which is available to authorized users.

Dopamine and glutamate in schizophrenia: biology, symptoms and treatment

“…Riluzole (2‐amino‐6‐trifluormethoxy benzothiazole) has also been shown to reduce synaptic glutamate levels through a wide range of mechanisms, and an initial trial found it to be effective in treating negative symptoms in schizophrenia, potentially by altering striatocortical connectivity. Similarly, lamotrigine inhibits glutamate release via inhibition of several ion channels, and attenuates the psychotomimetic effects of ketamine.…”

Hippocampal Hyperactivity as a Druggable Circuit-Level Origin of Aberrant Salience in Schizophrenia

“…A further relevant compound is the glutamate-release inhibitor riluzole ( de Boer et al, 2019 ) [although see ( da Silva et al, 2003 )]. Riluzole was effective in decreasing glutamate/glutamine (Glx) levels in anterior cingulate cortex (hippocampus was not reported) in treatment-resistant patients with schizophrenia, in whom Glx-levels also correlated with negative and cognitive symptoms ( Pillinger et al, 2019 ). Furthermore, riluzole-treatment was effective in reducing negative symptoms in patients with schizophrenia in a small-scale clinical trial ( Farokhnia et al, 2014 ).…”

Evaluation of NDEL1 oligopeptidase activity in blood and brain in an animal model of schizophrenia: effects of psychostimulants and antipsychotics

“…Interestingly, the drug of choice for treating TRS patients is the atypical antipsychotic clozapine (which also acts on serotonin pathways), as these patients usually are not responsive to treatment with typical antipsychotics (which mainly act on dopamine pathways) 27 , 28 . Studies have indicated that TRS may be particularly linked to aberrant neurodevelopment, as impaired cortical and striatal functional connectivity was observed in TRS 28 – 30 . In addition, we have also reported significant differences in NDEL1 enzyme activity between antipsychotic naïve first-episode psychosis (FEP) patients compared to HCs after treatment with risperidone, with a progressive decrease in NDEL1 activity observed during 2 months and/or 1 year of treatment with (atypical antipsychotic) risperidone, during which a significant improvement of symptoms was observed in all patients, with significant positive correlation observed between NDEL1 activity decrease and these symptoms amelioration, as assessed by PANSS 31 .…”