Treatment-Resistant Schizophrenia Patients Show Elevated Anterior Cingulate Cortex Glutamate Compared to Treatment-Responsive

Altered Glutamate and Regional Cerebral Blood Flow Levels in Schizophrenia: A 1H-MRS and pCASL study

“…Some off medication studies reported higher levels of glutamatergic metabolites (de la Fuente-Sandoval et al, 2011, 2013a, 2013bKegeles et al, 2012;Kraguljac et al, 2013), whereas others reported reduced or no difference (Goto et al, 2012;Wood et al, 2008). However, higher levels of glutamatergic metabolites do not appear to be specific to the off medication state since several studies reported higher glutamatergic metabolites in medicated patients (Aoyama et al, 2011;Bustillo et al, 2014;Chang et al, 2007;Theberge et al, 2003) and in treatment resistant patients taking medication (Demjaha et al, 2014;Egerton et al, 2012;Mouchlianitis et al, 2016). Finally, a rodent MRS study showed no effect of 6 months antipsychotic treatment on Glu or Gln levels (Bustillo et al, 2006).…”

The quest for biomarkers in Schizophrenia: from neuroimaging to machine learning

“…These findings where replicated in studies comparing treatment-resistant and treatment-responsive patients. Mouchlianitis and colleagues [33] demonstrated, for the first time, that chronically ill patients with treatment-resistant schizophrenia show significantly elevated anterior cingulate cortex glutamate levels when directly compared to treatment-responsive schizophrenia patients. In addition, a recent [18F]-DOPA PET study has found that patients treated with clozapine (treatment-resistant schizophrenia) show lower dopamine synthesis capacity than patients who have responded to first-line treatment [34].…”

“…In addition, a recent [18F]-DOPA PET study has found that patients treated with clozapine (treatment-resistant schizophrenia) show lower dopamine synthesis capacity than patients who have responded to first-line treatment [34]. Based on the findings described above it has been argued that elevated anterior cingulate glutamate may constitute a stable neurobiological trait in treatment-resistant patients, which is preserved after a number of treatment courses with different non-clozapine medications and that the effectiveness of clozapine or novel glutamatergic antipsychotics in treatment-resistant patients might be related to attenuation of glutamatergic dysfunction [33]. To address this question, future studies should use a prospective design, measuring glutamate in medication-naive patients and repeating it when treatment resistance has been determined.…”

Targeting glutamate to treat schizophrenia: lessons from recent clinical studies

“…What is needed is stratification by underlying biology. Genome-wide association studies recently identified a potential association between schizophrenia and variants at GRIN2A (the gene for the NR2A subunit of the NMDAR) (Lencz and Malhotra 2015), and studies using proton magnetic resonance spectroscopy (MRS) have found that patients who do not respond to conventional medications targeting the dopamine system have elevated glutamate levels compared with responders (Egerton et al 2012;Demjaha et al 2014;Mouchlianitis et al 2015). Thus, trials of glutamate targeting drugs could recruit patients with these genetic risk variants and/or glutamate abnormalities on imaging assessment.…”

“…This is a problem because one third of patients do not respond to standard medications (Beck et al 2014), and the drugs have limited efficacy for negative and cognitive symptoms. This is not surprising as both treatment resistance and negative and cognitive symptoms seem to involve other neurotransmitter systems (Mouchlianitis et al 2015). Therefore, there is a need to develop novel treatments targeting other neurotransmitters.…”