Glutamatergic Neurometabolites in Clozapine-Responsive and -Resistant Schizophrenia

Abstract

Background:According to the current schizophrenia treatment guidelines, 3 levels of responsiveness to antipsychotic medication exist: those who respond to first-line antipsychotics, those with treatment-resistant schizophrenia who respond to clozapine, and those with clozapine-resistant or ultra-treatment resistant schizophrenia. Proton magnetic resonance spectroscopy studies indicate that antipsychotic medication decreases glutamate or total glutamate + glutamine in the brains of patients with schizophrenia and may represent a biomarker of treatment response; however, the 3 levels of treatment responsiveness have not been evaluated.Methods:Proton magnetic resonance spectroscopy spectra were acquired at 3 Tesla from patients taking a second generation non-clozapine antipsychotic (first-line responders), patients with treatment-resistant schizophrenia taking clozapine, patients with ultra-treatment resistant schizophrenia taking a combination of antipsychotics, and healthy comparison subjects.Results:Group differences in cerebrospinal fluid-corrected total glutamate + glutamine levels scaled to creatine were detected in the dorsolateral prefrontal cortex [df(3,48); F = 3.07, P = .04, partial η2 = 0.16] and the putamen [df(3,32); F = 2.93, P = .05, partial η2 = 0.22]. The first-line responder group had higher dorsolateral prefrontal cortex total glutamate + glutamine levels scaled to creatine than those with ultra-treatment resistant schizophrenia [mean difference = 0.25, standard error = 0.09, P = .04, family-wise error-corrected]. Those with treatment-resistant schizophrenia had higher total glutamate + glutamine levels scaled to creatine in the putamen than the first-line responders (mean difference = 0.31, standard error = 0.12, P = .05, family-wise error-corrected) and those with ultra-treatment-resistant schizophrenia (mean difference = 0.39, standard error = 0.12, P = .02, family-wise error-corrected).Conclusions:Total glutamate + glutamine levels scaled to creatine in the putamen may represent a marker of response to clozapine. Future studies should investigate glutamatergic anomalies prior to clozapine initiation and following successful treatment.

Rapid detection of alteration of serum IgG in patients with schizophrenia after risperidone treatment by matrix‐assisted laser desorption ionization/time‐of‐flight mass spectrometry

“…In 2013, Nakagawa et al reported that transthyretin has the potential to be a treatment‐responsive biomarker for schizophrenia . In 2015, another study by Goldstein et al showed that total glutamate plus glutamine levels scaled to creatine in the putamen could represent a marker of response to antipsychotic medication . The present study has found that the IgG can potentially be a treatment response biomarker for schizophrenia.…”

Is treatment-resistant schizophrenia categorically distinct from treatment-responsive schizophrenia? a systematic review

“…All report controlling for basic demographics like age and sex but only three [17, 18, 27] report controlling for other confounders such as ethnicity, weight and smoking.…”

“…Medication status or history was not reported. Goldstein et al [27] performed a MRS study in 31 New Zealand patients (16 resistant, 15 responsive), acquiring data in the putamen, dorsolateral prefrontal cortex (DLPFC) and ACC. In contrast to Demjaha et al, they found no group differences in glutamate, NAA or choline.…”

“…Together these studies suggest that elevated ACC glutamate may associate with poor antipsychotic response. However, Goldstein et al [27], found no group differences in glutamate in the ACC, although glutamate plus glutamine (Glx) was elevated in the putamen in the treatment-resistant compared to responsive group, with the responsive group appearing equivalent to healthy volunteers. When subdividing within treatment-resistant patients this elevated Glx was specific to those who responded to clozapine, and not demonstrated in ultra-treatment resistant patients, suggesting a role in clozapine’s efficacy.…”

“…The study of Demjaha et al, also reported lower concentrations of NAA, generally viewed as a marker of neuronal integrity, in the ACC of treatment responsive compared to treatment-resistant patients [18]; however, this finding has not been replicated in other studies [20, 27]. …”