Magnetic Resonance Imaging in Studying Schizophrenia, Negative Symptoms, and the Glutamate System

Abstract

Schizophrenia is characterized by positive, negative, and cognitive symptoms. While positive symptoms occur periodically during psychotic exacerbations, negative and cognitive symptoms often emerge before the first psychotic episode and persist with low functional outcome and poor prognosis. This review article outlines the importance of modern functional magnetic resonance imaging techniques for developing a stratified therapy of schizophrenic disorders. Functional neuroimaging evidence on the neural correlates of positive and particularly negative symptoms and cognitive deficits in schizophrenic disorders is briefly reviewed. Acute dysregulation of dopaminergic neurotransmission is crucially involved in the occurrence of psychotic symptoms. However, increasing evidence also implicates glutamatergic pathomechanisms, in particular N-methyl-d-aspartate (NMDA) receptor dysfunction in the pathogenesis of schizophrenia and in the appearance of negative symptoms and cognitive dysfunctions. In line with this notion, several gene variants affecting the NMDA receptor’s pathway have been reported to increase susceptibility for schizophrenia, and have been investigated using the imaging genetics approach. In recent years, several attempts have been made to develop medications modulating the glutamatergic pathway with modest evidences for efficacy. The most successful approaches were those that aimed at influencing this pathway using compounds that enhance NMDA receptor function. More recently, the selective glycine reuptake inhibitor bitopertin has been shown to improve NMDA receptor hypofunction by increasing glycine concentrations in the synaptic cleft. Further research is required to test whether pharmacological agents with effects on the glutamatergic system can help to improve the treatment of negative symptoms in schizophrenic disorders.

Predictability of Autism, Schizophrenic and Obsessive Spectra Diagnosis: Toward a Damage Network Approach

“…Thus a common ASD-SCZS spectrum could be hypothesized, with a common overlap with OCD spectrum. Further evidence may implicate a common glutamatergic pathomechanism in ASD and SCZS (Gruber et al, 2014) and this could be the link to a common pharmacological role for medication modulating the glutamatergic pathway (Rojas, 2014).…”

Glutamate-dopamine matters in psychosis

“…They found the prevalence of ADHD medication in children aged 3-18 years in 2010 to be 0·95% in Asia and Australia, 4·48% in North America, 1·95% in northern Europe, and more research is warranted here in light of the positive correlation between anterior cingulate cortex glutamate concentration and symptom severity in a highly powered study of individuals with first-episode psychosis 5 and following a ketamine challenge, 6,7 the systematic evidence for raised MR spectroscopy indices of glutamatergic activity in psychosis, 6 and the preliminary observations suggesting that altered cortical glutamate function might be especially related to negative and cognitive symptom severity. 8 We believe that the interesting association between subcortical dopamine synthesis capacity, cortical glutamate, and psychotic symptoms reported by Jauhar and colleagues 1 warrants new research into the association between in vivo measures of neurotransmitter function and molecular mechanisms. In preclinical models, this could be achieved by a systematic investigation into how candidate mechanisms for psychotic disorders (ie, NMDA receptor hypofunction, GABAergic interneuron dysfunction, or increased striatal dopamine function), together and in isolation, affect assessments of dopamine synthesis capacity measured with 18F-L-dihydroxyphenylalanine (18F-DOPA) and glutamate indexed with MR spectroscopy.…”

Glycine Reuptake Inhibitors in the Treatment of Negative Symptoms of Schizophrenia

“…Schizophrenia may represent a group of mental disorders that simply share common symptoms, and thus, is not likely to respond to one uniform drug. In recent fMRI studies, it has been demonstrated that brain structural correlates are very heterogeneous among individuals with negative symptoms of SZ 41 . Correlating neurotransmitters, fMRI findings, PET and other biomarkers and clinical data to better understand the disease will hopefully result in more homogenous research samples, more accurate results and perhaps more individualized treatment plans 42 .…”