Hippocampal glutamate and verbal episodic memory in the psychosis spectrum: A preliminary report

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The Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) consortium categorized individuals with psychosis into 3 biologically distinct Biotypes (B1, B2, B3) based on cognitive and EEG measures. Deficient verbal episodic memory (VEM, a contributor to Biotype determination), is strongly associated with poor clinical outcome. Hippocampal glutamatergic circuits support VEM. Furthermore, glutamatergic mechanisms, implicated in cognitive and psychotic symptoms, are proposed as novel treatment targets. We used MRS to measure hippocampus glutamate and N-acetyl-aspartate (NAA) concentrations (non-contributors to Biotype) in psychosis vs. healthy-controls (HC). We examined VEM vs. glutamate relationships across DSM-IV diagnoses and Biotypes. We compared fits of linear and quadratic regression models. Glutamate was non-significantly lower in B1, higher in B2, and similar in B3 vs. HC. NAA did not differ. Quadratic models with Biotype-based groups provided best fits using the adjusted R 2 and AIC criteria. In B1, reduced glutamate tended to associate with deficient VEM, suggesting reduced excitatory glutamatergic signaling, which could be compensated by glutamate enhancing treatments, increasing production of synaptic glutamate or NMDAR mediated currents. In B2, higher glutamate and the accentuated inverted-U shaped VEM vs. glutamate relationship suggest high levels of dysregulated glutamatergic activity possibly related to deficient inhibitory GABAergic control. In B3, the independence of VEM and glutamate suggests that, in contrast to B1 and B2, B3 may be more sensitive to non-glutamatergic or GABAergic neurotransmitter system-targeted compounds to maintain healthy memory function. Because of the limited sample size, the interpretation of results is of a tentative nature. Results help explain the role of hippocampal glutamatergic neurotransmission in VEM deficits in psychotic disorders and motivate distinct treatment strategies for individuals with psychosis stratified by Biotype.

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