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Effect of mGluR2 positive allosteric modulation on frontostriatal working memory activation in schizophrenia

Abstract

Negative symptoms and cognitive deficits contribute strongly to disability in schizophrenia, and are resistant to existing medications. Recent drug development has targeted enhanced NMDA function by increasing mGluR2/3 signaling. However, the clinical utility of such agents remains uncertain, and markers of brain circuit function are critical for clarifying mechanisms and understanding individual differences in efficacy. We conducted a double-blind, placebo-controlled, randomized cross-over (14 day washout) pilot study evaluating adjunctive use of the mGluR2 positive allosteric modulator AZD8529 (80 mg daily for 3 days), in chronic stable patients with schizophrenia (n = 26 analyzed). We focused on 3 T fMRI response in frontostriatal regions during an n-back working memory task, testing the hypothesis that AZD8529 produces fMRI changes that correlate with improvement in negative symptoms and cognition. We found that AZD8529 did not produce significant group-average effects on symptoms or cognitive accuracy. However, AZD8529 did increase n-back fMRI activation in striatum (p < 0.0001) and anterior cingulate/paracingulate (p = 0.002). Greater drug-versus-placebo effects on caudate activation significantly correlated with greater reductions in PANSS negative symptom scores (r = −0.42, p = 0.031), and exploratory correlations suggested broader effects across multiple symptom domains and regions of interest. These findings demonstrate that fMRI responses to mGluR2 positive modulation relate to individual differences in symptom reduction, and could be pursued for future biomarker development. Negative clinical results at the group level should not lead to premature termination of investigation of this mechanism, which may benefit an important subset of individuals with schizophrenia. Imaging biomarkers may reveal therapeutic mechanisms, and help guide treatment toward specific populations.

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Fig. 1: N-Back fMRI Paradigm.
Fig. 2: Drug Effects on N-back fMRI Activation.
Fig. 3: fMRI-Symptom Relationship.

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Acknowledgements

This study was supported by AstraZeneca Pharmaceuticals LP. DHW was also supported by NIMH grant K23MH085096 and R01MH101111. TDS was supported by NIMH grant R01MH112847, R01MH113550 and ACTTION. The work was also supported by NIMH grants R01MH060722, P50MH064045, and T32MH019112. The authors thank Elizabeth Hanson, Raphael Gerraty, and Janina Seubert for assistance with data acquisition; Jeffrey Valdez for assistance with neuroimaging analysis; Warren Bilker for assistance with statistical analysis; and Monica Calkins for assistance with symptom assessment.

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REG, RCG, BT, SRZ, MAS, AJC, CK, MAE, DHW conceived and designed the study. DW, CK, MEM conducted study procedures and data collection. DW, DZ, KR, TDS, and MEM conducted data analysis. DHW and DZ drafted the paper. All authors reviewed and critically revised the paper and approved of it in its final form.

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Correspondence to Daniel H. Wolf.

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Drs MAS, SRZ, and AJC are former employees of AstraZeneca Pharmaceuticals LP, the study sponsor. The other authors declare no competing interests.

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Wolf, D.H., Zheng, D., Kohler, C. et al. Effect of mGluR2 positive allosteric modulation on frontostriatal working memory activation in schizophrenia. Mol Psychiatry (2021). https://doi.org/10.1038/s41380-021-01320-w

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