DOI: 10.1001/jamapsychiatry.2026.1674 ISSN: 2168-622X

Neurometabolites and Antipsychotic Response in Psychosis

Bridget King, Kirsten Borup Bojesen, Charlotte Crisp, Andrea de Bartolomeis, Lieuwe de Haan, Camilo de la Fuente-Sandoval, Kara Dempster, Richard J. Drake, Paola Dazzan, Bjørn H. Ebdrup, Lejia Fan, Ariel Graff-Guerrero, Birte Yding Glenthøj, Shiori Honda, Oliver Howes, Li-Chung Huang, Rene Kahn, James MacCabe, Marta Matrone, Kate Merritt, Meghan McIlwain, Philip McGuire, Shinichiro Nakajima, Stephen M. Lawrie, Lena Palaniyappan, Francisco Reyes-Madrigal, Bruce Russell, Akira Sawa, Sukhi Shergill, Krish D. Singh, Iris E. Sommer, James M. Stone, Junyu Sun, Sakiko Tsugawa, Fumihiko Ueno, Marieke van der Pluijm, Elsmarieke van de Giessen, James T. R. Walters, Kun Yang, Yen Kuang Yang, Matthew J. Kempton, Alice Egerton
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Importance

Revealing neurobiological markers of antipsychotic nonresponse in psychosis may aid outcome prediction and inform novel treatment targets.

Objective

To examine differences in neurometabolites in antipsychotic nonresponsive compared to antipsychotic-responsive psychosis using individual participant data and meta-analysis.

Data Sources

Web of Science was searched for studies published between January 1, 1980, and November 1, 2025. Authors of 21 eligible studies identified before August 2024 were invited to contribute individual participant data.

Study Selection

Eighteen studies examining neurometabolites by treatment response in psychosis contributed individual participant data for the mega-analysis. These studies plus a further 5 studies were included in the meta-analyses of standardized mean differences and variability.

Data Extraction and Synthesis

Individual participant data were analyzed using linear mixed models with study as a random effect. Subgroup analyses examined prospective designs and treatment-resistant samples. Published group means and standard deviations were extracted for meta-analyses.

Main Outcomes and Measures

Group differences in glutamate, glutamate plus glutamine, choline, myo-inositol, N -acetylaspartate, γ-aminobutyric acid, and glutathione in the medial frontal cortex, dorsolateral prefrontal cortex, thalamus, and basal ganglia.

Results

The mega-analysis included 1189 participants from 18 studies; of these, 476 were treatment nonresponders (mean [SD] age, 33.0 [12.5] years; 340 male), 427 were treatment responders (mean [SD] age, 30.3 [11.5] years; 299 male), and 286 were healthy control individuals (mean [SD] age, 31.0 [12.5] years; 170 male). Compared with the antipsychotic response group, nonresponders showed elevations in medial frontal glutamate (Glass Δ = 0.21; P  = .02), glutamate plus glutamine (Glass Δ = 0.29; P  = .002), choline (Glass Δ = 0.22; P  = .03), and myo-inositol (Glass Δ = 0.35; P  = .001); similar elevations were observed relative to control individuals. Elevated medial frontal glutamate plus glutamine in antipsychotic nonresponders compared with responders was also observed prospectively in first-episode psychosis (Glass Δ = 0.41; P  = .002), whereas myo-inositol elevations were greatest in individuals meeting criteria for treatment-resistance (Glass Δ = 0.64; P  = .001). The meta-analysis of 23 studies (1844 participants) also showed elevated medial frontal choline and myo-inositol in antipsychotic nonresponse compared with response.

Conclusions and Relevance

These findings provide evidence of an association between antipsychotic nonresponse in psychosis with elevations in medial frontal glutamate, choline, and myo-inositol. The presence of elevations in these markers supports the continued investigation of glutamate-acting and inflammatory pathway–associated interventions for psychosis and schizophrenia.

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