TY - JOUR
T1 - Neurometabolites and Antipsychotic Response in Psychosis
T2 - A Mega-Analysis
AU - King, Bridget
AU - Bojesen, Kirsten Borup
AU - Crisp, Charlotte
AU - De Bartolomeis, Andrea
AU - De Haan, Lieuwe
AU - De la Fuente-Sandoval, Camilo
AU - Dempster, Kara
AU - Drake, Richard J.
AU - Dazzan, Paola
AU - Ebdrup, Bjørn H.
AU - Fan, Lejia
AU - Graff-Guerrero, Ariel
AU - Glenthøj, Birte Yding
AU - Honda, Shiori
AU - Howes, Oliver
AU - Huang, Li Chung
AU - Kahn, Rene
AU - MacCabe, James
AU - Matrone, Marta
AU - Merritt, Kate
AU - McIlwain, Meghan
AU - McGuire, Philip
AU - Nakajima, Shinichiro
AU - Lawrie, Stephen M.
AU - Palaniyappan, Lena
AU - Reyes-Madrigal, Francisco
AU - Russell, Bruce
AU - Sawa, Akira
AU - Shergill, Sukhi
AU - Singh, Krish D.
AU - Sommer, Iris E.
AU - Stone, James M.
AU - Sun, Junyu
AU - Tsugawa, Sakiko
AU - Ueno, Fumihiko
AU - Van der Pluijm, Marieke
AU - Van de Giessen, Elsmarieke
AU - Walters, James T.R.
AU - Yang, Kun
AU - Yang, Yen Kuang
AU - Kempton, Matthew J.
AU - Egerton, Alice
N1 - Publisher Copyright:
© 2026 American Medical Association. All rights reserved, including those for text and data mining, AI training, and similar technologies.
PY - 2026/9/1
Y1 - 2026/9/1
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/105043778229
U2 - 10.1001/jamapsychiatry.2026.1674
DO - 10.1001/jamapsychiatry.2026.1674
M3 - Journal article
C2 - 42340705
AN - SCOPUS:105043778229
SN - 2168-622X
VL - 83
SP - 939
EP - 948
JO - JAMA Psychiatry
JF - JAMA Psychiatry
IS - 9
ER -