Association of Hippocampal Glutamate Levels With Adverse Outcomes in Individuals at Clinical High Risk for Psychosis | Psychiatry and Behavioral Health | JAMA Psychiatry | JAMA Network
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Original Investigation
November 14, 2018

Association of Hippocampal Glutamate Levels With Adverse Outcomes in Individuals at Clinical High Risk for Psychosis

Author Affiliations
  • 1Department of Psychosis Studies, Institute of Psychiatry, Psychology, and Neuroscience, King’s College London, London, United Kingdom
  • 2Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands
  • 3Cambridge Early Onset service, Cambridgeshire and Peterborough Mental Health Partnership National Health Service Trust, Cambridge, United Kingdom
  • 4Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom
  • 5Department of Neuroimaging, Institute of Psychiatry, Psychology, and Neuroscience, King’s College London, London, United Kingdom
  • 6Department of Psychology, University of Roehampton, London, United Kingdom
JAMA Psychiatry. 2019;76(2):199-207. doi:10.1001/jamapsychiatry.2018.3252
Key Points

Question  What is the association between hippocampal glutamate levels and subsequent clinical outcomes in individuals at clinical high risk for psychosis?

Findings  In this cross-sectional study of 86 individuals from the United Kingdom, baseline hippocampal glutamate levels were significantly higher in clinical high-risk individuals who developed psychosis or had poor functional outcome at a mean clinical follow-up of 18.5 months.

Meaning  The association between adverse clinical outcomes in individuals at clinical high risk for psychosis and increased baseline hippocampal glutamate levels may suggest that these measures could contribute to the stratification of clinical high-risk individuals according to future clinical outcomes.


Importance  Preclinical and human data suggest that hippocampal dysfunction plays a critical role in the onset of psychosis. Neural hyperactivity in the hippocampus is thought to drive an increase in subcortical dopamine function through glutamatergic projections to the striatum.

Objective  To examine the association between hippocampal glutamate levels in individuals at clinical high risk for psychosis and their subsequent clinical outcomes.

Design, Setting, and Participants  This cross-sectional study of 86 individuals at clinical high risk for psychosis and 30 healthy control individuals, with a mean follow-up of 18.5 months, was conducted between November 1, 2011, and November 1, 2017, at early detection services in London and Cambridge, United Kingdom.

Main Outcomes and Measures  Concentrations of glutamate and other metabolites were measured in the left hippocampus using 3-T proton magnetic resonance spectroscopy at the first clinical presentation. At follow-up, clinical outcomes were assessed in terms of transition or nontransition to psychosis using the Comprehensive Assessment of the At-Risk Mental State criteria and the level of overall functioning using the Global Assessment of Function scale.

Results  Of 116 total participants, 86 were at clinical high risk for psychosis (50 [58%] male; mean [SD] age, 22.4 [3.5] years) and 30 were healthy controls (14 [47%] male; mean [SD] age, 24.7 [3.8] years). At follow-up, 12 clinical high-risk individuals developed a first episode of psychosis whereas 74 clinical high-risk individuals did not; 19 clinical high-risk individuals showed good overall functioning (Global Assessment of Function ≥65), whereas 38 clinical high-risk individuals had a poor functional outcome (Global Assessment of Function <65). Compared with clinical high-risk individuals who did not become psychotic, clinical high-risk individuals who developed psychosis showed higher hippocampal glutamate levels (mean [SD], 8.33 [1.48] vs 9.16 [1.28] glutamate levels; P = .048). The clinical high-risk individuals who developed psychosis also had higher myo-inositol levels (mean [SD], 7.60 [1.23] vs 6.24 [1.36] myo-inositol levels; P = .002) and higher creatine levels (mean [SD], 8.18 [0.74] vs 7.32 [1.09] creatine levels; P = .01) compared with clinical high-risk individuals who did not become psychotic, and higher myo-inositol levels compared with healthy controls (mean [SD], 7.60 [1.23] vs 6.19 [1.51] myo-inositol levels; P = .005). Higher hippocampal glutamate levels in clinical high-risk individuals were also associated with a poor functional outcome (mean [SD], 8.83 [1.43] vs 7.76 [1.40] glutamate levels; P = .02). In the logistic regression analyses, hippocampal glutamate levels were significantly associated with clinical outcome in terms of transition and nontransition to psychosis (β = 0.48; odds ratio = 1.61; 95% CI, 1.00-2.59; P = .05) and overall functioning (β = 0.53; odds ratio = 1.71; 95% CI, 1.10-2.66; P = .02).

Conclusions and Relevance  The findings indicate that adverse clinical outcomes in individuals at clinical high risk for psychosis may be associated with an increase in baseline hippocampal glutamate levels, as well as an increase in myo-inositol and creatine levels. This conclusion suggests that these measures could contribute to the stratification of clinical high-risk individuals according to future clinical outcomes.