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Glutamatergic and GABAergic dysfunction are implicated in the pathophysiology of schizophrenia. Previous work has shown relationships between glutamate, GABA, and brain activity in healthy volunteers. We conducted a systematic review to evaluate whether these relationships are disrupted in psychosis. Primary outcomes were the relationship between metabolite levels and fMRI BOLD response in psychosis relative to healthy volunteers. 17 case-control studies met inclusion criteria (594 patients and 538 healthy volunteers). Replicated findings included that in psychosis, positive associations between ACC glutamate levels and brain activity are reduced during resting state conditions and increased during cognitive control tasks, and negative relationships between GABA and local activation in the ACC are reduced. There was evidence that antipsychotic medication may alter the relationship between glutamate levels and brain activity. Emerging literature is providing insights into disrupted relationships between neurometabolites and brain activity in psychosis. Future studies determining a link to clinical variables may develop this approach for biomarker applications, including development or targeting novel therapeutics., Competing Interests: Conflicts of interest MBW's primary employer is Invicro LLC., a contract research organization which provides services to the pharmaceutical and biotechnology industries. RMM has received honoraria for non-promotional talks for ‘Janssen, Sunovian, Otsuka, Lundbeck’. The remaining authors report no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Cognitive impairments in childhood are associated with increased risk of schizophrenia in later life, but the extent to which poor academic achievement is associated with the disorder is unclear., Methods: Major databases were searched for articles published in English up to 31 December 2019. We conducted random-effects meta-analyses to: (1) compare general academic and mathematics achievement in youth who later developed schizophrenia and those who did not; (2) to examine the association between education level achieved and adult-onset schizophrenia; and, (3) compare general academic achievement in youth at-risk for schizophrenia and typically developing peers. Meta-regression models examined the effects of type of academic assessment, educational system, age at assessment, measurement of educational level attained, school leaving age, and study quality on academic achievement and education level among individuals with schizophrenia., Results: Meta-analyses, comprising data of over four million individuals, found that: (1) by age 16 years, those who later developed schizophrenia had poorer general academic (Cohen's d = -0.29, p ⩽ 0.0001) and mathematics achievement (d = -0.23, p = 0.01) than those who did not; (2) individuals with schizophrenia were less likely to enter higher education (odds ratio = 0.49, p ⩽ 0.0001); and, (3) youth reporting psychotic-like experiences and youth with a family history of schizophrenia had lower general academic achievement (d = -0.54, p ⩽ 0.0001; d = -0.39, p ⩽ 0.0001, respectively). Meta-regression analyses determined no effect modifiers., Discussion: Despite significant heterogeneity across studies, various routinely collected indices of academic achievement can identify premorbid cognitive dysfunction among individuals who are vulnerable for schizophrenia, potentially aiding the early identification of risk in the population.