Proteomic Expression Profiles May Allow for Risk Stratification for Psychotic Disorders or Psychotic Episodes

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This study investigates whether proteomic biomarkers may aid in the prediction of the transition to psychotic disorder in the clinical high-risk state and adolescent psychotic experiences in the general population.

Researchers from Beaumont Hospital in Ireland found that individuals with high risk for psychosis had proteomic biomarkers which correlated with disease progression. These findings, from 2 case-control, diagnostic studies, were published in JAMA Psychiatry.

Individuals (N=344) meeting the clinical high-risk criteria for psychosis were recruited for a prospective cohort study at 11 international sites between 2010 and 2015. Participants donated plasma samples at baseline, 12, and 24 months. Transition from psychosis risk to nonorganic psychotic disorder was defined after a Comprehensive Assessment of At-Risk Mental States interview or by a review of clinical records.

Pregnant women (N=14541) who were due to deliver between 1991 and 1992 in the United Kingdom were recruited for a prospective birth cohort study. Plasma samples were obtained from the children of the recruited mothers at 12 years of age. Participants were assessed for psychotic experiences at age 12 and 18 years by the Psychosis-Like Symptoms Interview.

Study 1

A subset of 133 participants were chosen for a subanalysis. Among this subsample, 49 had transitioned to a psychotic state and 84 had not. In plasma samples, 345 proteins were identified, of which 166 were found in 80% of samples. The samples from transitioned and non-transitioned individuals showed differential expression for 56 proteins. After correcting for false positives, 35 proteins remained significant.

Incorporating baseline clinical data and proteomic data into a model allowed investigators to predict transition to a psychotic state (area under the receiver operating characteristic curve [AUC], 0.95; P <.001; sensitivity, 98.0%; specificity, 81.0%; positive predictive value [PPV], 75.0%; negative predictive value [NPV]; 98.6%). In which the highest predictive features were a-2-macroglobulim (A2M), immunoglobulin heavy constant m (IGHM), C4b-binding protein a chain (C4BPA), complement component 8 a chain (C8A), and phospholipid transfer protein (PLTP).

Study 2

Plasma samples from 121 individuals (55 participants with a psychotic episode at age 18 and 66 control samples) identified a total of 506 proteins, 265 of which were present in 80% of samples. At 12 years of age, 40 proteins were differentially expressed between individuals with and without a psychotic episode. After correcting for false positives, 5 remained significant (C4BPA, serum paraoxonase/arylesterase 1, IGHM, inhibin b chain, and clusterin).

Incorporating the proteomic features at 12 years predicted psychotic events at age 18 with an AUC of 0.74 (P <.001; sensitivity, 72.7%, specificity, 71.2%; PPV, 67.8%; NPV, 75.8%). The highest predictors were C4BPA, serum paraoxonase/arylesterase 1, vitamin K-dependent protein S, and lysozyme C.

The major limitation of this study was that without real-world validation, these results cannot be incorporated into clinical practice.

These results, after further validation, indicated it may be possible to incorporate proteomic data into clinical practice for prediction of transition from psychotic risk to a psychotic disorder, or, among the general population, risk for a psychotic episode. Although further studies are needed, these biomarkers may aid clinicians in stratifying patients by risk for psychotic events or developing a psychotic disorder.

Disclosure: Multiple authors declared affiliations with industry. Please refer to the original article for a full list of disclosures.


Mongan D, Föcking M, Healy C, et al. Development of proteomic prediction models for transition to psychotic disorder in the clinical high-risk state and psychotic experiences in adolescence. JAMA Psychiatry. 2020;e202459. doi: 10.1001/jamapsychiatry.2020.2459.