Medium-term Prediction of Clinically-relevant Outcomes in First-episode Schizophrenia Patients

Abstract BACKGROUND Predicting long-term outcomes in first-episode schizophrenia (FES) remains difficult, despite being especially important early in the illness, when timely intervention is most critical. Many potential predictors have been studied, but few are reliable enough to guide early treatment decisions. It also remains unclear how much data from the initial phase of illness is required to improve prognostic accuracy. METHODS We analysed 68 patients with first-episode schizophrenia (FES) assessed at baseline (V1; mean 0.5 years post-onset, YPO), one-year follow-up (V2; mean 1.2 YPO), and outcome (V3; mean 4.9 YPO). We trained elastic-net models to predict three V3 outcomes—negative symptoms (PANSS Negative factor; Wallwork/Fortgang), global functioning (GAF), and quality of life (WHOQOL-BREF psychological domain)—using either 23 V1 predictors alone or V1 predictors plus V2 data (43 predictors). Performance was evaluated with nested cross-validation on held-out data. RESULTS Using predictors from the first year (V1+V2), we achieved statistically significant out-of- sample prediction for all three V3 outcomes: PANSS Negative factor (Wallwork/Fortgang) R 2 =0.22— driven mainly by log(DUP), PANSS Negative at V1/V2, and PANSS Disorganized at V2; WHOQOL-BREF Psychological Health R 2 =0.22—driven mainly by WHOQOL Psychological Health at V2 and GAF at V2; and GAF R 2 =0.14—driven mainly by GAF at V2, PANSS Positive at V2, WHOQOL Psychological Health at V2, and hospitalization burden (before V1 and between V1–V2). With baseline-only predictors (V1), only PANSS Negative showed meaningful predictive power (R 2 =0.15); GAF and WHOQOL-BREF did not outperform the intercept-only baseline. CONCLUSION In FES, long-term functioning (GAF) and quality of life (WHOQOL-BREF) can not be predicted well from first-episode (V1) measures; at least an additional 1 year of follow-up is needed, implying these outcomes are driven by changes after onset that V1 misses. Negative symptoms differ: they are comparatively stable after initial antipsychotic treatment, and duration of untreated psychosis is their strongest predictor beyond baseline severity—consistent with early biology and treatment timing shaping their level and persistence. These contrasting patterns indicate different outcome phenotypes.