A distinct psychotic phenotype in pediatric narcolepsy type 1: a case-control study

Introduction: To determine whether pediatric patients with narcolepsy type 1 (NT1) who develop psychotic symptoms exhibit a distinct clinical and sleep-related phenotype compared with those with NT1 without psychosis. Methods: We report on clinical and polysomnographic features of nine consecutive pediatric patients observed at our center between 2014 and 2025, who developed psychotic symptoms either at NT1 onset or within one year from NT1 diagnosis, and on a control group of 96 consecutive NT1 patients without evidence of psychotic symptoms. Results: Final psychiatric diagnoses included very-early-onset schizophrenia, psychosis not otherwise specified, psychotic depression, obsessive-compulsive disorders, or autism spectrum disorder with psychotic features. Compared to control NT1 patients, NT1cases with psychosis showed much higher rates of psychiatric family history (OR = 36, 55.6% vs. 2.2%, p < 0.01), lower cerebrospinal fluid hypocretin-1 levels (4.9 ± 9.0 pg/mL vs. 18.9 ± 24.2 pg/mL, p = 0.02) and the following polysomnographic features: shorter nocturnal total sleep time (430.8 ± 86.5min vs. 503.7 ± 76.8min, p = 0.03), lower nocturnal sleep efficiency (75.6 ± 15.6% vs. 89.5 ± 7.6%, p = 0.02), and higher rate of daytime naps (3.7 ± 1.8 vs 2.6 ± 1.7, p = 0.04). Sleep-wake transition metrics indicated increased nocturnal sleep fragmentation, namely higher transition indices between wakefulness and sleep and between wakefulness NREM and REM sleep, respectively. Conclusions: Our findings suggest the presence of a pediatric NT1-psychotic phenotype characterized by more severe hypocretin deficiency and pronounced daytime and nighttime sleep disruption, suggesting that these features may reflect the interaction between hypocretin deficiency and broader neuro-developmental vulnerabilities. Early recognition of this phenotype may guide toward tailored treatment strategies and inform about prognosis in this complex disorder.