Real-world profiling of adolescents for precision psychiatry: gender-specific phenotypes in treatment-resistant early-onset schizophrenia

Background

Early-Onset Schizophrenia (EOS) is a severe neurodevelopmental disorder frequently complicated by high rates of treatment resistance (TR) [1, 2]. While Adult-Onset Schizophrenia exhibits a well-documented male predominance alongside sex-specific symptomatic variations, the epidemiological landscape in EOS-TR is markedly different, lacking a clear male predominance [3, 4]. Despite this epidemiological divergence, the precise symptomatological profiles and the presence of gender-specific clinical phenotypes at illness onset remain underexplored. Recognizing these early dimorphic presentations is fundamental to implementing tailored early interventions.

Aim of the study

This study aimed to provide a comprehensive symptomatological characterization of patients with EOS-TR, specifically focusing on identifying and quantifying gender-based phenotypic differences at the onset of the disease, prior to the development of treatment-resistance and clozapine therapy.

Methods

We conducted a retrospective, cross-sectional analysis on a real-world clinical cohort comprising 62 patients with EOS-TR (36 females, 26 males), admitted to the Villa Von Siebenthal Neuropsychiatric Hospital. To accurately capture the initial disease phenotype, symptomatological data were retrospectively extracted corresponding to the patients’ first psychotic episode (mean age at onset: 14.8 years). Thirteen key psychopathological domains were evaluated to assess the prevalence of distinct symptoms at illness onset. To determine the statistical significance of gender differences across these domains, we performed Pearson’s Chi-square tests and Fisher’s exact tests where appropriate. Statistical significance was established at p < 0.05.

Results

The analyzed sample exhibited a remarkably severe initial clinical presentation. Social withdrawal emerged as the most pervasive core symptom across the entire cohort (67.74%), demonstrating no significant difference between genders (males: 73.08%, females: 63.89%; p = 0.445). Crucially, the comparative analysis revealed two distinct, statistically significant gender-specific phenotypic clusters. Male patients demonstrated a predominantly externalizing and positive psychotic profile, characterized by significantly higher rates of psychomotor agitation (84.62% vs. 27.78%, p < 0.001), aggression (65.38% vs. 19.44%, p < 0.001), delusional ideation (73.08% vs. 30.56%, p = 0.001), and misperceptions (57.69% vs. 25.00%, p = 0.009). Conversely, female patients presented with a severe internalizing, affective, and self-destructive phenotype. This female-specific cluster was defined by significantly elevated rates of suicidal ideation (61.11% vs. 30.77%, p = 0.018), self-harm behaviors (69.44% vs. 30.77%, p = 0.003), depressed mood (69.44% vs. 38.46%, p = 0.015), and comorbid eating disorders (52.78% vs. 7.69%, p < 0.001).

Conclusion

Our findings challenge the assumption of a uniform clinical presentation in EOS-TR, highlighting profound gender-based phenotypic divergence at illness onset. Male adolescents predominantly exhibit a severe externalizing psychotic profile, whereas females present a complex internalizing picture driven by affective dysregulation and self-harm. Crucially, characterizing these distinct symptomatological clusters may serve as a valuable predictive tool in clinical practice. Identifying these severe, gender-specific phenotypes early could help clinicians recognize individuals with a heightened vulnerability to first-line antipsychotic failure. Consequently, we hypothesize that this targeted profiling could facilitate the earlier identification of treatment resistance, potentially supporting a more rapid transition to clozapine therapy and thereby helping to minimize the devastating neurodevelopmental impact of prolonged, inadequately treated psychosis [5].

References

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