¹CHUV, Department of Psychiatry, Lausanne, Switzerland

Background: Challenging behaviors (CB), including aggression, self-injury, and severe agitation, are a major cause of suffering and institutionalization in individuals with neurodevelopmental disorders (NDD). Their multifactorial nature often leads to empirical psychopharmacological escalation and polypharmacy. Variability in hepatic cytochrome P450 (CYP) activity may underlie paradoxical responses, rapid loss of efficacy, or toxicity even at low doses, yet systematic metabolic profiling remains rare in this population.

Aims & Objectives: To characterize CYP phenotypes in patients with severe NDD and CB, examine associations with pharmacoresistance and adverse drug reactions, and compare anomaly patterns across a gradient of clinical complexity, children, ambulatory adults, and inpatients hospitalized for crisis management (EPIONE unit).

Method: All patients of our cohort who underwent CYP phenotyping between January 2022 and 2025 were included (n = 89). Phenotyping covered six major hepatic enzymes (CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) and was conducted following defined clinical indications: psychotropic resistance (85 %), abnormal kinetic profiles (42 %), unexpected plasma levels (36 %), and severe or paradoxical side effects (31 %). CYP activity was categorized as slowed (–), accelerated (+), or marked (±2). Clinical and pharmacological data were retrospectively analyzed.

Results: Nearly all patients (99 %) displayed at least one CYP irregularity, averaging three per individual. Major anomalies (±2) were identified in 73 % of cases (mean = 1.4 per patient). Their prevalence increased with pharmacoresistance: 76 % in patients with <5 failed trials, 87 % in those with ≥5. Patients tested for side effects also showed a higher rate (89 %) compared to those without (70 %), while kinetic abnormalities were associated with similar frequencies (82 %). The density of anomalies was highest among EPIONE inpatients (87 %), supporting the hypothesis of a metabolic gradient of clinical complexity.

Discussion & Conclusions: CYP dysfunctions are pervasive and often cumulative in severe NDD with challenging behaviors. Their strong association with treatment resistance and adverse effects suggests a metabolic contribution to the progressive spiral of pharmacoresistance and behavioral decompensation. Early metabolic screening, triggered by atypical kinetics, unexpected plasma levels, or paradoxical responses, could help optimize psychopharmacological strategies and prevent escalation toward refractory, polypharmacy-driven crises.