Abstract
Triple X (47,XXX) syndrome is a sex chromosome aneuploidy associated with learning disabilities, attentional deficits, and social impairments. Its psychiatric manifestations, particularly psychosis, remain underrecognized. This case report describes a 13-year-old girl with 47,XXX syndrome who developed two recurrent psychotic episodes during adolescence and ultimately achieved sustained remission under clozapine, illustrating the need for individualized, genetically informed care. The patient initially presented with persecutory delusions, auditory hallucinations, behavioral changes, and functional decline. Comprehensive neurological, neuropsychological, and audiological assessments showed average overall cognitive functioning and no syndrome-specific sensory abnormalities. Psychotic symptoms emerged years after methylphenidate initiation and persisted during medication-free periods, arguing against stimulant-induced psychosis. Following partial response and poor tolerability to risperidone and aripiprazole, clozapine was introduced using a "start low, go slow" strategy. Low-dose clozapine (150 mg/day) produced complete remission within two months without hematological or cardiovascular adverse effects. Preventive metformin successfully mitigated antipsychotic-associated weight gain. A coordinated multidisciplinary follow-up integrating psychiatry, general medicine, neuropsychology, genetics, and school-based interventions proved essential to maintaining stability, supporting adherence, and promoting academic and social functioning. At one-year follow-up, the patient remained asymptomatic with improved daily functioning. This case reinforces emerging evidence that women with 47,XXX syndrome have an elevated lifetime risk of psychosis and may require tailored antipsychotic strategies due to syndrome-associated comorbidities. It highlights clozapine's potential effectiveness at low doses in genetically vulnerable adolescents, the value of preventive metabolic management, and the importance of integrating psychoeducational and environmental supports. More systematic data are needed to guide evidence-based management of psychosis in sex chromosome aneuploidies.