Pharmacoresistant Severe Mental Health Disorders in Children and Adolescents: Functional Abnormalities of Cytochrome P450 2D6

Susanne Thümmler, Emmanuelle Dor, Renaud David, Graziella Leali, Michele Battista, Alexia David, Florence Askenazy, Céline Verstuyft

Severe mental health disorders in children and adolescents represent a major public health problem. Despite adequate drug treatment, some patients develop pharmacoresistant disease. As a consequence, physicians are confronted with prescribing challenges, prolonged hospitalization and increased risk of adverse events, thus aggravating short-, medium-, and long-term prognosis. The majority of psychotropic treatments, particularly antipsychotics and antidepressants, are metabolized at hepatic level by cytochrome P450 (CYP), particularly by CYP3A4 and CYP2D6. SeveralCYP2D6genetic polymorphisms are described to be associated with ultrarapid (UM) or poor drug metabolism (PM), inducing clinical resistance and/or adverse events, and might therefore be related to pharmacoresistant severe mental health disease. A total of nine pharmacoresistant patients (four females, five males) aged 11-16 (mean 14.1) years have been genotyped forCYP2D6between January, 2015 and April, 2016. Patients were diagnosed with schizophrenia (n = 5), autism spectrum disorders (n = 2), intellectual disability with challenging behavior (n = 2), oppositional defiant disorder (n = 1), and post-traumatic stress and borderline personality disorders (n = 1). They had a treatment history with on average 6.1 (3-9) psychotropic, 5 (3-7) antipsychotic, and 3.4 (2-5) CYP2D6-metabolized antipsychotic and antidepressant molecules. Five patients (56%) presented functional anomalies of theCYP2D6gene: three patients were UM metabolizers with gene duplication and two patients were PM with *4/*41 and *3/*4 polymorphisms. Functional anomalies ofCYP2D6concerned more than half of our pediatric inpatient sample with pharmacoresistant disease. However, our case reports are limited by the low sample size. Nevertheless, knowledge of individual metabolism and in particularCYP2D6genotyping should be considered for clinical workup and therapy adjustment in resistant patients in child and adolescent psychiatry and might permit better treatment outcome, increased treatment adherence and diminished adverse events.