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Front Psychiatry. 2018 Jan 24;9:2. doi: 10.3389/fpsyt.2018.00002. eCollection 2018.

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

Author information

University Department of Child and Adolescent Psychiatry, Children's Hospitals of Nice CHU-Lenval, Nice, France.
CoBTek, Université Côte d'Azur, Nice, France.
Department of Child Psychiatry, Nice Children's Hospitals CHU-Lenval, Nice, France.
Department of Child and Adolescent Psychiatry, Hospital of Fréjus, Fréjus, France.
Service de génétique moléculaire, pharmacogénétique et hormonologie, Centre de Ressource Biologie Paris-Sud, Hôpital Bicêtre, Groupe Hospitalier Paris Sud, AP-HP, Le Kremlin Bicêtre, Nice, France.
Université Paris-Sud, UMR 1184, Faculté de médecine, Paris, France.



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. Several CYP2D6 genetic 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.

Case presentation:

A total of nine pharmacoresistant patients (four females, five males) aged 11-16 (mean 14.1) years have been genotyped for CYP2D6 between 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 the CYP2D6 gene: three patients were UM metabolizers with gene duplication and two patients were PM with *4/*41 and *3/*4 polymorphisms.


Functional anomalies of CYP2D6 concerned 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 particular CYP2D6 genotyping 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.


CYP2D6; antidepressants; antipsychotics; child and adolescent psychiatry; personalized medicine; pharmacogenetics

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