Pharmacogenetics Anomaly Research in Children and Adolescents With Pharmacological Resistance to Psychotropic Drugs (M4P)

Personalized Medicine: Pharmacogenetics Anomaly Research in Children and Adolescents With Pharmacological Resistance to Psychotropic Drugs

Psychotropic drugs are frequently used in children and adolescents in France with a prescription rate of 2.5%. Antipsychotics (PA) and antidepressants (AD), each concern 0.3% of the pediatric population (Kovess et al., 2015). Despite appropriate pharmacological treatment, some patients are drug-resistant and have persisting symptoms and ineffective psychotropic treatments. These children and adolescents are generally exposed to many psychotropic molecules and often to poly-therapy.

Most psychotropic treatments, especially AP and AD, are metabolised at the hepatic level by cytochrome P450 and in particular by CYP2D6. Duplication / multiplication of the CYP2D6 gene induces too rapid metabolism of drugs.

Demonstration of a CYP2D6 abnormality has a direct impact on the management of the patient and on the clinical decisions of the clinician. Thus, knowledge of individual metabolism will decrease the failure of treatment, improve quality of life and therapeutic compliance.

Study Overview

• Status: Completed
• Conditions: Psychotropic Drugs; Drug Resistance
• Intervention / Treatment: Other: gene abnormalities

Detailed Description

Psychotropic drugs are frequently used in children and adolescents in France with a prescription rate of 2.5%. Antipsychotics (PA) and antidepressants (AD) each concern 0.3% of the pediatric population (Kovess et al., 2015). Despite appropriate pharmacological treatment, some patients are drug-resistant and have persisting symptoms and ineffective psychotropic treatments. These children and adolescents are generally exposed to many psychotropic molecules and often to poly-therapy. Additionally, hospitalizations for child psychiatry, sometimes of prolonged duration, are frequent for these patients. In France, to date, the psychiatrist practitioner rarely uses pharmacogenetic evaluation as a complementary tool for prescribing psychotropic drugs. Nevertheless, an individualized prescription taking into consideration the patient's individual metabolism could greatly improve the benefit and reduce the risk of psychotropic treatments in the pediatric population.

Most psychotropic treatments, especially AP and AD, are metabolised at the hepatic level by cytochrome P450 and in particular by CYP2D6. Duplication / multiplication of the CYP2D6 gene induces too rapid metabolism of the drugs (ultrafast metabolizer). It is linked to a clinical inefficiency of treatments, and concerns up to 10% of the general population in southern Europe (Scordo et al., 2004).

In a preliminary study in Nice, an abnormality of CYP2D6 was found in 4 of the 7 patients tested with drug-resistant and / or with numerous adverse effects to the AP, of which 3 of the 5 pharmacologically resistant patients shows a duplication of the gene.

Demonstration of a CYP2D6 abnormality has a direct impact on the management of the patient and on the clinical decisions of the clinician. Thus, knowledge of individual metabolism will decrease the failure of treatment, improve quality of life and therapeutic compliance.

• Study Type: Interventional
• Enrollment (Actual): 22
• Phase: Not Applicable

Contacts and Locations

Study Locations

• France
  • Nice, France, 06200
    • Fondation Lenval Hôpitaux Pédiatriques de Nice CHU-LENVAL

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 18 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Pharmaco resistance to psychotropic drugs
• Obtaining the informed consent of the patient and his / her parents or legal guardian
• Affiliation to a social security system

Exclusion Criteria:

• Patient deprived of liberty

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: CYP2D6 gene abnormalities; A salivary sample (2 ml sample) which will allow the investigation of an anomaly of the metabolism of psychotropic drug.; Blood sampling will be performed to assess treatment tolerance (6 ml). A sample (4 ml) will be kept for possible future analyzes in relation to the objectives of this study for the recruiting center of Nice.; Electrocardiogram; Clinical exam; Clinical Global Impression Scale (CGI-S); Children's Global Assessment Scale (CGAS); Sheehan Disability Scale (SDS); Wechsler Preschool and Primary Scale of Intelligence III (WPPSI-III ); Wechsler Intelligence Scale for Children - 4 (WISC-4); Wechsler Adult Intelligence Scale 4 (WAIS 4); Diagnostic and Statistical Manual of Mental Disorders (DSM); Autism Diagnostic Interview (ADI)

Other: gene abnormalities; A salivary sample (2 ml sample) Blood sampling will be performed to assess treatment tolerance (6 ml)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
prevalence of a CYP2D6 duplication or polymorphisms	study the prevalence of a CYP2D6 duplication or polymorphisms associated with an ultrafast metabolizing phenotype in a population of children and adolescents who are drug-resistant to antipsychotic and antidepressant psychotropic drugs. performed by analysis of salivar sample	At baseline

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Psychiatric diagnosis and comorbidities	Diagnostic and Statistical Manual of Mental Disorders 5 DSM5	At baseline
Global Severity of illness	Clinical Global Impression scale (échelle CGI-I)	At baseline
Severity of illness for children	Children's Global Assessment Scale (CGAS)	At baseline
Current and previous psychotropic treatment	Number of different molecules (antipsychotic antidepressant) used during the therapeutic history of the patient, duration of treatment with each molecule, type and maximum dose of current and previous psychotropic treatments.	At baseline
Side effects in different psychotropic treatments	Type and severity of the adverse effects identified during the various psychotropic treatments will be collected. This collection will be carried out through the interrogation and study of the medical file	At baseline
New anomalies of CYP2D6 gene	To look for any other abnormality of the CYP2D6 gene not known to be associated with an ultrafast metabolizing phenotype	At baseline
Description of the clinical phenotype of patients	The characterization of the clinical phenotype will be carried out on the one hand by the standardized diagnostic interview MINI Mini International Neuropsychiatric Interview	At baseline

Collaborators and Investigators

• Sponsor: Fondation Lenval
• Investigators: Principal Investigator: Susanne THÜMMLER, MD, Fondation Lenval Hôpitaux Pédiatriques de Nice CHU-LENVAL

Study record dates

Study Major Dates

• Study Start (Actual): December 7, 2016
• Primary Completion (Actual): December 12, 2018
• Study Completion (Actual): January 31, 2019

Study Registration Dates

• First Submitted: February 22, 2017
• First Submitted That Met QC Criteria: April 13, 2017
• First Posted (Actual): April 14, 2017

Study Record Updates

• Last Update Posted (Actual): February 26, 2019
• Last Update Submitted That Met QC Criteria: February 25, 2019
• Last Verified: July 1, 2018

More Information

Terms related to this study

• Keywords: CYP2D6; Drug Resistance; cytochrom P450
• Additional Relevant MeSH Terms: Congenital Abnormalities
• Other Study ID Numbers: 16-HPNCL-02

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No