Genetic Study of Liver Enzymes in Patients With Side Effects From Antidepressants

Major Depressive Disorder Clinical Trial

Official title:

Pharmacogenetic Study of CYP450 2D6 and 2C19 in Patients With Significant Adverse Effects From Antidepressants

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00360256
• Other study ID #: CYP450 Antidepressant study
• Secondary ID: HAC File #: 06-0
• Status: Completed
• Phase: Phase 3
• First received: August 2, 2006
• Last updated: April 18, 2012
• Start date: June 2006
• Est. completion date: December 2007

Study information

• Verified date: April 2012
• Source: Georgia Regents University
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Observational

Clinical Trial Summary

The objective of this pilot study is to determine the genetic polymorphism rate of CYP450 2D6 and 2C19 metabolic enzymes in patients with significant adverse effects from antidepressants, compared to a population of patients who had no significant adverse effects from antidepressants metabolized by CYP2D6 and 2C19.

The hypothesis for the proposed research is that the rate of 2D6 and 2C19 alleles that are associated with poor metabolizer status in the treatment-intolerant population will far exceed the rate found in patient population who takes antidepressants without adverse effects.

Description:

Study Design This is a naturalistic study of sixty patients, which will include 30 patients who had side significant adverse reactions from treatment with antidepressants metabolized by CYP2D6 and 2C19 (TREATMENT-INTOLERANT group) and 30 patients who responded to treatment with same group of antidepressants without significant adverse effects (CONTROL group). The study is expected to last for one year.

Once recruitment, subject consent, and competency to participate have been achieved, the diagnosis will be assessed through clinical interview, aided by medical records, when available. A complete medication history will be taken including all known medications, their doses, and duration of use, to determine exposure to antidepressants metabolized by CYP450 2D6 and 2C19 and absence of concomitant CYP 2D6 and 2C19 inhibitors. A list of the antidepressants metabolized by CYP450 2D6 and 2C19 and their inhibitors is attached. If exposure is confirmed, each subject will be interviewed using the English version of UKU (Udvalg for Kliniske Undersogelser) Rating Scale14 to retrospectively assess their side effects from medications metabolized by CYP 2D6 and 2C19 enzymes. We will use the modules 1, 3 and 4 of the UKU, for "psychic", "autonomic" and respectively "other" side effects. Only patients who had marked side effects from one medication or either moderate or marked side effects from two medications metabolized by CYP 2D6 and 2C19 enzymes, according with UKU, will be included in the TREATMENT-INTOLERANT group. Subjects who have none or mild adverse effects, will be included in the CONTROL group. The subject interview is expected to last approximately ninety minutes and will be conducted by a sub investigator (Adriana Foster, MD).

The study participants will be asked to rinse mouth with water to remove food particles and spit saliva into a collection cup until the liquid level reaches the line indicated on the container (~2ml). We will use Oragene ™ DNA self-collection kit (DNA Genotek, Inc, Ottawa, Ontario, Canada).

The saliva will be transported to GEM Labs, located on MCG campus, by research staff. The genomic DNA will be extracted with the reagent and method supplied by the manufacturer, Oragene. This will be used as the template to amplify the relevant regions of CYP450 2D6 and 2C19. The PCR products will be randomly cleaved into 50 to 100 bp by digestion with DNase I. These fragments will be further labeled with phycoerythrin (PE), a fluorescent dye. The PE labeled fragments will be hybridized to the P450 Roche AmpliChip, washed, and scanned by the Affymetrix automated GeneChip fluidics Station 450Dx and the Affymetrix GeneChip scanner 3000Dx with GeneChip Operating Software Dx 1.1.3. The data will be analyzed by AmpliChip CYP450_US Data Analysis to determine the genotype for 2D6 (it totally assesses 27 mutation sites, deletion, and duplication) and 2C19 (2 mutation sites). Genotyping results will be analyzed by the same software to predict the phenotype (ultra rapid, extensive, intermediate, and poor metabolizer).

Overall, the study requires only one visit from the participant; after interviewing and saliva sample have been completed, the participant's role in the research will be fulfilled. This study will be carried out in its entirety at the Medical College of Georgia facilities. We hope to demonstrate that the rate of 2D6 and 2C19 alleles that are associated with poor metabolizer status in the treatment-intolerant population will far exceed the rate found in patient population who takes antidepressants without adverse effects.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 46
• Est. completion date: December 2007
• Est. primary completion date: December 2007
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 65 Years

Eligibility

Inclusion Criteria:

• Male and female patients between ages 18 and 65 of any ethnic background

• Diagnosis of major depressive disorder, dysthymic disorder or depressive disorder NOS.

• Experienced side effects on antidepressant metabolized by CYP 2D6 and 2C19 that required discontinuation of treatment

• Experienced side effects from 2 or more antidepressants metabolized by CYP 2D6 and 2C19

Exclusion Criteria:

Exclusion criteria:

• Patients with diagnosis of bipolar disorder or any anxiety disorder. We decided to exclude patients with these diagnoses, due to the fact that antidepressants may exacerbate symptoms of bipolar and anxiety disorders and there is a risk that these symptoms can be attributed instead to antidepressant adverse effects.

• Patients taking inhibitors of drugs metabolized by CYP 2D6 and 2C19

• Patients who are non-English speaking: the English version of the UKU side effects rating scale will be used. The rating of side effects depends on the patient interview and the information found in the medical record. To appreciate the extent of the side effects, the rater and the research participant must be speaking the same language. Thus, to include non-English speaking participants, both the research and the clinical staff would need to be fluently bilingual, which is not the case at MCG inpatient and outpatient treatment facilities.

Study Design

Time Perspective: Retrospective

Related Conditions & MeSH terms

• Depression
• Depressive Disorder
• Depressive Disorder, Major
• Major Depressive Disorder

Locations

Country	Name	City	State
United States	Medical College of Georgia, Dept. of Psychiatry and Health Behavior	Augusta	Georgia

Sponsors (2)

Lead Sponsor	Collaborator
Georgia Regents University	Hoffmann-La Roche

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Cytochrome P450 2D6 and 2C19 genotype		12/07	No
Secondary	Drug tolerability		December 2007	No