Major Depressive Disorder Clinical Trial
Official title:
Pharmacogenetic Study of CYP450 2D6 and 2C19 in Patients With Significant Adverse Effects From Antidepressants
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.
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.
;
Time Perspective: Retrospective
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