Genetic Study of Liver Enzymes in Patients With Side Effects From Antidepressants
Condition: Major Depressive Disorder
MeSH terms: Depressive Disorder; Depressive Disorder, Major
Study type: Observational

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.
    

Detailed 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.
    

Time perspective: Retrospective
Sampling method: Non-Probability Sample
Study population: 
        Depressed patients
      
Keywords: Depression; Amplichip P450 tests; Antidepressants