Pharmacodynamics and Pharmacokinetics of Citalopram and Escitalopram

Summary

This study is one component of a larger U01 grant that was submitted in August, 2004 to the NIGMS as part of the Pharmacogenomic Research Network. This study will enroll 1200 patients over 4 years.

It is known that functionally significant genetic polymorphisms for the cytochrome P450 (CYPs) can contribute to individual differences in response to specific selective serotonin reuptake inhibitors (SSRIs). However, a better understanding of the pharmacogenomics of both PK and PD for SSRI antidepressants will inform clinical practice. Therefore, we propose to evaluate the contribution of pharmacogenomics to variation in response to the highly specific SSRIs citalopram (a racemic mixture) and escitalopram (a chiral compound containing the active S-isomer of citalopram ) by correlating both PK and PD variation for these agents with intragene haplotypes in genes encoding proteins involved in citalopram metabolism, as well as central nervous system (CNS) pathways for monoamine neurotransmitter biosynthesis, metabolism, storage, release, reuptake, and receptors. In the future this "candidate pathway" intragene haplotype genotyping strategy will also be complemented by the application of genome-wide screens performed with DNA from subjects with extreme phenotypes for response to citalopram.

Phenotypes to be measured before and after the initiation of citalopram or escitalopram therapy will include determinations of serum citalopram and metabolite concentrations, treatment response as measured by Hamilton Rating Scale for Depression indices, and number and severity of side effects as determined by structured questionnaires. The hypothesis to be tested is that inherited variation in citalopram metabolism and transport (PK) and/or PD variation as a result of inherited variation in monoamine neurotransmitter biosynthesis, metabolism, reuptake, storage, receptors or signaling contribute to individual variation in citalopram antidepressant efficacy and/or side effects.

Conditions

• Depression

Interventions

DRUG

citalopram and escitalopram

escitalopram tablets starting at 10 mg, increase to 20 mg at 4 weeks if QIDS-C16 \> 5, keep at same dose if QIDS-C16 \< 5. citalopram tablet or solution starting at 2o mg, increase to 40 mg at 4 weeks if QIDS-C16 \> 5, keep at same dose if QIDS-C16 \< 5.

Sponsors & Collaborators

• National Institute of General Medical Sciences (NIGMS)

  collaborator NIH

• National Center for Research Resources (NCRR)

  collaborator NIH

• Mayo Clinic

  lead OTHER

Principal Investigators

• Daniel K Hall-Flavin, M.D. · Mayo Clinic

Study Design

Allocation

NA

Purpose

BASIC_SCIENCE

Masking

NONE

Model

SINGLE_GROUP

Eligibility

Min Age

18 Years

Max Age

85 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2005-03-31

Primary Completion

2013-05-31

Completion

2013-05-31

Countries

• United States

Study Locations