Pharmacodynamics and Pharmacokinetics of Citalopram and Escitalopram (PGRN-SSRI)

This study has been completed.
Sponsor:
Collaborators:
Information provided by (Responsible Party):
Daniel K. Hall-Flavin, Mayo Clinic
ClinicalTrials.gov Identifier:
NCT00613470
First received: January 30, 2008
Last updated: December 16, 2013
Last verified: December 2013
  Purpose

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.


Condition Intervention Phase
Depression
Drug: citalopram and escitalopram
Phase 1

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Basic Science
Official Title: Pharmacodynamics and Pharmacokinetics of Citalopram and Escitalopram

Resource links provided by NLM:


Further study details as provided by Mayo Clinic:

Primary Outcome Measures:
  • The change in HRS-D17 will constitute the major research outcome measure used to assess drug response phenotype because it is widely used in psychiatric research, making it possible to perform comparisons with other studies. [ Time Frame: baseline, 4 week and 8 week visits ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • QIDS-C16 (obtained by the CRC), and the QIDS-SR16 [ Time Frame: week 0, 4, and 8 ] [ Designated as safety issue: No ]

Enrollment: 927
Study Start Date: March 2005
Study Completion Date: May 2013
Primary Completion Date: May 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Citalopram and escitalopram

Citalopram tablet or solution starting at 20 mg, increase to 40 mg at 4 weeks if QIDS-C16 > 5, keep at same dose if QIDS-C16 < 5.

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.

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.


  Eligibility

Ages Eligible for Study:   18 Years to 85 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Outpatients or inpatients with nonpsychotic MDD.
  2. A score of >14 on the HRS-D17 (equivalent to 10 or greater on PHQ-9 which is used in primary care to assess depression) given that when medication exceeds the effect of placebo in primary care participants have a HRS-D17 >12. We added 2 HRS-D17 points to take into account the possibility of measurement error.
  3. Outpatients or inpatients for whom antidepressant treatment is deemed appropriate by the treating clinician.
  4. Subjects who are between 18-85 years of age.
  5. Participants who have general medical conditions (GMCs) which could conceivably be physiologically causing their depressive symptoms will receive treatment as usual for their GMCs as well as for their MDD.

Exclusion Criteria:

  • Subjects with medical contraindications that preclude citalopram or escitalopram treatment and those who have previously failed to respond to citalopram or escitalopram will be excluded. In addition, patients with schizophrenia, schizoaffective disorder, or who have Bipolar I disorder will be excluded because they have a primary psychiatric condition that requires a different initial treatment. Subjects currently on antidepressant medication with subtherapeutic results in terms of depression management will undergo a medication taper and discontinuation prior to initiation of citalopram or escitalopram treatment. The subject will be closely monitored by the primary physician or psychiatrist during the medication taper and discontinuation phase. The medication taper is left upto the treating physician's or psychiatrist's discretion. Study subjects who cannot be safely tapered from their medication or experience adverse effects during the taper will be excluded from the study. Study subjects using their antidepressant medication for management of nicotine dependence, chronic pain, migraine prophylaxis or other diagnoses will not be eligible for the study. Trazodone, Melatonin, and Diphenhydramine may be used as rescue medications for insomnia. Benzodiazepines may be used for treatment of anxiety and atomoxetine may be used for the treatment of attention deficit disorder. Study subjects currently on antipsychotic medications (e.g., typical and atypical antipsychotic drugs) and mood stabilizing agents (e.g., lithium, carbamazepine, valproate, lamotrigine, gabapentin, or other anticonvulsants) are not eligible for the study with the exception of those starting quetiapine after baseline. Subjects unable to give informed consent are excluded. Pregnant subjects will be excluded.
  Contacts and Locations
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Please refer to this study by its ClinicalTrials.gov identifier: NCT00613470

Locations
United States, Minnesota
Mayo Clinic
Rochester, Minnesota, United States, 55905
Sponsors and Collaborators
Mayo Clinic
Investigators
Principal Investigator: Daniel K Hall-Flavin, M.D. Mayo Clinic
  More Information

No publications provided by Mayo Clinic

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Daniel K. Hall-Flavin, MD, Assistant Professor of Psychiatry, College of Medicine, Mayo Clinic
ClinicalTrials.gov Identifier: NCT00613470     History of Changes
Other Study ID Numbers: 170-05, U01GM061388, UL1RR024150
Study First Received: January 30, 2008
Last Updated: December 16, 2013
Health Authority: United States: Institutional Review Board

Keywords provided by Mayo Clinic:
Depression
Antidepressants

Additional relevant MeSH terms:
Depression
Depressive Disorder
Behavioral Symptoms
Mood Disorders
Mental Disorders
Citalopram
Dexetimide
Serotonin Uptake Inhibitors
Neurotransmitter Uptake Inhibitors
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Serotonin Agents
Physiological Effects of Drugs
Antidepressive Agents, Second-Generation
Antidepressive Agents
Psychotropic Drugs
Central Nervous System Agents
Therapeutic Uses
Antiparkinson Agents
Anti-Dyskinesia Agents
Parasympatholytics
Autonomic Agents
Peripheral Nervous System Agents
Muscarinic Antagonists
Cholinergic Antagonists
Cholinergic Agents

ClinicalTrials.gov processed this record on September 15, 2014