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Cytochrome P450-2D6 Screening Among Elderly Using Antidepressants (CYSCE) (CYSCE)

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT01778907
First Posted: January 29, 2013
Last Update Posted: August 18, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Collaborator:
ZonMw: The Netherlands Organisation for Health Research and Development
Information provided by (Responsible Party):
Prof. Dr. Bob Wilffert, University of Groningen
  Purpose

Depression is common among elderly with an estimated prevalence of 5%. Due to ageing the national burden will double in the coming decade. Antidepressants as TCAs and SSRIs are effective in reducing symptoms, especially in people with severe depression. To optimize treatment efficacy and reduce side effects, the Pharmacogenetics Working Group of the Royal Dutch Pharmacists Association developed guidelines for dose-adaptation, for instance for antidepressants such as nortriptyline and venlafaxine based on their main relevant genotype (CYP2D6) accompanied by Therapeutic Drug Monitoring. Such personalized drug dosing based on pharmacogenetic information at the start of therapy can speed up the titration phase of antidepressants to establish an adequate maintenance dose. However, pharmacogenetic screening programs are expensive and evidence on effects and costs of such a program among elderly antidepressant starters from randomized controlled studies is lacking. The investigators will conduct a pragmatic randomized controlled trial to determine the effects and costs of pharmacogenetic screening information to optimize drug dosing in depressed elderly patients who start with nortriptyline or venlafaxine.

Objective: The primary objective is to determine the effects of pharmacogenetic screening for CYP2D6 on the time to reach adequate blood levels as an accepted proxy for adequate treatment. Secondary objectives include adverse drug reactions and cost-effectiveness

Study design: pragmatic randomized controlled intervention study


Condition Intervention Phase
Depression Depressive Disorder Poor Metabolizer Due to Cytochrome P450 CYP2D6 Variant Intermediate Metabolizer Due to Cytochrome P450 CYP2D6 Variant Ultrarapid Metabolizer Due to Cytochrome P450 CYP2D6 Variant Other: Genotype information accompanied by a drug dosing advice Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Screening
Official Title: Effects and Cost-Effectiveness of Pharmacogenetic Screening Among Elderly Starters With Antidepressants: A Pragmatic Randomized Controlled Trial

Resource links provided by NLM:


Further study details as provided by Prof. Dr. Bob Wilffert, University of Groningen:

Primary Outcome Measures:
  • Serum drug levels of nortriptyline or venlafaxine [ Time Frame: After 2, 4 and 6 weeks treatment started, after the 6th week sampling continues every 2 weeks untill adequate serum drug level is reached with an expected average of 8 weeks ]

    Serum drug levels will be assessed by 'dried blood spot' analysis, blood will be obtained by a fingerprick.

    Adequate serum drug levels is defined as: serum drug levels within the therapeutic window (for nortriptyline 50-150 µg/L, for venlafaxine 200-400 µg/L in combination with stable drug dosing for at least 3 weeks.



Secondary Outcome Measures:
  • Adverse drug events Questionnaire [ Time Frame: At start of treatment and from that moment on, every 2 weeks untill adequate drug serum levels are reached with an expected average of 8 weeks ]
    Adverse drug events will be assessed by a self-reported questionnaire (ASEC). Two different questionnaires will be used, one for the side-effects of venlafaxine and another one for nortriptyline. Both are based one the ASEC questionnaire.

  • Quality of life questionnaire [ Time Frame: After 2, 4 and 6 weeks treatment started and if adequate serum drug levels are not reached in 6 weeks, every 2 weeks, untill adequate serum drug levels are reached with an expected average of 8 weeks ]
    Quality of life will be assessed by the EQ5D questionnaire. This information will also be used for a cost-effectiveness analysis.

  • Productivity Questionnaire [ Time Frame: After 2, 4 and 6 weeks treatment started and if adequate serum drug levels are not reached in 6 weeks, every 2 weeks, untill adequate serum drug levels are reached with an expected average of 8 weeks ]
    Effects on productivity by means of the Short Form-Health and Labour Questionnaire, part Labour. This information will also be used for a cost-effectiveness analysis.

  • Self reported Severity of depression Questionnaire [ Time Frame: After 2, 4 and 6 weeks treatment started and if adequate serum drug levels are not reached in 6 weeks, every 2 weeks, untill adequate serum drug levels are reached with an expected average of 8 weeks ]
    Severity of depression by means of the QIDS-SR.

  • Drug use [ Time Frame: At inclusion, after 2, 4 and 6 weeks after inclusion and if adequate serum drug levels are not reached in 6 weeks, every 2 weeks, untill adequate serum drug level is reached with an expected average of 8 weeks ]
    Drug use, including exact dosing and duration of prescription will be assessed by self reported drug use by the patient. This information will also be used for a cost-effectiveness analysis.

  • Data on health care associated resource use [ Time Frame: After 2, 4 and 6 weeks treatment started and if adequate serum drug levels are not reached in 6 weeks, every 2 weeks, untill adequate serum drug levels are reached with an expected average of 8 weeks ]
    Data on health care associated resource use (e.g. visits to the specific specialists including diagnoses; drug use including exact dosing and durations of prescriptions; hospitalizations, inclusive exact intensities of care; and lab values if relevant). This information will also be used for a cost-effectiveness analysis.


Enrollment: 202
Actual Study Start Date: February 2013
Study Completion Date: June 2017
Primary Completion Date: May 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
No Intervention: Normal genotype- control (NG-C)
In the external control group, an advice for dose adaptation based on patients serum drug levels will be given to the physician according to current daily practice. Allocation to this arm is not based on randomization.
No Intervention: Deviating genotype -control (DG-C)
In the internal control group, an advice for dose adaptation based on patients serum drug levels will be given to the physician according to current daily practice
Experimental: Deviating genotype (DG-I)
In the intervention group, genotype information accompanied by a drug dosing advice will be given to the treating physician. Blood level of the drug will be communicated by a dedicated research team to the treating physician according to daily practice.
Other: Genotype information accompanied by a drug dosing advice
Dosing advices for deviating genotypes (Poor Metabolizer, Intermediate Metabolizer, Ultrarapid Metabolizer)based on the guidelines of the Royal Dutch Pharmacists Association (KNMP).

Detailed Description:
This study is a multicenter randomized controlled trial in which psychiatric elderly care centers participate in the Netherlands. Deviating genotypes are expected to be found in ~30% of the population, therefore the study consist out of two parts. First a basic study in which ~750 patients, starting with nortriptyline or venlafaxine will be genotyped to identify patients with deviating genotypes (Poor, Intermediate or Ultrarapid Metabolizers). Second in the main study 150 patients with a deviating genotype are randomly allocated to two study arms one with and one without information on the genotype. From the extensive metabolizers('normal'genotype) 75 patients are allocated to a third arm as an external control.
  Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:   60 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Major depression according to DSM-IV (296.2x, 296.3x) criteria for which the treating psychiatrist decided to start drug treatment with either nortriptyline or venlafaxine.
  • Competent to understand the informed consent procedure

Exclusion Criteria:

  • Use of clinically relevant CYP2D6 inhibitors
  • Use of clinically relevant CYP2D6 inducers
  • Use of other drugs that affect plasma levels as co-medication
  • Serious hepatic failure
  • Patients for which drug treatment with venlafaxine is started and a GFR < 30 ml/min.
  • Patients with the very rare genotype: Intermediate Metabolizer with duplications (IMDUP).
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01778907


Locations
Netherlands
GGZ WNB
Halsteren, Brabant, Netherlands
Jeroen Bosch Ziekenhuis
's-Hertogenbosch, Netherlands, 5200ME
Reinier van Arkel groep
's-Hertogenbosch, Netherlands, 5201DZ
GGz inGeest
Amsterdam, Netherlands, 1070BB
Parnassia
Den Haag, Netherlands, 2552KS
GGZ Centraal
Ermelo, Netherlands
Lentis
Groningen, Netherlands
University Medical Centre Groningen
Groningen, Netherlands
GGZ-NHN
Heiloo, Netherlands, 1851NG
GGZ Friesland
Leeuwarden, Netherlands
Isala Klinieken
Zwolle, Netherlands
Sponsors and Collaborators
University of Groningen
ZonMw: The Netherlands Organisation for Health Research and Development
Investigators
Principal Investigator: Bob Wilffert, Prof. Dr. University of Groningen
Principal Investigator: Eelko Hak, Prof. Dr. University of Groningen
  More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Prof. Dr. Bob Wilffert, University of Groningen
ClinicalTrials.gov Identifier: NCT01778907     History of Changes
Other Study ID Numbers: RUG11003
First Submitted: January 22, 2013
First Posted: January 29, 2013
Last Update Posted: August 18, 2017
Last Verified: August 2017

Keywords provided by Prof. Dr. Bob Wilffert, University of Groningen:
Pharmacogenetics
Depression
Depressive Disorder
Cytochrome P-450 CYP2D6
Antidepressive Agents, Tricyclic
Antidepressive Agents, Second-Generation
Poor Metabolizer Due to Cytochrome P450 CYP2D6 Variant
Intermediate Metabolizer Due to Cytochrome P450 CYP2D6 Variant
Ultrarapid Metabolizer Due to Cytochrome P450 CYP2D6 Variant
Multicenter studies

Additional relevant MeSH terms:
Depression
Depressive Disorder
Behavioral Symptoms
Mood Disorders
Mental Disorders
Antidepressive Agents
Antidepressive Agents, Tricyclic
Antidepressive Agents, Second-Generation
Psychotropic Drugs