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

Effects and Cost-Effectiveness of Pharmacogenetic Screening Among Elderly Starters With Antidepressants: A Pragmatic Randomized Controlled Trial

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

Study Overview

• Status: Completed
• Conditions: Depressive Disorder; Depression; Poor Metabolizer Due to Cytochrome P450 CYP2D6 Variant; Ultrarapid Metabolizer Due to Cytochrome P450 CYP2D6 Variant; Intermediate Metabolizer Due to Cytochrome P450 CYP2D6 Variant
• Intervention / Treatment: Other: Genotype information accompanied by a drug dosing advice

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.

• Study Type: Interventional
• Enrollment (Actual): 202
• Phase: Phase 4

Contacts and Locations

Study Locations

• Netherlands
  • 's-Hertogenbosch, Netherlands, 5200ME
    • Jeroen Bosch Ziekenhuis
  • 's-Hertogenbosch, Netherlands, 5201DZ
    • Reinier van Arkel groep
  • Amsterdam, Netherlands, 1070BB
    • GGz inGeest
  • Den Haag, Netherlands, 2552KS
    • Parnassia
  • Ermelo, Netherlands
    • GGz Centraal
  • Groningen, Netherlands
    • University Medical Centre Groningen
  • Groningen, Netherlands
    • Lentis
  • Heiloo, Netherlands, 1851NG
    • GGZ-NHN
  • Leeuwarden, Netherlands
    • GGZ Friesland
  • Zwolle, Netherlands
    • Isala Klinieken
  • Brabant
    • Halsteren, Brabant, Netherlands
      • GGZ WNB

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 60 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Screening
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Serum drug levels of nortriptyline or venlafaxine	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.	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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse drug events Questionnaire	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.	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
Quality of life questionnaire	Quality of life will be assessed by the EQ5D questionnaire. This information will also be used for a cost-effectiveness analysis.	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
Productivity Questionnaire	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.	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
Self reported Severity of depression Questionnaire	Severity of depression by means of the QIDS-SR.	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
Drug use	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.	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
Data on health care associated resource use	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.	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

Collaborators and Investigators

• Sponsor: University of Groningen
• Collaborators: 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

Publications and helpful links

General Publications

• Berm EJ, Hak E, Postma M, Boshuisen M, Breuning L, Brouwers JR, Dhondt T, Jansen PA, Kok RM, Maring JG, van Marum R, Mulder H, Voshaar RC, Risselada AJ, Venema H, Vleugel L, Wilffert B. Effects and cost-effectiveness of pharmacogenetic screening for CYP2D6 among older adults starting therapy with nortriptyline or venlafaxine: study protocol for a pragmatic randomized controlled trial (CYSCEtrial). Trials. 2015 Jan 31;16:37. doi: 10.1186/s13063-015-0561-0.
• Berm EJ, Brummel-Mulder E, Paardekooper J, Hak E, Wilffert B, Maring JG. Determination of venlafaxine and O-desmethylvenlafaxine in dried blood spots for TDM purposes, using LC-MS/MS. Anal Bioanal Chem. 2014 Apr;406(9-10):2349-53. doi: 10.1007/s00216-014-7619-9. Epub 2014 Feb 4.

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2013
• Primary Completion (Actual): May 1, 2017
• Study Completion (Actual): June 1, 2017

Study Registration Dates

• First Submitted: January 22, 2013
• First Submitted That Met QC Criteria: January 25, 2013
• First Posted (Estimate): January 29, 2013

Study Record Updates

• Last Update Posted (Actual): August 18, 2017
• Last Update Submitted That Met QC Criteria: August 15, 2017
• Last Verified: August 1, 2017

More Information

Terms related to this study

• Keywords: Depression; Depressive Disorder; Pharmacogenetics; Antidepressive Agents, Second-Generation; Cytochrome P-450 CYP2D6; Antidepressive Agents, Tricyclic; 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: Behavioral Symptoms; Mental Disorders; Mood Disorders; Depression; Depressive Disorder
• Other Study ID Numbers: RUG11003