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

NCT01778907 | Completed Phase 4

• 1 other identifier: RUG11003
• Study Type: interventional
• Target: 202
• Locations: 1 country
• Sites: 11

Brief Summary

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

Conditions

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

Keywords

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

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (6)

• Adverse drug events 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

  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

  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

  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

  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

Study Arms (3)

Normal genotype- control (NG-C)

NO INTERVENTION

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.

Deviating genotype -control (DG-C)

NO INTERVENTION

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

Deviating genotype (DG-I)

EXPERIMENTAL

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

Interventions

Genotype information accompanied by a drug dosing advice OTHER

Dosing advices for deviating genotypes (Poor Metabolizer, Intermediate Metabolizer, Ultrarapid Metabolizer)based on the guidelines of the Royal Dutch Pharmacists Association (KNMP).

Deviating genotype (DG-I)

Eligibility Criteria

• Age: 60 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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).

Sponsors & Collaborators

• University of Groningen: lead
• ZonMw: The Netherlands Organisation for Health Research and Development: collaborator

Study Sites (11)

GGZ WNB

Halsteren, North Brabant, Netherlands

Location

Jeroen Bosch Ziekenhuis

's-Hertogenbosch, 5200ME, Netherlands

Location

Reinier van Arkel groep

's-Hertogenbosch, 5201DZ, Netherlands

Location

GGz inGeest

Amsterdam, 1070BB, Netherlands

Location

GGZ Centraal

Ermelo, Netherlands

Location

Lentis

Groningen, Netherlands

Location

University Medical Centre Groningen

Groningen, Netherlands

Location

GGZ-NHN

Heiloo, 1851NG, Netherlands

Location

GGZ Friesland

Leeuwarden, Netherlands

Location

Parnassia

The Hague, 2552KS, Netherlands

Location

Isala Klinieken

Zwolle, Netherlands

Location

Related Publications (2)

• 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.

  PMID: 25636328 DERIVED

• 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.

  PMID: 24493333 DERIVED

MeSH Terms

Conditions

Depression; Depressive Disorder

Condition Hierarchy (Ancestors)

Behavioral Symptoms; Behavior; Mood Disorders; Mental Disorders

Study Officials

• Bob Wilffert, Prof. Dr.

  University of Groningen

  PRINCIPAL INVESTIGATOR

• Eelko Hak, Prof. Dr.

  University of Groningen

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: SCREENING
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Prof. Dr. Bob Wilffert

Study Record Dates

• First Submitted: January 22, 2013
• First Posted: January 29, 2013
• Study Start: February 1, 2013
• Primary Completion: May 1, 2017
• Study Completion: June 1, 2017
• Last Updated: August 18, 2017

Record last verified: 2017-08

Locations

NL (11)