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

NCT ID: NCT01778907

Last Updated: 2017-08-18

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 202 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-02-28
• Study Completion Date: 2017-06-30

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

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.

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: SCREENING
• Blinding Strategy: NONE

Study Groups

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.

Group Type: NO_INTERVENTION

No interventions assigned to this group

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

Group Type: NO_INTERVENTION

No interventions assigned to this group

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.

Group Type: EXPERIMENTAL

Genotype information accompanied by a drug dosing advice

Intervention Type: OTHER

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

Interventions

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).

Intervention Type: OTHER

Eligibility 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).

• Minimum Eligible Age: 60 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

ZonMw: The Netherlands Organisation for Health Research and Development

OTHER

Sponsor Role: collaborator

University of Groningen

OTHER

Sponsor Role: lead

Responsible Party

Prof. Dr. Bob Wilffert

Prof. Dr. Bob Wilffert

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Bob Wilffert, Prof. Dr.

Role: PRINCIPAL_INVESTIGATOR

University of Groningen

Eelko Hak, Prof. Dr.

Role: PRINCIPAL_INVESTIGATOR

University of Groningen

Locations

GGZ WNB

Halsteren, North Brabant, Netherlands

Jeroen Bosch Ziekenhuis

's-Hertogenbosch, , Netherlands

Reinier van Arkel groep

's-Hertogenbosch, , Netherlands

GGz inGeest

Amsterdam, , Netherlands

GGZ Centraal

Ermelo, , Netherlands

Lentis

Groningen, , Netherlands

University Medical Centre Groningen

Groningen, , Netherlands

GGZ-NHN

Heiloo, , Netherlands

GGZ Friesland

Leeuwarden, , Netherlands

Parnassia

The Hague, , Netherlands

Isala Klinieken

Zwolle, , Netherlands

Countries

Netherlands

References

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.

Reference Type: DERIVED

PMID: 25636328 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 24493333 (View on PubMed)

Other Identifiers

RUG11003

Identifier Type: -

Identifier Source: org_study_id