Clinical trial NCT01778907: Cytochrome P450-2D6 Screening Among Elderly Using Antidepressants (CYSCE)
Official title: Effects and Cost-Effectiveness of Pharmacogenetic Screening Among Elderly Starters With Antidepressants: A Pragmatic Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
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
Lead sponsor: University of Groningen
Sponsor class: OTHER
Collaborators: name: ZonMw: The Netherlands Organisation for Health Research and Development
First posted: 2013-01-29
Enrollment: 202
Sex: ALL
Minimum age (years): 60
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: SCREENING

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.

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).

Primary outcomes:
measure: Serum drug levels of nortriptyline or venlafaxine
timeFrame: 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:
measure: Adverse drug events Questionnaire
timeFrame: 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
measure: Quality of life questionnaire
timeFrame: 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
measure: Productivity Questionnaire
timeFrame: 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
measure: Self reported Severity of depression Questionnaire
timeFrame: 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
measure: Drug use
timeFrame: 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
measure: Data on health care associated resource use
timeFrame: 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
Other outcomes:
Locations:
city: Halsteren
country: Netherlands
facility: GGZ WNB
state: Brabant
city: 's-Hertogenbosch
country: Netherlands
facility: Jeroen Bosch Ziekenhuis
city: 's-Hertogenbosch
country: Netherlands
facility: Reinier van Arkel groep
city: Amsterdam
country: Netherlands
facility: GGz inGeest
city: Den Haag
country: Netherlands
facility: Parnassia
city: Ermelo
country: Netherlands
facility: GGZ Centraal
city: Groningen
country: Netherlands
facility: Lentis
city: Groningen
country: Netherlands
facility: University Medical Centre Groningen
city: Heiloo
country: Netherlands
facility: GGZ-NHN
city: Leeuwarden
country: Netherlands
facility: GGZ Friesland
city: Zwolle
country: Netherlands
facility: Isala Klinieken
Study officials:
affiliation: University of Groningen
name: Bob Wilffert, Prof. Dr.
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Groningen
name: Eelko Hak, Prof. Dr.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.