DepressionPhase 4CYSCENCT01778907
Cytochrome P450-2D6 Screening Among Elderly Using Antidepressants (CYSCE)
A Phase 4 study testing Genotype information accompanied by a drug dosing advice in people with Depression and Depressive Disorder, run by University of Groningen at 11 sites in Netherlands.
Trial 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. Read more about this study
- Who is it for?
- Ages 60 years and older
- Conditions the study is for
- Depression, Depressive Disorder, Poor Metabolizer Due to Cytochrome P450 CYP2D6 Variant
- What is being tested?
- Genotype information accompanied by a drug dosing advice
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 202 participants
- Where
- 11 sitesNetherlands
- Study dates
- Feb 2013to Jun 2017
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 60 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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).
Trial locations and contacts
11 sites in 1 country.
11 sites in 1 country
Netherlands11 sites
Jeroen Bosch Ziekenhuis
's-Hertogenbosch, 5200ME
Reinier van Arkel groep
's-Hertogenbosch, 5201DZ
GGz inGeest
Amsterdam, 1070BB
GGZ Centraal
Ermelo
Lentis
Groningen
University Medical Centre Groningen
Groningen
GGZ WNB
Halsteren, North Brabant
GGZ-NHN
Heiloo, 1851NG
GGZ Friesland
Leeuwarden
Parnassia
The Hague, 2552KS
Isala Klinieken
Zwolle
About this study
Official title: 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
Read the 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
- Being tested
- Genotype information accompanied by a drug dosing advice
- 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
- Medical subject headings
- Depression, Depressive Disorder
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Genotype information accompanied by a drug dosing adviceOther
Dosing advices for deviating genotypes (Poor Metabolizer, Intermediate Metabolizer, Ultrarapid Metabolizer)based on the guidelines of the Royal Dutch Pharmacists Association (KNMP).
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: Other: Genotype information accompanied by a drug dosing advice |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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
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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted29 Jan 2013 (estimated)
- Study startFeb 2013
- Primary completionMay 2017
- Study completionJun 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for DepressionStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Screening
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 202 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Groningen
- Sponsor type
- University, hospital or other
- Collaborators
- ZonMw: The Netherlands Organisation for Health Research and Development
- Responsible party
- Principal investigator, Prof. Dr. Bob Wilffert, University of Groningen
- Investigators
- Bob Wilffert, Prof. Dr., Principal investigator, University of GroningenEelko Hak, Prof. Dr., Principal investigator, University of Groningen
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01778907
- Sponsor's protocol ID
- RUG11003
- Acronym
- CYSCE
- Status last verified
- Aug 2017
- First submitted
- 22 Jan 2013
- Last updated
- 18 Aug 2017
- Results posted
- No
- Data monitoring committee
- No
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.
PubMed 25636328Berm 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.
PubMed 24493333
Study at a glance
From the registry record, last updated by the sponsor on 18 Aug 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Effects and Cost-Effectiveness of Pharmacogenetic Screening Among Elderly Starters With Antidepressants: A Pragmatic Randomized Controlled Trial
- ClinicalTrials.gov ID
- NCT01778907
- Acronym / sponsor ID
- CYSCE / RUG11003
- 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
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 202 participants (actual)
- Lead sponsor
- University of GroningenUniversity, hospital or other
- Collaborators
- ZonMw: The Netherlands Organisation for Health Research and Development
- Study start
- Feb 2013 (actual)
- Primary completion
- May 2017 (actual)
- Study completion
- Jun 2017 (actual)
- First posted
- 29 Jan 2013 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Screening
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| 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 | Other: Genotype information accompanied by a drug dosing adviceIn 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. |
Who may qualify
- Ages
- 60 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (2 listed)
- 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
Key exclusion criteria (6 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Genotype information accompanied by a drug dosing adviceDosing advices for deviating genotypes (Poor Metabolizer, Intermediate Metabolizer, Ultrarapid Metabolizer)based on the guidelines of the Royal Dutch Pharmacists Association (KNMP). | Other | Deviating genotype (DG-I) |
Primary outcome
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.
6 secondary outcomes
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
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
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
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
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
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
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 18 Aug 2017.
- Derived from this study: PubMed 25636328Berm 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.
- Derived from this study: PubMed 24493333Berm 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Bob Wilffert, Prof. Dr. principal investigator
University of Groningen
Eelko Hak, Prof. Dr. principal investigator
University of Groningen
11 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Genotype information accompanied by a drug dosing advice in people with Depression and Depressive Disorder, run by University of Groningen at 11 sites in Netherlands.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 2 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 18 Aug 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 11 sites in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01778907, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Aug 2017; AzTrials last refreshed its copy on 30 Oct 2026.