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

Study Overview
=================
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.

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

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

Intervention / Treatment
-----------------
* Other: Genotype information accompanied by a drug dosing advice


Participation Criteria
=================
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).

Ages Eligible for Study
-----------------
Minimum Age: 60 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Normal genotype- control (NG-C)<br>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)<br>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)<br>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<br>* Dosing advices for deviating genotypes (Poor Metabolizer, Intermediate Metabolizer, Ultrarapid Metabolizer)based on the guidelines of the Royal Dutch Pharmacists Association (KNMP).<br>|

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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
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