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

University of Groningen

Status and phase: Completed; Phase 4

Conditions: Ultrarapid Metabolizer Due to Cytochrome P450 CYP2D6 Variant; Depression; Intermediate Metabolizer Due to Cytochrome P450 CYP2D6 Variant; Depressive Disorder; Poor Metabolizer Due to Cytochrome P450 CYP2D6 Variant

Treatments: Other: Genotype information accompanied by a drug dosing advice

Study type: Interventional

Funder types: Other

Identifiers

NCT01778907

RUG11003

Details and patient eligibility

About

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

Full 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.

Enrollment: 202 patients

Sex: All

Ages: 60+ years old

Volunteers: No Healthy Volunteers

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).

Trial design

Primary purpose: Screening

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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202 participants in 3 patient groups

Normal genotype- control (NG-C)

No Intervention group

Description:

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 group

Description:

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 group

Description:

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.

Treatment:

Other: Genotype information accompanied by a drug dosing advice