Pharmacogenetics Informed Tricyclic Antidepressant Dosing (PITA)

Study Overview
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Brief Summary
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Tricyclic Antidepressants (TCA's) are the cornerstone of treatment for patients with severe Major Depressive Disorder (sMDD). Current dosing is guided by repeated measurements of blood levels. Compared to patients with a normal metabolization function, for those with increased CYP450 enzyme activity it takes longer to reach a therapeutic drug level. The consequent delay of drug efficacy is associated with a prolonged treatment period, increased risk of suicidal behaviour and eventually lower remission rates. For those with reduced CYP450 activity higher rates of side effects are expected. An innovative TCA dosing strategy, taking the genetic variants of CYP2D6 and CYP2C19 into account may help to reduce the above mentioned problems. Up till now, the current guidelines for CYP450 pharmacogenetics based TCA dosing have not been systematically evaluated for effectiveness and cost-effectiveness in larger groups of patients. Such evaluation is necessary before broad implementation of these guidelines can be advocated. In the present study 200 patients with sMDD who are treated with nortriptyline, clomipramine or imipramine are randomized over two strategies: dosing based both on CYP450-genotype and blood level measurements and dosing as usual (standard doses plus blood levels). We hypothesize that genotype informed dosing results in faster attainment of therapeutic drug levels, lower rates of side effects, earlier symptom relief and lower levels of health- and working related costs.

Official Title
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Pharmacogenetics to Improve Personalized Antidepressant Dosing in Patients With Severe Depression;a Randomized Controlled Trial Using Tricyclic Antidepressants

Conditions
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Depressive Disorder, Major

Intervention / Treatment
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* Drug: TCA treatment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients are in- and outpatients, having a primary diagnosis of severe major depressive disorder (SCID-I diagnosis in agreement with DSM-5 criteria and a Hamilton Rating Scale for Depression score ≥ 19 (HAM-D-17-item version), aged 18-65 years, who, according to their physician, are eligible for treatment with a TCA (Nortriptyline (NOR), Clomipramine (CLOMI) or Imipramine (IMI)). The choice of the specific TCA is at the discretion of the physician in attendance. Exclusion Criteria: Psychotic depression Bipolar I or II disorder. Schizophrenia or other primary psychotic disorder. Drug or alcohol dependence in the past 3 months. Mental Retardation (IQ < 80). For women: pregnancy or possibility for pregnancy without adequate contraceptive measures. Breastfeeding. Serious medical illness affecting the CNS, including but not restricted to M Parkinson, SLE, brain tumour, CVA. Relevant medical illness as contra-indication for TCA use, such as recent myocardial infarction. Other drugs influencing the pharmacokinetics of the TCAs as based on a list of interacting drugs. In case of psychotropic co-medication only a benzodiazepine in a dose equivalent up to 4 mg lorazepam will be allowed.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This study is a randomized controlled clinical trial.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Genotype-guided TCA treatment<br>Genotype guided dosing of the TCAs in patients with a PM,IM,EM or UM phenotype based on pharmacogenetic test. | Drug: TCA treatment<br>* All patients fulfilling inclusion criteria will be genotyped for CYP2C19 and CYP2D6 genes. Based on the genetic test results patients will be classified into a metabolisation phenotype (UM, EM, IM or PM).<br>|
| Active Comparator: Standard TCA treatment<br>Standard dosing of TCA in patients with a PM,IM, EM or UM phenotype based on pharmacogenetic test | Drug: TCA treatment<br>* All patients fulfilling inclusion criteria will be genotyped for CYP2C19 and CYP2D6 genes. Based on the genetic test results patients will be classified into a metabolisation phenotype (UM, EM, IM or PM).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to TCA plasma concentration in the therapeutic range | Time to TCA plasma concentration in the therapeutic range | During the 7 weeks treatment phase | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Reduction of depressive symptoms | HAM-D reduction | Difference between measurements at baseline and after 7 weeks of treatment | 
| Highest level of side effects | summary measure: FIBSER | During the 7 weeks treatment phase | 
| Economic Evaluation (Cost Effectiveness) | Utility based on EQ5D5L measurement | 26 weeks after the start of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pharmacogenetics, Antidepressive Agents