Pharmacogenetics Informed Tricyclic Antidepressant Dosing (PITA) (PITA)

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

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.

Study Overview

• Status: Completed
• Conditions: Depressive Disorder, Major
• Intervention / Treatment: Drug: TCA treatment

• Study Type: Interventional
• Enrollment (Actual): 125
• Phase: Phase 4

Contacts and Locations

Study Locations

• Netherlands
  • Nijmegen, Netherlands, 6500 HB
    • Radboudumc Dept of Psychiatry

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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:

1. Psychotic depression
2. Bipolar I or II disorder.
3. Schizophrenia or other primary psychotic disorder.
4. Drug or alcohol dependence in the past 3 months.
5. Mental Retardation (IQ < 80).
6. For women: pregnancy or possibility for pregnancy without adequate contraceptive measures.
7. Breastfeeding.
8. Serious medical illness affecting the CNS, including but not restricted to M Parkinson, SLE, brain tumour, CVA.
9. Relevant medical illness as contra-indication for TCA use, such as recent myocardial infarction.
10. 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: SINGLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Genotype-guided TCA treatment; Genotype guided dosing of the TCAs in patients with a PM,IM,EM or UM phenotype based on pharmacogenetic test.	Drug: TCA treatment; 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).
ACTIVE_COMPARATOR: Standard TCA treatment; Standard dosing of TCA in patients with a PM,IM, EM or UM phenotype based on pharmacogenetic test	Drug: TCA treatment; 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).

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Radboud University Medical Center
• Collaborators: ZonMw: The Netherlands Organisation for Health Research and Development
• Investigators: Principal Investigator: Joost Janzing, MD PhD, Radboudumc Dept of Psychiatry

Study record dates

Study Major Dates

• Study Start (ACTUAL): May 23, 2018
• Primary Completion (ACTUAL): February 2, 2022
• Study Completion (ACTUAL): July 13, 2022

Study Registration Dates

• First Submitted: May 23, 2018
• First Submitted That Met QC Criteria: June 6, 2018
• First Posted (ACTUAL): June 7, 2018

Study Record Updates

• Last Update Posted (ACTUAL): November 29, 2022
• Last Update Submitted That Met QC Criteria: November 28, 2022
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Keywords: Pharmacogenetics; Antidepressive Agents
• Additional Relevant MeSH Terms: Mental Disorders; Mood Disorders; Depressive Disorder; Depressive Disorder, Major
• Other Study ID Numbers: 848016004

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No