Pharmacogenetics Informed Tricyclic Antidepressant Dosing (PITA)

NCT03548675 | Completed Phase 4 DMC

• 1 other identifier: 848016004
• Study Type: interventional
• Target: 125
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Depressive Disorder, Major

Keywords

Pharmacogenetics; Antidepressive Agents

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (3)

• Reduction of depressive symptoms

  Difference between measurements at baseline and after 7 weeks of treatment

• Highest level of side effects

  During the 7 weeks treatment phase

• Economic Evaluation (Cost Effectiveness)

  26 weeks after the start of treatment

Study Arms (2)

Genotype-guided TCA treatment

EXPERIMENTAL

Genotype guided dosing of the TCAs in patients with a PM,IM,EM or UM phenotype based on pharmacogenetic test.

Drug: TCA treatment

Standard TCA treatment

ACTIVE COMPARATOR

Standard dosing of TCA in patients with a PM,IM, EM or UM phenotype based on pharmacogenetic test

Drug: TCA treatment

Interventions

TCA treatment DRUG

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).

Genotype-guided TCA treatment; Standard TCA treatment

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Radboud University Medical Center: lead
• ZonMw: The Netherlands Organisation for Health Research and Development: collaborator

Study Sites (1)

Radboudumc Dept of Psychiatry

Nijmegen, 6500 HB, Netherlands

Location

Related Publications (2)

• Dalhuisen I, Biemans T, Vos CF, Hark ST, van Oostrom I, Spijker J, Wijnen B, van Exel E, van Mierlo H, de Waardt D, Arns M, Tendolkar I, Janzing J, van Eijndhoven P. A comparison between rTMS and antidepressant medication on depressive symptom clusters in treatment-resistant depression. Eur Arch Psychiatry Clin Neurosci. 2025 Sep;275(6):1799-1807. doi: 10.1007/s00406-025-02012-0. Epub 2025 Apr 23.

  PMID: 40266345 DERIVED

• Vos CF, Ter Hark SE, Schellekens AFA, Spijker J, van der Meij A, Grotenhuis AJ, Mihaescu R, Kievit W, Donders R, Aarnoutse RE, Coenen MJH, Janzing JGE. Effectiveness of Genotype-Specific Tricyclic Antidepressant Dosing in Patients With Major Depressive Disorder: A Randomized Clinical Trial. JAMA Netw Open. 2023 May 1;6(5):e2312443. doi: 10.1001/jamanetworkopen.2023.12443.

  PMID: 37155164 DERIVED

MeSH Terms

Conditions

Depressive Disorder, Major

Condition Hierarchy (Ancestors)

Depressive Disorder; Mood Disorders; Mental Disorders

Study Officials

• Joost Janzing, MD PhD

  Radboudumc dept of Psychiatry

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Masking Details: Prescribing physicians will be unblinded for the genotype and the resulting metabolization phenotype. Outcome assessments will be performed by blinded researchers and the patients themselves (self-assessments).
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: This study is a randomized controlled clinical trial.

Study Record Dates

• First Submitted: May 23, 2018
• First Posted: June 7, 2018
• Study Start: May 23, 2018
• Primary Completion: February 2, 2022
• Study Completion: July 13, 2022
• Last Updated: November 29, 2022

Record last verified: 2022-11

Locations

NL (1)