Pharmacogenetics Informed Tricyclic Antidepressant Dosing (PITA)

Depressive Disorder, Major Clinical Trial

— PITA  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03548675
• Other study ID #: 848016004
• Status: Completed
• Phase: Phase 4
• Start date: May 23, 2018
• Est. completion date: July 13, 2022

Study information

• Verified date: November 2022
• Source: Radboud University Medical Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 125
• Est. completion date: July 13, 2022
• Est. primary completion date: February 2, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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.

Related Conditions & MeSH terms

• Depressive Disorder
• Depressive Disorder, Major

Intervention

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).

Locations

Country	Name	City	State
Netherlands	Radboudumc Dept of Psychiatry	Nijmegen

Sponsors (2)

Lead Sponsor	Collaborator
Radboud University Medical Center	ZonMw: The Netherlands Organisation for Health Research and Development

Country where clinical trial is conducted

Netherlands, 

Outcome

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