Clinical trial NCT03548675: Pharmacogenetics Informed Tricyclic Antidepressant Dosing (PITA)
Official title: Pharmacogenetics to Improve Personalized Antidepressant Dosing in Patients With Severe Depression;a Randomized Controlled Trial Using Tricyclic Antidepressants
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Depressive Disorder, Major
Keywords: Pharmacogenetics
Antidepressive Agents
Lead sponsor: Radboud University Medical Center
Sponsor class: OTHER
Collaborators: name: ZonMw: The Netherlands Organisation for Health Research and Development
First posted: 2018-06-07
Enrollment: 125
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This study is a randomized controlled clinical trial.
Primary purpose: TREATMENT

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.


Eligibility criteria: 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.

Primary outcomes:
measure: Time to TCA plasma concentration in the therapeutic range
timeFrame: During the 7 weeks treatment phase
Secondary outcomes:
measure: Reduction of depressive symptoms
timeFrame: Difference between measurements at baseline and after 7 weeks of treatment
measure: Highest level of side effects
timeFrame: During the 7 weeks treatment phase
measure: Economic Evaluation (Cost Effectiveness)
timeFrame: 26 weeks after the start of treatment
Other outcomes:
Locations:
city: Nijmegen
country: Netherlands
facility: Radboudumc Dept of Psychiatry
Study officials:
affiliation: Radboudumc dept of Psychiatry
name: Joost Janzing, MD PhD
role: PRINCIPAL_INVESTIGATOR
References: