Depressive Disorder, MajorPhase 4PITANCT03548675
Pharmacogenetics Informed Tricyclic Antidepressant Dosing (PITA)
A Phase 4 study testing TCA treatment in people with Depressive Disorder, Major, run by Radboud University Medical Center at 1 site in Netherlands.
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. Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- Depressive Disorder, Major
- What is being tested?
- TCA treatment
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 125 participants
- Where
- 1 siteNetherlands
- Study dates
- 23 May 2018to 13 Jul 2022
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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.
Show all 10Show fewer
- 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.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: 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.
- Conditions
- Depressive Disorder, Major
- Being tested
- TCA treatment
- Keywords
- Pharmacogenetics, Antidepressive Agents
- Medical subject headings
- Depressive Disorder, Major
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
TCA treatmentDrug
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).
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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 Receives: Drug: TCA treatment |
What is being measured
The primary outcome is the main question the study is designed to answer.
Time to TCA plasma concentration in the therapeutic range
Time to TCA plasma concentration in the therapeutic range
Measured: During the 7 weeks treatment phase
Secondary outcomes (3)
Reduction of depressive symptoms
HAM-D reduction
Measured: Difference between measurements at baseline and after 7 weeks of treatment
Highest level of side effects
summary measure: FIBSER
Measured: During the 7 weeks treatment phase
Economic Evaluation (Cost Effectiveness)
Utility based on EQ5D5L measurement
Measured: 26 weeks after the start of treatment
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted7 Jun 2018
- Study start23 May 2018
- Primary completion2 Feb 2022
- Study completion13 Jul 2022
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Depressive Disorder, MajorStudies of the same condition, open and under way.
- More trials run by Radboud University Medical CenterThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- This study is a randomized controlled clinical trial.
- Masking
- Single blind
- Who is masked
- Outcomes assessor
- Enrolment
- 125 participants (actual)
Sponsor and investigators
- Lead sponsor
- Radboud University Medical Center
- Sponsor type
- University, hospital or other
- Collaborators
- ZonMw: The Netherlands Organisation for Health Research and Development
- Responsible party
- Sponsor
- Investigators
- Joost Janzing, MD PhD, Principal investigator, Radboudumc dept of Psychiatry
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03548675
- Sponsor's protocol ID
- 848016004
- Acronym
- PITA
- Status last verified
- Nov 2022
- First submitted
- 23 May 2018
- Last updated
- 29 Nov 2022
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
Publications
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.
PubMed 40266345Vos 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.
PubMed 37155164
Study at a glance
From the registry record, last updated by the sponsor on 29 Nov 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Pharmacogenetics to Improve Personalized Antidepressant Dosing in Patients With Severe Depression;a Randomized Controlled Trial Using Tricyclic Antidepressants
- ClinicalTrials.gov ID
- NCT03548675
- Acronym / sponsor ID
- PITA / 848016004
- Conditions
- Depressive Disorder, Major
- Keywords
- Pharmacogenetics, Antidepressive Agents
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 125 participants (actual)
- Lead sponsor
- Radboud University Medical CenterUniversity, hospital or other
- Collaborators
- ZonMw: The Netherlands Organisation for Health Research and Development
- Study start
- 23 May 2018 (actual)
- Primary completion
- 2 Feb 2022 (actual)
- Study completion
- 13 Jul 2022 (actual)
- First posted
- 7 Jun 2018 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind (outcomes assessor)
- Number of arms
- 2
- Model description
- This study is a randomized controlled clinical trial.
| Arm | Type | Receives |
|---|---|---|
| Genotype-guided TCA treatment | Experimental | Drug: TCA treatmentGenotype guided dosing of the TCAs in patients with a PM,IM,EM or UM phenotype based on pharmacogenetic test. |
| Standard TCA treatment | Active comparator | Drug: TCA treatmentStandard dosing of TCA in patients with a PM,IM, EM or UM phenotype based on pharmacogenetic test |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (1 listed)
- 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.
Key exclusion criteria (10 listed)
- 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).
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| TCA treatmentAll 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). | Drug | Genotype-guided TCA treatment, Standard TCA treatment |
Primary outcome
Time to TCA plasma concentration in the therapeutic range
Time frame: During the 7 weeks treatment phase
Time to TCA plasma concentration in the therapeutic range
3 secondary outcomes
Reduction of depressive symptoms
Time frame: Difference between measurements at baseline and after 7 weeks of treatment
Highest level of side effects
Time frame: During the 7 weeks treatment phase
Economic Evaluation (Cost Effectiveness)
Time frame: 26 weeks after the start of treatment
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 29 Nov 2022.
- Derived from this study: PubMed 40266345Dalhuisen 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.
- Derived from this study: PubMed 37155164Vos 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Joost Janzing, MD PhD principal investigator
Radboudumc dept of Psychiatry
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing TCA treatment in people with Depressive Disorder, Major, run by Radboud University Medical Center at 1 site in Netherlands.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 29 Nov 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Time to TCA plasma concentration in the therapeutic range (time frame: During the 7 weeks treatment phase). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03548675, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 29 Nov 2022.