Clinical trial NCT05210153: Personalized Sertraline Dosing in Patients With Depression
Official title: Utility of Plasma Drug Level Monitoring and CYP2C19 Genotyping in Dose Personalization of Sertraline
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Depressive Disorder, Major
Keywords: Sertraline
Cytochrome p 450 cyp2c19
Precision medicine
Psychiatry
Pharmacogenetics
Serotonin Uptake Inhibitors
Lead sponsor: University of Belgrade
Sponsor class: OTHER
Collaborators: name: Clinical Centre of Serbia
name: Institute of Mental Health, Serbia
name: Military Medical Academy, Belgrade, Serbia
First posted: 2022-01-27
Enrollment: 148
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Study population includes outpatients suffering from Major Depressive disorder who are previously untreated, and are seeking medical help for the first time.

Brief summary: The aims of this study are to:

1. Determine the proportion of participants who are underdosed or overdosed under recommended dosing regimen of sertraline for the depression treatment (100 mg/day)
2. Determine and quantify clinical benefits of personalized sertraline dosing regimen based on the sertraline blood level monitoring
3. Retrospectively estimate whether the information on CYP2C19 genotype is useful in prediction of sertraline blood level.

Detailed description: Sertraline is an antidepressant extensively metabolized by the polymorphic CYP2C19 enzyme. Based on CYP2C19 genotype, patients can be classified as:

* Normal metabolizers (Normal CYP2C19 enzyme capacity)
* Intermediate metabolizers (Decreased CYP2C19 enzyme capacity)
* Poor metabolizers (No CYP2C19 enzyme capacity)
* Ultra rapid metabolizers (Increased CYP2C19 enzyme capacity)

Adequate sertraline exposure is needed to achieve optimal clinical response in the treatment of depression: too low drug plasma levels can lead to the lack of pharmacological effect, whereas too high drug plasma levels increases the incidence of adverse effects. There is evidence that patients with variant CYP2C19 genotypes have abnormal sertraline exposure and could benefit from sertraline dose personalization, but precise evidence-based protocol for personalized dosing of sertraline has not been developed yet. This multicentric observational clinical trial is designed to collect crucial information for the development of such protocol that will be based on drug plasma level monitoring and/or CYP2C19 genotyping.

Course of the study will be as follows:

Initial Visit (V0):

Participant will be enrolled at this point if inclusion criteria are met. Sertraline therapy will be initiated at the standard dose of 100 mg/day during next 2 weeks, or alternatively, started with 50 mg/day during first week and then increased to 100 mg/day during second week. General and socio-demographic information about the participant will be collected together with the baseline measurements: clinical questionnaires, anthropometric measurements, cardiological assessments, and the blood sample will be taken for biochemical analyses.

Mid-Visit (VK):

This visit takes place two weeks after the initial visit (V0) when sertraline blood level is expected to reach the steady state. Blood sample will be taken from the participants at the end of the dose interval (before the morning dose) for the purpose of therapeutic drug monitoring. Plasma sertraline levels will then be measured before the next visit and an independent clinician will allocate patients into one out of two cohorts based on whether or not sertraline levels were optimal (20-40 ng/ml). If sertraline levels were outside this interval, independent clinician will adjust the dose; sertraline level lower than 3 ng/ml indicates noncompliance and results in dropout, level between 3 and 10 ng/ml results in dose increase to 200 mg/day, level between 10 and 20 ng/ml results in dose increase to 150 mg/day, level between 20 and 40 ng/ml results in treatment continuation with 100 mg/day, and level higher than 40 ng/ml results in dose decrease to 50 mg/day.

Visit 1 (V1):

Visit 1 takes place two weeks after VK and 4 weeks after the initiation of the sertraline therapy. Without the knowledge of the attending clinician, independent clinician will adjust sertraline doses accordingly. Attending clinician will then assess the participants using standardized questionnaires, participants will be anthropometrically and cardiologically examined, and blood samples will be taken for the purposes of therapeutic drug monitoring and biochemical analyses.

Visit 2 (V2):

Visit 2 is the final follow-up visit and it will be done 4 weeks after the Visit 1 and 8 weeks after the sertraline initiation. All participants will be assessed for psychometrical, anthropometrical and cardiological parameters, and blood samples will be taken again for the purposes of therapeutic drug monitoring and biochemical analysis.

If needed, additional participants who are already on the stable sertraline monotherapy can be enrolled into study starting from VK. In this case, besides the blood sample for the therapeutic drug monitoring, all assessment usually done at initial visit (V0) will be performed during VK.

Eligibility criteria: Inclusion Criteria:

* Diagnosed Major Depressive Disorder
* Starting monotherapy with sertraline
* Signed written informed consent

Exclusion Criteria:

* Patient's requests to leave the study
* Patients who had taken sertraline before
* Dementia
* Severe liver function impairment (abnormal AST/ALT ratio)
* Severe kidney function impairment (abnormal creatinine clearance)
* History of drug addiction (sporadic use is permitted)
* Suicide risk
* Patients who are taking strong CYP2C19 inhibitors
* Severe adverse drug reaction

Primary outcomes:
measure: Change from Baseline Depression severity score at week 8
timeFrame: 8 Weeks
measure: Adverse drug reaction severity score at week 8
timeFrame: 8 Weeks
Secondary outcomes:
measure: Number of participants with sertraline plasma concentrations outside the therapeutic window
timeFrame: at Week 2
measure: Retrospectively determined regression formula for prediction of sertraline plasma levels at Vk based on CYP2C19 metabolizer status
timeFrame: 8 Weeks
measure: Change from Baseline Depression severity score at week 4
timeFrame: 4 Weeks
measure: Adverse drug reaction severity score at week 4
timeFrame: 4 Weeks
Other outcomes:
measure: Perception of stress score at baseline
timeFrame: Baseline
measure: Perception of stress score at week 4
timeFrame: 4 Weeks
measure: Perception of stress score at week 8
timeFrame: 8 Weeks
measure: Anxiety symptoms severity score at baseline
timeFrame: Baseline
measure: Anxiety symptoms severity score at week 4
timeFrame: 4 weeks
measure: Anxiety symptoms severity score at week 8
timeFrame: 8 Weeks
measure: Clinical Global Impression (CGI) Severity of illness score at baseilne
timeFrame: Baseline
measure: Clinical Global Impression (CGI) Severity of illness score at week 4
timeFrame: 4 Weeks
measure: Clinical Global Impression (CGI) Severity of illness score at week 8
timeFrame: 8 weeks
measure: Clinical Global Impression (CGI) global improvement score at week 4
timeFrame: 4 weeks
measure: Clinical Global Impression (CGI) global improvement score at week 8
timeFrame: 8 weeks
measure: Clinical Global Impression (CGI) Efficacy index at week 4
timeFrame: 4 weeks
measure: Clinical Global Impression (CGI) Efficacy index at week 8
timeFrame: 8 Weeks
measure: Questionnaire of early childhood and recent traumatic experiences
timeFrame: Baseline
measure: QT interval at baseline
timeFrame: Baseline
measure: QT interval at week 4
timeFrame: 4 Weeks
measure: QT interval at week 8
timeFrame: 8 Weeks
measure: Cortisol plasma levels at Baseline
timeFrame: Baseline
measure: Cortisol plasma levels at week 4
timeFrame: 4 Weeks
measure: Cortisol plasma levels at week 8
timeFrame: 8 Weeks
measure: Employment status
timeFrame: Baseline
measure: Marital status
timeFrame: Baseline
measure: Education level
timeFrame: Baseline
Locations:
city: Belgrade
country: Serbia
facility: Clinical Centre of Serbia
city: Belgrade
country: Serbia
facility: Institute of Mental Health
city: Belgrade
country: Serbia
facility: Military Medical Academy
Study officials:
References:
citation: Pennebaker JW, Susman JR. Disclosure of traumas and psychosomatic processes. Soc Sci Med. 1988;26(3):327-32. doi: 10.1016/0277-9536(88)90397-8.
citation: Braten LS, Haslemo T, Jukic MM, Ingelman-Sundberg M, Molden E, Kringen MK. Impact of CYP2C19 genotype on sertraline exposure in 1200 Scandinavian patients. Neuropsychopharmacology. 2020 Feb;45(3):570-576. doi: 10.1038/s41386-019-0554-x. Epub 2019 Oct 24.
citation: Milosavljevic F, Bukvic N, Pavlovic Z, Miljevic C, Pesic V, Molden E, Ingelman-Sundberg M, Leucht S, Jukic MM. Association of CYP2C19 and CYP2D6 Poor and Intermediate Metabolizer Status With Antidepressant and Antipsychotic Exposure: A Systematic Review and Meta-analysis. JAMA Psychiatry. 2021 Mar 1;78(3):270-280. doi: 10.1001/jamapsychiatry.2020.3643.