Personalized Sertraline Dosing in Patients With Depression

NCT ID: NCT05210153

Last Updated: 2022-11-08

Basic Information

• Recruitment Status: UNKNOWN
• Total Enrollment: 148 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2020-07-16
• Study Completion Date: 2023-11-30

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.

Conditions

Depressive Disorder, Major

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: PROSPECTIVE

Study Groups

Standard dose

Patients are allocated to this group at visit V1 if 100 mg/day sertraline dose resulted in optimal sertraline exposure (20-40 ng/ml) as measured at VK. These patients continue to be treated with 100 mg/day during the V1-V2 period.

Sertraline

Intervention Type: DRUG

Drug: Sertraline, a selective serotonin reuptake inhibitor (SSRI), is commercially known as Sidata® or Zoloft® in Serbia. The recommended dose for Major depressive disorder is 100 mg/day. It is recommended to start therapy with 50 mg/day, and in the case of lack of therapeutic effect dose should be increased in 50 mg increments every 2 weeks until intended pharmacological effect is reached. Dose can be increased up to the maximum dose is 200 mg/day. Sertraline is also indicated for treatment of Obsessive-compulsive disorder, Generalized anxiety disorder, Social anxiety disorder (Social phobia), Panic disorder (with or without agoraphobia) and Post-traumatic Stress Disorder by Medicines and Medical Devices Agency of Serbia.

Drug levels are expected to be 50% higher in CYP2C19 poor metabolizers as compared to normal metabolizers, but no specific dosing recommendations are given by the Medicines and Medical Devices Agency of Serbia.

Adjusted dose

Patients are allocated to this group at visit V1 if 100 mg/day sertraline dose resulted in high (\>40 ng/ml) or low (\<20 ng/ml) sertraline exposure, as measured at VK. These patients continue to be treated with the adjusted sertraline dose, different from 100 mg/day, during the V1-V2 period.

Sertraline

Intervention Type: DRUG

Drug: Sertraline, a selective serotonin reuptake inhibitor (SSRI), is commercially known as Sidata® or Zoloft® in Serbia. The recommended dose for Major depressive disorder is 100 mg/day. It is recommended to start therapy with 50 mg/day, and in the case of lack of therapeutic effect dose should be increased in 50 mg increments every 2 weeks until intended pharmacological effect is reached. Dose can be increased up to the maximum dose is 200 mg/day. Sertraline is also indicated for treatment of Obsessive-compulsive disorder, Generalized anxiety disorder, Social anxiety disorder (Social phobia), Panic disorder (with or without agoraphobia) and Post-traumatic Stress Disorder by Medicines and Medical Devices Agency of Serbia.

Drug levels are expected to be 50% higher in CYP2C19 poor metabolizers as compared to normal metabolizers, but no specific dosing recommendations are given by the Medicines and Medical Devices Agency of Serbia.

Interventions

Sertraline

Drug: Sertraline, a selective serotonin reuptake inhibitor (SSRI), is commercially known as Sidata® or Zoloft® in Serbia. The recommended dose for Major depressive disorder is 100 mg/day. It is recommended to start therapy with 50 mg/day, and in the case of lack of therapeutic effect dose should be increased in 50 mg increments every 2 weeks until intended pharmacological effect is reached. Dose can be increased up to the maximum dose is 200 mg/day. Sertraline is also indicated for treatment of Obsessive-compulsive disorder, Generalized anxiety disorder, Social anxiety disorder (Social phobia), Panic disorder (with or without agoraphobia) and Post-traumatic Stress Disorder by Medicines and Medical Devices Agency of Serbia.

Drug levels are expected to be 50% higher in CYP2C19 poor metabolizers as compared to normal metabolizers, but no specific dosing recommendations are given by the Medicines and Medical Devices Agency of Serbia.

Intervention Type: DRUG

Other Intervention Names

Zoloft; Lustral

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 60 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Clinical Centre of Serbia

OTHER

Sponsor Role: collaborator

Institute of Mental Health, Serbia

UNKNOWN

Sponsor Role: collaborator

Military Medical Academy, Belgrade, Serbia

OTHER

Sponsor Role: collaborator

University of Belgrade

OTHER

Sponsor Role: lead

Responsible Party

Marin Jukic

Assistant Professor, PhD

Responsibility Role: PRINCIPAL_INVESTIGATOR

Locations

Clinical Centre of Serbia

Belgrade, , Serbia

Site Status: RECRUITING

Institute of Mental Health

Belgrade, , Serbia

Site Status: RECRUITING

Military Medical Academy

Belgrade, , Serbia

Site Status: NOT_YET_RECRUITING

Countries

Serbia

Central Contacts

Marin M Jukić, PhD

Role: CONTACT

marin.jukic@pharmacy.bg.ac.rs

+381 11 3951 314

Facility Contacts

Zorana Pavlović, M.D.

Role: primary

zorana.pavlovic@med.bg.ac.rs

+381 11 366 2093

Čedo Miljević, M.D.

Role: primary

cedo.miljevic@med.bg.ac.rs

+381 11 3307 500

Zvezdana Stojanović, M.D.

Role: primary

vma@mod.gov.rs

+381 11 3609386

References

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.

Reference Type: BACKGROUND

PMID: 3279521 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 31649299 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 33237321 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

6066800-S

Identifier Type: -

Identifier Source: org_study_id