Personalized Sertraline Dosing in Patients With Depression (PsyCise-S)

Utility of Plasma Drug Level Monitoring and CYP2C19 Genotyping in Dose Personalization of Sertraline

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.

Study Overview

• Status: Withdrawn
• Conditions: Depressive Disorder, Major
• Intervention / Treatment: Drug: Sertraline

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.

• Study Type: Observational

Contacts and Locations

Study Locations

• Serbia
  • Belgrade, Serbia, 11000
    • Military Medical Academy
  • Belgrade, Serbia, 11000
    • Institute of Mental Health
  • Belgrade, Serbia, 11000
    • Clinical Centre of Serbia

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 56 years (Adult)
• Accepts Healthy Volunteers: N/A

• 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.

Description

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

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
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.	Drug: 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.; Other Names: Zoloft; Lustral
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.	Drug: 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.; Other Names: Zoloft; Lustral

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from Baseline Depression severity score at week 8	Measured with clinician reported 21-item Hamilton rating scale for depression (HAM-D). Scale gives a score from 0 to 52 where higher score represents higher depression severity and worse outcome.	8 Weeks
Adverse drug reaction severity score at week 8	Measured with clinician reported UKU (Udvalg for Kliniske Undersogelser) side effect rating scale. Scale gives summary score from 0 to 3 where higher scores correspond to the greater side-effects severity and worse outcome.	8 Weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants with sertraline plasma concentrations outside the therapeutic window	Therapeutic window is defined by sertraline plasma concentrations of 20-40 ng/ml	at Week 2
Retrospectively determined regression formula for prediction of sertraline plasma levels at Vk based on CYP2C19 metabolizer status	CYP2C19 metabolizer status will be determined based on genotype as follows: Poor metabolizer: *2/*2, *2/*3, *3/*3 Intermediate metabolizer: *1/*2, *1/*3 Normal metabolizer: *1/*1 Ultra-rapid metabolizer: *1/*17, *17/*17 Several covariates will be considered: Body mass index, Creatinine clearance, AST/ALT (Aspartate aminotransferase / Alanine aminotransferase) ratio.	8 Weeks
Change from Baseline Depression severity score at week 4	Assessed with 21-item Hamilton rating scale for depression (HAM-D). Scale gives a score 0-52 where higher score is equivalent to the more severe depression and worse uotcome.	4 Weeks
Adverse drug reaction severity score at week 4	Measured with clinician reported UKU (Udvalg for Kliniske Undersogelser) side effect rating scale. Scale gives summary score from 0 to 3 where higher scores correspond to the greater side-effects severity and worse outcome.	4 Weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Perception of stress score at baseline	Measured with self-reported Perceived stress scale (PSS). Scale gives scores from 0 to 40 where higher scores correspond to the higher severity of perceived stress and worse outcome.	Baseline
Perception of stress score at week 4	Measured with self-reported Perceived stress scale (PSS). Scale gives scores from 0 to 40 where higher scores correspond to the higher severity of perceived stress and worse outcome.	4 Weeks
Perception of stress score at week 8	Measured with self-reported Perceived stress scale (PSS). Scale gives scores from 0 to 40 where higher scores correspond to the higher severity of perceived stress and worse outcome.	8 Weeks
Anxiety symptoms severity score at baseline	Measured with Hamilton anxiety rating scale (HAM-A). Scale gives scores from 0 to 56 where higher scores correspond to the higher severity of anxiety symptoms and worse outcome.	Baseline
Anxiety symptoms severity score at week 4	Measured with Hamilton anxiety rating scale (HAM-A). Scale gives scores from 0 to 56 where higher scores correspond to the higher severity of anxiety symptoms and worse outcome.	4 weeks
Anxiety symptoms severity score at week 8	Measured with Hamilton anxiety rating scale (HAM-A). Scale gives scores from 0 to 56 where higher scores correspond to the higher severity of anxiety symptoms and worse outcome.	8 Weeks
Clinical Global Impression (CGI) Severity of illness score at baseilne	Measured with Clinical Global Impression scale for the severity of illness (CGI-S). Scale gives scores from 0 to 7 where higher scores correspond to the higher illness severity and worse outcome.	Baseline
Clinical Global Impression (CGI) Severity of illness score at week 4	Measured with Clinical Global Impression scale for the severity of illness (CGI-S). Scale gives scores from 0 to 7 where higher scores correspond to the higher illness severity and worse outcome.	4 Weeks
Clinical Global Impression (CGI) Severity of illness score at week 8	Measured with Clinical Global Impression scale for the severity of illness (CGI-S). Scale gives scores from 0 to 7 where higher scores correspond to the higher illness severity and worse outcome.	8 weeks
Clinical Global Impression (CGI) global improvement score at week 4	Measured with Clinical Global Impression scale for the global improvement (CGI-I). Scale gives scores from 0 to 7 where higher scores correspond to the worse illness improvement and worse outcome.	4 weeks
Clinical Global Impression (CGI) global improvement score at week 8	Measured with Clinical Global Impression scale for the global improvement (CGI-I). Scale gives scores from 0 to 7 where higher scores correspond to the worse illness improvement and worse outcome.	8 weeks
Clinical Global Impression (CGI) Efficacy index at week 4	Measured with Clinical Global Impression scale - Efficacy index (CGI-E). Scale gives scores from 1 to 5 where higher scores correspond to the better outcome and beneficial drug efficacy/tolerability ratio.	4 weeks
Clinical Global Impression (CGI) Efficacy index at week 8	Measured with Clinical Global Impression scale - Efficacy index (CGI-E). Scale gives scores from 1 to 5 where higher scores correspond to the better outcome and beneficial drug efficacy/tolerability ratio.	8 Weeks
Questionnaire of early childhood and recent traumatic experiences	Self-reported 13 item questionnaire by Pennebaker, J.W. & Susman, J.R. (1988)	Baseline
QT interval at baseline	Determined on the electrocardiogram	Baseline
QT interval at week 4	Determined on the electrocardiogram	4 Weeks
QT interval at week 8	Determined on the electrocardiogram	8 Weeks
Cortisol plasma levels at Baseline		Baseline
Cortisol plasma levels at week 4		4 Weeks
Cortisol plasma levels at week 8		8 Weeks
Employment status	Coded as follows: Unemployed,; Employed; monthly incomes <40 000 RSD (~385$),; Employed; monthly incomes 40 000-80 000 RSD (~385$-770$),; Employed; monthly incomes >80 000 RSD (~770$).	Baseline
Marital status	Coded as follows: Unmarried,; Married,; Divorced,; Widowed	Baseline
Education level	Coded as follows: Primary education (8 years),; High school diploma (8+3 or 8+4 years),; Associate's degree (8+4+2 or 8+4+3 years),; Bachelor's degree (8+4+4 years) or higher	Baseline

Collaborators and Investigators

• Sponsor: University of Belgrade
• Collaborators: Clinical Centre of Serbia; Military Medical Academy, Belgrade, Serbia; Institute of Mental Health, Serbia

Publications and helpful links

General Publications

• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): July 16, 2020
• Primary Completion (Actual): September 1, 2023
• Study Completion (Actual): September 1, 2023

Study Registration Dates

• First Submitted: December 21, 2021
• First Submitted That Met QC Criteria: January 13, 2022
• First Posted (Actual): January 27, 2022

Study Record Updates

• Last Update Posted (Actual): May 15, 2026
• Last Update Submitted That Met QC Criteria: May 12, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Psychiatry; Pharmacogenetics; Precision medicine; Sertraline; Serotonin Uptake Inhibitors; Cytochrome p 450 cyp2c19
• Additional Relevant MeSH Terms: Mental Disorders; Mood Disorders; Depressive Disorder; Depressive Disorder, Major; Organic Chemicals; Hydrocarbons; Hydrocarbons, Cyclic; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Polycyclic Compounds; Amines; 1-Naphthylamine; Sertraline
• Other Study ID Numbers: 6066800-S

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Individual participant data (IPD) will be shared for all parameters relevant for two primary outcomes of this study.

This will include, but is not limited to IPD data on: CYP2C19 metabolizer status and CYP2C19 genotype, HAM-D scores, UKU-scale scores and measured sertraline blood concentrations.

• IPD Sharing Time Frame: Starting from the time of publication of the main summary study results.
• IPD Sharing Access Criteria: IPD will be accessible to everyone.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No