Personalized Sertraline Dosing in Patients With Depression

Study Overview
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Brief Summary
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The aims of this study are to: Determine the proportion of participants who are underdosed or overdosed under recommended dosing regimen of sertraline for the depression treatment (100 mg/day) Determine and quantify clinical benefits of personalized sertraline dosing regimen based on the sertraline blood level monitoring Retrospectively estimate whether the information on CYP2C19 genotype is useful in prediction of sertraline blood level.

Detailed Description
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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.

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

Conditions
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Depressive Disorder, Major

Intervention / Treatment
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* Drug: Sertraline


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Standard dose<br>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<br>* 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.<br>* Other names: Lustral;|
| Adjusted dose<br>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<br>* 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.<br>* Other names: Lustral;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sertraline, Cytochrome p 450 cyp2c19, Precision medicine, Psychiatry, Pharmacogenetics, Serotonin Uptake Inhibitors