Systematic review and meta-analysis on the therapeutic reference range for escitalopram: Blood concentrations, clinical effects and serotonin transporter occupancy

Luzie Eichentopf; Christoph Hiemke; Andreas Conca; Jan Engelmann; Manfred Gerlach; Ursula Havemann-Reinecke; Gudrun Hefner; Vincenzo Florio; Maxim Kuzin; Klaus Lieb; Margareta Reis; Thomas G Riemer; Alessandro Serretti; Georgios Schoretsanitis; Gerald Zernig; Gerhard Gründer; Xenia M Hart

doi:10.3389/fpsyt.2022.972141

Systematic review and meta-analysis on the therapeutic reference range for escitalopram: Blood concentrations, clinical effects and serotonin transporter occupancy

Front Psychiatry. 2022 Oct 17:13:972141. doi: 10.3389/fpsyt.2022.972141. eCollection 2022.

Authors

Luzie Eichentopf¹, Christoph Hiemke^{2

3}, Andreas Conca^{3

4}, Jan Engelmann⁵, Manfred Gerlach^{3

6}, Ursula Havemann-Reinecke^{3

7}, Gudrun Hefner^{3

8}, Vincenzo Florio⁹, Maxim Kuzin^{3

10}, Klaus Lieb¹¹, Margareta Reis^{12

13}, Thomas G Riemer¹⁴, Alessandro Serretti¹⁵, Georgios Schoretsanitis^{3

16

17

18}, Gerald Zernig^{3

19

20}, Gerhard Gründer^{1

3}, Xenia M Hart^{1

3}

Affiliations

¹ Department of Molecular Neuroimaging, Medical Faculty Mannheim, Central Institute of Mental Health, Heidelberg University, Mannheim, Germany.
² Department of Psychiatry and Psychotherapy, Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center of Mainz, Mainz, Germany.
³ Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP)-Work Group "Therapeutic Drug Monitoring", Nürnberg, Germany.
⁴ Department of Psychiatry, Central Hospital, Sanitary Agency of South Tyrol, Bolzano, Italy.
⁵ Department of Psychiatry and Psychotherapy, Johannes Gutenberg University Medical Center Mainz, Mainz, Germany.
⁶ Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Würzburg, Würzburg, Germany.
⁷ Department of Psychiatry and Psychosomatics, University of Göttingen, Göttingen, Germany.
⁸ Vitos Clinic for Forensic Psychiatry, Forensic Psychiatry, Eltville, Germany.
⁹ Department of Psychiatry, Comprensorio Sanitario di Bolzano, Bolzano, Italy.
¹⁰ Clienia Schlössli AG, Psychiatric and Psychotherapeutic Private Clinic, Academic Teaching Hospital of the University of Zurich, Oetwil am See, Switzerland.
¹¹ Department of Psychiatry and Psychotherapy, University Medical Center Mainz, Mainz, Germany.
¹² Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
¹³ Department of Clinical Chemistry and Pharmacology, Skåne University Hospital, Lund, Sweden.
¹⁴ Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Clinical Pharmacology and Toxicology, Berlin, Germany.
¹⁵ Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
¹⁶ Department of Psychiatry, Psychotherapy and Psychosomatics, Hospital of Psychiatry, University of Zurich, Zurich, Switzerland.
¹⁷ Department of Psychiatry, Behavioral Health Pavilion, Northwell Health, The Zucker Hillside Hospital, Glen Oaks, NY, United States.
¹⁸ Department of Psychiatry, Zucker School of Medicine at Northwell/Hofstra, Hempstead, NY, United States.
¹⁹ Department of Pharmacology, Medical University of Innsbruck, Innsbruck, Austria.
²⁰ Private Practice for Psychotherapy and Court-Certified Witness, Hall in Tirol, Austria.

Abstract

Introduction: A titration within a certain therapeutic reference range presupposes a relationship between the blood concentration and the therapeutic effect of a drug. However, this has not been systematically investigated for escitalopram. Furthermore, the recommended reference range disagrees with mean steady state concentrations (11-21 ng/ml) that are expected under the approved dose range (10-20 mg/day). This work systematically investigated the relationships between escitalopram dose, blood levels, clinical effects, and serotonin transporter occupancy.

Methods: Following our previously published methodology, relevant articles were systematically searched and reviewed for escitalopram.

Results: Of 1,032 articles screened, a total of 30 studies met the eligibility criteria. The included studies investigated escitalopram blood levels in relationship to clinical effects (9 studies) or moderating factors on escitalopram metabolism (12 studies) or serotonin transporter occupancy (9 studies). Overall, the evidence for an escitalopram concentration/effect relationship is low (level C).

Conclusion: Based on our findings, we propose a target range of 20-40 ng/ml for antidepressant efficacy of escitalopram. In maintenance treatment, therapeutic response is expected, when titrating patients above the lower limit. The lower concentration threshold is strongly supported by findings from neuroimaging studies. The upper limit for escitalopram's reference range rather reflects a therapeutic maximum than a tolerability threshold, since the incidence of side effects in general is low. Concentrations above 40 ng/ml should not necessarily result in dose reductions in case of good clinical efficacy and tolerability. Dose-related escitalopram concentrations in different trials were more than twice the expected concentrations from guideline reports.

Systematic review registration: [https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=215873], identifier [CRD42020215873].

Keywords: SERT occupancy; adverse drug reaction; antidepressant response; blood level; clinical effects; escitalopram; reference range; therapeutic drug monitoring.

Publication types

Systematic Review