Antidepressant efficacy is correlated with plasma levels: mega-analysis and further evidence
Open accessAbstract
The debate around optimal target dose for first-line antidepressants (ADs) is still ongoing. Along this line, therapeutic drug monitoring (TDM) represents one of the most promising tools to improve clinical outcome. Nevertheless, a few data exist regarding the concentration-effect relationship of first-line ADs which limits TDM implementation in routine clinical practice. We conducted the first patient-level concentration-response mega-analysis including data acquired by us previously and explored the concentration dependency of first-line AD (206 subjects). Further, new data on mirtazapine are reported (18 subjects). Hamilton Depression Rating Scale-21 administered at baseline, at month 1 and month 3 was used as the measure of efficacy to assess antidepressant response (AR). When pooling all four first-line ADs together, normalized plasma levels and AR significantly fit a bell-shaped quadratic function with a progressive increase of AR up to around the upper normalized limit of the therapeutic reference range with a decrease of AR at higher serum levels. Our results complement the available evidence on the issue and the recent insights gained from dose-response studies. A concentration-dependent clinical efficacy, such as previously demonstrated for tricyclic compounds, also emerge for first-line ADs. Our study supports a role for TDM as a tool to optimize AD treatment to obtain maximum benefit.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Development of a Rating Scale for Primary Depressive Illness
Hamilton, M. (1967) · British Journal of Social and Clinical Psychology · doi:10.1111/j.2044-8260.1967.tb00530.x · Cited by 8,410 · see citing works
Stewart, L. A., & Tierney, J. F. (2002) · Evaluation & the Health Professions · doi:10.1177/0163278702025001006 · Cited by 581 · see citing works
Meyer, J. H., Wilson, A. A., Sagrati, S., Hussey, D., Carella, A., Potter, W. Z., Ginovart, N., Spencer, E. P., Cheok, A., & Houle, S. (2004) · American Journal of Psychiatry · doi:10.1176/appi.ajp.161.5.826 · Cited by 517 · cited 1× · see citing works
“This has extensively been observed in the literature considering the pharmacodynamic properties of first-line ADs which require a minimum percentage of enzyme/receptor blockage to provide any clinical efficacy (Meyer et al., 2004).”
BackgroundConsensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology: Update 2017
Hiemke, C., Bergemann, N., Clement, H. ‐., et al. (2018) · Pharmacopsychiatry · doi:10.1055/s-0037-1600991 · Cited by 327 · see citing works
Furukawa, T. A., Cipriani, A., Cowen, P. J., Leucht, S., Egger, M., & Salanti, G. (2019) · The Lancet Psychiatry · doi:10.1016/s2215-0366(19)30217-2 · Cited by 322 · see citing works
Addressing the Side Effects of Contemporary Antidepressant Drugs: A Comprehensive Review
Wang, S.-M., Han, C., Bahk, W.-M., Lee, S.-J., Patkar, A. A., Masand, P. S., & Pae, C.-U. (2018) · Chonnam Medical Journal · doi:10.4068/cmj.2018.54.2.101 · Cited by 299 · see citing works
Bollini, P., Pampaliona, S., Tibaldi, G., Kupelnick, B., & Munizza, C. (1999) · British Journal of Psychiatry · doi:10.1192/bjp.174.4.297 · Cited by 274 · see citing works
Mirtazapine versus other antidepressive agents for depression
Larsen, J. (2012) · Prescriber · doi:10.1002/psb.850 · Cited by 226 · see citing works
Jakubovski, E., Varigonda, A. L., Freemantle, N., Taylor, M. J., & Bloch, M. H. (2015) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2015.15030331 · Cited by 197 · see citing works
Riley, R. D., Simmonds, M. C., & Look, M. P. (2007) · Journal of Clinical Epidemiology · doi:10.1016/j.jclinepi.2006.09.009 · Cited by 195 · see citing works
Mirtazapine versus other antidepressive agents for depression
Watanabe, N., Omori, I. M., Nakagawa, A., Cipriani, A., Barbui, C., Churchill, R. C., & Furukawa, T. A. (2011) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd006528.pub2 · Cited by 161 · see citing works
Reis, M., Aamo, T. O., Spigset, O., & Ahlner, J. (2009) · Therapeutic Drug Monitoring · doi:10.1097/ftd.0b013e31819114ea · Cited by 153 · see citing works
Schoretsanitis, G., Paulzen, M., Unterecker, S., Schwarz, M., Conca, A., Zernig, G., Gründer, G., Haen, E., Baumann, P., Bergemann, N., et al. (2018) · The World Journal of Biological Psychiatry · doi:10.1080/15622975.2018.1439595 · Cited by 147 · see citing works
Self-citationTricyclic Antidepressant Concentrations in Plasma
Perry, P. J., ZEILMANN, C., & Arndt, S. V. (1994) · Journal of Clinical Psychopharmacology · doi:10.1097/00004714-199408000-00002 · Cited by 138 · see citing works
Current role of LC-MS in therapeutic drug monitoring
Saint‐Marcoux, F., Sauvage, F., & Marquet, P. P. (2007) · Analytical and Bioanalytical Chemistry · doi:10.1007/s00216-007-1320-1 · Cited by 111 · see citing works
Fabbri, C., Tansey, K. E., Perlis, R. H., Hauser, J., Henigsberg, N., Maier, W., Mors, O. N., Placentino, A., Rietschel, M., Souery, D., et al. (2018) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2018.05.009 · Cited by 104 · see citing works
Boedhoe, P. S. W., Heymans, M. W., Schmaal, L., Abe, Y., Alonso, P., Ameis, S. H., Anticevic, A., Arnold, P. D., Batistuzzo, M. C., Benedetti, F., et al. (2019) · Frontiers in Neuroinformatics · doi:10.3389/fninf.2018.00102 · Cited by 104 · see citing works
Hieronymus, F., Nilsson, S., & Eriksson, E. (2016) · Translational Psychiatry · doi:10.1038/tp.2016.104 · Cited by 100 · see citing works
Meta‐analysis and mega‐analysis: A simple introduction
Eisenhauer, J. G. (2020) · Teaching Statistics · doi:10.1111/test.12242 · Cited by 86 · see citing works
The Relationship Between Antidepressant Response and Tricyclic Antidepressant Plasma Concentrations
Perry, P. J., PFOHL, B. M., & Holstad, S. G. (1987) · Clinical Pharmacokinetics · doi:10.2165/00003088-198713060-00003 · Cited by 77 · see citing works
Müller, M. J., Dragičević, A., Fric, M., et al. (2003) · Pharmacopsychiatry · doi:10.1055/s-2003-39983 · Cited by 73 · see citing works
Application of cross-species PET imaging to assess neurotransmitter release in brain
Finnema, S., Scheinin, M., Shahid, M., Lehto, J., Borroni, E., Bang-Andersen, B., Sallinen, J., Wong, E. H. F., Farde, L., Halldin, C., et al. (2015) · Psychopharmacology · doi:10.1007/s00213-015-3938-6 · Cited by 69 · see citing works
Therapeutic Drug Monitoring for Antidepressant Drug Treatment
Haji, E. O., Hiemke, C., & Pfuhlmann, B. (2012) · Current Pharmaceutical Design · doi:10.2174/138161212803523699 · Cited by 57 · see citing works
Escitalopram plasma levels and antidepressant response
Florio, V., Porcelli, S., Saria, A., Serretti, A., & Conca, A. (2017) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2017.06.009 · Cited by 54 · see citing works
Self-citationCharlier, C., Pinto, E., Ansseau, M., & Plomteux, G. J. (2002) · Journal of Psychopharmacology · doi:10.1177/026988110201600413 · Cited by 49 · see citing works
The Influence of Smoking on the Serum Level of Duloxetine
Fric, M., Pfuhlmann, B., Laux, G., Riederer, P., Distler, G., Artmann, S., Wohlschläger, M., Liebmann, M., & Deckert, J. (2008) · Pharmacopsychiatry · doi:10.1055/s-2008-1073173 · Cited by 47 · see citing works
Haji, E. O., Tadić, A., Wagner, S., Dragičević, A., Müller, M. J., Boland, K., Rao, M.-L., Fric, M., Laux, G., & Hiemke, C. (2011) · Journal of Clinical Psychopharmacology · doi:10.1097/jcp.0b013e318218f503 · Cited by 43 · see citing works
Cheng, Q., Huang, J., Xu, L., Li, Y., Li, H., Shen, Y., Zheng, Q., & Li, L. (2020) · International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyz062 · Cited by 38 · see citing works
Mega-trials vs. meta-analysis: Precision vs. heterogeneity?
Shrier, I., Platt, R. W., & Steele, R. J. (2006) · Contemporary Clinical Trials · doi:10.1016/j.cct.2006.11.007 · Cited by 37 · see citing works
Duloxetine plasma level and antidepressant response
Donatis, D. D., Florio, V., Porcelli, S., Saria, A., Mercolini, L., Serretti, A., & Conca, A. (2019) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2019.01.001 · Cited by 37 · see citing works
Self-citationTherapeutic Drug Monitoring (TDM) in Psychiatry (Part I)
Preskorn, S. (2014) · Journal of Psychiatric Practice · doi:10.1097/01.pra.0000445247.54048.68 · Cited by 35 · see citing works
Early antidepressant efficacy modulation by glutamatergic gene variants in the STAR⁎D
Fabbri, C., Drago, A., & Serretti, A. (2012) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2012.07.006 · Cited by 32 · see citing works
Self-citationHaji, E. O., Tadić, A., Wagner, S., Dragivevic, A., Müller, M., Boland, K., Rao, M., Fric, M., Laux, G., & Hiemke, C. (2013) · Pharmacopsychiatry · doi:10.1055/s-0033-1354370 · Cited by 25 · see citing works
Steady-State Clinical Pharmacokinetics of Bupropion Extended-Release in Youths
Daviss, W. B., Perel, J. M., Birmaher, B. B., Rudolph, G. R., Melhem, I., Axelson, D., & Brent, D. A. (2006) · Journal of the American Academy of Child & Adolescent Psychiatry · doi:10.1097/01.chi.0000237704.05143.bd · Cited by 24 · see citing works
Therapeutic Drug Monitoring of Antidepressants
Fiaturi, N., & Greenblatt, D. J. (2018) · Handbook of experimental pharmacology · doi:10.1007/164_2018_161 · Cited by 20 · see citing works
[11C]Mirtazapine binding in depressed antidepressant nonresponders studied by PET neuroimaging
Smith, D. F., Stork, B. S., Wegener, G., Ashkanian, M., Jakobsen, S., Bender, D., Audrain, H., Vase, K. H., Hansen, S. B., Videbech, P., et al. (2009) · Psychopharmacology · doi:10.1007/s00213-009-1587-3 · Cited by 18 · see citing works
Receptor occupancy of mirtazapine determined by PET in healthy volunteers
Smith, D. F., Stork, B. S., Wegener, G., Jakobsen, S., Bender, D., Audrain, H., Jensen, S. B., Hansen, S. B., Rodell, A. B., & Rosenberg, R. (2007) · Psychopharmacology · doi:10.1007/s00213-007-0877-x · Cited by 17 · see citing works
Donatis, D. D., Porcelli, S., Zernig, G., Mercolini, L., Giupponi, G., Serretti, A., Conca, A., & Florio, V. (2021) · The World Journal of Biological Psychiatry · doi:10.1080/15622975.2021.1938668 · Cited by 12 · see citing works
Self-citationPharmacokinetic and Pharmacodynamic Principles
Zernig, G., & Hiemke, C. (2020) · Springer eBooks · doi:10.1007/978-3-319-56015-1_1-1 · Cited by 4 · see citing works
Self-citation
Flagged first, then by citations
Research works printed but not linked: 4
- [9]9. Eichentopf L. (2021). ‘Escitalopram: Drug monitoring for dose titration? Systematic literature review on the therapeutic and the dose-related reference range’. Manuscript in preparation.
- [23]23. Kenakin T (2018). A pharmacology primer: techniques for more effective and strategic drug discovery. Academic Press.
- [25]25. Moré JJ (1978). The Levenberg-Marquardt algorithm: implementation and theory. Watson GA, editors. In: Numerical analysis. Springer (Lecture Notes in Mathematics). pp. 105– 116.
- [27]27. National Collaborating Centre for Mental Health (UK) (2010). Depression: The treatment and management of depression in adults (updated edition). British Psychological Society (National Institute for Health and Clinical Excellence: Guidance). 22132433
Cited by
Sorted by citations
McIntyre, R. S., Alsuwaidan, M., Baune, B. T., Berk, M., Demyttenaere, K., Goldberg, J. F., Gorwood, P., Ho, R., Kasper, S., Kennedy, S. H., et al. (2023) · World Psychiatry · doi:10.1002/wps.21120 · Cited by 836 · see citing works
Scala, M., Fabbri, C., Fusar-Poli, P., Di Lorenzo, G., Ferrara, M., Amerio, A., Fusar-Poli, L., Pichiecchio, A., Asteggiano, C., Menchetti, M., et al. (2024) · CNS Spectrums · doi:10.1017/s1092852924002268 · Cited by 9 · see citing works
“Second, measuring plasma psilocin levels, as is done with current antidepressants, 50 may help optimize the dose.”
Self-citation
- Authors
- Cellini, L., De Donatis, D., Zernig, G., De Ronchi, D., Giupponi, G., Serretti, A., Xenia, H., Conca, A., & Florio, V.
- Affiliations
- University of Bologna (IT)
- Department of Psychiatry, Comprensorio Sanitario di Bolzano, Bolzano, Italy
- Innsbruck Medical University (AT)
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna
- Department of Molecular Neuroimaging, Central Institute of Mental Health, University of Heidelberg, Mannheim, Germany
- Corresponding author
- Serretti, Alessandro
- Venue
- International Clinical Psychopharmacology
- Published
- 2021-12-13
- Volume
- 37
- Issue
- 2
- Pages
- 29-37
- ISSN
- 0268-1315 (ISSN-L)
- PMC
- PMC9648983
- OpenAlex
- W4200512926
- Cited by
- 24
- References
- 39
- Citations by year
- 2026: 5 · 2025: 2 · 2024: 9 · 2023: 5 · 2022: 3
- FWCI
- 2.48
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- International Clinical Psychopharmacology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion, cc-by)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Health Sciences › Medicine › Pharmacology › Antibiotics Pharmacokinetics and Efficacy
- Keywords
- antidepressants, therapeutic drug monitoring, plasma drug concentration, concentration-dependent effects, first-line antidepressants, antidepressant response, mirtazapine, dose-response relationship, depression, mega-analysis, Hamilton Depression Rating Scale
- MeSH terms
- Mirtazapine, Antidepressive Agents, Humans, Treatment Outcome, Drug Monitoring
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
