Evidence map›Paper›PMID 26552940›Full record

SynthesisThe American journal of psychiatry2016

Systematic Review and Meta-Analysis: Dose-Response Relationship of Selective Serotonin Reuptake Inhibitors in Major Depressive Disorder.

Ewgeni Jakubovski, Anjali L Varigonda, Nicholas Freemantle, Matthew J Taylor, Michael H Bloch

Abstract readMeta-AnalysisSystematic Review
PubMed Full text at PMC Publisher
In one paragraph

Synthesis in The American journal of psychiatry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 56 papers, 8 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
56citing papers in PubMed, 8 pooled it
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

56 citing papers in PubMed, 8 syntheses or guidelines pooled it.

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  6. Item-based analysis of the effects of duloxetine in depression: a patient-level post hoc study.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2020
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  11. Emotion-based brain mechanisms and predictors for SSRI and CBT treatment of anxiety and depression: a randomized trial.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2019
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  16. Optogenetic Stimulation of Novel Tph2-Cre Rats Advances Insight into Serotonin's Role in Locomotion, Reinforcement, and Compulsivity.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2025
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  18. A framework for inferring and analyzing pharmacotherapy treatment patterns.BMC medical informatics and decision making · 2024
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4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

5 authors.

Ewgeni JakubovskiFrom the Yale Child Study Center, New Haven, Conn.; the University of Vermont College of Medicine, Burlington, Vt.; Child Study Center and Department of Psychiatry, Yale University, New Haven, Conn.; the Department of Primary Care and Population Health, University College London; and the Department of Psychosis Studies, King's College London.
Anjali L VarigondaFrom the Yale Child Study Center, New Haven, Conn.; the University of Vermont College of Medicine, Burlington, Vt.; Child Study Center and Department of Psychiatry, Yale University, New Haven, Conn.; the Department of Primary Care and Population Health, University College London; and the Department of Psychosis Studies, King's College London.
Nicholas FreemantleFrom the Yale Child Study Center, New Haven, Conn.; the University of Vermont College of Medicine, Burlington, Vt.; Child Study Center and Department of Psychiatry, Yale University, New Haven, Conn.; the Department of Primary Care and Population Health, University College London; and the Department of Psychosis Studies, King's College London.
Matthew J TaylorFrom the Yale Child Study Center, New Haven, Conn.; the University of Vermont College of Medicine, Burlington, Vt.; Child Study Center and Department of Psychiatry, Yale University, New Haven, Conn.; the Department of Primary Care and Population Health, University College London; and the Department of Psychosis Studies, King's College London.
Michael H BlochFrom the Yale Child Study Center, New Haven, Conn.; the University of Vermont College of Medicine, Burlington, Vt.; Child Study Center and Department of Psychiatry, Yale University, New Haven, Conn.; the Department of Primary Care and Population Health, University College London; and the Department of Psychosis Studies, King's College London.

Funding

YALE UNIVERSITY CLINICAL AND TRANSLATIONAL SCIENCE AWARD PROGRAMUL1RR024139 · NCRR · YALE UNIVERSITY · PI SHERWIN, ROBERT S · 2006 to 2011
$56.8M
Research Training for Medical Students & Physician-Scientists in Child PsychiatryR25MH077823 · NIMH · YALE UNIVERSITY · PI ANDRES S MARTIN · 2006 to 2026
$4.0M
Longitudinal Structural MRI Study of Adulthood Outcome in Tourette SyndromeK23MH091240 · NIMH · YALE UNIVERSITY · PI BLOCH, MICHAEL H · 2010 to 2014
$902k
NCRR NIH HHS UL1 RR024139NIMH NIH HHS K23 MH091240NIMH NIH HHS K23MH091240NIMH NIH HHS R25 MH077823
6 · The paper itself

Abstract

objectivePrevious studies suggested that the treatment response to selective serotonin reuptake inhibitors (SSRIs) in major depressive disorder follows a flat response curve within the therapeutic dose range. The present study was designed to clarify the relationship between dosage and treatment response in major depressive disorder.

methodThe authors searched PubMed for randomized placebo-controlled trials examining the efficacy of SSRIs for treating adults with major depressive disorder. Trials were also required to assess improvement in depression severity at multiple time points. Additional data were collected on treatment response and all-cause and side effect-related discontinuation. All medication doses were transformed into imipramine-equivalent doses. The longitudinal data were analyzed with a mixed-regression model. Endpoint and tolerability analyses were analyzed using meta-regression and stratified subgroup analysis by predefined SSRI dose categories in order to assess the effect of SSRI dosing on the efficacy and tolerability of SSRIs for major depressive disorder.

resultsForty studies involving 10,039 participants were included. Longitudinal modeling (dose-by-time interaction=0.0007, 95% CI=0.0001-0.0013) and endpoint analysis (meta-regression: β=0.00053, 95% CI=0.00018-0.00088, z=2.98) demonstrated a small but statistically significant positive association between SSRI dose and efficacy. Higher doses of SSRIs were associated with an increased likelihood of dropouts due to side effects (meta-regression: β=0.00207, 95% CI=0.00071-0.00342, z=2.98) and decreased likelihood of all-cause dropout (meta-regression: β=-0.00093, 95% CI=-0.00165 to -0.00021, z=-2.54).

conclusionsHigher doses of SSRIs appear slightly more effective in major depressive disorder. This benefit appears to plateau at around 250 mg of imipramine equivalents (50 mg of fluoxetine). The slightly increased benefits of SSRIs at higher doses are somewhat offset by decreased tolerability at high doses.

Indexed as

CitalopramDose-Response Relationship, DrugFluoxetineFluvoxamineHumansMajor Depressive DisorderParoxetineSelective Serotonin Reuptake InhibitorsSertralineTreatment OutcomeCitalopramFluoxetineFluvoxamineParoxetineSelective Serotonin Reuptake InhibitorsSertraline

Identifiers

PMID26552940
PMCPMC4975858

What OpenQuestion holds

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Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.