Cited by 250Treatment of Major DepressionPain Management and Placebo EffectPsychotherapy Techniques and Applications

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Is There a Delay in the Antidepressant Effect? A Meta-Analysis

Posternak, Michael A., Zimmerman, Mark·2005·The Journal of Clinical Psychiatry

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Abstract

Objectives It has long been thought that there is a delay of several weeks before a true antidepressant effect occurs, although this theory has increasingly come into question. The goals of this meta-analysis were to determine whether significant drug-placebo separation occurs during the first 2 weeks of treatment and to ascertain whether the timing of response to antidepressant medication and placebo is distinct. Data sources Seventy-six double-blind, placebo-controlled trials conducted between 1981 and 2000, included in a recently published meta-analysis that evaluated placebo response rates in depressed outpatients, were reviewed. In addition, each issue of 6 psychiatric journals from January 1992 through December 2001 was reviewed. Study selection Forty-seven studies that evaluated antidepressant medications with established efficacy, performed weekly or biweekly (every other week) evaluations, and presented the time course of improvement as measured by the Hamilton Rating Scale for Depression were included in our meta-analysis. Data synthesis The time course of improvement on active medication and placebo was nearly identical, as 60.2% and 61.6% of the improvement that occurred on active medication and placebo, respectively, took place during the first 2 weeks of treatment. Drug-placebo differences were not only present but were most pronounced during the first 2 weeks of treatment and diminished in a stepwise fashion thereafter. A series of subanalyses confirmed that th…

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Pharmacological management of unipolar depression
Malhi, G. S., Hitching, R., Berk, M., Boyce, P. M., Porter, R., & Fritz, K. (2013) · Acta Psychiatrica Scandinavica · doi:10.1111/acps.12122 · Cited by 41
“After commencing antidepressant treatment, there is usually a delay of 7–10 days before a discernible response emerges (25, 26) and, in practice, evidence of an antidepressant effect is most likely to occur within the first 2 weeks of treatment (25– 27).”
Background
A Metaanalysis of Clinical Trials Comparing Moclobemide with Selective Serotonin Reuptake Inhibitors for the Treatment of Major Depressive Disorder
Papakostas, G., & Fava, M. (2006) · Canadian journal of psychiatry. Revue canadienne de psychiatrie · doi:10.1177/070674370605101208 · Cited by 44
“In studies that reported the response rates, discontinuation rates, or adverse event rates graphically rather than numerically, we extracted the rates for treatment groups by measuring each data point as performed in a recent, large metaanalysis of antidepressant clinical trials (16).”
Homeostatic cAMP regulation by the RGS7 complex controls depression-related behaviors
Orlandi, C., Sutton, L. P., Muntean, B. S., Song, C., & Martemyanov, K. A. (2018) · Neuropsychopharmacology · doi:10.1038/s41386-018-0238-y · Cited by 36
Randomized controlled study of early medication change for non-improvers to antidepressant therapy in major depression – The EMC trial
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“For the risk group of patients without improvement in the first two weeks of treatment, remission and response rates range between 4–14 and 11–19 percent (Henkel et al., 2009; Hennings et al., 2009; Katz et al., 2004; Nierenberg et al., 2000; Papakostas et al., 2006; Posternak and Zimmerman, 2005; Stassen et al., 2007…”
Background
The role of clinical variables, neuropsychological performance and SLC6A4 and COMT gene polymorphisms on the prediction of early response to fluoxetine in major depressive disorder
Gudayol‐Ferré, E., Herrera‐Guzmán, I., Camarena, B., Cortés‐Penagos, C., Herrera‐Abarca, J. E., Martínez‐Medina, P., la Cruz, D. C.-D., Hernández, S., Genis, A. D., Carrillo-Guerrero, M. Y., et al. (2010) · Journal of Affective Disorders · doi:10.1016/j.jad.2010.06.002 · Cited by 42
Clinical application of antidepressant pharmacogenetics: Considerations for the design of future studies
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Ensemble Learning for Early‐Response Prediction of Antidepressant Treatment in Major Depressive Disorder
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“Two meta-analyses revealed that antidepressant treatment response can take place early in the course of treatment 14,15 and two meta-analyses demonstrated that early improvement after the ﬁ rst 2 weeks of antidepressant treatment can predict subsequent treatment outcome with high sensitivity in…”
Background
Is switching antidepressants following early nonresponse more beneficial in acute-phase treatment of depression?: A randomized open-label trial
Nakajima, S., Uchida, H., Suzuki, T., Watanabe, K., Hirano, J., Yagihashi, T., Takeuchi, H., Abe, T., Kashima, H., & Mimura, M. (2011) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2011.08.008 · Cited by 39
“…meta-analyses show not only that antidepressants start to exert their antidepressant efficacy within a couple of weeks (Papakostas, et al., 2006; Posternak and Zimmerman, 2005; Taylor, et al., 2006), but also that early nonresponse to initial antidepressant treatment is a predictor for…”
Background
Timing of Clinical Improvement and Symptom Resolution in the Treatment of Major Depressive Disorder
Papakostas, G. I., Crawford, C. M., Scalia, M. J., & D, M. F. M. (2007) · Neuropsychobiology · doi:10.1159/000115779 · Cited by 26
“while a recent meta-analysis of published, placebo-controlled trials of antidepressants for MDD reports a numerically greater drug versus placebo difference in depressive symptom improvement during the first 2 weeks of treatment than at endpoint [”
Result
Ketamine in Major Depressive Disorder: Mechanisms and Future Perspectives
Shin, C., & Kim, Y. (2020) · Psychiatry Investigation · doi:10.30773/pi.2019.0236 · Cited by 47
Combination antidepressant therapy for major depressive disorder: Speed and probability of remission
Stewart, J. W., McGrath, P. J., Blondeau, C., Deliyannides, D. A., Hellerstein, D. J., Norris, S., Amat, J., Pilowsky, D. J., Tessier, P., Laberge, L., et al. (2013) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2013.12.001 · Cited by 37
Effect of omega-3 fatty acids for indicated prevention of young patients at risk for psychosis: When do they begin to be effective?
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“on typical antidepressant drugs also usually occur within the first two weeks of treatment (Posternak and Zimmerman, 2005).”
Background
Serum brain-derived neurotrophic factor and glucocorticoid receptor levels in lymphocytes as markers of antidepressant response in major depressive patients: A pilot study
Rojas, P. S., Rosemarie Fritsch, M., Rojas, R., Jara, P., & Fiedler, J. L. (2011) · Psychiatry Research · doi:10.1016/j.psychres.2011.04.032 · Cited by 37
“, 1984), there is a large body of evidence suggesting that a true response to an antidepressant can be observed within the first 14 days of treatment (Nierenberg et al., 2000; Katz et al., 2004; Posternak and Zimmerman, 2005; Papakostas et al., 2006; Taylor et al., 2006; Stassen et al., 2007; Tadic et al., 2010a).”
BackgroundResult
Modeling Trajectory of Depressive Symptoms Among Psychiatric Inpatients: A Latent Growth Curve Approach
Clapp, J. D., Grubaugh, A. L., Allen, J. G., Mahoney, J., Oldham, J. M., Fowler, J. C., Ellis, T., Elhai, J. D., & Frueh, B. C. (2013) · The Journal of Clinical Psychiatry · doi:10.4088/jcp.12m07842 · Cited by 37
Targeting TrkB neurotrophin receptor to treat depression
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“Moreover, regardless of indication, the clinical efficacy of antidepressant drugs only becomes evident after a considerable delay (> 1 week) [7] .”
Background
A randomized, double-blind, and placebo-controlled trial of quetiapine augmentation of fluoxetine in major depressive disorder
Garakani, A., Martinez, J. M., Marcus, S. M., Weaver, J. C., Rickels, K., D, M. F. M., & Hirschowitz, J. (2008) · International Clinical Psychopharmacology · doi:10.1097/yic.0b013e328301a74c · Cited by 40
“However, there has been recent evidence that the ‘delayed-onset hypothesis’ may be inaccurate, and that there is a noticeable response within the first week of initiation of treatment (Katz et al., 2004; Posternak and Zimmerman, 2005; Taylor et al., 2006).”
Background
Behavioural and computational methods reveal differential effects for how delayed and rapid onset antidepressants effect decision making in rats
Hales, C. A., Houghton, C. J., & Robinson, E. S. J. (2017) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2017.09.008 · Cited by 41
“…MDD only report subjective changes in mood weeks after beginning to take antidepressants (Anderson et al., 2000), with a meta-analysis of timing of onset of antidepressant ef ﬁ cacy ﬁ nding that the majority of improvement was apparent after two weeks of treatment (Posternak and Zimmerman, 2005).”
Background
Early Prediction of Fluoxetine Response for Han Chinese Inpatients With Major Depressive Disorder
Lin, C., Lane, H., Chen, C., Juo, S. H., & Yen, C. (2011) · Journal of Clinical Psychopharmacology · doi:10.1097/jcp.0b013e318210856f · Cited by 31
Peripheral blood and neuropsychological markers for the onset of action of antidepressant drugs in patients with Major Depressive Disorder
Tadić, A., Wagner, S., Gorbulev, S., Dahmen, N., Hiemke, C., Braus, D. F., & Lieb, K. (2011) · BMC Psychiatry · doi:10.1186/1471-244x-11-16 · Cited by 33
“000 patients treated with virtually all groups of ADs strongly suggesting that a true drug response can be observed within the first 10-14 days of treatment [15-25].”
Background
Daily process methodology for measuring earlier antidepressant response
Lenderking, W. R., Hu, M., Tennen, H. A., Cappelleri, J. C., Petrie, C. D., & Rush, A. J. (2008) · Contemporary Clinical Trials · doi:10.1016/j.cct.2008.05.012 · Cited by 37
“A recent metaanalysis suggests the possibility that drug effects may be present during the first twoweeks of therapy [16], though this is not yet a generally-accepted finding.”
Background
Clinical features and drug induced side effects in early versus late antidepressant responders
Fabbri, C., Marsano, A., Balestri, M., Ronchi, D. D., & Serretti, A. (2013) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2013.05.020 · Cited by 33
Is it worth assessing progress as early as week 2 to adapt antidepressive treatment strategy? Results from a study on agomelatine and a global meta-analysis
Gorwood, P. A. P. M., Bayle, F., Vaïva, G., Courtet, P., Corruble, E., & Llorca, P. (2013) · European Psychiatry · doi:10.1016/j.eurpsy.2012.11.004 · Cited by 31
“[37] showing that drug-placebo differences were most pronounced during the first 2 weeks of antidepressant treatment.”
Background
The relationship between antidepressant and analgesic responses: findings from six placebo-controlled trials assessing the efficacy of duloxetine in patients with major depressive disorder
Fishbain, D. A., Detke, M. J., Wernicke, J., Chappell, A. S., & Kajdasz, D. K. (2008) · Current Medical Research and Opinion · doi:10.1185/03007990802429627 · Cited by 31
Sleep and major depressive disorder: a review of non-pharmacological chronotherapeutic treatments for unipolar depression
Cunningham, J. E. A., Stamp, J. A., & Shapiro, C. M. (2019) · Sleep Medicine · doi:10.1016/j.sleep.2019.04.012 · Cited by 37
Taking computerized CBT beyond primary care.
Learmonth, D., & Rai, S. (2008) · British Journal of Clinical Psychology · doi:10.1348/014466507x248599 · Cited by 30
Rationale and design of the randomised clinical trial comparing early medication change (EMC) strategy with treatment as usual (TAU) in patients with Major Depressive Disorder - the EMC trial
the EMC Study Group, Tadić, A., Gorbulev, S., Dahmen, N., Hiemke, C., Braus, D. F., Roschke, J., van Calker, D., Wachtlin, D., Kronfeld, K., et al. (2010) · Trials · doi:10.1186/1745-6215-11-21 · Cited by 28
“A further meta-analysis [21] comprising 3418 placebo- and 5158 verum-treated patients found nearly identical time courses of improvement on placebo and active medication: 60.”
Method
A pilot effectiveness study: placebo-controlled trial of adjunctive L-triiodothyronine (T3) used to accelerate and potentiate the antidepressant response.
Posternak, M., Novak, S., Stern, R., Hennessey, J., Joffe, R., Prange, A., & Zimmerman, M. (2008) · International Journal of Neuropsychopharmacology · doi:10.1017/s1461145707007663 · Cited by 29
“=9.59, d.f.=1, p=0.002) than the 62.7 % rate reported in a recent meta-analysis of antidepressant trials ( Posternak and Zimmerman, 2005 ).”
ResultInfluentialSelf-citation
Causality of stem cell based neurogenesis and depression – To be or not to be, is that the question?
Feldmann, R. E., Sawa, A., & Seidler, G. H. (2006) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2006.06.007 · Cited by 26
“In addition, several meta-analyses found no evidence to supportDART, but rather suggest true antidepressant/antipsychotic effects to occur already within the first 1 to 2 weeks (Agid et al., 2003; Posternak and Zimmerman, 2005).”
Background
Early improvement as a predictor of eventual antidepressant treatment response in severely depressed inpatients
Vermeiden, M., Kamperman, A., Vulink, M. E., van den Broek, W. W., & Birkenhäger, T. (2014) · Psychopharmacology · doi:10.1007/s00213-014-3765-1 · Cited by 28
“Three meta-analyses (Posternak and Zimmerman 2005; Papakostas et al. 2006; Taylor et al. 2006) concluded that antidepressant response can take place early in the course M.”
Background
Association of a functional polymorphism in the adrenomedullin gene (ADM) with response to paroxetine
Glubb, D. M., McHugh, P., Deng, X., Joyce, P. R., & Kennedy, M. A. (2009) · The Pharmacogenomics Journal · doi:10.1038/tpj.2009.33 · Cited by 29
Time to response for duloxetine 60 mg once daily versus placebo in elderly patients with major depressive disorder
Raskin, J., Xu, J. Y., & Kajdasz, D. K. (2007) · International Psychogeriatrics · doi:10.1017/s1041610207005649 · Cited by 31
“Although not done specifically in elderly populations, several recent reviews and meta-analyses of antidepressant drug trials, primarily focused on the selective serotonin reuptake inhibitors (SSRIs), suggest that evaluations could be done within one week or even as early as the first few days after starting treatment…”
BackgroundMethodResultInfluential
Efficacy and safety of zuranolone in Japanese adults with major depressive disorder: A double‐blind, randomized, placebo‐controlled, phase 2 clinical trial
Kato, M., Nakagome, K., Baba, T., Sonoyama, T., Okutsu, D., Yamanaka, H., Shimizu, R., Motomiya, T., & Inoue, T. (2023) · Psychiatry and Clinical Neurosciences · doi:10.1111/pcn.13569 · Cited by 28
“A metaanalysis of 76 double-blind, placebo-controlled trials shows that in general, the effect of antidepressant is slow.(6,39) Similarly, another meta-analysis of 28 placebo-controlled, randomized controlled trials (n = 5872) of SSRIs reported that the treatment response was greatest in the first week.”
Background

Authors: Posternak, M. A., & Zimmerman, M.
Affiliations: Brown University (US)
ORCID: Zimmerman, Mark
Venue: The Journal of Clinical Psychiatry
Publisher: Physicians Postgraduate Press, Inc
Published: 2005-02-15
Volume: 66
Issue: 02
Pages: 148-158
ISSN: 0160-6689 (ISSN-L)
DOI: 10.4088/jcp.v66n0201
OpenAlex: W2089202379
Cited by: 250
References: 0
Citations by year: 2026: 6 · 2025: 9 · 2024: 10 · 2023: 6 · 2022: 10 · 2021: 10 · 2020: 9 · 2019: 11 · 2018: 6 · 2017: 14 · 2016: 7 · 2015: 9 · 2014: 10 · 2013: 19 · 2012: 12
FWCI: 13.17
Type: journal article
Language: en
Open access: closed
Locations: The Journal of Clinical Psychiatry (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
Life Sciences › Neuroscience › Cognitive Neuroscience › Pain Management and Placebo Effect
Social Sciences › Psychology › Clinical Psychology › Psychotherapy Techniques and Applications
Keywords: depression, Hamilton Depression Rating Scale
MeSH terms: Antidepressive Agents, Depressive Disorder, Double-Blind Method, Drug Administration Schedule, Humans, Placebos, Psychiatric Status Rating Scales, Time Factors, Cohort Studies, Placebo Effect, Randomized Controlled Trials as Topic, Treatment Outcome

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Is There a Delay in the Antidepressant Effect? A Meta-Analysis

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