Interruption of selective serotonin reuptake inhibitor treatment: Double-blind, placebo-controlled trial
Open accessAbstract
Background: Abrupt interruption of therapy with selective serotonin reuptake inhibitors (SSRIs) has been associated with somatic and psychological symptoms. Aims: Systematically to assess symptoms and effects on daily functioning related to interruption of SSRI therapy. Method: Patients treated with fluoxetine, setraline or paroxetine underwent identical five-day periods of treatment interruption and continued active treatment under double-blind, order-randomised conditions, with regular assessment of new symptoms. Results: Placebo substitution for paroxetine was associated with increases in the number and severity of adverse events following the second missed dose, and increases in functional impairment at five days. Placebo substitution for sertraline resulted in less pronounced changes, while interruption of fluoxetine was not associated with any significant increase in symptomatology. Conclusions: Abrupt interruption of SSRI treatment can result in a syndrome characterised by specific physical and psychological symptoms. Incidence, timing and severity of symptoms vary among SSRIs in a fashion that appears to be related to plasma elimination characteristics.
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Withdrawal symptoms are more common when SSRIs are given in higher doses or for longer periods.
“Withdrawal symptoms are more common when SSRIs are given in higher doses 55,56 , or for longer periods 55 .”
From Tapering of SSRI treatment to mitigate withdrawal symptoms (2019) · cites this paper as [55]
The Symptom measures section reports no significant relationship between either dose or time on treatment and new symptoms. The Clinical relevance section also says the authors did not find increased risk with longer exposure; page numbers are unavailable in our copy. (LLM, conf=0.93)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredA hyperbolic relationship has been demonstrated between dose of SSRI and risk of withdrawal symptoms.
“Furthermore, a hyperbolic relationship exists between dose of SSRI and reduction of depressed mood, as demonstrated in a mega-analysis 67 ; a hyperbolic relationship has also been demonstrated between dose of SSRI and risk of withdrawal symptoms 55 .”
From Tapering of SSRI treatment to mitigate withdrawal symptoms (2019) · cites this paper as [55]
The Symptom measures section reports no significant relationship between SSRI dose and new symptoms after treatment interruption. The Relationships to plasma drug concentrations section likewise says doses did not correlate with interruption symptoms in any drug group. It reports an association with the percentage reduction in plasma concentration across drug groups, not a hyperbolic dose–risk relationship. Page numbers are unavailable in our copy. (LLM, conf=0.88)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredA hyperbolic relationship exists between dose of SSRI and reduction of depressed mood.
“Furthermore, a hyperbolic relationship exists between dose of SSRI and reduction of depressed mood, as demonstrated in a mega-analysis 67 ; a hyperbolic relationship has also been demonstrated between dose of SSRI and risk of withdrawal symptoms 55 .”
From Tapering of SSRI treatment to mitigate withdrawal symptoms (2019) · cites this paper as [55]
This paper is cited for the second clause of the sentence, concerning SSRI dose and withdrawal symptoms, not the depressed-mood claim attributed to citation 67. In 'Symptom measures' (page unavailable), it reports no significant relationship between dose and new symptoms after treatment interruption; 'Relationships to plasma drug concentrations' likewise reports no dose–symptom correlation. It does not demonstrate the claimed hyperbolic relationship. (LLM, conf=0.88)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredAcute withdrawal syndromes have been reported over decades in various case reports and were later confirmed in placebo-controlled treatment-interruption trials and systematic reviews.
“Acute withdrawal syndromes have been reported over decades in various case reports (e.g. Bloch et al., 1995; Kostic et al., 2024; Kramer et al., 1961) and were later confirmed in placebo-controlled treatment-interruption trials (e.g. Michelson et al., 2000; Rosenbaum et al., 1998), and systematic reviews (e.g. Davies and Read, 2019; Fava et al., 2015, 2018).”
From Post-acute withdrawal syndrome (PAWS) after stopping antidepressants: a systematic review with meta-narrative synthesis (2025) · cites this paper as Michelson et al., 2000
The prevalence of discontinuation symptoms differs according to the pharmacological profile of SSRI.
“and to differ in prevalence according to the pharmacological profile of SSRI [20,21]”
From Withdrawal Symptoms after Selective Serotonin Reuptake Inhibitor Discontinuation: A Systematic Review (2015) · cites this paper as [21]
Case reports of new withdrawal symptoms (hypomania, anxiety, restless sleep, nightmares, depersonalization, formication, headache) after discontinuation of trazodone were published.
“Case reports of new withdrawal symptoms (i.e., hypomania, anxiety, restless sleep, nightmares, depersonalization, formication, headache) after discontinuation of trazodone were published [98-101].”
From Acute and Persistent Withdrawal Syndromes Following Discontinuation of Psychotropic Medications (2020) · cites this paper as [99]
The Discussion and Symptom measures passages describe symptoms after interruption of paroxetine or sertraline, not trazodone. Searches for trazodone withdrawal and trazodone discontinuation case reports found no passage addressing the claimed case reports or symptom list. Page numbers were unavailable in our copy. (LLM, conf=0.76)
Experimental — accuracy not yet measuredMajor complications of withdrawal may occur, such as seizures, suicide and psychoses, and in cases of barbiturate or alcohol abuse, even death.
“However, major complications of withdrawal may occur, such as seizures, suicide and psychoses [10] , and, in cases of barbiturate or alcohol abuse, even death [25] .”
From New Classification of Selective Serotonin Reuptake Inhibitor Withdrawal (2015) · cites this paper as [25]
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- [11]11. ROY TAMURA, PhD, ROSALINDA G. TEPNER, RPh, Lilly Research Laboratories, Indianapolis ROY TAMURA, PhD, ROSALINDA G. TEPNER, RPh, Lilly Research Laboratories, Indianapolis Correspondence: Dr David Michelson, Lilly Research Laboratories, Lilly Corporate Center, Drop Code Correspondence: Dr David Michelson, Lilly Research Laboratories, Lilly Corporate Center, Drop Code 2423, Indianapolis, IN 46285,USA.Tel: (317) 277-6443; Fax: (317) 277-3262; e-mail: 2423, Indianapolis, IN 46285,USA.Tel: (317) 277-64 43; Fax: (317) 277-3262; e-mail: dmichelson dmichelson@ @lilly.com lilly.com (First received 26 February 1999, final revision 25 June 1999, accepted 17 August 1999) (First received 26 February 1999, final revision 25 June 1999, accepted 17 August 1999) https://doi.org/10.1192/bjp.176.4.363 Published online by Cambridge University Press 1. 1. Dizziness Dizziness 2. 2. Nausea Nausea 3. 3. Unusual dreams Unusual dreams 4.
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“…case reports (e.g. Bloch et al. , 1995; Kostic et al. , 2024; Kramer et al. , 1961) and were later confirmed in placebo-controlled treatment-interruption trials (e.g. Michelson et al. , 2000; Rosenbaum et al. , 1998), and systematic reviews (e.g. Davies and Read, 2019; Fava et al. , 2015, 2018).”
- Authors
- Michelson, D., Fava, M., Amsterdam, J., Apter, J., Londborg, P., Tamura, R., & Tepner, R. G.
- Affiliations
- Eli Lilly (United States) (US)
- University of Pennsylvania (US)
- Princeton University (US)
- Corresponding author
- Michelson, David
- ORCID
- Michelson, David
- Venue
- British Journal of Psychiatry
- Publisher
- Royal College of Psychiatrists
- Published
- 2000-04
- Volume
- 176
- Issue
- 4
- Pages
- 363-368
- ISSN
- 0007-1250 (ISSN-L)
- 1472-1465
- OpenAlex
- W2178264880
- Cited by
- 181
- References
- 19
- Citations by year
- 2026: 5 · 2025: 8 · 2024: 5 · 2023: 1 · 2022: 3 · 2021: 2 · 2020: 3 · 2019: 7 · 2018: 6 · 2017: 5 · 2016: 1 · 2015: 7 · 2014: 3 · 2013: 8 · 2012: 6
- FWCI
- 6.48
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The British Journal of Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Health Sciences › Medicine › Psychiatry and Mental health › Electroconvulsive Therapy Studies
- Health Sciences › Medicine › Psychiatry and Mental health › Bipolar Disorder and Treatment
- Keywords
- selective serotonin reuptake inhibitors, treatment interruption, fluoxetine, sertraline, paroxetine, adverse events, functional disability, plasma elimination, antidepressant discontinuation
- MeSH terms
- Adult, Analysis of Variance, Mental Disorders, Double-Blind Method, Female, Fluoxetine, Humans, Male, Risk Factors, Substance Withdrawal Syndrome, Selective Serotonin Reuptake Inhibitors, Paroxetine
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