Elsevier

Biological Psychiatry

Volume 44, Issue 2, 15 July 1998, Pages 77-87
Biological Psychiatry

Original Articles
Selective serotonin reuptake inhibitor discontinuation syndrome: a randomized clinical trial

https://doi.org/10.1016/S0006-3223(98)00126-7Get rights and content

Abstract

Background: Recent reports describe discontinuation-emergent adverse events upon cessation of selective serotonin reuptake inhibitors including dizziness, insomnia, nervousness, nausea, and agitation. We hypothesized that interruption of fluoxetine treatment would be associated with fewer discontinuation-emergent adverse events than interruption of sertraline or paroxetine treatment, based on fluoxetine’s longer half-life.

Methods: In this 4-week study, 242 patients with remitted depression receiving maintenance therapy with open-label fluoxetine, sertraline, or paroxetine for 4–24 months had their maintenance therapy interrupted with double-blind placebo substitution for 5–8 days. The Symptom Questionnaire (SQ), the Discontinuation-Emergent Signs and Symptoms checklist, the 28-item Hamilton Depression Rating Scale, and the Montgomery–Asberg Depression Rating Scale were used to assess somatic distress and stability of antidepressant response.

Results: Two hundred twenty patients (91%) completed the study. Following interruption of therapy, fluoxetine-treated patients experienced fewer discontinuation-emergent events than either sertraline-treated or paroxetine-treated patients (p < .001). The mean SQ somatic symptom scale score in fluoxetine-treated patients was significantly lower than that in sertraline-treated and paroxetine-treated patients (p < .001). Fluoxetine-treated patients also experienced less reemergence of depressive symptoms than sertraline-treated or paroxetine-treated patients (p < .001).

Conclusions: Abrupt interruption of antidepressant therapy for 5–8 days was associated with the emergence of new somatic and psychological symptoms in patients treated with paroxetine and to a lesser degree sertraline, with few symptoms seen with fluoxetine.

Introduction

Major depressive disorder is a recurrent illness that often requires long-term antidepressant therapy to minimize the risks of relapse and recurrence. During any long-term pharmacologic treatment regimen, the potential for deviations from the prescribed dosing instructions is substantial. Patient noncompliance with treatment regimens has been reported to be as high as 82% (Buckalew and Sallis 1986), but generally it is estimated to be between 20% and 50% Olivier-Martin 1986, Young et al 1986.

Since becoming available in the late 1980s, selective serotonin reuptake inhibitors (SSRIs) have emerged as first-line drugs for treating depressive disorders, perhaps in part because of the greater simplicity of dosing relative to the older tricyclic antidepressants (TCAs). In addition, while not proven to be more efficacious than the TCAs, the SSRIs present an improved safety and tolerability profile during treatment (Montgomery et al 1994).

The possibility of adverse effects upon discontinuation of a TCA is well documented Ceccherini-Nelli et al 1993, Dilsaver et al 1983, Dilsaver and Greden 1984. Symptoms may include abdominal pain, anorexia, chills, diaphoresis, diarrhea, fatigue, headache, malaise, myalgia, nausea, vomiting, and weakness (Lejoyeux et al 1996). To minimize these effects, gradual tapering of the TCA dose at the end of the treatment course has become standard practice.

Less is known regarding the relative tolerability of abrupt discontinuation of the SSRIs at the end of treatment; however, recent reports have described apparent discontinuation-emergent signs and symptoms occurring upon cessation of SSRI treatment Barr et al 1994, Einbinder 1995, Fava and Grandi 1995, Frost and Lal 1995, Kasantikul 1995, Koopowitz and Berk 1995, Leiter et al 1995, Louie et al 1994, Pyke 1995, Stoukides and Stoukides 1991. Dizziness, headache, nausea, vomiting, diarrhea, movement disorders, insomnia, irritability, visual disturbance, lethargy, anorexia, tremor, electric shock sensations, and lowered mood have all been reported in association with cessation of SSRI treatment Coupland et al 1996, Lejoyeux et al 1996, Price et al 1996. During clinical trials designed to assess the efficacy of paroxetine in obsessive–compulsive disorder and panic disorder, between 35% and 50% of patients experienced discontinuation-emergent events following cessation of therapy Barr et al 1994, Keuthen et al 1994, Oehrberg et al 1995, and a medication taper did not always prevent their occurrence Barr et al 1994, Keuthen et al 1994. Discontinuation-emergent symptoms are usually mild and transient, but debilitating symptoms causing severe discomfort and absenteeism have been reported Barr et al 1994, Koopowitz and Berk 1995.

Previous studies have suggested that the risk for these events is related to drug half-life, but these studies have been retrospective, lacking placebo control, and without a consistent and systematic method for collection of adverse events Bhaumik and Wildgust 1996, Coupland et al 1996, Gillespie et al 1996, Keuthen et al 1994, Lazowick and Levin 1995, Oehrberg et al 1995, Price et al 1996.

The purpose of the current study was to examine in a prospective, controlled manner the effects of abrupt interruption of long-term antidepressant treatment that mimics intermittent noncompliance. We hypothesized that because fluoxetine has a longer half-life than sertraline or paroxetine (van Harten 1993), interruption of fluoxetine treatment would be associated with fewer discontinuation-emergent adverse events than interruption of sertraline or paroxetine treatment.

Section snippets

Study design

This was a multicenter open-label, 4-week study, which included a 1-week (5–8 days) randomized double-blind, placebo-substitution period. The primary objective of the study was to compare the mean number of discontinuation-emergent events following a treatment interruption (placebo-substitution) period in patients with remitted depression on maintenance therapy with fluoxetine, sertraline, or paroxetine. Secondary objectives were to compare specific reported adverse events and to assess

Baseline patient comparisons

The treatment groups were demographically comparable at baseline. Mean duration of therapy, mean HDRS28 scores, and mean MADRS scores also were comparable, as shown in Table 1.

Of the 242 patients randomized to the experimental conditions, 231 remained eligible for Study Period II; 192 patients were assigned to interrupted therapy (placebo substitution) for 1 week and 39 patients were assigned to continue on active therapy.

Two hundred twenty patients (91%) completed the study. Four patients

Discussion

In the present study, patients with interrupted fluoxetine treatment experienced statistically significantly fewer adverse events than patients with interrupted sertraline or paroxetine treatment, as assessed by the DESS checklist, SQ somatic symptom scale, and spontaneously reported adverse events. Furthermore, sertraline-treated and paroxetine-treated patients but not fluoxetine-treated patients experienced a reemergence of depressive symptoms, as assessed by the HDRS28 and MADRS.

A number of

Acknowledgements

This work was sponsored by Eli Lilly and Company.

Drs. Rosenbaum and Fava are employees of Massachusetts General Hospital, Boston, Massachusetts. The other authors are all employees and minor stockholders of Eli Lilly and Company, Indianapolis, Indiana.

Lilly Research Laboratories would like to acknowledge Clinical Studies, Ltd., 2 Charles Street, Providence, Rhode Island, for assistance in conducting this study at 12 of its community-based research centers. The authors would also like to thank

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