ORIGINAL ARTICLE
Characteristics of Escitalopram Discontinuation
Syndrome: A Preliminary Study
Norio Yasui-Furukori, MD, PhD, Kojiro Hashimoto, MD, PhD, Shoko Tsuchimine, PhD, Tetsu Tomita, MD, PhD,
Norio Sugawara, MD, PhD, Masamichi Ishioka, MD, PhD, and Kazuhiko Nakamura, MD, PhD
Background: Antidepressant discontinuation syndrome (ADS) frequently occurs in patients who undergo an abrupt discontinuation of their
antidepressant medication.
Methods: We evaluated 25 consecutive outpatients with depression
who discontinued their use of escitalopram. The presence of ADS was
evaluated according to the Antidepressants Discontinuation Syndrome
checklist.
Results: Antidepressant discontinuation syndrome was observed in 14
of 25 patients. Frequent symptoms were dizziness (44%), muscle tension
(44%), chills (44%), confusion or trouble concentrating (40%), amnesia
(28%), and crying (28%). The treatment doses and plasma concentrations
of escitalopram were significantly higher in patients with ADS than in patients without ADS. No group differences were observed regarding age,
sex, or duration of escitalopram treatment before the discontinuation.
Conclusions: These findings suggest that a higher dose and lower clearance of escitalopram lead to a higher risk of ADS. Very slow tapering is
recommended for all patients.
Key Words: escitalopram, antidepressant discontinuation syndrome, dose,
concentrations
(Clin Neuropharm 2016;39: 125–127)
A
ntidepressant discontinuation syndrome (ADS) occurs in
approximately 20 percent of patients after an abrupt discontinuation of an antidepressant medication that was taken for
at least 6 weeks.1,2 Typical ADS symptoms include flu-like symptoms, insomnia, nausea, imbalance, sensory disturbances, and
hyperarousal. These symptoms are usually mild, last for 1 to
2 weeks, and are rapidly mediated with a reinstitution of the antidepressant medication.1,2
Long-term use of selective serotonin reuptake inhibitors
(SSRIs) increases the synaptic levels of serotonin via blockade
of the serotonin reuptake pump.3 The block results in a downregulation of postsynaptic receptors.3,4 A temporary deficiency
of synaptic serotonin may occur after an abrupt withdrawal of
SSRIs.3,4 This deficiency is compounded by the fact that the
down-regulated receptors will remain in their relatively hypoactive
state for days or even weeks.3,4 This down-regulation may directly
or indirectly result in ADS via the downstream effects on other
Department of Neuropsychiatry, Graduate School of Medicine, Hirosaki University, Hirosaki, Japan.
Address correspondence and reprint requests to Norio Yasui-Furukori, MD,
PhD, Department of Neuropsychiatry, Graduate School of Medicine,
Hirosaki University, Hirosaki, 036-8562, Japan; E-mail:
yasufuru@hirosaki-u.ac.jp
Conflicts of Interest and Source of Funding: Funded by a Grant-in-Aid for
Scientific Research (KAKENHI) from the Japan Society for the Promotion
of Research (JSPS, 15 K19239, 15 K19710, and 15H04754) and a grant
from the Hirosaki Research Institute for Neurosciences.
Norio Yasui-Furukori has received grant/research support or honoraria from and
has worked with Asteras, Dainippon, Eli Lilly, GSK, Janssen-Pharma,
Meiji. Mochida, MSD, Otsuka, Pfizer, Takada, and Yoshitomi. The other
authors declare that they have no competing interests. The funders had no
role in the study design, data collection or analysis, decision to publish, or
preparation of the manuscript.
Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
DOI: 10.1097/WNF.0000000000000139
Clinical Neuropharmacology • Volume 39, Number 3, May/June 2016
neurotransmitter systems (eg, norepinephrine, dopamine, and γaminobutyric acid) that are implicated in depressive and anxiety
disorders.3,4 Because tricyclic antidepressants and monoamine
oxidase inhibitors are also serotonergically active, the same mechanism is implicated for the respective ADSs. However, tricyclic
antidepressants also affect the cholinergic system.3,4 Thus, rapid
discontinuation may cause parkinsonism symptoms and balance problems. Because monoamine oxidase inhibitors alter
α2-adrenergic and dopaminergic receptors, discontinuation may
cause agitation and psychosis.3,4
Escitalopram is used to treat patients with anxiety and major
depressive disorders.5 This drug exerts a highly selective, potent,
and dose-dependent inhibitory effect on human serotonin transport.6 By inhibiting the reuptake of serotonin into presynaptic
nerve endings, the drug enhances the activity of serotonin in the
central nervous system. Escitalopram contains serotonin norepinephrine reuptake inhibitors, including racemic citalopram.7,8
Escitalopram is approved for use at clinical doses of 10 and
20 mg (5 mg in certain subpopulations or as an initial dose).
When administered orally, escitalopram reaches Tmax within
5 hours and is 56% protein bound. Escitalopram reaches steadystate concentrations in the blood within 1 to 2 weeks.9,10
The risk factors of ADS after escitalopram treatment are
poorly understood.11,12 Therefore, we evaluated the characteristics of ASD induced by escitalopram withdrawal, including its
pharmacokinetic profile, in a series of 25 consecutive depression
patients.
METHODS
The subjects included 25 consecutive Japanese outpatients
with depression who discontinued their use of escitalopram. The
patients who had a repeated recurrence of depression, who had
had residual depression symptoms, or in whom we could not confirm medication compliance were excluded from the study. The
subjects in the present study had been treated with more than
10 mg/d of escitalopram for longer than 6 months. After careful
confirmation of remission for at least 3 months, the doses were
tapered to 5 mg/d, and each time interval between dose alterations was greater than 4 weeks. For example, a dose of 20 mg/d
was decreased to 15 mg/d for at least 4 weeks, subsequently decreased to 10 mg/d for at least 4 weeks, then decreased to
5 mg/d for at least 4 weeks, and finally discontinued. The dose
tapering regime was determined by the psychiatrists in charge
of the patients on the basis of their clinical observations. No
drugs other than some hypnotics such as brotizolam (n = 3) and
zolpidem (n = 4) were taken by the subjects. The study was approved by the ethics committee of Hirosaki University, and all
participants provided written informed consent.
To evaluate the discontinuation syndrome, we used the
discontinuation-emergent signs and syndromes (DESS) checklist.13 The DESS checklist is a patient-rated instrument that queries for signs and symptoms associated with the discontinuation
of an SSRI treatment. Assessment of possible discontinuationemergent events was conducted using the DESS checklist. The
43-item list was developed by the investigators on the basis of
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125
Clinical Neuropharmacology • Volume 39, Number 3, May/June 2016
Yasui-Furukori et al
TABLE 1. Percentage of DESS Reported by 10% of Patient in a
Previous Report by Rosenbaum et al13
Prevalence in
Prevalence in
No.
Total Subjects Total Subjects
Subjects
(N = 25)
With ASD (n = 14)
Dizziness
Muscle tension
Chills
Confusion or trouble
concentrating
Crying
Amnesia
Emotional lability
Dreaming
Diarrhea
Shaking
Worsened mood
Nervousness
Depersonalization
Unsteady gait
Irritability
Agitation
Trouble sleeping
Anger
Muscle aches
Vomiting
Headache
Nausea
Sweating
Fatigue
Panic
Sore eyes
11
11
11
10
44
44
44
40
79
79
79
71
7
7
6
6
6
6
5
5
5
5
4
4
4
4
4
4
3
3
3
1
1
1
28
28
24
24
24
24
20
20
20
20
16
16
16
16
16
16
12
12
12
4
4
4
50
50
43
43
43
43
36
36
36
36
29
29
29
29
29
29
21
21
21
7
7
7
an evaluation of signs and symptoms reported in the available literature. Among the 43-item list, we selected 25 items from the DESS
that are reported by more than 10% of patients on the basis of a
report by Rosenbaum et al,13 including agitation, amnesia, anger,
chills, confusion or trouble concentrating, crying, depersonalization, diarrhea, dizziness, dreaming, emotional lability, fatigue, headache, irritability, muscle ache, muscle tension, nausea, nervousness,
panic, shaking, sore eyes, sweating, difficulty sleeping, unsteady
gait, vomiting, and worsened mood. The DESS checklist was
given to all patients on the day of medication discontinuation.
The DESS checklist was collected at every clinic visit, usually
at 2-week intervals. For confirmation, we asked each patient to
answer the following question: “During the past 14 days, have
you experienced any changes in the following symptoms?” Patients chose 1 of 5 responses (new symptoms, old but worsened
symptoms, old but improved symptoms, old and unchanged
symptoms, symptoms not present). Discontinuation symptoms
were observed until 4 weeks after the discontinuation. We defined
discontinuation syndrome as 3 simultaneous, new, or worsened
signs and symptoms because there are no criteria for discontinuation syndrome using DESS in previously reported studies. No
signs or symptoms were confirmed before the discontinuation
in our subjects.
Blood samples (5 mL) were obtained 14 to 16 hours after
the last 5-mg/d dose of escitalopram (just after discontinuation).
The plasma samples were frozen and maintained at −20°C
until analysis. The plasma concentrations of escitalopram and
desmethylescitalopram were analyzed in duplicate using highperformance liquid chromatographic methods that were developed
in our laboratory.14 The lowest limit of detection was 1.0 ng/mL,
and the intra-assay and interassay coefficients of variation were less
than 8.9% for both compounds.
The statistical analyses were performed using χ2 and Student
t tests. A P value of 0.05 or less was regarded as significant. SPSS
21.0 for Windows (SPSS Japan Inc, Tokyo) was used for
statistical analyses.
RESULTS
Discontinuation syndrome after escitalopram treatment was
present in 14 (56%) of 25 patients in our study. Frequent symptoms included dizziness (44%), muscle tension (44%), chills
(44%), confusion or trouble concentrating (40%), amnesia (28%),
and crying (28%) (Table 1). We readministered escitalopram
because of severe discontinuation syndrome symptoms in 2 of
14 patients.
Age, sex, and duration of escitalopram treatment did not
differ between the ADS and non-ADS groups before dose tapering. The duration of tapering was significantly longer in patients
with ADS than in patients without ADS. The treatment dose and
the plasma concentrations of escitalopram were significantly
higher in patients with ADS than patients without ADS (Table 2).
DISCUSSION
More than 50% of our patients developed escitalopraminduced ADS. We expected to observe a lower incidence of ADS.
TABLE 2. Characteristics of Subject With and Without ADS Induced by Escitalopram
Age, y
Sex, male, n (%)
Treatment dose, mg/d
Duration of treatment dose, d*
Duration of tapering, d
Plasma levels of ECIT, ng/mL†
Plasma levels of EDCIT, ng/mL†
Without ADS (n = 11)
With ADS (n = 14)
Significance
35.4 (19.7)
5 (45)
14.1 (4.9)
188 (149)
49 (39)
14.2 (19.7)
3.8 (1.9)
35.6 (10.7)
4 (29)
18.6 (3.1)
196 (123)
136 (89)
36.5 (29.4)
10.2 (15.5)
NS
NS
P < 0.05
NS
P < 0.05
P < 0.05
NS
*Duration of treatment dose just before the tapering.
†Steady-state plasma levels at 5 mg/d of escitalopram just before discontinuation.
ECIT indicates escitalopram; EDCIT, esdesmethylcitalopram; NS, no significant.
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Clinical Neuropharmacology • Volume 39, Number 3, May/June 2016
Generally, ADS is more common in patients who discontinue
therapeutic agents with relatively short half-lives, such as paroxetine (15–20 hours), than in patients who discontinue agents with
longer half-lives, such as fluoxetine (4–6 days).15 This evidence
suggests that the use of therapeutic drugs with a relatively short
half-life is a risk factor for development of ADS after discontinuation. The basic pharmacokinetic properties of escitalopram are
described herein. Escitalopram is metabolized in parallel by at
least 2 CYP enzymes, CYP3A4 and CYP2C19 (and to a lesser
extent by CYP2D6).10 The elimination half-life of escitalopram
is 27 to 33 hours, which is longer than that of paroxetine but
shorter than that of fluoxetine.15 In our study, a diagnosis of
ADS was made if a patient presented with at least 1 sign or symptom included in the DESS checklist. We may have overestimated
the percentage because ADS, anxiety, and depressive symptoms
are very similar. To confirm our findings, additional doubleblind, active control trials are required with larger samples.
The results of this study demonstrated that a higher dose
of escitalopram is associated with a higher prevalence of ADS.
Age, sex, and duration of escitalopram treatment did not differ between groups before tapering. Antidepressant discontinuation
syndrome was observed in 1 of 7 patients treated with 10 mg/d
and 13 of 18 patients treated with more than 15 mg/d (P =
0.0213 in 2-tailed analysis). Therefore, it is reasonable to conclude that a higher dose of escitalopram is a risk factor for developing ADS. Antidepressant discontinuation syndrome occurred
in many patients despite that we used a longer period of tapering
in patients who received relatively higher doses of escitalopram
and that we administered 5-mg/d escitalopram to all patients for
at least 4 weeks before discontinuation.
We observed that a relatively high steady-state concentration of escitalopram (at a dose of 5 mg/d) is a risk factor for
ADS. Because clearance is approximately inversely proportional
to the elimination half-life, patients with relatively high concentrations of escitalopram tend to have lower clearance and a longer
elimination half-life. This observation does not agree with the
long-accepted theory that ADS is more common in patients who
discontinue the use of agents with relatively short half-lives.
Because of the high dose and concentrations of escitalopram
at 5 mg/d, we assume that these patients had a very high concentration of escitalopram during the treatment. Therefore, a longterm high concentration of escitalopram may be a risk factor for
ADS. Plasma concentrations of escitalopram are significantly
higher in poor CYP2C19 metabolizers than in patients who
are extensive CYP2C19 metabolizers.16 The primary reason for
the higher ADS prevalence in the present study may be a higher
proportion of poor CYP2C19 metabolizers (among Japanese
subjects).17
This study has several limitations. First, we did not apply
a double-blind, placebo-active, controlled study design. Such a
design would be better for determining the prevalence of ADS
because symptoms and signs of recurrence are very similar to
those of ADS. Second, we did not evaluate the clinical symptoms
during treatment. Himei and Okumura suggested that ADS with
paroxetine in depressed patients is associated with adverse reactions to paroxetine during the early treatment phase.18 Third,
we did not measure the plasma concentration of escitalopram
during treatment (especially important at the dose of 20-mg/d
escitalopram). We also did not identify which patients had the
CYP2C19 genotype. Finally, this study was conducted with a
very small number of subjects. Therefore, we could not apply logistic regression analyses. For these reasons, our findings are
preliminary. Future studies with a polished design and a large
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Escitalopram Discontinuation Syndrome
number of subjects are required to overcome these disadvantages and to confirm our preliminary findings.
In conclusion, our results suggest that ADS induced by
escitalopram withdrawal is common. Relatively high doses and/or
high concentrations of escitalopram are risk factors for ADS.
Very gradual tapering over an extended period of time is recommended for all patients.
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