Am J Psychiatry 154:1760-1762, December 1997
© 1997 American Psychiatric
Association
Emergence of Adverse Events Following Discontinuation of Treatment With
Extended-Release Venlafaxine
Maurizio Fava, M.D.,
Rosemarie Mulroy, B.A., Jonathan Alpert, M.D., Ph.D.,
Andrew A. Nierenberg, M.D., and Jerrold F. Rosenbaum,
M.D.
 |
ABSTRACT |
OBJECTIVE:
The rate of adverse events following discontinuation of treatment
with extended-release venlafaxine was compared with the rate
associated with discontinuation of placebo administration.
METHOD: The subjects were 20 outpatients with major depressive
disorder who had participated in a multicenter, double-blind,
placebo-controlled study of the efficacy of the new extended-release
formulation of venlafaxine. RESULTS: During the 3 days after
discontinuation of treatment with the study drug, seven (78%)
of the nine venlafaxine-treated subjects and two (22%) of the
nine placebo-treated patients reported the emergence of adverse
events, a statistically significant difference. CONCLUSIONS:
These results suggest that clinicians discontinuing venlafaxine
treatment should consider tapering the medication dose gradually.
(Am J Psychiatry 1997; 154:1760–1762)
|
INTRODUCTION |
There is
now accumulating evidence that a substantial proportion of patients
who abruptly discontinue taking selective serotonin reuptake
inhibitors (SSRIs) report characteristic adverse events, such as
dysphoria, anxiety, irritability, hot and cold flashes, excessive
sweating, flu-like symptoms, nausea, diarrhea, fatigue,
lightheadedness, dizziness, headaches, insomnia, and vivid dreams
(1–3).
The discontinuation-emergent symptoms that have been reported with
SSRIs usually resolved with time, resumption of treatment with the
SSRI, anticholinergic drug use, or the addition of an SSRI with a
longer half-life, such as fluoxetine (2,
3).
On the basis of these anecdotal observations, it has been recommended
that clinicians discontinuing SSRI treatment consider tapering the
drug dose gradually, with reinstitution of the SSRI if substantial
discontinuation symptoms develop (4).
Even though venlafaxine is considered by some to be a serotonin
and norepinephrine reuptake inhibitor, there is substantial
evidence that its in vitro pharmacological properties and its
side effect profile, at least in lower doses, are similar to
those of the SSRIs (1).
Following an initial case report by Farah and Lauer (5),
Louie et al. (6)
described the occurrence of dysphoria and gastrointestinal symptoms
in three patients within 3 days after discontinuation of venlafaxine
treatment. It is interesting that the symptoms experienced by two of
these patients were similar to those experienced by the same
subjects after they stopped taking SSRIs.
Since our site was one of 12 centers participating in a safety and
efficacy study of the new extended-release formulation of venlafaxine
for major depression, we decided to compare the rate of emergence of
adverse events after discontinuation of venlafaxine treatment with
the rate for discontinuation of placebo administration among the
patients enrolled at our site. Since adverse events upon abrupt
discontinuation of SSRIs are thought to occur more frequently with
SSRIs that have relatively shorter half-lives than with drugs that
have longer half-lives, such as fluoxetine (1),
we hypothesized that withdrawal symptoms would be relatively common
after discontinuation of venlafaxine, which has a relatively short
half-life.
|
METHOD
|
At our
site at the Depression Clinical and Research Program of the
Massachusetts General Hospital, 20 outpatients 18 years of age or
older participated in a multicenter, double-blind, placebo-controlled
study of the efficacy of extended-release venlafaxine. Written
informed consent was obtained from all patients before
protocol-specified procedures were carried out. The study
participants had met the DSM-IV criteria for major depressive
disorder as determined by the Structured Clinical Interview for
DSM-III-R—Patient Version (7)
and had been required to have a score of 20 or higher on the 21-item
Hamilton Depression Rating Scale (8)
at screening and to have had no greater than a 20% decrease in
Hamilton depression score at the baseline visit. The study included a
1-week placebo washout period followed by an 8-week double-blind
treatment period, during which one-half of the patients were assigned
to treatment with extended-release venlafaxine and the other one-half
of the patients were assigned to placebo. During the first 2
weeks of double-blind treatment, the patients received either 75
mg/day of extended-release venlafaxine or placebo. After 2 weeks
of treatment, if clinically indicated to improve response, the
dose of extended-release venlafaxine was increased to 150 mg/day.
After 4 weeks of treatment, a further increase in dose to 225
mg/day was allowed, if clinically indicated. All of the study
completers taking two or three capsules per day were required
to taper their study medication by reducing the dose by one
capsule per week, while those taking one capsule of study medication
per day (75 mg of extended-release venlafaxine or placebo) were
allowed to stop taking the medication without further tapering.
The exclusion criteria included pregnancy or breast feeding;
serious suicidal risk; serious or unstable medical illness;
history of seizure disorder; psychotic disorders not elsewhere
classified; bipolar disorder; history of drug or alcohol dependence
within the previous year; previous treatment with venlafaxine;
myocardial infarction within 6 months; major abnormalities in
laboratory test results; use of investigational drugs, antipsychotic
drugs, or ECT within 30 days; use of fluoxetine within 21 days;
use of monoamine oxidase inhibitors within 14 days; and use of
other psychotropic drugs within 7 days of the start of the
double-blind treatment.
We enrolled and randomly assigned 20 subjects, 11 men and nine
women, with a mean age of 36.5 years (SD=10.7). Their mean score
on the Hamilton depression scale was 21.4 (SD=2.1). The primary
efficacy variables were the final ratings on the total Hamilton
depression scale, the Montgomery-Åsberg Depression Rating Scale
(9),
the Clinical Global Impression scale (10),
and the depressed mood item on the Hamilton depression scale.
These scales were administered at every visit by the study
psychiatrists. The efficacy results are not reported here but will be
the subject of a future publication based on the pooled results. Four
patients did not complete the 8-week double-blind phase: two were
taking placebo and two were taking venlafaxine. Only two of the
dropouts were followed after discontinuation of the study
medication (one taking venlafaxine and one taking placebo).
The emergence of any new symptom or adverse event during the
period following discontinuation of study drug administration
(posttaper period) was assessed with general inquiry (an open-ended
question) by the study psychiatrists at the time of the first
visit after discontinuation; this first visit occurred a mean
of 5 days (SD=1) after discontinuation of venlafaxine treatment.
Both the patients and study psychiatrists were blind to treatment
type when the information about adverse events was obtained.
This information was gathered for all of the completers and for
two of the patients who stopped taking the study medication after 6
weeks of study.
The one-tailed Fisher's exact test was used to compare the rates
of adverse events during the posttaper period among the patients
taking venlafaxine and the patients taking placebo. The Mann-Whitney
U test was used to compare the numbers of withdrawal symptoms
during the posttaper period in the two groups (venlafaxine versus
placebo) and to compare the Hamilton depression scores of the
patients who reported withdrawal symptoms and those who did
not. The Spearman rank correlation method was used to examine
the relationship between Hamilton depression score at endpoint
and the number of withdrawal symptoms. Finally, the multiple
linear regression method was used to assess the relationship
between number of withdrawal symptoms and treatment group
(venlafaxine or placebo), after adjustment for endpoint Hamilton
depression score.
|
RESULTS |
During the
3 days after study drug discontinuation, seven (78%) out of the nine
venlafaxine-treated subjects (95% confidence interval=0.46–0.93) and
only two (22%) out of the nine placebo-treated patients (95%
confidence interval=0.06–0.55) reported the emergence of adverse
events (p=0.03, one-tailed Fisher's exact test). The nine patients
who reported adverse events after treatment discontinuation had
significantly lower endpoint scores on the Hamilton depression scale
(mean=6.2, SD=3.4) than the nine patients who did not (mean=12.1,
SD=5.7) (z=2.4, p<0.02). The most common adverse events after
venlafaxine discontinuation were dizziness or lightheadedness (N=4),
excessive sweating (N=2), irritability (N=2), dysphoria (N=2), and
insomnia (N=2).
The number of adverse events during the posttaper period was
significantly higher among the nine venlafaxine-treated patients
(mean=2.8, SD=2.3) than among the nine placebo-treated patients
(mean=0.4, SD=1.0) (z=2.3, p<0.03). In addition, among the
nine venlafaxine-treated patients, the mean numbers of moderate
and mild adverse events were 1.1 (SD=2.1) and 1.7 (SD=1.5),
respectively. Among the nine placebo-treated patients, however,
the mean numbers of moderate and mild adverse events were only
0.2 (SD=0.7) and 0.2 (SD=0.4), respectively. We also observed a
statistically significant (r=–0.5, N=18, p<0.05) inverse
relationship between endpoint Hamilton depression score and number of
adverse events after treatment discontinuation. Finally, the number
of adverse events during the posttaper period was significantly
related (partial F=4.6, df=2,15, p<0.05) to treatment assignment
(venlafaxine versus placebo), after adjustment for endpoint Hamilton
depression score.
|
DISCUSSION |
The
results from our site showed a significantly greater number of
adverse events after discontinuation of venlafaxine treatment than
after discontinuation of placebo administration. Although adverse
events emerged after discontinuation of antidepressant treatment
mostly among patients with fewer depressive symptoms at endpoint, the
relationship between number of adverse events and treatment
assignment (venlafaxine versus placebo) remained statistically
significant after adjustment for depression severity at endpoint. We
also found that the percentage of subjects reporting adverse events
after discontinuation of venlafaxine treatment was significantly
higher than the percentage for placebo, despite the relatively small
number of subjects.
The symptoms reported in our study after venlafaxine discontinuation
(i.e., dizziness, lightheadedness, excessive sweating, irritability,
dysphoria, and insomnia) are similar to those reported after
discontinuation of SSRI treatment (1).
The physiologic mechanism underlying the emergence of adverse events
after discontinuation of venlafaxine treatment is not known yet.
The strengths of our study are that the follow-up of patients
completing the double-blind trial at our site was consistent
and systematic and that the clinicians assessing these adverse
events were blind to treatment assignment. The main limitation
of our study is the small number of subjects.
Our results suggest that discontinuation-emergent adverse events
are fairly common among venlafaxine-treated patients, and
consequently clinicians should consider tapering the venlafaxine dose
gradually. Larger, double-blind studies are needed to confirm our
findings.
|
FOOTNOTES |
Received Jan. 2, 1997; revision received June 24, 1997;
accepted July 3, 1997. From the Depression Clinical and Research
Program, Massachusetts General Hospital. Address reprint requests
to Dr. Fava, Depression Clinical and Research Program, WACC 812,
Massachusetts General Hospital, 15 Parkman St., Boston, MA 02114;
favam@A1.mgh.harvard.edu
(e-mail). Supported in part by a grant from Wyeth-Ayerst
Laboratories.
|
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