Original article 257
Jay D. Amsterdama and Justine Shultsb
monotherapy of bipolar type II and bipolar
a double-blind, placebo-substitution,
However, this difference was not clinically meaningful. No
hypomanic switch episodes were observed during study
phase II. Despite the limited sample size resulting in
insufficient power to detect statistical significance
relapse rates or change in YM R scores between treatment
conditions, these preliminary data appear to support
previous observations demonstrating
continuation fluoxetine monotherapy
effective for some patients with BP II or BP NOS MDE
with a low manic switch rate. Larger-scale studies are
needed to confirm these findings. Int Clin Psychopharmacol
20:257-264 @ 2005 Lippincott Williams & Wilkins.
patients (0.2:t 0.4) (P= 0.01).
that initial and
may be safe and
International Clinical Psychopharmacology 2005, 20:257-264
manic switch episode, SSRI
therapy, bipolar depression, bipolar type II
"Depression Research Unit, Department of Psychiatry and bCenter for Clinical
Epidemiology and Bio-statistics, University of Pennsylvania School of Medicine,
Philadelphia, Pennsylvania, USA.
Research Unit, University Science Center, Third Floor, 3535 Market Street,
Philadelphia, PA 19104, USA.
Tel: + 1 2156623462; fax: + 1 2156626443;
and requests for reprints to Jay D. Amsterdam, Depression
Current guidelines for the treatment of bipolar type II
(BP II) major depressive episode (MDE) recommend using
either mood stabilizer monotherapy or the combination
of a mood stabilizer with a selective serotonin reuptake
inhibitor (SSRI). These guidelines are the result of concern
over SSRI-induced manic switch episodes. We previously
showed that fluoxetine monotherapy
an initial treatment for BP II and BP NOS MDE with
a low manic switch rate. We now present the results of a
fluoxetine monotherapy in BP II and BP NOS patients who
have recovered from their MDE. This was a two-phase
study. In study phase I, patients received open-label
fluoxetine monotherapy 20 mg daily for up to 8 weeks.
Responders with a final 17-item Hamilton Rating Scale
for Depression (HAM-D) score ~ 9 were enrolled into
study phase II which consisted of double-blind,
20 mg daily for up to 6 months. Outcome measures
included the 17-item HAM-D and Young Mania Rating
(YMR) scales. Changes in YMR scores were assessed
using generalized estimating
was assessed using Kaplan-Meier
and Fisher's exact test. In study phase 11,43% of
fluoxetine-treated patients and 100% of placebo-treated
patients relapsed during continuation
The mean increase in YMR score in study phase II was
slightly higher in the fluoxetine-treated
may be effective as
continuation study of
therapy with fluoxetine
equation analysis. Relapse
patients (3.0:t 1.8)
Received 28 September 2004 Accepted 1 8 May 2005
consider them to be in need of treatment (Cassano et ai,
1999) and, as a result, BP II disorder is generally diagnosed
when the patient seeks treatment for a major depressive
episode (MDE) (Benazzi, 1997; Cassano et ai, 1999;
Ghaemi et al, 2001). The incidence of BP II MDE may
vary widely depending upon the ascertainment method
used (Benazzi, 1997; Goodwin and Ghaemi, 1998; Ghaemi
et ai, 1999; Ghaemi et aL, 2000). Surveys of clinical
populations have found the rates of BP II disorder to be as
high as 45% of patients who were previously diagnosed with
unipolar MDE (Benazzi, 1997; Goodwin and Ghaemi,
1998). This is largely the result of a failure to recognize
previous hypomanic episodes that can frequently be of
short duration and characterized by an enhanced sense of
well-being, or by symptoms of irritability and agitation.
These brief hypomanic episodes stand in stark contrast to
the more frequent and prolonged BP II MDEs.
Bipolar type II (BP II) disorder is the most common
phenotype of BP disorder (Simpson t't ol, 1993; Benazzi
et 01., 1997; Akiskal and Pinto, 1999; Benazzi, 1999;
Akiskal, 2003; Berk and Dodd, 2005). Its clinical course is
characterized by a preponderance of depressive episodes
with a lifetime history of one or more hypomanic episodes
lasting at least 4 days (Dunner et ol, 1976; Akiskal, 1996).
BP II disorder is diagnostically stable over time (Akiskal,
1996, 2003) and rarely evolves into 'BP type I (manic-
depressive) disorder (Ayuso-Gutierre?; and Ramos-Brieva,
1982; Faedda et ol, 1993; Coryell et ol, 1995). BP II
disorder is often difficult to recognize, and frequently
goes undiagnosed (Benazzi, 1997, 1 <)99; Cassano et ol,
1999; Akiskal, 2003; Goldberg, 2003; Berk and Dodd,
2005). BP II patients often do not rec<?gnize
of their hypomanic symptoms or, if recbgnized, they rarely
0268-1315 @ 2005 Lippincott Williams & Wilkins
258 International Clinical Psychopharmacology 2005, Vol 20 No 5
Although some investigators have suggested that BP I and
BP II disorders may be distinct' clinical and biochemical
entities (Goodwin and Jamison, 1990») the majority of
treatment studies have grouped BP I and BP II disorders
together. This has resulted in a paucity of information
about the most appropriate initial and continuation
treatment for BP II MDE (Berk and Dodd, 2005).
MDE do receive antidepressant monotherapy (Benazzi,
1997, 1999; Cassano et ol, 1999; Berk and Dodd, 2005),
and some studies have suggested that the rate of drug-
induced mania in BP II MDE may be considerably lower
than previously thought (Amsterdam and Brunswick,
2003). Although cases of SSRl-induced mania have been
reported (Feder, 1990; Stoll et d, 1994; Heimann and
March, 1996), controlled clinical trials of SSRl mono-
therapy in BP II MDE patients have reported good
efficacy and a relatively low manic switch rate (Benfield
etol, 1986; Cohnetol, 1989; Simpson and DePaulo, 1991;
Maj, 1997; Amsterdam et ol, 2004). Unfortunately, many
of these studies have included patients with BP I disorder
as well, and many of the patients were also taking a mood
There is debate as to whether antidepressant therapy is
even effective for BP MDE (Montgomery et al, 2000;
Geddes and Goodwin, 2001; Ghaemi et al, 2004). Several
controlled trials of antidepressant add-on therapy in BP I
and BP II MDE patients taking established mood
stabilizer therapy have failed ~o demonstrate clear-cut
antidepressant efficacy (Young etd , 2000; Nemeroff etal,
2001; Post et al, 2003), althou~ this contention has not
been a universal finding (Kupfer et al, 2001).
In the present study, we present data from a prospective,
double-blind, placebo-substitution study of the safety
and efficacy of initial and continuation fluoxetine
mono therapy 20mg daily in BP II MDE and BP NOS
Current treatment recommendations for the use of
antidepressants in BP II MDE are largely based upon
the treatment approach to BP I MDE, which discourages
the use of antidepressants due to concern over the risk of
drug-induced manic switch episodes (Wehr and Goodwin,
1979; Wehr and Goodwin, 1987; J:lrien et aI., 1994; Boerlin
et aI., 1998; Ghaemi et 01., 1999). Current guidelines for
the treatment of BP II MDE suggest initiating mood
stabilizer monotherapy for patie~ts with mild depressive
symptoms, and using a mood stabilizer in combination
with a selective serotonin reuptake inhibitor (SSRI) for
more severe depressive symptoms (American Psychiatric
Association, 1994; Treatment of Bipolar Disorder Expert
Consensus Panel, 1996; Yatham et aI., 1997; Sachs et aI.,
2000; American Psychiatric Association, 2002). It is
further recommended that SSRI therapy be limited to a
low dose for the briefest possible time. Tricyclic
antidepressants are to be avoided altogether in BP
MDE (American Psychiatric Association, 1994; Treatment
of Bipolar Disorder Expert Consensus Panel, 1996;
Yatham et 01., 1997; Sachs et aI., 20PO; American Psychiatric
Association, 2002). A BP disorders' expert panel has
suggested initiating treatment fOJ" BP MDE with a mood
stabilizer alone and to avoid antidepressant monotherapy
altogether (Yatham et aI., 1997). More recently, Sachs et al.
(2000) published treatment guidelines recommending
starting mood stabilizer therapy alone for BP MDE of
mild to moderate severity, and combining a mood
stabilizer and an antidepressant for patients with severe
BP MDE. None of these treatment algorithms recom-
mend the use of antidepressant monotherapy for BP
MDE, and none of the guidelines appear to make the
distinction between therapy for BP I and BP II MDE.
All subjects were provided with a detailed description of
the purpose and procedures of the study in accordance
with the ethical standards set forth by the Institutional
Review Board of the University. All subjects provided
their written informed consent before enrolling in the
This was a two-phase trial. Phase I of the study consisted
of all patients receiving open-label fluoxetine monother-
apy 20 mg daily for 8 weeks. During this study phase, the
fluoxetine dose could be reduced to 10 mg daily for
adverse events during weeks 1-4 of treatment. However,
the dose of fluoxetine had to be maintained at 20 mg daily
during the final 4 weeks of study phase I. Efficacy and
safety measures were obtained after weeks 1,2,4,6 and 8
of treatment. Remission was defined as a final 17-item
Hamilton Depression Rating (HAM-D) (Hamilton, 1960)
score:::; 9, or a final 17-item 'atypical symptom' HAM:-D
score:::; 9 (Reimherr et ai, 1998) after week 8 of
treatment. Patients with a final HAM-D score:::; 99 were
eligible to be enrolled into study phase II, which
consisted of randomized, double-blind, placebo-substitu-
tion, continuation treatment with fluoxetine monother-
apy for 6 months. Patients randomized to fluoxetine
monotherapy condition continued their dose at 20 mg
daily. Patients randomized to the placebo condition were
provided with identically appearing medication capsules.
The use ofSSRI monotherapyfof the treatment ofBP II
MDE is an area of current con~roversy (Ghaemi et a/.,
2000; Amsterdam and Brunswick, 2003; Post eta/., 2003).
Nevertheless, many patients with undiagnosed BP II
During study phase II, efficacy and safety measures were
obtained after weeks 2,4,8, 12, 16,20 and 26 of double-
blind therapy. However, the actual measurement times
varied slightly betWeen subjects and, accordingly, the
Fluoxetine monotherapy of BP II and BP NOS major depression Amsterdam and Shults 259
resulted in YMR scores that were above zero at many
actual day of measurement after the study phase II
baseline visit was used for statistical anlilysis. Relapse was
defined as an increase in the week 8 (!phase II baseline)
17-item HAM-D score ~ 14 plus DSM-IV criteria of
MDE. Concomitant use of lorazepam 0.5-1.0 mg or
chloral hydrate 250-1500 mg at bedtime was permitted
for severe insomnia during study phase I (but was rarely
used). All efficacy and safety measures were performed
by study doctors who had undergone inter-rate:r reliability
training with the 17-item HAM-D and Young Mania
Rating (YMR) (Young et al, 1978) scales.
Patients receiving ineffective antidepressant therapy
before enrolling in the trial had their medication
discontinued for at least 7 days [14 days for a monoamine
oxidase (MAO) inhibitor] before starting fluoxetine
mono therapy. None of the patients were taking a mood
stabilizer or an atypical neuroleptic agent immediately
preceding enrollment in the study. The purpose of this
lead-in period of up to 14 days was to avoid a drug
interaction from previous psychotropic medication
(e.g. MAO inhibitors).
Outpatients aged ~ 18 years, with a DSM-1V Axis I
diagnosis of BP II or BP NOS disor&r and a current
diagnosis of MDE were eligible for the trial. All patients
had a baseline 17-item HAM-D score ~ 18. Patients were
excluded from the study if they had a history of mania,
psychosis, rapid cycling affective disorder with ~ 4
affective episodes in the preceding year, current alcohol
or substance abuse, alcohol or substance dependence
within the preceding 3 months, non-response to flu ox-
etirie therapy in the current MDE, or a previous
sensitivity to fluoxetine. Pregnant or nursing women
were excluded, as were patients with an unstable medical
condition, or a serum thyrotropin le~el ~ 5 ~IU. Other
exclusion criteria were the presence of any clinically
significant cardiac disease, malignancy, presence of
central nervous system disorder (e.g. Parkinson's disease,
dementia), presence of significant hepatic or renal
disease, use of chemotherapy, use of over-the-counter
preparations (e.g. St. John's Wort), use of tranquilizers,
barbiturates or other sedative and hypnotic medications.
Phase I of the study has been described elsewhere
(Amsterdam et aI., 2004). Patients who responded during
study phase I were randomly assigned to continuation
therapy with either fluoxetine 20 mg daily or placebo for
up to 6 months. Double-blind study conditions were
maintained until the end of the trial.
Descriptive statistics for the assessment of demographic
and clinical variables included frequencies, means,
medians, SDs and ranges (Table 1). Time to relapse
during double-blind treatment was compared betWeen
treatment conditions using Kaplan-Meier analysis
(Fig. 1) and the log-rank test for equality of survival
distributions. The proportion of patients who relapsed
when taking fluoxetine monotherapy versus placebo was
compared using Fisher's exact test. Change in YMR
scores over time were assessed using generalized
estimating equation (GEE) analysis that included the
A complete psychiatric and medical history was obtained
using the Structured Diagnostic Interview for DSM-IV
(SCID) format (First et al, 1994). All patients had a
physical examination including blood pressure, pulse and
weight, along with a complete blood count, blood
chemistry profile, a serum pregnancy test in pre- and
peri-menopausal women, urinalysis, urine drug screen and
a 12-lead electrocardiogram. A listing of previous
psychotropic drug treatment preceding study enrollment,
and a list of concomitant medication was obtained.
and outcome procedures
Study phase I
Study phase II
Outcome measures included the 28-it~m HAM-D rating
(Williams, 1988) with the embedded 17-item HAM-D
rating (Reimherr eo! 01., 1998) and the YMR scale. The
HAM-D and YMR ratings were scored by the study rater
without attribution as to the origin of the particular
symptom. For example, the symptom of insomnia or
agitation that were scored on the HAM;.D rating were also
scored on the YMR as hypomanic ratings at the same
study visit, even though the patient may not have
demonstrated hypomania at the time. This rating method
Illness duration (years)
MDE duration (months)
Previous hypomanic episodes ~ 4 days
Previous hypomanic episodes <4 days
Baseline 17-item HAM-D
Baseline YMR score
HAM-D. Hamilton Rating Scale for Depression; YMR, Young Mania Rating.
260 International Clinical Psychopharmacology 2005, Vol 20 No 5
treatment condition (fluoxetine versus placebo), time
(measured in days after phase II baseline), and a group-
time interaction variable in the regression model. The
GEE analysis is equivalent to a regression analysis, but
allows for more than one observation per subject and
adjusts for any intra-subject correlation of measurements.
A group-time interaction term that deviates significantly
from zero would indicate that the change in YMR scores
over time differs significantly for patients taking fluox-
etine versus placebo. Because subjects were treated after
relapse~ for a fair comparison of placebo versus fluoxetine,
the GEE analysis was limited to YMR observations
made up to the time of relapse. For subjects who did
not relapse during double-blind therapy, all YMR scores
were included in the GEE analysis. In addition, Students
I-test was used to compare the mean change from
each patient's study phase II baseline YMR score to
their largest phase II YMR score between treatment
groups. The mean changes for each group, with 95%
confidence intervals, were also computed. Table 2 shows
the mean YMR score (and number of patients) during
study phase II together with YMR scores exceeding zero.
Table 2 includes all positive YMR scores measured in
phase II, including scores after relapse. Statistical
analyses were conducted using STATA 8.0, with a two-
sided P < 0.05 considered statistically significant.
A total of 43 patients were enrolled into phase I of the
trial. Of these, six patients (14%) were screen failures
who did not receive study medication because they either
withdrew their consent to participate in the study (n = 5)
or were non-compliant (n = 1) with the study protocol.
Thirty-seven patients received fluoxetine monotherapy:
34 had BP II MDE and three had BP NOS MDE. Of the
37 patients, 14 (37.8%) discontinued treatment before
the completing study phase I: two (5.4%) for adverse
events, three (8.1%) for lack of efficacy, two (5.4%) for
non-compliance and seven (18.9%) who withdrew their
consent. Fourteen patients responded during study phase
I with a final 17-item HAM-D score ~ 9. Of these, two
patients withdrew their consent to participate in the
double-blind study phase, and 12 patients were rando-
mized to continuation treatment with either fluoxetine
monotherapy 20 mg daily (n = 8) or placebo (n = 4).
The clinical and demographic characteristics of the
patients' samples in study phase I and study phase II
are shown in Table 1.
Study phase I
Results of study phase 1 have been described previously
(Amsterdam et aI:, 2004) and are briefly summarized here.
Of the 37 patients in study phase 1,14 (37.8%) responded
to initial fluoxetine mono therapy with a final week 8
17-item HAM-D score ~ 9. There was an overall reduc-
tion of the mean baseline 17-item HAM-D score from
21.7:t 3.9 to 14.8:t 8.3 by study week 8, using last
observation carried forward analysis (P < 0.001, Wilcoxon
paired sample test). A similar finding was also observed
using the GEE analysis (P < 0.001). Three patients
(8.1%) had an elevated YMR score on at least tWo
consecutive study visits. Using a moderately conservative
total YMR cut-off score of ~ 12 for the presence of
hypomanic symptoms, five (13.5%) of the patients had a
YMR score ~ 12 at any point during treatment. None
monotherapy or placebo.
survival curves during continuation fluoxetine
Table 2 Mean:t SD YMR scores during fluoxetine or placebo treatment
1 O.5:t 7.8
.Patient number at each study visit reflects the available sample size with a Young Mania Rating (YMR) score >0.
Fluoxetine monotherapy of BP II and BP NOS major depression Amsterdam and Shults 261
of the patients discontinued fluoxetjne therapy due to
American Psychiatric Association, 2002). This recommen-
dation is based upon concerns arising from TCA-induced
manic switch episodes (Wehr and Goodwin, 1979; Wehr
and Goodwin, 1987; Prein and Rush, 1996; Montgomary
et 01., 2000; Goldberg and Truman, 2003; Ghaemi et al,
2004). In this context, a recent retrospective comparison
of antidepressant treatment in 41 BP MDE patients
found a substantially higher manic switch rate in the BP
patients taking antidepressant mono therapy (84%) com-
pared to BP patients taking an established mood
stabilizer (32%) (Ghaemi et al, 2004). Similarly, a recent
review on the sl;lbject of antidepressant-induced mania
found a 20-40% drug-induced manic and hypomanic
switch rate in published BP MDE studies (Goldberg and
Truman, 2003). In these studies, manic switch episodes
occurred with a similar frequency in the presence, or
absence, of mood stabilizer therapy, especially in BP
patients with previous drug-induced mania and in BP
patients taking multiple antidepressants (Goldberg and
Study phase II
Twelve patients participated in the ~ndomized, double-
blind, continuation phase with either fluoxetine mono-
therapy (n = 8) or placebo (n = 4). Relapse of MDE
during double-blind therapy was observed in 43% of
fluoxetine-treated pati~nts and in 100% of placebo-
treated patients (P = 0.08, Fisher's exact). Although this
difference did not achieve statisti4al significance, it
appears to indicate a trend towards tr~atment differences
between conditions. Figure 1 indicat~s that the median
time to relapse was slightly snorter in the fluoxetine-
treated patients compared to that observed in the
placebo-treated group, although the difference was not
statistically significant (P= 0.19).
Table 2 displays the mean :t SD YMR scores at phase II
baseline visit (week 8) and at subseq4ent phase II study
Despite these cautionary recommendations, SSRI mono-
therapy has been used in patients with BP MDE for more
than 2S years (Saletu et 01:, 1977). Results from more
recent, controlled prospective trials have confirmed these
early findings and have found that SSRIs may be safe and
effective for the short term a treatment of BP MDE
(Benfield et 01:, 1986; Cohn et 01:, 1989; Simpson and
DePaulo, 1991; Maj, 1997; Amsterdam, 1998; Grunze
et al, 2000; Kupfer et 01:, 2001; Amsterdam and Brunswick,
2003). For example, a multi-site study of citalopram as an
add-on therapy for BP MDE patients who were resistant
to initial 4-week mood stabilizer monotherapy found that
64% of citalopram-treated patients responded, with a only
a 6.7% manic switch rate (Kupfer et 01:,2001). By contrast,
a double blind, placebo-controlled
paroxetine versus imipramine in patients with BP I
MDE taking established lithium or valproic acid therapy
did not demonstrate superior antidepressant efficacy
compared to placebo, although this study was not
adequately powered to detect a drug versus placebo
difference (Nemeroff et 01:, 2001). Similarly, Post et 01:
(2003) found a relatively poor antidepressant efficacy in
all BP MDE patient groups studied.
add-on study of
The mean change in YMR score (~ghest YMR score
versus baseline YMR score) during study phase II was
3.0:t 1.8 [95% confidence interval (CI) = 1.3-4.7] for the
fluoxetine condition versus 0.2:t 0.45: (95% CI = -0.4-
0.8) for the placebo condition (P = 0.01, I-test). Despite
the modestly higher YMR scores in the, fluoxetine-treated
patients (versus the placebo group), tqis small difference
was not clinically meaningful. Moreo~er, when all YMR
scores were examined over time using! the GEE analysis,
no difference in the rate of increase in individual YMR
scores was observed between treatment conditions.
Similarly, when patients were examined for YMR
scores ~ 8 (a very conservative estimate of hypomanic
syndrome), no patient in either treatment condition had a
YRM score ~ 8. Thus, no patient in stildy phase II had a
YMR score that was considered to bb clinically mean-
ingful. None of the patients in study phase II met DSM-
N diagnostic criteria for hypomanic episode. Finally,
there were no treatment-related seriou$ adverse events in
study phase II.
Although combination SSRI and mood stabilizer therapy
may represent an advance in the treatment of BP II MDE
over mood-stabilizer therapy alone (Kupfer ef ol, 2001),
mood stabilizer therapy may also expose patients to
additional side-effects (Youngefal., 2000) and the need to
monitor plasma drug levels, hepatic enzyme levels and
thyroid hormone levels. A recent retrospective study of
more than 2000 patients found that SSRIs were equally
effective in unipolar and BP MDE (Grunze ef aI., 2001).
Similarly, we observed good short-term
fluoxetine monotherapy 20 mg daily in 89 unipolar versus
A recent expert clinician panel on the treatment of BP
MDE concluded that the efficacy of SSRJ monotherapy,
or combined SSRI and mood stabilize~ therapy, has not
been established (Prien and Rush, 1 Q96). Most expert
consensus panels recommend the cautious use of SSRIs
for the treatment of BP MDE, and that SSRIs be
prescribed only in combination with a mood stabilizer for
more severely ill patients (American Psychiatric Associa-
tion, 1994; Treatment of Bipo)ar Disorder Expert Con-
sensus Panel, 1996;Yatham eta/., 1997; Sachs eta/., 2000;
262 International Clinical Psychopharmacology 2005, Vol 20 No 5
89 BP II and NOS MDE patients, with the BP patients
showing a hypomanic switch rate of only 3.8% (Amster-
dam et ol, 1998).
switch rate of 3.6% in 28 BP II patients and a hypomanic
switch rate of 0.8% in 241 unipolar MDE patients taking
fluoxetine monotherpy for 6 months. The results from
the present study also suggested the presence of a low
hypomanic switch rate in recovered BP II MDE patients
during continuation fluoxetine monotherapy. Although
we observed a slightly higher mean YMR score of
3.0:t 1.8 in the fluoxetine condition versus 0.2 :t 0.5 in
the placebo condition (P = 0.01), this difference was not
clinically meaningful because YMR scores ~ 16 are
generally considered to define mild manic symptoms.
Moreover, a longitudinal GEE analysis found no signifi-
cant difference in the rate of change in YMR scores
between treatment conditions during continuation ther-
apy. Using a conservative total YMR cut-off score of ~ 8
to identify patients with mild symptoms of hypomania,
we observed no patient in either treatment group with a
YMR score ~ 8 during continuation therapy. Further-
more, we observed no DSM N hypomanic episodes
during continuation therapy.
There are fewer data available on the efficacy and safety
of SSRI monotherapy of BP II i disorder during continua-
tion treatment. In a two-phase, multi-site, placebo-
substitution study (Amsterdametal, 1998), we examined
the efficacy and safety of continuation fluoxetine
monotherapy 20 mg daily after 16 months in 28 recovered
BP II MDE and BP NOS MOB: patients (compared with
27 recovered unipolar MOE patients). We observed a
slightly lower relapse rate in the BP (22%) versus the
unipolar (33%) patients (ch~ squared = 0.5; d.f. = 1;
P = not significant, Kaplan-M~ier survival) during con-
tinuation fluoxetine monotherapy.
Although, in the present st~dy, we were unable to
demonstrate a statistically s!ignificant difference in
relapse rates during continuatioh fluoxetine monotherapy
(43%) versus placebo therapy (100%) (P = 0.08, Fisher's
exact test), there was a trend towards greater relapse in
the placebo-treated patients. Moreover, the relapse rate
for the continuation flouxetine ~onotherapy group in the
preseI:lt study was similar to the relapse rate observed in
recovered unipolar patients during continuation fluox-
etine mono therapy in an earlier long-term fluoxetine
study (Reimherr et al, 1998).
Several caveats should be considered in the interpreta-
tion of the present data. The cohort sizes in study phase
n were limited, resulting in insufficient power to detect
statistical significance in relapse rates or to detect a
significant difference in the rate of change in YMR scores
betWeen treatment conditions during continuation ther-
apy. This occurred despite the fact that 100% of placebo-
treated patients versus 43% of fluoxetine-treated patients
relapsed. This lack of power resulted from an unantici-
pated low response rate to initial fluoxetine treatment in
study phase I. It is possible that the response rate to
initial fluoxetine therapy would have been higher if the
treatment duration had been longer (Quitkin et al, 2003),
or if the dose of fluoxetine had been higher. However, a
recent analysis by our group of 71 BP II MDE patients
taking fluoxetine monotherapy up to 80 mg daily for 10
weeks found a remission rate of only 38% (Shults and
Our original estimate for treatm~nt response in phase I of
the present study was 60% (after a 20% drop out for
screen failures or side-effects). This would have resulted
in 10 patients per treatment c~ndition during phase II
double-blind therapy and would! have resulted in greater
statistical power to detect pote*tial differences in group
survival. However, only 14 patiemts (38%) met the HAM-
D criteria of ~ 9 for response in study phase I, which
resulted in smaller than expecte~ cohort samples in study
phase II. Despite this shortc\)ming, our findings do
suggest a substantial trend towards fluoxetine superiority
over placebo during continuatIon therapy. The strict
application of a P < 0.05 cut-off value for statistical
significance has sometimes b~en criticized as being
arbitrary and overly dependant on sample size. We would
suggest that that the results of the present study,
although not statistically signific~nt at the P < 0.05 level,
should also be interpreted in tejrms of the actual group
differences that were observed; in relapse rates during
continuation therapy. We are presently conducting a
larger, follow-up study to verifY what is suggested by
these preliminary results.
Three patients in the present study had BP NOS MDE.
These patients had a history of definite mood swings
characterized by at least one episode of elevated mood
with additional manic symptoms; however, these patients
could not endorse an episode duration lasting at least 4
days. In this regard, the gradation between BP syndromes
is often difficult to establish (Simpson et al, 1991;
Benazzi, 1997; Cassano et ai, 1999; Ghaemi et al, 2001;
Akiskal, 2003). It is possible that patients with BP NOS
disorder may be clinically distinct from patients with BP
II disorder and that they may be less likely to experience
fluoxetine-induced manic symptoms.
There is a paucity of data on the rate of manic switch
episodes during long-term SSRE monotherapy of BP II
disorder. In a previous double-blind, placebo-substitution
study (Amsterdam et al, 1998), we observed a hypomanic
We did not employ a patient-recorded daily chrono-record
to identify sub-syndromal manic episodes. As a result, it is
possible that we missed the presence of ultra-short or
Fluoxetine monotherapy of BP II and BP NOS major depression Amsterdam and Shults 263
mild hypomanic episodes that occurred between study
visits. As a result, the rate of hypomanic symptoms may
have been higher than those detected; Furthermore, a
higher fluoxetine dose may have resu1ted in a higher
frequency of manic switch episodes.
Finally, we did not measure plasma lev~ls of fluoxetine
and norfluoxetine, which may have prdvided additional
information on the low response rate in s~udy phase I and
the difference in relapse rates in study pl)ase II. However,
a previous study in 839 unipolar and BP h MDE patients
treated with fluoxetine monotherapy 20 ~g daily for up to
9 months found no relationship betwe~n plasma levels
and initial response efficacy (Amsterdam et d, 1997) or
between plasma levels and relapse rates during continua-
tion therapy (Brunswick et ai, 2002). Similarly, in a
previous study, Brunswick et ai (2001) also observed the
presence of substantial residual fluoxeti~e and norfluox-
etine plasma levels in some patients many weeks after
they were randomized to double-blind placebo therapy.
This factor suggests that, in the presen~ trial, the fairly
rapid relapse of patients in both treatmeqt conditions was
not simply the result of the absence of citculating plasma
concentrations of fluoxetine.
In summary, we examined the safety land efficacy of
fluoxetine monotherapy 20mg daily fornp II MDE and
BP NOS MDE. As reported previously (Amsterdam etal,
2004), we observed a 38% remission rate! with a HAM-D
score ~ 9, and 8.1% hypomania switch ra~e, during study
phase I. During continuation therapy, 43% of fluoxetine-
treated patients and 100% of placebo-1reated patients
relapsed (P < 0.08). There were slightly ~ore hypomanic
symptoms reported in the fluoxetine-~reated patients
compared to the placebo group (P < 0.0]), although this
difference was not clinically meaningf~l. Despite the
limited sample size of the continuati<>n study phase
resulting in insufficient power to d~tect statistical
significance in relapse rates or change I in YMR scores
betWeen treatment conditions, these Rreliminary data
appear to support previous observations I that initial and
continuation fluoxetine monotherapy mby be safe and
effective for some patients with BP II Of' BP NOS MDE
with a low manic switch rate. Larger-s~ale studies are
needed to confirm these findings.
This study was partially supported by an Investigator
Initiated Trial grant from Lilly Resear~h Laboratories
(Eli Lilly & Company), and by the Jack Warsaw Fund for
Research in Biological Psychiatry (Depr~ssion Research
Unit, University of Pennsylvania Medical! Center).
Akiskal HS, Pinto 0 (1999). The evolving bipolar spectrum. Prototypes I, II, III,
and IV. Psychiatr Clin North Am 22:517-534.
Akiskal HS (2003). Validating 'hard' and 'soft' phenotypes within the bipolar
spectrum: continuity or discontinuity? J Affective Disord 73:1-5.
American Psychiatric Association (1994). Practice guidelines for the treatment of
patients with bipolar disorder. Am J Psychiatry 151 (suppl):1-36.
American Psychiatric Association (2002). Practice guidelines for the treatment of
patients with bipolar disorder (revision). Am J Psychiatry 159(suppl):1-50.
Amsterdam JD (1998). Efficacy and safety of venlafaxine in bipolar type-II major
depressive episode. J Clin Psychopharmaco/18:414-417.
Amsterdam JD, Fawcett J, Ouitkin FM, Reimherr FW, Rosenbaum J, Michelson D,
et a/. (1997). Fluoxetine and norfluoxetine plasma levels in major depression:
A multi-center study. Am J Psychiatry 154:963-969.
Amsterdam JD, Garcia-Espana F, Schweizer E, Fawcett J, Ouitkin FM, Reimherr
FW, et ai. (1998). Fluoxetine and bipolar II major depressive episode. J C/in
Amsterdam JD, Brunswick DJ (2003). Antidepressant
type II major depression. Bipolar Disord 5:388-395.
Amsterdam JD, Shults J, Brunswick DJ, Hundert M (2004). Short-term fJuoxetine
monotherapy for bipolar type II or bipolar NOS major depression -low manic
switch rate. Bipolar Disord 6:75-81.
Ayuso-Gutierrez JL, Ramos-Brieva JA (1982). The course of manic-depressive
illness: a comparative study of bipolar I and bipolar II patients. J Affect Disord
Benazzi F (1997). Prevalence of bipolar II disorder in outpatient depression:
a 203-case study in private practice. J Affect Disord 3:163-166.
Benazzi F (1999). Bipolar II disorder is common among depressed outpatients.
Psychiatry Clin Neurosci 53:607-609.
Benfield P, Heel RC, Lewis SP (1986).
dynamic and pharmacokinetic properties,
depressive illness. Drugs 32:481-508.
BeN< M, Dodd S (2005). Bipolar II disorder: a review. Bipolar Disord 7:11-21.
Boerlin HL, Gitlin M, Zoellner LA, Hammen CL (1998).
and antidepressant-induced mania: A naturalistic study. J Clin Psychiatry
Brunswick DJ, Amsterdam JD, Fawcett J, Ouitkin FM, Reimherr FW, Rosenbaum
JF, et a/. (2001). Fluoxetine and norfluoxetine plasma levels after discontinu-
ing fJuoxetine therapy. J C/in Psychopharmaco/21
Brunswick DJ, Amsterdam JD, Fawcett J, Ouitkin FM, Reimherr FW, Rosenbaum
JF, et a/. (2002). Fluoxetine and norfJuoxetine plasma concentrations
relapse-prevention treatment. J Affect Disord 68:243-249.
Cassano GB, DelrOsso L, Frank E, Miniati M, Fagiolini A, Shear K, et a/. (1999).
The bipolar spectrum: a clinical reality in search of diagnostic criteria and an
assessment methodology. J Affect Disord 54:319-328.
Coryell W, Endicott J, Maser JD, Keller MB, Leon AC, Akiskal HS (1995). Long-
term stability of polarity distinctions in the affective disorders. Am J Psychiatry
Cohn JB, Collins G, Ashbrook E, Wernicke JF (1989). A comparison of fJuoxetine,
imipramine and placebo in patients with bipolar depressive disorder. Int C/in
Dunner DL, Fleiss JL, Fieve RR (1976). The course of development of mania in
patients with recurrent depression. Am J Psychiatry 133:905-908.
Faedda GL, Tondo L, Baldessarini RJ, Suppes T, Tohen M (1993). Outcome after
rapid versus gradual discontinuation of lithium treatment in bipolar disorders.
Arch Gen Psychiatry 50:448-455.
Feder R (1990). Fluoxetine-induced mania (Letter). J C/in Psychiatry 51:
First MB, Spitzer RL, Gibbon M, Williams JBW (1994).
Interview for Axis I DSM-IV Disorders -Patient
American Psychiatric Press.
Geddes J, Goodwin G (2001). Bipolar disorder: clinical uncertainty, evidence-
based medicine and large scale
monotherapy for bipolar
Fluoxetine: a review of its pharmaco-
and therapeutic efficacy in
Edition. Washington, DC:
randomised trials. Br J Psychiatry
Ghaemi SN, Sachs GS, Chiou AM, Pandurangi AK, Goodwin
bipolar disorder still underdiagnosed?
J Affect Disord 52:135-144.
Ghaemi SN, Boiman EE, Goodwin FK (2000). Diagnosing bipolar disorder and
the effect of antidepressants: a naturalistic study. J C/in Psychiatry 61:
Ghaemi SN, Ko JY, Goodwin FK (2001).
antidepressant view of the world. J Psychiatr Pract 7:287-297.
Ghaemi SN, Klara JR, Ko JY, Baldassano CF, Kontos NJ, Baldessarini RJ (2004).
Antidepressant treatment in bipolar
Psychiatry 161 :163-165.
Goldberg JF (2003). When do antidepressants
disorder? J Psychiatr Pract 9:181-194.
The bipolar spectrum and the
versus unipolar depression. Am J
worsen the course of bipolar
Akiskal H (1996). The spectrum of bipolar disorder beyond DSM. J Clin
264 International Clinical Psychopharmacology 2005, Vol 20 No 5
Goldberg JF, Truman CJ (2003). Antidepressant-induced
current controversies. Bipolar Disord 5:407.
Goodwin FK, Jamison KR (1990). Manic Depressive Illness. New York, NY:
Oxford University Press.
Goodwin FK, Ghaemi SN (1998). Understanding manic-depressive illness. Arch
Gen PsychiatJy 55:23-25.
Grunze H, Schlosser S, Walden J (2000).
treatment of bipolar depression. World J Bioi Psychiatry 1 :129-136.
Hamilton M (1960). A rating scale for depression. J Neurol Neurosurg Psychiatry
Heimann SW, March JS (1996). SSRI-induced
Adol Psychiatry 35:4.
Kupfer DJ, Chengappa KNR, Gelenberg AJ, Hirschfeld RMA, Goldberg JF, Sachs
GS, et a/. (2001). Citaloprarn as adjunctive therapy in bipolar depression.
J Clin Psychiatry 62:985-990.
Maj M (1997). Selection of the initial drug (s) in the treatment of bipolar disorder,
depressed phase. Mod Probl PharmacopsychiatJy 25:66-77.
Montgomery SA, Schatzberg AF, Guelti JD, Kasper S, Nemeroff C, Swann A,
et a/. (2000). Pharmacotherapy of depression and mixed states in bipolar
disorder. J Affect Disord 59:S39-S56.
Nemeroff CB, Evans DL, Gyulai L, Sachs GS, Bowden CL, Gergel IP, et al.
(2001). Double-blind, placebo-controlled
paroxetine in the treatment of bipolar depression.
Post RM, Leverich GM, Nolen WA, Kupka RW, Altshuler LL, Frye MA, et al.
(2003). A re-evaluation of the role of antidepressants
bipolar depression: data from the Stanley Foundation
Bipolar Disord 5:396-406.
Prien RF, Rush AJ (1 996). National Institute of Mental Health Workshop Report
on the Treatment of Bipolar Disorder. Bioi Psychiatry 40:215-220.
Prien RF, Kupfer DJ, Mansky PA, Small JG, Tuason VB, Vos CB, et al. (1994).
Drug therapy in the prevention of recurrences in unipolar and bipolar affective
disorders. Arch Gen Psychiatry 41:1096-1104.
Ouitkin FM, Petkova E, McGrath P, Nunes E, Taylor B, Beasley C, et aI. (2003).
When should a trial of fluoxetine for major depression be declared failed?
Am J Psychiatry 160:734-140.
mania: an overview of
New perspectives in the acute
mania (letter). JAm Acad Child
comparison of imipramine and
Am J Psychiatry 158:
in the treatment of
Reimherr FW, Amsterdam JD, Fawcett J, Quitkin FM, Rosenbaum J, Beasley C,
et a/. (1998). Optimal length of continuation therapy: a prospective assessment
during fluoxetine long-term treatment. Am J Psychiatty 55:1247-1253.
Sachs GS, Printz DJ, Kahn DA, Carpenter D, Docherty JP (2000). Medication
treatment of bipolar disorder. Postgrad Med 2000; special issue: 1-104.
Saletu B, Schjerve M, Grunberger
Auvoxamine-a new serotonin re-uptake inhibitor: first clinical and psycho-
metric experiences in depressed patients. J Neural Trans 41 :17-36.
Shults J, Amsterdam J D (2004). Low manic switch rate during SSRI treatment of
bipolar major depression. Abstract of the 157th Annual
American Psychiatric Association, New York.
Simpson SG, DePaulo JR (1991). Fluoxetine treatment of bipolar II depression.
J Clin Psychopharmaco/11 :52-54.
Simpson SG, Folstein SE, Meyers DA, McMahon FJ, Brusco DM, DePauo JR Jr
(1993). Bipolar II: the most common bipolar phenotype? Am J Psychiatty
Stoll AL, Mayer PV, Kolbrener M, Goldstein E, Suplit B, Lucier J, et a/. (1994).
Antidepressant-associated mania: a controlled Comparison with spontaneous
mania. Am J Psychiatty 151 :1642-1645.
Treatment of Bipolar Disorder Consensus Panel (1996). The Exper1 Consensus
Panel for Bipolar Disorder. J Clin Psychiatry 57(suppI12A):2-89.
Wehr TA, Goodwin FK (1979). Rapid cycling in manic-depressives
tricyclic antidepressants (TCA). Arch Gen Psychiatry 36:555-559.
Wehr TA, Goodwin FK (1987). Can antidepressants cause mania and worsen the
course of affective illness? Am J Psychiatty 144:1403-1411.
Williams JBW (1988). A structured interview guide for the Hamilton Depression
Rating Scale. Arch Gen Psychiatry 45:742-747.
Yatham LN, Kusumakar V, Parikh SV, Haslam DRS, Matte R, Sharma V, et a/.
(1997). Bipolar depression: treatment options. Can J Psychiatty
Young RC, Biggs JT, Ziegler VE, Meyer DA (1978). Rating-scale for mania-
reliability, validity and sensitivity. ar J Psychiatty 133:429-435.
Young LT, Joffe RT, Robb JC, MacQueen GM, Marriott M, Patelis-Siotis I (2000).
Double-blind comparison of addition of a second mood stabilizer versus an
antidepressant to an initial mood stabilizer for treatment of patients with
bipolar depression. Am J Psychiatty 157:124-126.~
J, Schanda H, Arnold OH (1977).
Meeting of the