Article

Risk of Switch in Mood Polarity to Hypomania or Mania in Patients With Bipolar Depression During Acute and Continuation Trials of Venlafaxine, Sertraline, and Bupropion as Adjuncts to Mood Stabilizers

University of Texas at Dallas, Richardson, Texas, United States
American Journal of Psychiatry (Impact Factor: 12.3). 02/2006; 163(2):232-9. DOI: 10.1176/appi.ajp.163.2.232
Source: PubMed

ABSTRACT

The authors examined the comparative risks of switches in mood polarity into hypomania or mania during acute and continuation trials of adjunctive antidepressant treatment of bipolar depression.
One hundred fifty-nine patients with bipolar I disorder or bipolar II disorder participated in a total of 228 acute (10-week) randomized trials of bupropion, sertraline, or venlafaxine as an adjunct to a mood stabilizer. Patients in 87 of these trials entered continuation treatment for up to 1 year. Antidepressant response and the occurrence of subthreshold brief hypomania (emergence of brief hypomania [at least 1 but <7 days] or recurrent brief hypomania) and threshold switches (emergence of full-duration hypomania [> or =7 days] or mania) were blindly assessed by using clinician-rated daily reports of mood-associated dysfunction on the National Institute of Mental Health Life Chart Method.
Threshold switches into full-duration hypomania and mania occurred in 11.4% and 7.9%, respectively, of the acute treatment trials and in 21.8% and 14.9%, respectively, of the continuation trials. The rate of threshold switches was higher in the 169 trials in patients with bipolar I disorder (30.8%) than the 59 trials in patients with bipolar II disorder (18.6%). The ratio of threshold switches to subthreshold brief hypomanias was higher in both the acute (ratio=3.60) and continuation trials (ratio=3.75) of venlafaxine than in the acute and continuation trials of bupropion (ratios=0.85 and 1.17, respectively) and sertraline (ratios=1.67 and 1.66, respectively). In only 37 (16.2%) of the original 228 acute antidepressant trials, or in only 23.3% of the patients, was there a sustained antidepressant response in the continuation phase in the absence of a threshold switch.
Adjunctive treatment with antidepressants in bipolar depression was associated with substantial risks of threshold switches to full-duration hypomania or mania in both acute and long-term continuation treatment. Of the three antidepressants included in the study, venlafaxine was associated with the highest relative risk of such switching and bupropion with the lowest risk.

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Article
232 Am J Psychiatry 163:2, February 2006ajp.psychiatryonline.org
Risk of Switch in Mood Polarity to Hypomania or Mania
in Patients With Bipolar Depression During Acute and
Continuation Trials of Venlafaxine, Sertraline, and
Bupropion as Adjuncts to Mood Stabilizers
Gabriele S. Leverich, M.S.W.,
L.C.S.W.-C.
Lori L. Altshuler, M.D.
Mark A. Frye, M.D.
Trisha Suppes, M.D., Ph.D.
Susan L. McElroy, M.D.
Paul E. Keck, Jr., M.D.
Ralph W. Kupka, M.D., Ph.D.
Kirk D. Denicoff, M.D.
Willem A. Nolen, M.D., Ph.D.
Heinz Grunze, M.D.
Maria I. Martinez, M.A.
Robert M. Post, M.D.
Objective: The authors examined the
comparative risks of switches in mood po-
larity into hypomania or mania during
acute and continuation trials of adjunc-
tive antidepressant treatment of bipolar
depression.
Method: One hundred fifty-nine patients
with bipolar I disorder or bipolar II disor-
der participated in a total of 228 acute
(10-week) randomized trials of bupro-
pion, sertraline, or venlafaxine as an ad-
junct to a mood stabilizer. Patients in 87
of these trials entered continuation treat-
ment for up to 1 year. Antidepressant re-
sponse and the occurrence of subthresh-
old brief hypomania (emergence of brief
hypomania [at least 1 but <7 days] or re-
current brief hypomania) and threshold
switches (emergence of full-duration hy-
pomania [7 days] or mania) were blindly
assessed by using clinician-rated daily re-
ports of mood-associated dysfunction on
the National Institute of Mental Health
Life Chart Method.
Results: Threshold switches into full-du-
ration hypomania and mania occurred in
11.4% and 7.9%, respectively, of the acute
treatment trials and in 21.8% and 14.9%,
respectively, of the continuation trials.
The rate of threshold switches was higher
in the 169 trials in patients with bipolar I
disorder (30.8%) than the 59 trials in pa-
tients with bipolar II disorder (18.6%). The
ratio of threshold switches to subthresh-
old brief hypomanias was higher in both
the acute (ratio=3.60) and continuation
trials (ratio=3.75) of venlafaxine than in
the acute and continuation trials of bu-
propion (ratios=0.85 and 1.17, respec-
tively) and sertraline (ratios=1.67 and
1.66, respectively). In only 37 (16.2%) of
the original 228 acute antidepressant tri-
als, or in only 23.3% of the patients, was
there a sustained antidepressant re-
sponse in the continuation phase in the
absence of a threshold switch.
Conclusions: Adjunctive treatment with
antidepressants in bipolar depression was
associated with substantial risks of thresh-
old switches to full-duration hypomania
or mania in both acute and long-term
continuation treatment. Of the three anti-
depressants included in the study, ven-
lafaxine was associated with the highest
relative risk of such switching and bupro-
pion with the lowest risk.
(Am J Psychiatry 2006; 163:232–239)
There is considerable controversy regarding the rate of
response to antidepressants and the risk of a switch in
mood polarity into hypomania or mania when these
agents are used as adjunctive treatment to mood stabiliz-
ers in bipolar illness (1–8). We previously reported the
acute response and switch rates when one of three sec-
ond-generation antidepressants (bupropion, sertraline, or
venlafaxine) was added to mood stabilizers in a 10-week
randomized acute treatment trial (9).
Here we present 1) results of a more extended evalua-
tion of the same patient cohort in which we used a contin-
uous daily mood measure (the National Institute of Men-
tal Health [NIMH] Life Chart Method [LCM] [10, 11]) and
2) results from a continuation phase lasting up to 1 year
for patients who responded to acute treatment. Use of cli-
nicians’ continuous daily prospective ratings with the
LCM allowed us to assess the severity and duration of four
categories of hypomania or mania ranging from brief sub-
threshold hypomanias to a full switch in mood polarity to
mania that was associated with at least some days of mod-
erate dysfunction. We also blindly rated the degree of anti-
depressant response by using the Clinical Global Impres-
sion Bipolar Version (CGI-BP) during acute and
continuation antidepressant treatment.
Much of the controversy in the literature about the rates
of switches in mood polarity in patients with bipolar dis-
order who receive antidepressants may be due to several
study characteristics that are specifically addressed in this
analysis. In this study, we 1) rated a continuum of mood
states ranging from brief hypomania to mania with dys-
function, rather than using only a single-threshold or di-
chotomous measure of mood switches; 2) conducted pro-
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Am J Psychiatry 163:2, February 2006 233
LEVERICH, ALTSHULER, FRYE, ET AL.
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spective blind assessments both in the 10-week acute
randomized trial phase and in the continuation phase that
included putative responders to acute antidepressant
treatment; and 3) included substantial numbers of pa-
tients with rapid cycling and patients without rapid cy-
cling and of bipolar I and bipolar II disorder patients.
Method
The general characteristics of the patient population and the
study methods have been presented in detail elsewhere (12, 13).
Briefly, all patients participated in the former Stanley Foundation
Bipolar Network (14–16) and gave specific written informed con-
sents for participation in both the Network and later in this spe-
cific study after the study procedures had been fully explained.
The patients’ characteristics are summarized in Table 1. A total of
72.3% (N=115) of the patients received a diagnosis of bipolar I dis-
order according to the Structured Clinical Interview for DSM-IV
Axis I Disorders, and 25.2% (N=40) of the whole cohort had rapid
cycling at Network entry.
Bipolar disorder patients with depression that occurred in the
context of ongoing treatment with at least one mood stabilizer at
clinically therapeutic blood levels were randomly assigned to re-
ceive bupropion, sertraline, or venlafaxine adjunctively. Life
charts were available for 159 of the original 184 patients described
in the cross-sectional evaluation of the acute clinical trial (9). Pa-
tients who did not respond acutely to the initial antidepressant
were offered blind rerandomization to one of the other two drugs.
In this fashion, 16 patients received bupropion in the second or
third acute randomization, 26 received sertraline, and 27 received
venlafaxine. The total number of drug exposures was 228, includ-
ing 66 exposures to bupropion, 76 to sertraline, and 86 to ven-
lafaxine. For simplicity, hereafter we will use the termtrial” to re-
fer to each drug “exposure.” A total of 87 antidepressant
continuation trials—24 for bupropion, 32 for sertraline, and 31 for
venlafaxine—were assessed.
The rerandomization enabled us to assess the maximal num-
ber of acute and continuation trials for each drug. The number of
continuation trials was of particular interest because we postu-
lated that response rates would not differ among the three drugs
in the acute treatment phase but that venlafaxine would have the
highest switch rate in continuation treatment. This hypothesis
was based on the observations of Sachs et al. (17, 18) of a higher
switch rate with the noradrenergic tricyclic agent desipramine
than with bupropion.
The average maximum doses achieved in the acute phase were
286 mg/day (SD=132) for bupropion, 192 mg/day (SD=104) for
sertraline, and 195 mg/day (SD=112) for venlafaxine. These doses
were maintained in the continuation phase. The baseline regi-
men of an average of 1.96 (SD=1.01) of mood stabilizers (in the
first randomization) was held constant; these drugs included lith-
ium, anticonvulsants, antipsychotics, benzodiazepines, and on-
going thyroid hormone treatment. Adherence to the antidepres-
sant treatment was assessed by pill counts. Study medication for
the following week(s) was dispensed during study visits, and pa-
tients were required to return unused pills. Patients were seen
weekly for the first 2 weeks, then at least biweekly during the 10-
week acute treatment phase, and at least once every month dur-
ing the continuation phase unless more frequent visits were re-
quired because of clinical status. The overall rate of adherence
was high, and no significant differences were found in the pill
counts among the three drugs.
On the basis of patients’ daily reports of their degree of mood-
associated dysfunction, clinicians completed the LCM daily rat-
ings of depression or mania on a 4-point severity scale (13, 14)
during each study visit. The reliability and validity of this scale
have been previously documented (19, 20). Two raters (G.S.L. and
R.M.P.), who were blind to the antidepressants used by the pa-
tients, evaluated a graphic depiction of the daily LCM ratings for
each acute and continuation trial for antidepressant response
and emergence of hypomania or mania (Figure 1). A CGI-BP rat-
ing of 1 (very much improved) or 2 (much improved) in depres-
sion was considered an antidepressant response.
We modified Angsts classification (21) to develop four catego-
ries of hypomania and mania: 1) brief hypomania, a period of at
least 1 but <7 continuous days during which the patient had an
LCM rating of mild severity of hypomania; 2) recurrent brief hy-
pomania, which consisted of two or more episodes of brief hypo-
mania over the course of a drug trial; 3) switch to full-duration hy-
pomania, a period of 7 continuous days during which the
patient had an LCM rating of mild severity of mania; and 4) a
TABLE 1. Demographic and Clinical Characteristics of Depressed Patients With Bipolar Disorder Randomly Assigned to
Receive Bupropion, Sertraline, or Venlafaxine as an Adjunct to Mood Stabilizers
Characteristic
Patients Who Received
Bupropion
(N=50)
Patients Who Received
Sertraline
(N=50)
Patients Who Received
Venlafaxine
(N=59)
All Patients
(N=159)
N % N % N % N %
Gender
Male 26 52 27 54 30 50.8 83 52.2
Female 24 48 23 46 29 49.2 76 47.8
Bipolar disorder diagnosis
Bipolar I disorder 36 72.0 36 72.0 43 72.9 115 72.3
Bipolar II disorder 13 26.0 14 28.0 15 25.4 42 26.4
Bipolar disorder not otherwise specified 1 2.0 0 0 1 1.7 2 1.3
Rapid cycling 14 28.0 11 22.0 15 25.4 40 25.2
Mean SD Mean SD Mean SD Mean SD
Age (years) 41.6 11.5 43.2 13.5 40.1 11.5 41.6 12.2
Age at onset of illness (years)
a
20.8 11.7 26.0 13.9 23.1 11.8 23.3 12.5
Number of previous hospitalizations
a
Hospitalizations for mania 1.3 2.2 1.5 3.3 2.9 5.4 1.8 3.8
Hospitalizations for depression 1.3 2.1 1.6 1.8 2.2 4.1 1.9 3.1
Number of previous episodes
a
Hypomania/mania 12.9 7.2 11.0 7.9 12.0 7.7 11.9 7.6
Depression 15.8 6.0 12.7 7.7 13.9 7.4 14.1 7.1
a
Not ascertained in several patients in each group.
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switch to mania, an episode that contained at least 2 days during
which the patient had an LCM rating of moderate or greater se-
verity of mania. It is noteworthy that our criterion for full-dura-
tion hypomania of 7 days is more conservative than the DSM-IV
criteria for hypomania, which require only 4 days. The 7-day du-
ration was needed to clearly distinguish full-duration hypoma-
nias from the brief hypomanias described by Angst (21), which
have a median duration of 3 days.
For each antidepressant trial, only the most severe form of
classification of hypomania/mania observed was considered in
the switch rates reported here. Moreover, because the brief hy-
pomanias would presumably have been missed or ignored in
most other studies and might be considered clinically nonprob-
lematic because of their brevity and lack of association with
functional impairment, we did not consider them as full or
threshold switches.
The interrater reliability for the LCM-based rating of antide-
pressant response and the four classifications of hypomania or
mania was high, with the two blind raters independently arriving
at identical categorizations 93% of the time. Minor discrepancies
were readily resolved by consensus. After all ratings were com-
pleted, the blind was broken, and the data for all the acute and
continuation trials as a group were analyzed first and then the
data for each of the three drugs were analyzed separately. Re-
sponse and switch rates were analyzed by using chi-square tests,
and the ratios of brief hypomanias to full switches in the acute
and continuation trials were examined. Data for trials in rapid-cy-
cling patients were compared to those for trials in patients with
non-rapid-cycling disorder. Survival analyses were performed to
assess the number of days to a switch to full-duration hypomania
or mania in patients with bipolar I disorder, compared to bipolar
II disorder patients, and in the first randomization sequence,
compared with the subsequent ones.
Results
Overall Response to Adjunctive Antidepressants
and Switch Rates
As Table 2 shows, 111 (48.7%) of the 228 acute antide-
pressant trials were associated with a rating of much im-
proved or very much improved on the CGI-BP. In the acute
treatment phase, brief hypomania occurred in 4.8% of the
trials and recurrent brief hypomania in 7.0% of the trials. A
switch into full-duration hypomania occurred in 11.4% of
trials, and a switch into mania in 7.9% of trials, for a com-
bined switch rate of 19.3% during the 10-week acute anti-
depressant augmentation trials. This rate is similar to the
20.7% switch rate observed in the first acute randomiza-
tion by using only Young Mania Rating Scale or CGI-BP
criteria (9). In the current study, if the antidepressant re-
sponders who had a full switch (N=37) were excluded, the
overall response rate in the absence of a switch was 32.5%
(74 of the 228 trials). Overall, 87 (38.2%) of the 228 acute
trials resulted in sufficient improvement for patients to be
offered inclusion in the antidepressant continuation
phase, which lasted up to 1 year. The patients with suffi-
cient improvement included several with minimal im-
provement (classified here as nonresponders) and several
who had a switch (but who subsequently restabilized).
As Table 2 shows, 21.8% of antidepressant continuation
trials were associated with a full hypomania and 14.9%
with a mania, for a combined switch rate of 36.8%. In 67.8%
of the continuation trials, patients showed an antidepres-
sant response, but 22 of the 59 antidepressant responders
also experienced a switch. The response rate in the ab-
sence of a switch was 42.5% (37 of 87 evaluable continua-
tion trials) or only 16.2% (37 of 228) of the original intent-
to-treat acute trials. This result rate equated to 37 of 159 pa-
tients (23.3%) who experienced a sustained antidepressant
response without a switch in the continuation phase.
Survival analysis showed that the overall switch rate and
the individual-drug switch rates observed in the first ran-
domization did not differ from those in the rerandomiza-
tions. The rates of switching also were not related to the
type or number of mood stabilizers received in the base-
line regimen (lithium versus an anticonvulsant versus an
atypical antipsychotic).
TABLE 2. Emergence of Subthreshold Hypomania and Threshold Switches in Trials of Antidepressant Augmentation of
Mood Stabilizers in Depressed Patients With Bipolar Disorder
Antidepressant and Study Phase
Trials in Which
Patients Responded
to Antidepressants
a
Trials in Which Patients Had
Antidepressant-Associated
Hypomania or Mania
Subthreshold Hypomania
Brief Hypomania
Recurrent Brief
Hypomania Total
N% N% N% N%
Bupropion
Acute phase (10-week trial) (N=66) 32 48.5 4 6.1 9 13.6 13 19.7
Continuation phase (up to 1 year) (N=24) 15 62.5 1 4.2 5 20.8 6 25.0
Sertraline
Acute phase (10-week trial) (N=76) 42 55.3 5 6.6 4 5.3 9 11.8
Continuation phase (up to 1 year) (N=32) 22 68.8 1 3.1 5 15.6 6 18.8
Venlafaxine
Acute phase (10-week trial) (N=86) 37 43.0 2 2.3 3 3.5 5 5.8
Continuation phase (up to 1 year) (N=31) 22 71.0 2 6.5 2 6.5 4 12.9
All antidepressants
b
Acute phase (10-week trial) (N=228) 111 48.7 11 4.8 16 7.0 27 11.8
Continuation phase (up to 1 year) (N=87) 59 67.8 4 4.6 12 13.8 16 18.4
a
Much or very much improved on Clinical Global Impression Bipolar Version rating for depression.
b
Randomized or rerandomized trial.
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LEVERICH, ALTSHULER, FRYE, ET AL.
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Survival analysis showed a higher rate of full switches in
the trials in patients with bipolar I disorder, compared to
those in patients with bipolar II disorder (Figure 2) (p=
0.03). Other demographic and illness variables, including
gender, age of onset, history of rapid cycling, or a past his-
tory of an antidepressant-related switch into hypomania
or mania, were not significant correlates of the risk of
switching in this study. A surprising result was that the pa-
tients without a positive family history of unipolar or bipo-
lar affective illness in first-degree relatives had a higher
risk of a switch during treatment with antidepressants
than those who had such a family history.
Response and Switch Rates Associated With
Individual Antidepressants
Antidepressant response and switch rates were not sig-
nificantly different among the three antidepressants in ei-
ther the acute or the continuation phase (Table 2). How-
ever, as Figure 3 illustrates, in both the acute and
continuation phases, the ratio of threshold switches to
subthreshold hypomanias was lowest with bupropion and
was three times higher for venlafaxine. The ratio for sertra-
line was closer to the ratio for bupropion than to the ratio
for venlafaxine.
As Table 3 shows, more switches occurred in the rapid-
cycling group than in the non-rapid-cycling group, al-
though none of the differences were significant. In the
small number of trials including rapid-cycling patients in
the continuation phase, the switch rate was 16.7% for bu-
propion, 40% for sertraline, and 62.5% for venlafaxine.
Discussion
We found a continuum of hypomanic to manic manifes-
tations during antidepressant augmentation of mood sta-
bilizers in patients with bipolar depression. The contin-
uum ranged from subthreshold (brief and recurrent brief)
hypomania to threshold switches, including full-duration
hypomania and mania associated with some dysfunction.
These findings from the assessment of a range of switch
thresholds in the same study may help explain the very dif-
ferent switch rates reported in previous studies in the liter-
ature. If only switches into mania (as defined in this study)
are considered, then the switch rate of 7.9% in the acute
treatment trials (and 14.9% in continuation trials) in this
cohort would be consistent with rates found in many other
acute treatment studies (2, 7, 8). If one also considers full-
duration hypomania (lasting a week or more) as a switch
(even though many patients and clinicians would not see
these extended hypomanias as clinically problematic),
then a threshold switch occurred in 19.3% of the acute tri-
als and 36.7% of the continuation trials. The switch rate
that we found in the continuation trials is similar to the
35% switch rate that was deemed likely to be related to use
of an antidepressant in a previous uncontrolled study in
which retrospective life charts were used (22).
The current study revealed a lower risk of switching in
patients with bipolar II disorder than in patients with bi-
polar I disorder in the acute as well as the continuation tri-
als. These findings extend those of Altshuler et al. (23),
who examined data from the acute treatment phase only
and used the Young Mania Rating Scale and CGI-BP crite-
ria for a switch.
In the continuation phase, the switch rate was almost
twice as high as that observed in the 10-week acute phase,
as might be expected on the basis of the much longer pe-
riod of observation. Subtracting the number of continua-
tion trials associated with a switch from those with an an-
tidepressant response yielded a 42.5% overall response
rate (37 of 87) in the evaluable group that entered the con-
tinuation phase. However, only these 37 (16.2%) remained
from the original 228 acute intent-to-treat antidepressant
trials, or 23.3% of the patients had a long-term antidepres-
sant response without a switch into hypomania or mania
in both phases.
Individual Drug Switch Rates
In the cross-sectional analysis of the acute treatment
phase in which the Young Mania Rating Scale or CGI-BP
severity cutoff scores were used to identify switches in this
same cohort, venlafaxine also had a significantly higher
switch rate, compared with bupropion or sertraline (9).
Those findings are consistent with the current observa-
tions (Figure 3) of a threefold higher ratio of the two types
of full switches to the two types of subthreshold brief hy-
pomanias during treatment with venlafaxine, compared
to bupropion, and a more than twofold higher ratio with
venlafaxine, compared to sertraline.
These data support and extend the findings of Vieta et
al. (24) that the combined reuptake inhibitor venlafaxine
was associated with a greater risk of a switch, compared to
another serotonin selective antidepressant, paroxetine.
Trials in Which Patients Had
Antidepressant-Associated
Hypomania or Mania
Ratio of
Threshold
Switches
to Subthreshold
Hypomanias
Threshold Switch
Full-Duration
Hypomania Mania Total
N% N% N%
7 10.6 4 6.1 11 16.7 0.85
4 16.7 3 12.5 7 29.2 1.17
9 11.8 6 7.9 15 19.7 1.67
7 21.9 3 9.4 10 31.3 1.66
10 11.6 8 9.3 18 20.9 3.60
8 25.8 7 22.6 15 48.4 3.75
26 11.4 18 7.9 44 19.3 1.64
19 21.8 13 14.9 32 36.8 2.00
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This difference was likely to be related to the additional
noradrenergic actions of venlafaxine. This possibility is
also suggested by the findings of Sachs et al. (17, 18), who
observed more switches in patients taking the potent nor-
adrenergic reuptake inhibitor desipramine than in pa-
tients taking bupropion, which increases dopamine in the
striatum and has weaker effects on norepinephrine.
In the cross-sectional analysis of the data from the acute
phase (9), rapid-cycling patients showed a higher switch
rate while taking venlafaxine, compared to the other
drugs. In the current analysis of both the acute and contin-
uation antidepressant trials, the switch rates in trials in
patients with a history of rapid cycling were not signifi-
cantly different from the rates in trials in patients without
rapid cycling, although venlafaxine was associated with
the highest and bupropion with the lowest switch rate in
both the acute and continuation phases in patients with
rapid cycling. These findings not only highlight the likely
higher risks associated with venlafaxine (9, 24) but also
support initial open observations (25) of a relatively low
risk of switches with bupropion, even in patients with
rapid cycling, when it was given in combination with a
mood stabilizer such as lithium.
Study Limitations
Several methodological factors limit the interpretation
and inferences drawn from this study. The generalizability
of these data from this outpatient cohort to other nonaca-
demically based populations of patients with bipolar ill-
ness remains uncertain. Twenty-five percent of the study
patients had a past history of rapid cycling. Although this
rate of rapid cycling is similar to that reported for other co-
horts (26), patients with rapid cycling are typically ex-
cluded from antidepressant studies reported in the litera-
ture (2), and such exclusions may yield lower switch rates
in those studies. However, patients with rapid cycling were
included in an earlier open-label trial (27) and represented
22.1% of the population in a controlled trial of quetiapine
in acute depression (28). In the study of lamotrigine by
Calabrese et al. (29), 28% of the recently depressed pa-
tients had rapid-cycling bipolar disorder. These data sug-
gest that the proportion of patients with rapid cycling in
this study of acute depression was not atypical.
Twenty-five (13%) of the original 184 patients in the
acute randomization (9) did not have adequate life chart
data to allow ratings of antidepressant improvement or
switches in the current study. However, there was no evi-
dence that these 25 patients, for whom other cross-sec-
tional ratings were available, differed significantly from
those with life chart data that were suitable for analysis.
Another possible limitation of this study is the fact that
some patients in the acute phase were randomly assigned
to receive a second or third antidepressant if they did not
respond to the first, and the current analyses include data
for patients who were and were not previously exposed to
another antidepressant. Analyzing the data for the three
randomizations separately by survival analysis revealed
that receiving a drug in the first randomization, versus a
later (second or third) randomization, did not make a sig-
nificant difference in either the response or switch rates.
Thus, we included data from both the first and the later
randomized trials in the current analysis for simplicity of
presentation and to allow assessment of the highest num-
ber of continuation trials of a given drug in order to have
the greatest power to detect differences among the three
drugs.
At the same time, data from the rerandomization, which
involved 69 of the first 159 patients assigned to receive an
antidepressant, yielded additional clinical information. As
in the observations of Sachs et al. (18), we found a lack of
consistency for switching in the same individual during
treatment with various second-generation antidepres-
sants with different mechanisms of action.
Finally, in the absence of a placebo group, it was not
possible to differentiate the switches directly related to an-
TABLE 3. Threshold Switches in Trials of Antidepressant Augmentation of Mood Stabilizers in Depressed Patients With
Bipolar Disorder With and Without Rapid Cycling
Study Phase and Antidepressant
Trials in Patients With Rapid Cycling
Trials in Patients
Without Rapid Cycling
Trials With Threshold
Switches
Trials With Threshold
Switches Analysis
NN%NN%χ
2
(df=1) p
Acute phase (10-week trial)
a
Bupropion 18 2 11.1 48 9 18.8 0.55 0.46
Sertraline 16 4 25.6 60 11 18.3 0.35 0.55
Venlafaxine 23 6 26.1 63 12 19.0 0.50 0.48
All antidepressants 57 12 21.1 171 32 18.7 0.15 0.70
Continuation phase (up to 1 year)
b
Bupropion 6 1 16.7 18 6 33.3 0.61 0.44
Sertraline 5 2 40.0 27 8 29.6 0.21 0.65
Venlafaxine 8 5 62.5 23 9 39.1 1.31 0.25
All antidepressants 19 8 50.0 68 23 33.8 0.44 0.51
a
No difference between antidepressants in trials in patients with rapid cycling (χ
2
=1.57, df=2, p=0.46) and in trials in patients without rapid
cycling (χ
2
=0.01, df=2, p=0.99).
b
No significant difference between antidepressants in trials in patients with rapid cycling (χ
2
=2.97, df=2, p=0.23) and in trials in patients with-
out rapid cycling (χ
2
=0.50, df=2, p=0.78).
Page 5
Am J Psychiatry 163:2, February 2006 237
LEVERICH, ALTSHULER, FRYE, ET AL.
ajp.psychiatryonline.org
tidepressant treatment from those related to the natural
course of bipolar illness.
Clinical Implications
The clinical implications of the current findings are
highly suggestive but not definitive. They support the view
that in an academically based outpatient cohort of pa-
tients with bipolar disorder, antidepressant augmenta-
tion, in general, is not likely to yield a high rate of sus-
tained antidepressant response without a switch
throughout both the acute and continuation treatment
phases (1, 5). Although the risk for switching in patients
with bipolar I disorder was approximately linear for the
first 75 days of antidepressant augmentation for all three
drugs (Figure 2), thereafter it continued on this same steep
trajectory for venlafaxine but became more gradual for
bupropion. For sertraline, the slope was intermediate
(closer to that for venlafaxine), and then no further
switches were seen after day 160.
Given that naturalistic studies show that patients with
bipolar disorder spend a threefold greater amount of time
depressed than manic (30–33), even when antidepressants
are used liberally, it appears that alternatives to adjunctive
treatment with antidepressants are needed (34–37).
In a study of one alternative, Young and colleagues (7)
found less than satisfactory response rates both for the ad-
dition of an antidepressant to a mood stabilizer and for
FIGURE 1. Example of a Graphic Depiction of Daily NIMH Life Chart Method Ratings Showing Instances of Subthreshold
Hypomanias and Threshold Switches
Severe
Threshold
Switches
Subthreshold
Brief Hypomanias
1. Brief
hypo-
mania
(<7 days)
2. Recurrent
brief hypo-
mania
(<7 days)
3. Hypomania
(7 days)
4. Mania
(including
some
dysfunction)
1. 2. 3. 4.
High moderate
Low moderate
Mild
Days
Depression
Mania
Mild
Low moderate
High moderate
Severe
FIGURE 2. Time to Threshold Switch in Trials of Antidepres-
sant Augmentation of Mood Stabilizers in Depressed
Patients With Bipolar I Disorder, Compared to Patients
With Bipolar II Disorder
a
a
Significant difference in time to switch between patients with bipo-
lar I disorder and patients with bipolar II disorder (χ
2
=4.46, df=1,
p=0.03). Baseline numbers of subjects are reported for the study
groups.
1.0
0.8
0.6
0.5
Cumulative Proportion Without a Switch
0.2
0.0
Patients with bipolar I disorder (N=115)
Patients with bipolar II
disorder (N=44)
Censored
0 100 200 300
Time to Switch (days)
400 500
FIGURE 3. Ratio of Threshold Switches to Subthreshold
Brief Hypomanias in Trials of Bupropion, Sertraline, and
Venlafaxine as an Adjunct to Mood Stabilizers in
Depressed Patients With Bipolar Disorder
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
Ratio of Threshold Switches to
Subthreshold Brief Hypomanias
Acute
Antidepressant
Trials (10 weeks)
Continuation
Antidepressant
Trials (1 year)
More Threshold Than
Subthreshold
Phenomena
More Subthreshold
Than Threshold
Phenomena
Venlafaxine
Sertraline
Bupropion
Page 6
238 Am J Psychiatry 163:2, February 2006
ADJUNCTIVE ANTIDEPRESSANTS IN BIPOLAR DEPRESSION
ajp.psychiatryonline.org
the addition of a second mood stabilizer. Given the prom-
ising antidepressant effects of lamotrigine (29, 38) and
some of the atypical antipsychotics in initial studies (28,
39, 40), it may be useful to conduct direct randomized
comparisons of augmentation of a mood stabilizer with an
antidepressant to that with lamotrigine or an atypical an-
tipsychotic (13, 37) in instances of breakthrough bipolar
depression.
Received Jan. 18, 2005; revision received May 12, 2005; accepted
July 12, 2005. From the Biological Psychiatry Branch, NIMH; the De-
partment of Psychiatry and Biobehavioral Science, David Geffen
School of Medicine, University of California, Los Angeles; West Los An-
geles Veterans Affairs (VA) Medical Center, Los Angeles; University of
Texas–Southwestern Medical Center, Dallas; the Psychopharmacol-
ogy Research Program, Department of Psychiatry, University of Cin-
cinnati College of Medicine, Cincinnati; the Mental Health Care Line
and General Clinical Research Center, Cincinnati VA Medical Center,
Cincinnati; Altrecht Institute for Mental Health Care, Utrecht, the
Netherlands; the Department of Psychiatry, University Hospital,
Groningen, the Netherlands; and the Psychiatric Clinic of Ludwig
Maximilians University, Munich. Address correspondence and reprint
requests to Ms. Leverich, NIMH, Bldg. 10, Room 3S239, 10 Center Dr.,
MSC-1272, Bethesda, MD 20892–1272; levericg@mail.nih.gov (e-
mail).
Supported by NIMH and the Stanley Medical Research Institute.
Drugs and matching placebos were provided by GlaxoSmithKline
(bupropion), Pfizer U.S. Pharmaceuticals (sertraline), and Wyeth Phar-
maceuticals (venlafaxine).
The authors thank Sun Hwang and David Luckenbaugh for statisti-
cal support, Jeffrey Hatef and Sean O’Neill for technical support and
provision of randomization tables, and Chris Gavin for manuscript
preparation.
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  • Source
    • "These investigators concluded that continuation adjunctive antidepressant treatment would probably maintain response with a modest risk of manic symptoms. By contrast, Leverich et al. (2006) found that only 23% of bipolar subjects receiving maintenance antidepressant (plus mood stabilizer) therapy had sustained antidepressant response without mood conversion episodes. Similarly , Schneck et al. (2008) followed 1191 bipolar patients (75% bipolar type I) for one year and found a 34% recovery rate, with a 61% mood conversion rate during antidepressant therapy. "
    [Show abstract] [Hide abstract] ABSTRACT: Objective: Compare the safety and effectiveness of continuation antidepressant versus mood stabilizer monotherapy for preventing depressive relapse in bipolar II disorder. Methods: Subjects ≥18 years old with bipolar II depression (n=129) were randomized to double-blind venlafaxine or lithium monotherapy for 12 weeks. Responders with a ≥50% reduction in depression score were continued for an additional 6 months of relapse-prevention monotherapy. Primary outcome was depressive relapse during continuation monotherapy. Secondary outcomes included sustained response rate from initiation of treatment to study end-point, relapse hazard, time to relapse, change in mania ratings, and frequency of treatment-emergent sub-syndromal hypomania and/or depressive episodes. Results: Venlafaxine produced greater sustained response rate versus lithium (p<0.0001); however, there was no difference in relapse rate for venlafaxine (7.5%) versus lithium (26.7%) (p=0.079); relapse hazard (p=0.073), or time to relapse (p=0.090) between treatment conditions during continuation monotherapy. There were no group differences in mania rating scores over time and no difference in frequency or duration of syndromal or sub-syndromal hypomanic episodes. There were more sub-syndromal depressive episodes during lithium monotherapy (p=0.03). Limitations: Sample size was limited by the lower sustained response rate for lithium versus venlafaxine; study was not specifically powered to detect differences in treatment-emergent hypomanic or depressive episodes between groups. Conclusion: Results suggest that continuation venlafaxine monotherapy may provide similar prophylactic effectiveness relative to lithium, with no difference in treatment-emergent hypomanic episodes and without the need for frequent serum lithium level and metabolic monitoring. Larger, prospective trials are needed to confirm these observations.
    Full-text · Article · Jun 2015 · Journal of Affective Disorders
  • Source
    • "Concerns about inducing mania surely contribute to the routine exclusion of patients with identified BD from controlled trials of antidepressant drugs, contributing to the dearth of investigations of bipolar depression. Evidence of long-term, prophylactic benefit of antidepressants is even more limited, with greater concerns about increased long-term risk of mania, emotional destabilization or more rapid cycling of mood-states (Ghaemi et al., 2003Ghaemi et al., , 2008Ghaemi et al., , 2010 Leverich et al., 2006 ; Post et al., 2006 ; Pacchiarotti et al., 2011b ; Sussman et al., 2012 ; Valentí et al., 2012 ). One meta-analysis of 12 heterogeneous , short-term trials that included both BD I and II patients in acute depression found that antidepressants of various types yielded a rather large apparent superiority in pooled response-rates vs. placebo or other control treatments, averaging 86 % [ Gjisman et al., 2004 ). "
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  • Source
    • "pion, increase AA signaling and turnover in the rat brain. [139‑141] These findings are intriguing, considering that antidepressant treatment in bipolar patients often leads to a switch from a depressive to a manic/hypomanic state [142,143] and that, among antidepressants, bupropion is the drug associated with the lowest risk of inducing switching. [144,145] Taken together, these findings suggest that manic/hypomanic phases might be associated with a higher rate of AA signaling, an interesting hypothesis that would need more in‑depth research. [146] Novel neuroimaging techniques such as positron emission tomography with 11C‑labeled fatty acids might help to better clarify the AA turnove"
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