Review Article
A systematic review of the evidence on the
treatment of rapid cycling bipolar disorder
Rapid cycling is a descriptive term that refers to
the presence of four or more discrete mood
episodes during a one-year period in the context
of bipolar disorder. In the DSM-IV, rapid cycling
is a course specifier for bipolar disorder and is
defined by the occurrence of at least four mood
episodes (mania, hypomania, depression, or
mixed) during the preceding year (1). The term
rapid cycling was first coined in 1974, when
Dunner and Fieve (2) described a group of
lithium-unresponsive manic-depressive patients
who were noted to have at least four episodes of
mania and ⁄ or depression per year. Clinical studies
which thereafter investigated the correlates of
rapid cycling bipolar disorder have suggested that
it is more frequent in women and is associated
with hypothyroidism and bipolar II disorder (3).
The clinical importance of this condition derives
from its relatively high point prevalence (ranging
from 10% to 20% among clinical samples) (1) and
its associations with longer illness duration (4)
and greater illness severity. Indeed, patients who
experience a rapid cycling course have been
reported to demonstrate a worse global functioning
Fountoulakis KN, Kontis D, Gonda X, Yatham LN. A systematic
review of the evidence on t he treatment of rapid cycli ng bipolar
disorder.
Bipolar Disord 2013: 15: 115–137. 2013 John Wiley & Sons A ⁄ S.
Published by Blackwell Publishing Ltd.
Objective: Rapid cycling is associated with longer illness duration and
greater illness severity in bipolar disorder. The aim of the present study
was to review the existing published randomized trials investigating the
effect of treatment on patients with rapid cycling bipolar disorder.
Methods: A MEDLINE search was conducted using combinations of
the following key words: bipolar and rapid or rapid-cycling or rapid
cycling and randomized. The search was conducted through July 16,
2011, and no conference proceedings were included.
Results: The search returned 206 papers and ultimately 25 papers were
selected for review. Only six randomized, controlled trials specifically
designed to study a rapid cycling population were found. Most data were
derived from post hoc analyses of trials that had included rapid cyclers.
The literature suggested that: (i) rapid cycling patients perform worse in
the follow-up period; (ii) lithium and anticonvulsants have comparable
efficacies; (iii) there is i nconclusive evidence on t he comparative acute or
prophylactic efficacy of the combination of anticonvulsants versus
anticonvulsant monotherapy; (iv) aripiprazole, olanzapine, and
quetiapine are effective against acute bipolar episodes; (v) olanzapine
and quetiapine appear to be equally effective to anticonvulsants during
acute treatment; (vi) aripiprazole and olanzapine appear promising for
the maintenance of response of rapid cyclers; and (vii) there might be an
association between antidepressant use and the presence of rapid cycling.
Conclusion: The literature examining the pharmacological treatment
of rapid cycling is still sparse and therefore there is no clear consensus
with respect to its optimal pharmacological management. Clinical trials
specifically studying rapid cycling are needed in order to unravel the
appropriate management of rapid cycling bipolar disorder.
Konstantinos N Fountoulakis
a
,
Dimitrios Kontis
b
, Xenia Gonda
c
and Lakshmi N Yatham
d
a
Third Department of Psychiatry, School of
Medicine, Aristotle University of Thessaloniki,
Thessaloniki,
b
First Psychiatric Department,
Psychiatric Hospital of Attica, Athens, Greece,
c
Department of Pharmacodynamics, Faculty of
Medicine, and Department of Clinical and
Theoretical Mental Health, Semmelweis University,
Budapest, Hungary,
d
Department of Psychiatry,
University of British Columbia, Vancouver, Canada
doi: 10.1111/bdi.12045
Key words: bipolar – randomized – rapid cycling
– review – treatment
Received 2 August 2011, revised and accepted for
publication 14 October 2012
Corresponding author:
Dimitrios Kontis, M.D., Ph.D.
First Psychiatric Department
Psychiatric Hospital of Attica
374 Athinon Avenue
Athens 12462
Greece
Fax: +30-2102110920
E-mail: dimkontis@gmail.com
Bipolar Disorders 2013: 15: 115–137
2013 John Wiley and Sons A/S
Published by Blackwell Publishing Ltd.
BIPOLAR DISORDERS
115
(5) and may be at a higher risk for serious suicide
attempts (6). However, controversies still exist
regarding the necessary criteria for diagnosis, the
etiology, the longitudinal stability (7), and treat-
ment of rapid cycling.
Several strategies have been used to treat this
condition, given that a rapid cycling course has
been recognized as an independent predictor of
inadequate treatment response in bipolar disorder
(2, 8). Studies have investigated the effects of the
standard mood stabilizers (lithium, divalproex, and
carbamazepine) used either as monotherapy or in
combination, and also the utility of atypical
antipsychotics and antidepressants (9). The role
of antidepressants in the development of rapid
cycling still remains an issue of debate, with some
studies associating them with the onset or worsen-
ing of rapid cycling (10, 11), while others fail to
replicate this association after controlling for
major depression (6, 12). In the search for more
effective treatment approaches, even experimental
agents such as levothyroxine or melatonin have
been employed, with mixed results (9, 13–16). The
number of studies that have investigated the
pharmacological management of rapid cycling is
limited, and there are only a few that have directly
compared specific treatment alternatives for rapid
cycling patients. Additionally, the number of trials
using a randomized design was also few. Conse-
quently, there is no clear consensus with respect to
the optimal pharmacological management of rapid
cycling.
The aim of the current paper was to review
published randomized clinical trials assessing the
efficacy of various treatments in acute mood
episodes and in prevention of relapse of mood
episodes in patients with rapid cycling bipolar
disorder.
Materials and methods
A MEDLINE search was conducted using combi-
nations of the following key words: bipolar and
rapid or rapid-cycling or rapid cycling and random-
ized. The search was conducted through July 16,
2011, and no conference proceedings were included.
Results
The search returned 206 papers for initial evalua-
tion. Papers from randomized studies and their
post hoc analyses reporting separate data on acute
or maintenance treatment response for patients
with a rapid cycling course or in which the majority
of patients were rapid cyclers were selected.
Twenty-five papers that presented such results
were found, 24 of which reported on the original
or post hoc analysis data, and one of which was a
meta-analysis that included randomized as well as
non-randomized studies. It is important to mention
that most studies presented the effects of treat-
ments in rapid cycling patients; however, there
were also studies comparing the efficacy of treat-
ment in rapid versus non-rapid cycling bipolar
disorder patients (17–27). Table 1 lists the details
of these studies; however, some of the studies
shown in the table provide different analyses of
pivotal trials and should not be considered sepa-
rate trials (olanzapine studies).
Treatment of acute mood episodes in patients with rapid
cycling bipolar course
Antidepressant monotherapy
Escitalopram. In the Parker et al. study (28), 10
outpatients having a diagnosis of bipolar II disor-
der and a history of mood episodes that occurred
at least monthly were recruited. Patients were
required to not have previously received any
antidepressant, mood-stabilizing, or neuroleptic
medication. The study was a randomized, double-
blind, placebo-controlled, cross-over trial of escit-
alopram (10 mg) versus placebo with a nine-month
duration. There was a no-treatment baseline period
of three months (baseline phase) to ensure that
subjects met criteria for episode frequency. Sub-
jects compliant with and completing baseline
period requirements were then randomized to
receive escitalopram or placebo for three months
(phase 2), and then crossed over to receive the
alternative compound for the final three-month
period (phase 3). Subjects were assessed at the start
of the study, and every month thereafter for the
entire nine-month period. Parker et al. reported
that escitalopram reduced the severity of depressive
episodes as measured by the Hamilton Depression
Rating Scale (HDRS) and also reduced the per-
centage of days high or low and impaired when
compared with placebo. A weak trend for reduc-
tion in hypomania failed to support concerns that
prescriptions of antidepressants would increase
switch rates in patients with bipolar disorder. The
study did not provide data on the effects of
escitalopram on depression remission rates. In
terms of its funding, the study was not sponsored
by a pharmaceutical company, but rather, the
manufacturer of escitalopram provided the study
capsules, as acknowledged by the authors. How-
ever, it should be noted that the small sample size
should be taken into account when interpreting
these findings, and the fact that the study was not
Fountoulakis et al.
116
Table 1. Treatment of rapid cycling bipolar disorder
Study design Efficacy
Funding from the
pharmaceutical
industry Conclusions
a
Affective
switching
rates
Acute treatment
Antidepressant monotherapy
Escitalopram
Parker et al.
2006 (28)
Escitalopram
versus PLA
9-month RCT with
cross-over (3 months
drug-free, 3 months
escitalopram,
3 months PLA)
N = 10 medication
-naı
¨
ve BD-II rapid
cycling patients
(at least monthly
episodes):
Depressed (n = 6)
Euthymic (n = 4)
Primary outcome:
not defined
Escitalopram: (i)
significant
reduction in
depression
(HDRS) severity,
percentage of
days depressed
or high, and
percentage of
days impaired
versus PLA; (ii)
no worsening of
illness course; (iii)
remission of
depression: not
reported
No Escitalopram > PLA Switching to
(hypo)mania:
weak
reduction
with
escitalopram
Venlafaxine
Amsterdam
et al. 2009 (17)
VENLF versus LITH
Post hoc analysis of one
12-week randomized,
parallel-group, open-label
study
Rapid cyclers versus
non-rapid cyclers
(lifetime history)
presenting with a
BD-II MDE
VENLF (n = 12)
LITH (n = 15)
Primary outcome:
HDRS-28 rating
VENLF: (i) greater
reduction in HDRS-28
versus LITH, higher
rate of responders
and remitters; (ii)
equal pro
portion of mood
conversions versus
LITH in rapid
cyclers; (iii) no
significant
differences in
mean YMRS
change scores
over time,
between rapid
and non-rapid
cycling patients;
(iv) remission of
depression:
higher rates
of remitters
in VENLF-
treated
patients
No VENLF > LITH No difference
in mood
switch
between
VENLF and
LITH
Antipsychotic monotherapy
Aripiprazole
Suppes et al.
2008 (29)
ARI versus PLA
Post hoc analysis of two
pooled 3-week RCTs
in rapid cyclers (past
12 months) with an
acute manic or mixed
BD-I episode
N = 103:
ARI (n = 52)
PLA (n = 51)
Primary outcome:
YMRS change
ARI: significantly reduced
mean YMRS total scores
at endpoint in rapid
cycling patients and
greater responder and
remitter rates versus PLA
Yes ARI > PLA Not reported
Bipolar disorder rapid cycling treatment review
117
Table 1. (Contiuned).
Study design Efficacy
Funding from the
pharmaceutical
industry Conclusions
a
Affective
switching
rates
Olanzapine
Suppes et al.
2005 (21)
OLAN versus DIVAL
Post hoc analysis
for rapid cyclers
(past 12 months)
of one 47-week
RCT comparing
OLAN to DIVAL
for bipolar manic
or mixed episodes
Rapid cyclers (n = 144):
OLAN (n = 76)
DIVAL (n = 68)
Non-rapid
cyclers (n = 106)
Primary outcome:
YMRS change
(i) Rapid cycling patients
did less well during the
extended observation
period than non-rapid
cycling patients,
regardless of treatment;
(ii) rapid cycling patients
receiving DIVAL
appeared to be at
some advantage over
non-rapid cycling
patients receiving DIVAL
in terms of manic
symptoms improvement;
(iii) among rapid cycling
patients, OLAN and
DIVAL appeared equal
in YMRS change while
among non-rapid cycling
patients OLAN appeared
superior; (iv) there was a
difference in response
over time in HDRS,
independently of
treatment; (v) no
differences in CGI
severity scale between
rapid cycling groups; (vi)
remission: not reported
Yes OLAN = DIVAL Rapid
cyclers
demonstrate a
non-significant trend
to switch into
depression
more often,
regardless
of treatment
Vieta et al.
2004 (19)
OLAN versus PLA
Post hoc analysis
for rapid cycling
(past 12 months)
manic patients from
two randomized
clinical trials
Rapid cyclers (n = 90):
OLAN (n = 44)
PLA (n = 46)
Non-rapid cyclers
(n = 164)
Primary outcome
not defined
Clinical response rates:
OLAN = 76.7%
PLA = 50%
(i) Improvement of mania
was similar in rapid
cyclers and non-rapid
cyclers; (ii) rapid cyclers
showed an earlier
response; (iii) remission:
in fewer patients with a
rapid cycling course
Yes OLAN > PLA Rapid
cyclers
more likely
to switch into
depression
Shi et al.
2004 (20)
OLAN versus PLA
Post hoc analysis of
one 3-week and one
4-week RCT to
determine the effect of
olanzapine on
the PANSS-Cognitive
score
N = 254 (35%
rapid cyclers)
Primary outcome:
PANSS-Cognitive
score
OLAN-treated patients
experienced modest but
significant improvement
in PANSS-Cognitive
score, regardless of
course (rapid or
non-rapid cycling)
Remission: not
applicable
Yes OLAN > PLA Not applicable
Fountoulakis et al.
118
Table 1. (Contiuned).
Study design Efficacy
Funding from the
pharmaceutical
industry Conclusions
a
Affective
switching
rates
Baldessarini
et al. 2003 (18)
OLAN versus PLA
Post hoc analysis of
pooled data from one
3-week and one
4-week RCT in manic
patients among 10
subgroup pairs of
interest (including
rapid cyclers during
the previous year)
Rapid cyclers (n = 54):
OLAN (n = 33)
PLA (n = 21)
Primary outcome:
antimanic treatment
efficacy (proportion
of subjects
attaining ‡ 50% YMRS
reduction)
(i) Similar drug ⁄ PLA
superiority and
responsiveness to OLAN
was found and responses
were independent of
recent rapid cycling; (ii)
patients who were
relatively more responsive
to OLAN were younger at
illness onset, lacked prior
substance abuse, and
had not previously
received AP treatment;
(iii) remission:
not reported
Yes OLAN > PLA Not reported
Sanger et al.
2003 (31)
OLAN versus PLA
A priori planned
secondary sub
-analysis for patients
with a rapid cycling
course (in the
preceding year)
recruited in one 3-
week RCT in acutely ill
manic or mixed BD
patients
Rapid cyclers (n = 45):
OLAN (n = 19)
PLA (n = 26)
Primary outcome:
change in YMRS
Clinical response
rates:
OLAN = 58%
PLA = 28%
(i) Significantly fewer
PLA patients completed
treatment, and more than
half discontinued due
to lack of efficacy;
(ii) OLAN reduced
YMRS total
scores significantly
more than PLA; (iii)
clinical responses,
defined as ‡ 50%
improvement in
YMRS, were achieved
in 58% of OLAN
patients, compared
with 28% of
PLA patients;
(iv) remission: not
reported
Yes OLAN > PLA Not reported
Quetiapine
Suppes et al.
2010 (22)
QUET versus PLA
Post hoc analysis of
one 8-week RCT in
acutely depressed
adults with BD-I or BD-
II, with or without rapid
cycling in the previous
12 months
Rapid cyclers (n = 74):
QUET (n = 36)
PLA (n = 38)
Primary outcome:
change in MADRS
QUET XR 300 mg
once daily was
significantly more
effective (change in
MADRS) than PLA in
patients with a rapid
cycling course
Remission: not
reported for rapid
cyclers
Yes QUET > PLA Not reported
Bipolar disorder rapid cycling treatment review
119