The Prospective Course of Rapid-Cycling Bipolar Disorder: Findings From the STEP-BD

Article (PDF Available)inAmerican Journal of Psychiatry 165(3):370-7; quiz 410 · April 2008with29 Reads
DOI: 10.1176/appi.ajp.2007.05081484 · Source: PubMed
Abstract
In a naturalistic follow-up of adult bipolar patients, the authors examined the contributions of demographic, phenomenological, and clinical variables, including antidepressant use, to prospectively observed mood episode frequency. For 1,742 bipolar I and II patients in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), episodes of mood disorders were evaluated for up to 1 year of treatment. At entry, 32% of the patients met the DSM-IV criteria for rapid cycling in the prestudy year. Of the 1,742 patients, 551 (32%) did not complete 1 year of treatment. Among the 1,191 patients remaining, those with prior rapid cycling (N=356) were more likely to have further recurrences, although not necessarily more than four episodes per year. At the end of 12 months, only 5% (N=58) of the patients could be classified as rapid cyclers; 34% (N=409) had no further mood episodes, 34% (N=402) experienced one episode, and 27% (N=322) had two or three episodes. Patients who entered the study with earlier illness onset and greater severity were more likely to have one or more episodes in the prospective study year. Antidepressant use during follow-up was associated with more frequent mood episodes. While DSM-IV rapid cycling was prospectively observed in only a small percentage of patients, the majority of these patients had continued recurrences at lower but clinically significant rates. This suggests that cycling is on a continuum and that prevention of recurrences may require early intervention and restricted use of antidepressants.
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The
Prospective
Course of
Rapid-Cycling
Bipolar
Disorder: Findings From
the
STEP-BD
Christopher
D.
Schneck,
M.D.
David
J.
Miklowitz, Ph.D.
Sachiko Miyahara, M.S.
Mako Araga, M.S.
Stephen
Wisniewski,
Ph.D.
Laszlo
Gyulai,
M.D.
Michael H.
Allen. M.D.
Michael
E. Thase,
M.D.
Gary
S. Sachs, M.D.
Objective: In
a naturalistic
follow-up of
adult bipolar
patients,
the authors exam-
ined
the contributions
of
demographic,
phenomenological,
and clinical
variables,
including
antidepressant
use,
to
prospec-
tively observed
mood
episode frequency.
Method:
For
1,742
bipolar
land ll
pa'
tients
in
the
Svstematic Treatment
En'
hancement Program for
Bipolar Disorder
(STEP-BD),
episodes
of
mood
disorders
were
evaluated
for
up to 1
year
of treat-
ment.
Results: At entry, 32oA
of
the
patients
met
the
DSM-lV
criteria for rapid cycling
in
the
prestudy year.
Of
the 1
,742
pa-
tients, 551
(32%)
did not complete
1
year
of
treatment.
Among
the
1,191
patients
remaining,
those
with
prior
rapid cycling
(N=356)
were
more
likely to have
further
recurrences, although
not
necessarily
more than four episodes
per
year.
At
the
end
of
12 months,
only
5%
(N=58)
of the
patients
could be classified as
rapid
cy-
clersi 34o/o
(N=409)
had
no further mood
episodes,
3a%
(N=402)
experienced
one
episode, and 27o/o
(t{=322)
had two or
three
episodes. Patients
who
entered the
studv
with
earlier illness
onset and
greater
severity
were more
likely to have
one or
more
episodes
in the
prospective
study
year.
Antidepressant
use during
fol-
low-up was
associated
with
more
fre-
quent
mood
episodes.
Conclusions:
While DSM-lV
rapid cycling
was
prospectively
observed
in only a
small
percentage
of
patients,
the
majority
of
these
patients
had
continued
recur-
rences
at
lower
but clinically
significant
rates.
This
suggests that
cycling
is
on a
continuum and
that
prevention
of
recur-
rences may require early
intervention
and restricted
use
of antidepressants.
(Am
I
Psychiotry 2O08;
165:37(1377)
unner and Fieve
(1)
originally coined the term
"rapid
cycling" to describe those
bipolar
patients
who
proved
unresponsive to lithium
monotherapy, noting
that
this subset of
patients
had
experienced
four
or more
af-
fective episodes within
a
year
and
hence
were
"rapid
cy-
clers."
The
two most consistent
characteristics of rapid
cycling
thus far have been
associations
with
female
gen-
der and
bipolar II
disorder,
predictors
that have
proven
to
be of
limited
clinical utility
given
their
modest relation-
ship to
the frequency of mood
episodes
(2).
Despite
stud-
ies
over
the
last
30
years,
fundamental
questions
remain
unanswered,
such
as
what
other
clinical
factors
place pa-
tients
at risk
for
cycling,
whether or not
rapid cycling
is a
transitory
phenomenon
in
the
course of
bipolar
illness,
whether the occurrence of four
or more episodes defines
a distinct subtype
with
unique
course
features,
and
whether
rapid-cycling
patients respond
especially
poorly
to
antidepressants.
In addition
to risk factors,
research on
the course
of
rapid
cycling has
failed to examine
the outcomes of
pa-
tients
who
continue to have recurrences but at
rates fewer
than
four
episodes
per year.
Such
patients
likely are
com-
mon in clinical
practice, yet
whether or
not
their
phenom-
enology, course of illness,
and
response to
treatments
are
similar to
those
of
patients
with DSM-Iv-defined
rapid cy-
cling remains largely
unexplored.
Bauer et
al.
(3),
in their
study examining
the validity
of
rapid cycling
as a
course
modifier,
found
that
the
percentage
of
patients who expe-
rienced two
or
three
episodes
per yeeu
(39.5%)
was higher
than the
percentage
who experienced
rapid
cycling
(34.8%)
during
a
prospective
follow-up.
If
patients
with
such
"frequent
cycling"
are more similar
to those
with
rapid cycling than
those without it,
cycling
may be
better
considered as a continuum
(4).
The
purpose
of
our
current
study
was
to distinguish
clinical features
of
patients
with bipolar
I
or
II
disorder
who developed rapid
cycling
from those
of
patients
who
did not,
by
prospectively
examining
the course
of
rapid cy-
cling
over
1
year. The
participants were
the
first 2,000
en-
trants
into the Systematic
Treatment
Enhancement
Pro-
gram
for
Bipolar
Disorder
(STEP-BD)
(5)
who
were
followed
for
up
to
I
year.
Given
the results
of our
prior
cross-sectional study
(6),
we hypothesized
that riskfactors
for the development
of
rapid cycling
would
include
greater
illness
severity
at intake and
younger age at
onsei
of illness.
We
also
hypothesized
that
patients who expen
.
enced two
or three
mood
episodes in the
follow-up
year
were more clinically
and
phenomenologically similar to
This
article
is featured in
this month's
AJP
nrr
.
,
,
is
the
subject
of
a cnne course
(p.
404,
and is
discussed in an editorial by
Dr.
Ghaemi
(p.
300).
370 a
j
p. psy
c h i atryo n
I i n
e. o
rg
Am
J
Psychiatry
'165:3.
March
2OOB
rapid-cycling patients
than to
those without
rapid
cycling.
Finally,
we
examined
whether
the use of
antidepressants
affected
cycling frequency
and outcome in
this
naturalis-
tic cohort.
Method
Study Overview
The
Systematic
Treatment
Enhancement Program
for
Bipolar
Disorder
(STEP-BD)
was
a study funded
by the
National
Institute
of Menta]
Hea-lth to
evaluate
the
course
and outcome
of
patients
rvith bipolar
disorder
(5).
The study
combined naturalistic
and
randomized
approaches
to assess somatic
and
psychosocial
in-
terventions in
the treatment of all
phases
of
bipolar illness. Re-
gardless
of whether
patients
were participating
in randomized
trials, they
received the
same ongoing
assessments of treatment
and outcome.
Our current
study
examined
outcomes of
patients
involved in
the
"standard
care
pathway,"
in which
patients
were
followed naturalistically
and
treated
by using
"best
practices"
guidelines
(5).
Participants
Patients
had to meet
the DSM-IV criteria for bipolar
I or
II dis-
order, bipolar
disorder not
otherwise
specified,
or cyclothymia.
Patients were
required
to be at
least 15 years
of age. All
partici-
pants provided
written
informed consent.
Patients entered the
study
in
syndromal, subsy'ndromal, or recovered
states. A
more
complete description
of the STEP-BD
participants
was reported
by
Kogan
et
al.
(7).
lntake Assessrn ents
The
Affective Disorder
Evaluation
(8)
is an
intake
assessment
tool
intended
for routine
use by
practicing
clinicians.
It includes
numerous
questions
on
present
illness,
past
psychiatric
history
family history,
medical
history,
and mental status. In addition, it
includes
a modified version
of
the mood
and
psychosis
modules
from
the Structured Clinical Interview for
DSM-IV
(SCID).
For the
current study,
the
Affective
Disorder
Evaluation was
used
to
as-
sess age at study entry, age
at onset
of mood episodes,
number
of
prior
episodes,
periods
ofrecovery, current medications, and cur-
rent
mood
state.
A
srudy
psychiatrist
completed the Affective Dis-
order
Evaluation with
the
patient
at study entry.
The Mini International
Neuropsychiatric Interview
(MlNl)
is
a
semistructured interview designed to identit/
major
axis I
psychi-
atric disorders. In validation
and
reliability
studies, the
MINI was
compared to
the
patient
edition
of the
SCID
for DSM-III-R and
found to have
acceptably high
validity
and reliability scores
(9).
ln
the
present
study, the MINI Plus Version
5.0,
administered to the
patient
by study
research personnel
(psychologists,
social
work-
ers,
or
psychiatric
nurses),
was used to confirm the bipolar
diag-
nosis.
I)iagnostic
discrepancies betrveen
the
Affective Disorder
Eveiluation
and MINI
were
resolved by consensus discussion
be-
tween
the research
staff member and the study
psychiatrist.
Follow-Up Assessments
The
Clinical Monitoring Form
(10)
is a l-page assessment tool
used
by
study clinicians to document symptom and treatment
characteristics of
patients
at each clinical visit.
lt
consists of mod-
ified
versions
of
the SCID
current
mood modules, associated
symptoms,
current
medications, compliance and adverse
effects,
laboratorv data, and summary scores
(i.e.,
clinical
status,
Clinical
(ilobal
Impression severity
rating, and Global
Assessment of
Functioning Scale
IGAFI
score). Intraclass
correlations ofphysi-
cians'
interrater reliabiiity
with
gold
standard
ratings
for the de-
pression
and mania
items
of the Clinical Monitoring Form ranged
irom 0.83 to 0.99. The
treating
psychiatrists
were
periodically
Am
I
Psychiatry 165:3,
March 2OOB
s(tiNrcK, MtKLOwtIZ.
MrYAJ-{ARA.
tt
At_
monitored
to ensure
that the
standards
for
ratings
with
the
Clini-
cal
Monitoring
Form were maintained
(5).
The number
of Clinical Monitoring
Forms
generated
over
the
course of treatment varied
among individual
patients,
as treat-
ment was
naturalistic
and
patients
were
seen as
often
as the treat-
ing
psychiatrist
deemed clinically appropriate. STEP-BD
ciini.
cians assigned
one of eight
clinical states to each
patient
at eaclr
clinic
visit.
Four
of the clinical
status
definitions
corresponded to
DSM-IV criteria
for
major
depression, mania, hypomania, and
mixed episodes.
The
remaining
four clinical
definitions charac-
terized subsl'ndromal or recovered
states and
were
assigned ac-
cording to the number and
duration
of mood
sy'rnptoms
present
(if
any).
In addition
to the
preceding
measures,
researchers adminis-
tered the Young Mania Rating
Scale
(l
I)
and Montgomery-Asberg
Depression
Rating Scale
(MADRS) (12)
to
patients
at study
entry
to determine the severity of illness. Scores on
these instruments
were used
as
predictors
of rapid cycling during the
prospective
study
year.
Cycling Determination
at Study
Entry
Data from
the Affective Disorder
Evaluation were
used to
de-
termine the number of
prior
affective episodes^
Patients
were de-
scribed as having
prior
rapid
cycling
if
they had
experienced four
or
more mood
episodes
in
the
prior
12 months, with
depressive
episodes
lasting
at
least
2 weeks,
manic
episodes
lasting
at
least I
week, or hypomanic episodes lasting at ieast 4 days. Patients rvlrrr
did
not
meet these criteria were designated as
nonrapid
cyclers.
The
groups
with and
without
rapid
cycling were further stratified
by
bipolar
I versus bipolar II
diagnosis.
Treatment
The
pharmacotherapy procedures
were based on expert con-
sensus
guidelines,
such as those
published
byAPA
(13)
and others
(14).
The
treatment choices were
presented
in
tiers, correspond-
ing to treatments
considered
"first
line"
in one or
more
published
guidelines, "second line,"
etc. Physicians and
patients
consulted
a
"menu
of reasonable choices"
in
deciding
on augmentations
or
substitutions; for more
information,
see
reference 15.
Cycling Determination and
Outcome
Groups
During
Prospective Yeor
Because we
considered
that
arxy
mood changes
were
clinically
important, notjust recurrences
at
rates
greater
than
four
episodes
per
year,
we
created
four outcome
groups
based
on
patients'pro-
spectively observed cycle
frequencies. Patients
were
categorized
as having no episodes, one episode,
two or three episodes,
or
rapid cycling
(four
or
more
episodes).
Patients
who
did not com-
plete
I2
months of treatment
were
placed
in a
fifth
category,
"dropped"
(terminated
the study
early), so that
we
could compare
the
clinical characteristics of
patients
who were and
were
not able
to
complete
12 months of treatment.
Phase changes were determined
by using the Clinical
Monitor-
ing Form. Episodes
were
considered
separate if a
patient's
mood
changed
from
one
state
to one ofopposite
polariry
or ifthe
pa-
tient
had achieved euthyrnia for at
least
B
weeks and then experi-
enced
a mood episode
meeting the DSM-IV criteria
for mania,
hypomania, a mixed state, or depression.
Moods
that changed
in
intensity or
quality
within
the same
polarity
(e.g.,
from hypoma-
nia to
mania
or
from mania to a mixed
state) were
not
counted
as
phase
changes.
Statistical
Analyses
The
four
outcome
groups
(no
episodes, one
episode, two
or
three episodes, rapid
cycling) were
first
compared
on
gender, bi-
polar
subtype, age,
age at onset
of
illness,
and
prior
rapid cycling
status
by means
of
t tests and chi-square
analyses.
In
addition,
aj
p. p
sych i atry o n
I i n
e. o
rg 371
{*I,JRSI
OT,
RA'3ID,CYCL!NG
IJIPOI.AR
Di5ORDER
FIGURE
1.
Patients
Included
in
Study
of Rapid
Cycling
Dur_
ing
1
Year
of Treatment
for
Bipolar
Disorder
[nrolled
in
SttP-Bu
stanrlarO
!""*++
care
patlnvav
(N-2.000)
i
,"",..""
'--'--'-.}
]
I
"'
,-^'ry*-
lvtet
cnteria
for bipolar
t or
i
I
ll
tliiurdcr
and lv<'re
eligiblc
i
lor
inrlr"rsion
(N=1,ti67)
l_,.
-..
"-.''::.:*
" ""*--*J
.
'.'''-
'
\:
In<ludecl
in l-year
treatment
I
i
N-l,l,tZ):
i*.*+il,
Did
not
complete 1
vear
I
Bipolar
|
(N-1,,102)
i
nf
treatment (N=551,
3196)
j
eipolar tt
iN=440)
i
'".
.-.
_".-
-."....-."..
...-f*,"
_. .. ^.,*__**..,:
Colnpleted
'l
year
of
lreatment
iN--1.19-i)
*;il-t.".'l
al
-l-vtaf
follow.up
iN,=40!-i,34,1i)
L***
entry
scores
on the
MADRS,
Young
Mania
Rating
Scale,
and
GAF
were
used
as
predictors
of cycling
outcome.
Using
survival
ana-
l1'tic
and logistic
regression
models,
we
examined
whether prior
rapid
cyclir-rg
status
or clinical
and demographic
variables
(his-
tory of
rapid
cycling,
age
at
onset, entry
MADRS,
young
Mania
Rating
Scale,
and
GAF scores,
age at
study entry, gender,
and
bi-
polar
subtype)
predicted
the likelihood
of l) dropping
out
during
the study
year
or 2)
having no
episodes,
one
episode,
two
or three
episodes,
or
four
or
more
episodes.
To identify
naturally
occur-
ring
cutoff
points
that
might
separate
cycling categories,
we
plot-
ted
the number
of
prospectively
occurring
mood
episodes
against
baseline
scores
on
the MADRS,
Young Mania
Rating
Scale,
and
GAF
and age
at illness
onset.
Depressed patients
would
be expected
to
be
seen by
their
psy-
chiatrists
more
often,
and in turn,
psychiatrists
would have
a
greater
opportunity
to
observe cycling.
Therefore,
we examined
the
relation
of
baseline
symptom
scores
to
prospectively
ob-
served
cycling
with
the number
of
psychiatric
visits
covaried.
'Io
determine
the relationship
between
cycling
outcome
and
antidepressant
use, we
entered
antidepressant
use
and baseline
MADRS
score into
a logistic
regression
model
to
predict
member-
ship in
one
of the four
prospective
outcome groups.
A single
mul-
tivariate
logistic
regression
model determined
which predictors
rvere
redundant.
All
statistical
tests were
two-tailed.
Results
Figure
I
presents
an overview
of the study.
The
study
group
consisted
of
the first
2,000
patients
enrolled in
STEP-BD
and
assessed
between
November
1999
and April
2002.
Patients
diagnosed
with bipolar
disorder not
orher-
wise
specified,
schizoaffective
disorder,
cyclothymia,
or
unspecified
condition
were
excluded
from our
analysis,
as
were patients
with incomplete
data.
Of the L,742 patients
irrcluded,
75o/o werc
diagnosed
with
bipolar
I
disorder
and
25o/owerc
diagnosed
with
bipolar
II disorder.
A
total of
551
patients
(32Vo
of
the original
I,242)
did not
complete
i
year
of
treatment
and were
designated
as dropped.
During
the
I
year
of
prospective
follow-up,
only
58
(5%)
of the re-
maining
l,lg1
patients
had four
or
more
mood
disorder
episodes
(DSM-IV
rapid
cycling)
(Figure
r).
The
mean
age
of the
patients
in
the study
was
40.4
years
(SD=12.9;.
Other demographic
characteristics
are
pre-
sented in Table
1. The
majority
of the
study
group
were
Caucasian,
female,
and college
educated.
Table
2
presents
clinical
features
of the
participants
at study
entry.
patients
entered
the
STEP-BD
in
a
variety
of
symptomatic
states,
with
approximately
one-half
of the
group
classified
as ei-
ther recovering
or recovered.
A
total of562
ofthe original
1,742
patients (32%)
reported
rapid
cycling
in the
12
months
before
study
entry.
The
proportion
of
patients
who
reported
rapid
cycling
in
the
prestudy
year
was higher
for
patients
with
bipolar
II disorder
than for those with
bi
polar
I
disorder
(Table
2).
Analysis
of Dropouts
Multivariate
logistic
regression
revealed
that
age
at
study
entry
(X2=5.6,
df=1,
p=0.02),
GAF
score
at
study
entry
(X2-5.6,
df=1,
p=g.orr,
and
prior
history
of
rapid cycling
(X2=6.5,
df=1,
p=Q.91)
were
independent predictors
of
dropping
out of
the
study,
while
age at onset
of
illness,
en-
try
scores on
the MADRS
and Young
Mania
Rating
Scale,
gender,
and bipolar
subtype
were
not. Kaplan-Meier
sur-
vival analysis
revealed
that patients
with
a history
of
prior
rapid
cycling
were
slightly
more likely
to
drop out-and
to
drop out
earlier-than patients
without prior
rapid
cy-
cling. Among
the 562
patients
with
prior
rapid cycling,
206
{37V")
did not
complete
I
year
of treatment,
while
343
(29Vo)
of the 1,180
patients
without
a history
of rapid cv
cling
did not
complete
I
year
(y2=9.7,
df=1,
p=0.003)
Predictors
of Cycling
During 7-Yeor
Prospectivt,
Period
Demographic
and illness
variables.
Table 3
shows de-
mographic
and
clinical risk factors
for
episode
recur-
rences
and
their relationships
to cycling
outcome.
Younger
age at
onset of
bipolar illness
was
a
significant
predictor
of increased
recurrence.
Patients who
had
no
prospectively
observed
mood episodes
were
older
at
the
onset of
illness, while
patients
in all
of the other cycling
groups
developed
bipolar illness
significantly
earlier. Bi-
polar
subtype
was not
predictive
of cycling
outcome. Fe-
male gender
also did not
emerge
as a
predictor
of the de-
velopment
of frequent
cycling
(two
or three episodes)
or
rapid
cycling
(X2=7.7,
df=3,
p=Q.Qgl,;.
Prior rapid
cycling. Compared
to
patients
who had not
been classified
as rapid
cyclers
during the
prior
!€dr, 1-.:1
tients who
entered
the
study
with
a recent histoty
of ra1. ,
cycling were
more likely
to have
at
least
one
prospectivell,
observed episode
during
the follow-up
year.
Of
the
356
pa-
tients
with rapid
cycling in
the
prestudy
year,
only
67
(197o)
maintained
stability
throughout
the l2-month
Excluderi
frrim
analysis for
bipolar
disorder
not
other.
wise
specified,
schizo-
a{fective
disorder,
cyclo-
thymia,
0r unspecified
condition
(N=133)
Excluded
for
ancomplete
data
(N-1251
Two
or
threc
episodes
at
1'year
tollow-up
\N-Tz,21%)
l-our
or more
episodes
(rapid
cycling)
at
1-year follow-up
(N=58,59e)
372
a1
p.
psyc
h i atryon
I i ne.org
Am
J
Psychiatry
165:3,
Morch 2008
TABLE
1. Demographic
Characteristics
of 1,742
patients
With
Bipolar Disorder
Assessed for
a Study
of Rapid
Cycling
SCHNECK, I\4IKLOWITZ.
IT4IYAHARA, EI-,:II-.
TABLE
2.
Clinical Status at Study Entry
of
1,742
Patients
With Bipolar Disorder
in
a Study of
Rapid
Cycling
Demograph ic
Characteristic
Cli nical Characteristic
Sex
Female
Male
Marital
statusa
Never
married
Married
Living
as
married
Separated
Divorced
Widowed
Race
Caucasian
African
American
Native
American,
Eskimo,
or Aleut
Asian
or
Pacific lslander
No
primary
race,
other,
unknown
Education
b
Less
than
high
school diploma
High
school or General Equivalency Diploma
At least 1
year
of college
Technical
school
or associate
degree
College
degree
Graduate or
professional
degree
Annual
income
(dollars)c
<10,000
1 0,000-29,999
30,000-74,999
75,000-149,999
>150,000
Su btype
Bipolar I
Bipolar ll
Patients
reporting rapid
cycling in
the
prior
year (N=552)a
Bipolar I
Bipolar
ll
Clinical
statusb
Recoveredc
Recoveringd
Depressede
Manice
Hypomanice
Mixede
Continued
sym
ptomaticr
RougheningB
1
,013
729
553
561
/6
327
29
1,595
71
11
30
35
58
1,302
440
75
25
J5
5
20
2
92
,l
392
30
170
39
478
27
341 20
459
26
533
603
131
8
153
I
664
a
N=1,61 1.
b
ti=t,60B.
c
N=1,508.
study,
compared to 342
(41%)
of
the
patients
without
rapid
cycling in the
prestudy year
(Table
3).
Baseline clinical
severity. Higher entry MADRS
scores
(covering
the week
before study entry)
predicted
a
greater
likelihood of experiencing
one episode, tvvo or
three
epi-
sodes,
or
rapid
cycling in
the
follow-up
year
(Table
3).
Likewise,
patients
with
higher entry scores on
the
Young
Mania Rating Scale were
more
likely
to
have
frequent or
rapid
cycles in the follow-up
year.
In
an analogous fashion,
lower
GAF scores
at entry
predicted
a
greater
likelihood of
experiencing frequent
or rapid
cycling.
Multivariate
prediction
of
rapid cycling.
Consistent
with
our univariate analyses,
multivariate
logistic
regres-
sion revealed
that
prior
rapid cycling as well
as
intake
scores on the MADRS, Young
Mania
Rating
Scale, and
GAF
were independent
predictors
of
rapid
cycling, versus sta-
ble
status,
in
the
prospective
year.
Odds ratios
and 95%
confidence intervals
(CIs)
showed significant effects
for
prior
rapid cycling
(odds
ratio=4.4,957o CI=2.1-9.0,
p<0.0001),
intake
MADRS score
(odds
ratio=1.15,
95%
CI=
l.l--1.2,
p<0.0001),
intake
score
on the Young
Mania Rat-
ing Scale
(odds
ratio=l.l,95To
CI=1.0-1.1,
p=0.0007),
and
intake
GAF score
(odds
ratio=0.95, 95To Cl=o.92-0.98,
p-
0.002). Age, age at
onset, and bipolar subtype were not as-
sociated with future
rapid
cycling
once the
baseline clini-
cal
variables were
cov€uied.
An interesting finding was
that
the same
predictors
significantly distinguished
between
Am
J
Psychiotry 165:3,
March
2OO8
a
Significant
difference
between
subtypes
(X
=10.9,
df=1,
p=0.0009)
b
N=1,741 .
c
Having
two or
fewer
moderate symptoms
for
8 or more consecu-
tive
weeks.
d
Having
two
or
fewer
moderate
symptoms
for less
than 8 consecu-
tive
weeks.
e
Clinical
status
definition
corresponds to
DS[ll-lV criteria.
r
Having three or more moderate
symptoms
but not meeting DSM
criteria for mood episode, and not recovered
in
prior
B
weeks.
8
Having
three or
more
moderate
symptoms
but
not
meeting DSM
criteria for mood episode, but
previously
recovered.
patients
who
had
tvvo or three episodes
and
those
with no
prospective
episodes.
The
association between baseline
illness severiw an(i
number
of
prospectively
observed episodes appeared t{
be linear. It did
not
appear that
patients
with four
or
more
episodes were
uniquely
distinguishable
from
patients
with
one to three episodes in terms
of intake
scores on the
MADRS
(Figure
2), Young Mania Rating Scale, or GAF or in
terms
of age at
illness onset.
Number of
psychiatry
visits. As
expected, the number
of
psychiatry
visits varied
significantly
by
prospective
cy-
cling
status.
Stable
patients
had
the
fewest visits
(mean=
7.0,
SD=3.8)
while rapid cyclers had the
most
(mean=16.3,
SD=6.3;. Patients
with
high initial
MADRS scores were
seen more often during follow-up
(F=45.8,
df=1, 1592,
p<0.0001),
but
Clinical Monitoring
Form visits
(X2=155.6,
df=3,
p<0.0001)
and MADRS scores
(X2=178.2,
df=3,
p<0.0001)
independently
predicted
cycling status at fol-
low-up. Entry scores on the Young
Mania Rating
Scale
were
unrelated
to the number of visits
(F=73.5,
df=1,
l5UI
p=0.02),
but Young scale scores
(X2=85.7
,
df=3,
p<0.00r,
;
and visits
(x2=200.4,
df=3,
p<0.0001) were
independerr,i
predictive
of cycling status after
visit count
was
covaried.
Effects of Antidepressant
Use
Antidepressant use was common
during the first
year
of
1
treatment. A total of 720
patients
(60%)
received antide'
I
pressants
at some
time during the follow-up
year,
and 471
(40%)
did not.
Of the
patients
who took antidepressants,
45%
took them
with a mood
stabilizer
(lithium,
dival-
proex,
lamotrigine, or carbamazepine),
6% took them with
+t)
225
428
165
435
308
201
394
485
287
14'l
14
27
10
27
19
13
26
32
19
9
aj
p. psyc
h i
at
ryo
n I i n
e.
o rg 373
{{)t-t R5*
{}*: R.4
F}t O-Cy(Lt i'.t
S t3t
pC)
t-A R
n | soR Dr R
TABLE
3.
Relation
of Baseline
Characteristics
to
Number
of Mood Disorder
Episodes
During
1 Year
of
Treatment
for
1,-t
9
l
Patients
With
Bipolar
Disorder
___
Number of Mood Disorder
Episodes in 1-Year Follow-Up
Characteristic
at Studv Entrv
Two or Three
Four or l\,lore
Episodes Episodes
(rapid
(N=322)
cycling)
(N=s8)
No
Episodes
(N=a09)
One Episode
(N=402)
Significant Difference in
Logistic ReBression
Analysis
Mean
SD
Age
(years)
4'1.9 13.5
Age at
onset of illness
(years)
19.9
9.3
Scores
on clinical measures
Montgomery-Asberg
Depressio n 7.5
7.0
Rating
Scale
Young
Mania Rating
Scale 4.5
5.3
GlobalAssessment of Functioning
69.4 10.8
Scale
17.3
9.9 19.4 10.8
23.7
9.9 308.2
Mean
SD Mean
SD
4't.2 12.2
40.4 12.4
16.9
8.4 16.8
8.3
5.9 6.0 8.5 7.5
60.7 11.5
57.0 10.7
292
110
df
3
5
o/o
xz
df
q
q
N
37
21
YtN%
33 206 30
34 116 24
33 236 27
36 86 28
N
233
169
N
222
"t87
312
Mean SD
X'
39.2 9.8
17.7 8.0 32.0
12.5 7 .4 105.0
56.0
9.2
242.5
p
<0.0001
<0.0001
<0.0001
<0.0001
p
<0.000.1
<0.000.t
Gender
Female
(N=698)
Male
(N=493)
Bipolar
subtype
Bipolar |
(N=888)
Bipolar ll
(N=303)
History of rapid
cycling
in
prior
yea
r
Rapid cycling
(N=356)
No
rapid
cycling
(N=835)
Antidepressant use
during
follow'up
year
Antidepressant
use
(N=720)
No antidepressant use
(N=471)
o/-
32
38
35
32
19
4B
10
67
342
t5/
185
120
34
282 34
263
37
139
30
38329
22263
31487
21 10 2
225
97
77.9
69.1
184
225
26
48
an
atypical
antipsychotic
(risperidone,
olanzapine,
que-
tiapine, ziprasidone,
or clozapine), 43% took
them
with
both a mood stabilizer
and an atypical antipsychotic, and
69/o took
an antidepressant only.
Antidepressant
use during the
follow-up
year
was
con-
sistently associated
with more
frequent cycling
(Table
3).
After controlling for
MADRS score at study entry,
we
found that
patients
who received
antidepressants were
3.8
times
(95Vo
CI=|.7-8.5,
p=9.961;
as
likely
to
experience
rapid cycling, 2.0 times
(95%
CI=1.4-2.9)
as likely to have
two or three episodes
(p=0.0001)
,
and 1.7 times
(95%
CI=
1.2-2.3)
as
likely
to
have one
episode
(p=0.001)
during the
follow-up
year
compared to
patients
who did not receive
antidepressants.
Discussion
The
present
study examined the course of cycling in
a
large
group
of bipolar
patients
(N=1,742)
over the course
of I
year
of
treatment.
Although
we found
the occurrence
of four
or
more
episodes
in
the
follow-up
year
to
be
rare
(only
5%
of
patients),
recurrences at lower bur still clini-
cally relevant rates continued:
6l%
of
the
participants
ex-
perienced
between one and three episodes
over
the
l2
months of
follow-up.
TIre observed rate of DSM-IV-defined rapid
cycling
was
much lower in
the
follow-up year
(5%
of
patients)
than in
the
year
before entry into STEP-BD
(32%).
This difference
is
similar to the findings of Coryell et
al.
(15,
16), who ob-
served that the
percentage
of rapid-cycling
patients
de-
creased from approximately l97o in
the
first
year
of treat-
ment
to 5% over the next
2-5
years.
In the second study by
Coryell et al.
(16),
in
which
patients were
followed
for ap-
proximately
15
years,
four
of
five cases of
rapid cycling
ended within 2
years
of their onset.
Collectively, these re-
sults support the notion that
rapid cycling
is
a transitory
phenomenon
in
the
course
of bipolar
illness.
The low
prevalence
of rapid cycling
in
our
prospective
study
may
have been attributable to several other factors.
First,
rapid cycling determined at study entry
was diag-
nosed
retrospectively,
while the
prospective
observation
used strict DSM-IV mood criteria and a
minimum durr
tion of 8 consecutive
weeks of
euthymia
between
ep:
sodes. Second,
patients'recollections
of
the
number of
ci'
cles they experienced
in
the
prior
year
may have
been
subject to retrospective bias
in
reporting
(i.e.,
exaggera-
tion
of
the number
of
episodes). Third,
the use of a
week-
to-week
prospective
assessment
method, such as the
LIFE
(17),
may have
revealed
episodes that
were
not
captured
by
psychiatric visits given
as
clinically needed. Last,
the
"model
practice procedures"
treatment
employed by
STEP-BD
psychiatrists
specially trained
in
treating mood
disorders may
have
had
a
positive
impact on
the outcome
of
patients
with a
history of rapid cycling.
Nevertheless, our findings
demonstrate that
a reported
history of recent rapid cycling
is
prognostically
significant.
Compared
to
patients without rapid cycling
in
the
year
be-
fore the study,
patients
who
reported
rapid cycling
in the
prior
year
were
far
less
likely
to
be
stable
during the
course
of the follow-up
year
(41%
versus
19%, respectively)
and
were
more likely to have
prospectively
observed cycling,
regardless
of cycling
frequency.
Whereas
patients
with
374
aj
p. psych
i at
ryon
I i n
e.org
Am
J
Psychiatry 165:3,
March 20OB
prior
rapid
cycling
and
patients
without
prior
rapid
cy-
cling
were equally
likely
to have one
episode in
the follow-
up
year
(34%
for
each group), prior
rapid
cyclers
were
more
likely
to experience
two or
three episodes
(38%
ver-
sus 22Vo)
and
three times
as
likely
to
experience
rapid
cy-
cling during
follow-up
(9%
versus
37o). In
our multivariate
regression
analysis,
a history
of rapid
cycling emerged
as
the strongest predictor
of cycling
in the
prospective
year,
regardless
of cycling
frequency.
The
predictive
validity
of recent
cycling is
consistent
with
results reported
by Bauer
et al.
(3),
whose rapid-cy-
cling
patients
had
significantly
more episodes
than
non-
rapid-cycling patients
during 12
or
more
months of
pro-
spective
follow-up. From
a
clinical
standpoint,
we would
not anticipate
differences
in the management
of
patients
experiencing
two or
three episodes
in
a
year
and
those
with rapid
cycling.
Our
data suggest that
patients
who re,
port
a recent history
of rapid
cycling
(ue
more vulnerable
to cycling
in
the
immediate future
and
that
caution should
be
exercised
in
prescribing
any
medication with
potential
cycle-promoting
activity.
Severity
ofillness
at study entry
proved
to
be
a signifi-
cant
predictor
of
cycling
outcome.
Patients
entering
the
study more depressed,
more manic,
or with
poorer
func-
tioning were more likely
to cycle in
the
follow-up year.
The
differences observed
between the
scores of stable
patients
and those with
cycling episodes were clinica-lly
meaning-
ful:
entry MADRS scores
for
patients
who
had any
pro-
spectively observed
episodes
were in the
moderately de-
pressed
range,
whereas
those
who
remained stable
for the
prospective
year
had scores indicating
euthymia.
On
the
Young
Mania Rating
Scale, clinically significant
elevations
in scores
portended
later
rapid cycling, i.e., entry
scores
indicating
mild
hypomania were
found in
patients
who
later became
rapid cyclers. Finally,
the
GAF scores
re-
vealed
a
clinically
meaningful
B-13-point separation be-
tween
patients
who remained
stable and
those
who
went
on to have cycling.
The
pattern
of findings
suggests
that
illness
severity,
particularly
in
regard to depressive
symp-
toms and level
of functioning, is
an
important
clinical in-
dicator in
predicting
which
patients
€ue more r,rrlnerable
to episode recurrence.
Patients
who
had stable, nonepisodic
courses
began
their
illness
at
approximately age
20,
whereas
patients
who
proved
less
stable
over
the
course oftheyear, regard-
less
of cycle frequency,
began their
illness approximately 3
years
earlier, in
their midteens. There have
now been sev-
eral studies
(f
6,
18,
19)
in which this relationship
has
been
borne out, and it
suggests that
early
onset
of the disease
eiicits developmental
vulnerability
to cycling. However,
age at illness onset
did not
prove
to be a significant
predic-
tor of rapid cycling when
more
proximal predictors-such
as baseline illness
severity
eurd recent history
ofrapid cy-
cling--were taken
into account.
A
central
question
in
the treatment
of bipolar disorder,
and more specifically
rapid cycling,
is whether
or not
anti-
Am
I
Psychiotry
165:3, Morch 20OB
SCHNECK, MIKLOWIfZ.
MIYAHAf?A.
ET
i\1.
FIGURE
2. Box
Plots of
Baseline Depression
Score in Rela-
tion
to Number
of
Mood
Disorder
Episodes During
1
year
of
Treatment
tor 1,742
Patients With Bipolar
Disordera
60
012345678
Number
of
Prospectively
Observed
Mood
Episodes in Follow-Up Year
a
No
discernible
cutoff
points
were observed. Particularly noteworthy
was
the lack of a noticeable difference at four
episodes
per year,
which
is the DSM-lV definition for rapid
cycling.
depressants
are of
benefit
or
if
they destabilize the
course
of illness
(20,
2l). In our
study, antidepressant exposure
was
associated with worse cycling,
after we
statistically
controlled
for
the
severity ofbaseline
depression. In each
outcome
group,
the likelihood
of
cycling
increased
lin-
early
with antidepressant use
during the first
year,
such
that
patients
with
antidepressant use were more th:Lr
three
times as likely
to be
rapid
cyclers as
were
patie;;
without
such use.
We
recognize
that our results concerning antidepres'
sant use
must
be
viewed
cautiously.
First
and
foremost,
patients who
received
antidepressants
were not random-
ized to treatment.
Because
of the naturalistic design
of
the
study, we
were
unable to
control
for numerous teatment
factors, such as antidepressant dose, total
time
of
antide-
pressant
exposure,
types
ofantidepressants
used, and the
presence
of concomitant medications. Thus, we
cannot
conclude that
antidepressants bore a direct
causal rela-
tionship
to increased
cycling. Furthermore, antidepres-
sants may
have
improved
the
course of bipolar disorder in
ways different from those
examined
here,
such
as enhanc-
ing functioning
or
quality
of
life.
Our results can be contrasted with two
previous
studies
by Coryell et al.
(15,
16),
both of which
indicated
that
r',,
sodes ofdepression
precede
rapid
cycling,
independent
i,,
exposure
to
antidepressants.
The
authors of
these studie:,
concluded
that
the
relationship
between antidepressants
and
phase
shifting was
associative
but not causative.
In
the
present
study,
we
found a relationship between anti-
depressant use and cycling even after controlling
for the
baseline level of
depression.
However, our
design
did
not
allow us to control
for
the level of depression
at the time
the antidepressants
were given.
00
o
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i-sr]Rs[
(}f
f{AFis-cycltht6
BtpoLAR
L}t50Rtr[R
We failed
to find
any naturally
occurring
cutoff
point
to
distinguish patients
with
four
or more
episodes
from
those
with
two or
three episodes
per
year.
Box
plots
of
MADRS,
Young
Mania
Rating
Scale,
and GAF
scores and
age
at onset
of illness revealed
a nearly linear
relationship
between
these
clinical
measures
and the number
of
epi-
sodes in
the follow-up year.
Similar to
the cycling
pattern
in
the examination
by Kupka
et al.
(4),
rapid
cycling in
our
study
existed
along
a continuum
and suggests
that
a di-
mensional,
rather
than categorical,
approach may
better
conceptualize
the
phenomenon
of frequent
cycling.
\iVhile
a
prior
history
of cycle frequency
may have
influ-
enced
the number
of
psychiatric
visits
during the
prospec-
tive
period,
both the
depression
score at study entry
and
the number
of
visits
independently
predicted
cycle fre-
quency
at follow-up.
Thus,
patients
with more
serious ill-
nesses were
likely
to be seen
by
psychiatrists
more
fre-
quently,
but
the association
between illness
severity and
cycle frequency
could
not be accounted
for by this
con-
found.
Nonetheless,
researchers
examining
the
phenome-
non of rapid
cycling
should take frequency
of observation
into
account when
interpreting
results,
particularly
in
nat-
uralistic
studies.
Several limitations
of our
study deserve further
com-
ment. The
STEP-BD was based
at academic, specialry
and
tertiary-care
sites across the
United States, which may
have
attracted a more
select
population
than might
be
found
in the
general
communify. The
population
of the
STEP-BD
was of limited
diversity in both race
and socio-
economic
status, which
limits the
generalizability
of our
findings
to more diverse
populations.
Many
patients
were
on complex
and changing
polypharmacy
regimens,
and
thus the number
of medication variables was
too
great
to
allow a more in-depth
analysis
of
individual
pharmaco-
logical treatments
and their
potential
benefits or liabili-
ties. Finally,
observation intervals
greater
than
1
year
may
be
needed
to assess whether rapid
cycling represents a
lifelong r,rrlnerability
with
poorer prognosis
or simply
a
course modifier
that requires longer
than
I
year
to resolve.
Future studies
specifically examining
age at onset and
its relationship
to
long-term
outcome may
be most war-
ranted,
as delaying
or avoiding the introduction
of antide-
pressants
at a
young
age may enhance
the
long-term
out-
come of this
treatment-refractory variant.
Newer agents,
such as
quetiapine
and lamotrigine, may
be
increasingly
useful,
as
recent
studies have
demonstrated their efficacy
in
treating the
depressed
phase
ofboth rapid-cycling
pa-
tients
and those with nonrapid
cycling
(22,23).
Receaved AuE. 24, 2005; revisions
received April 1
3 and
Aug.
6,
2OO7',
accepted Aug. 1
8, 2OO7
(doi:
1
O.1
1 7
6/ appi.alp.2007.O5081 484). From
the Department
of Psychiatry,
University of Colorado Health Sciences
Centen Address
correspondence and reprint requests
to Dr. Schneck,
Department
of Psychiatry,
University of Colorado Health
Sciences
Center, Box A011-'l5, 4455
East 12th Ave., Denver,
CO 80220;
christopher.schneck@uchsc.edu (e-mail).
Dr. Wisniewski
has
served as a consultant
to Case
western
Univer-
sity, Cyberonics, lmaRx
Therapeutics, Bristol-Myers
Squibb, and
Orga-
non.
Dr.
Gyulai has
provided
CME lectures for
Abbott Laboratories;
and
an
NIMH-funded
clinical trial in which
he
participates
receives
risperidone
from
Janssen.
Dr. Allen has
received research
support
from
Abbott,
Alexza, Bristol-Myers
Squibb,
and
Pfizer;
he has
servecl
on
the speakers
bureaus of Astrazeneca,
Bristol-Myers Squibb,
and
Pfizer;
and he has
been a
consultant for Abbott, Alexza, Bristol-Myers
Squibb,
and
Pfizer.
Dr. Thase has
served as an
advisor or consultant
to Astrazeneca,
Bristol-Myers
Squibb, Cephalon,
Cyberonics,
Eli
Lilly,
GlaxosmithKline,
Janssen,
MedAvante,
Neuronetics, Novartis,
Orga-
non,
Sepracor, Shire,
Supernus, and Wyeth; he has
also served on the
speakers bureaus
of
Astrazeneca,
Bristol-Myers
Squibb, Cyberonics,
Eli Lilly,
GlaxoSmithKline,
Organon, Sanofi-Aventis, and Wyeth; he has
provided
expert testimony for
Jones
Day
(Wyeth
litigation)
and
Phil-
lips
Lytle
(GlaxosmithKline
litigation); he is
a shareholder with Med-
Avante; he
receives income from
royalties and/or
patents
with Amer-
ican Psychiatric Publishing,
Guilford
Publications,
and Herald House;
and his wife is
the senior medical
director
for Advogent.
Dr. Sachs has
received research
support from Abbott, Astrazeneca,
Bristol-Myers
Squibb, Eli Lilly,
claxosmithKline,
Janssen,
Memory Pharmaceuticals,
NIMH, Novartis,
Pfizer, Repligen,
Shire, and
wyeth; he has
served on
the speakers bureaus of Abbott, Astrazeneca, Bristol-Myers
Squibb,
Eli Lilly, GlaxoSmithKline,
Janssen,
Memory Pharmaceuticals, Novar-
tis, Pfizer,
Sanofi-Aventis, and Wyeth; he has
served as an advisory
board member
or consultant
for
Abbott, Astrazeneca, Bristol-Myers
Squibb, Cephalon,
CNS
Response, Elan Pharmaceuticals,
Eli Lilly,
GlaxoSmithKline,
Janssen,
Memory Pharmaceuticals, Merck, Novar-
tis, Organon, Pfizer, Repligen, Sanofi-Aventis,
Shire,
Sigma-Tau,
Solvay, and wyeth;
and his spouse is a shareholder with Concordant
Rater Systems. Drs.
Schneck,
Miklowi?,
and Miyahara and
Ms. Araga
report no
competing
interests.
Funded in whole
or
in
oart with federal funds under NIMH contract
N01-MH-40001.
Any opinions, findings,
and conclusions or
recommendations
ex-
pressed
in
this
publication
are those of the authors and do not
nec-
essarily
reflect
the
views
of NIMH. The Publication Committee of the
Systematic
Treatment
Enhancement Program for Bipolar Disorder
(STEP-BD)
approved this article.
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