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Olanzapine
There have been few reports about the use of olanzapine in rapid-cycling bipolar
disorder (Demopulos et al., 2000; Bhana and Perry, 2001), Demopulos et al.
(2000) published a preliminary report of a cohort of patients with rapidly cycling
bipolar I disorder who participated in the double-blind, placebo-controlled
3-week study of acute mania. Their results indicated that olanzapine 5“20 mg/day
monotherapy (n ¼ 19) was significantly superior to placebo (n ¼ 25) in improving
YMRS scores relative to baseline (À14 versus À4, P ¼ 0.05). Additionally, signifi-
cantly more olanzapine than placebo recipients had improvements of ! 30%
from baseline YMRS scores (84 versus 36%, P ¼ 0.002). However, their sample
size was too small to draw any generalizable conclusions.
80 O. Elhaj and J. R. Calabrese



Quetiapine
Ghaemi et al. (2001) reported limited results with 40 BP-I rapid-cycling subjects to
be followed in up to 1 year of open prospective follow-up of quetiapine treatment,
with or without a concomitant mood stabilizer. Sixteen subjects were recruited at
the time of presentation. Assessments were done utilizing HAM-D, YMRS, along
with GCI-BP and a daily mood chart. Patients entered the study with any mood
symptomatology severe enough to require added medication intervention.
Eight subjects received concomitant lithium and/or divalproex or concomitant
lamotrigine. Only one patient was taking an antidepressant (fluoxetine). The results
showed that the mean dosage of quetiapine was 159.4 Æ 161.5 mg/day. Preliminary
data analysis at weeks 4, 8, and 12 indicated improvement in both HDRS and
YMRS ratings. At week 8, depressive symptom improvement tended towards
statistical significance, but not at week 12. Manic symptom improvement was
statistically significant at weeks 4 and 12. CGI-BP ratings indicated improvement
in both manic and depressive symptoms for week 2 onwards, with statistical
significance for manic symptoms at week 4, and overall bipolar illness at weeks
4 and 8. Drop-out and side-effect data were also analyzed. Weight change was
minimal, with a mean amount of 1.2 lb (0.5 kg) lost at 14.9 weeks™ mean follow-up.
It was concluded in this preliminary analysis of a partially recruited data set that
early indications at 3-month follow-up are that quetiapine improves rapid-cycling
symptoms in bipolar disorder. Further controlled studies will definitely be needed
to clarify the role of quetiapine in the management of bipolar disorder generally,
and in rapid cycling in particular.


Combination therapy
The need sometimes to combine mood stabilizers in the treatment of rapid-cycling
bipolar disorder has received more recognition lately (Sachs et al., 2000b;
American Psychiatric Association, 2002), especially in the face of the fact that
many patients with rapid-cycling bipolar disorder do not achieve bimodal stabil-
ization with the currently available treatment strategies (Calabrese et al., 2001).
Calabrese et al. (2001) reported in two studies evaluating combination therapy
in rapid cycling in bipolar disorder with and without comorbid substance abuse.
The first study evaluated the spectrum of efficacy of combined lithium and
divalproex treatment over 6 months in a prospectively defined cohort of 215
patients with rapid-cycling BP-I or BP-II disorder. Data are from the open
stabilization phase of an ongoing and still blinded 20-month maintenance study
designed to compare the efficacy of lithium monotherapy with divalproex mono-
therapy after 6 months of treatment with both medications concurrently.
81 Rapid-cycling bipolar disorder



Table 3.2 Baseline characteristics and outcome of subjects in two ongoing rapid-cycling,
6-month combined lithium and divalproex maintenance treatment

Without With
ADA (n ¼ 215) ADA (n ¼ 84)

Characteristics
Female 64 38
Bipolar I 31 66
Bipolar II 69 34
Circular continuous 92 98
Cycling
Outcome
Mood stabilization 25 17
Early full remission of ADA NA 25
Premature discontinuation
Poor compliance 29 44
Refractory depression 20 16
Refractory hypomania/mania/mixed states 6 9

Values are percentage unless otherwise specified.
ADA, alcohol and drug abuse; NA, not applicable.


Inclusion criteria included the presence of rapid cycling and an episode of hypo-
mania or mania within the 3 months prior to study entry, along with the absence of
comorbid substance abuse. Patients were mostly women with BP-II disorder
presenting in the depressed phase of their illness. The median number of affective
episodes meeting DSM-IV criteria in the 12 months prior to study entry was eight.
Patients were required to have minimum therapeutic concentrations of 0.8 mmol/l
of lithium and 50 mg/ml of valproate. Both intent-to-treat analyses and responder
analyses on completers were carried out. Of the 55 patients who failed to be
randomly assigned because they were non-responsive to combined treatment,
76% were experiencing refractory depression and 24% were experiencing refrac-
tory hypomania/mania/mixed states. Of the completers, only one-half met criteria
for a marked bimodal response and were randomly assigned to the maintenance
phase of the study; 61% of patients met criteria for a marked antidepressant
response, and 88% met criteria for a marked antimanic response (Tables 3.2
and 3.3).
The second study evaluated the spectrum of efficacy of combined treatment
with lithium and divalproex in a cohort of 84 patients with rapid-cycling BP-I or
BP-II disorder comorbid with a current history of either abuse of, or dependence
on, alcohol, cannabis, and/or cocaine. Data are derived from the open stabilization
82 O. Elhaj and J. R. Calabrese



Table 3.3 Responder analyses on completers after 6 months of combined lithium and
divalproex in bipolar rapid cycling

Without With
ADA (n ¼ 109) ADA (n ¼ 28)

Mood stabilization 50 37
Time required (months) 4.7 5.4
Marked antimanic effect 88 77
Cycling into depression (n) 42 16
Marked antidepressant effect 61 59
Cycling into hypomania/mania/mixed states (n) 13 9

Values are percentages unless otherwise specified.
ADA, Alcohol and drug abuse.



phase of an ongoing and still blinded 6-month maintenance study designed to
compare the efficacy of lithium monotherapy with the combination of lithium and
divalproex after 6 months of open stabilization with the combination. Inclusion
criteria included presence of rapid cycling and an episode of hypomania or mania
within the 3 months preceding study entry, and meeting DSM-IV criteria for
either abuse of, or dependence on, alcohol, cannabis, and/or cocaine. All patients
were required to attend a 12-step-based intensive outpatient chemical dependence
treatment program. Patients enrolled were mostly men with BP-I disorder pre-
senting in the depressed phase. However, manias and mixed states were more
commonly observed at study entry as compared with the cohort of non-comorbid
patients with rapid cycling. The median number of affective episodes meeting
DSM-IV criteria in the 12 months prior to study entry was eight. Of the 28 subjects
who were not randomly assigned because they were non-responsive to combined
treatment, 64% were experiencing refractory depression and 36% were experien-
cing refractory hypomania/mania/mixed states. Twenty-five percent of patients
met criteria for an early remission to their alcohol or drug-abuse disorder at the
end of open stabilization. The responder analyses indicated that, of 39 completers,
only 37% met criteria for a marked bimodal response and were randomly assigned
to the maintenance phase of the study; 59% of patients met criteria for a marked
antidepressant response, and 77% met criteria for a marked antimanic response
(Tables 3.2 and 3.3).
The final results of these two studies will shed long-awaited light on the efficacy
of the, apparently needed, combined pharmacotherapy for this challenging sub-
type of bipolar disorder, especially with its high comorbidity rate with alcohol- and
substance-related disorders.
83 Rapid-cycling bipolar disorder



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