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Treatment efficacy outcome criteria specifically for rapid cycling are not well
established. Calabrese et al. (2000) reported results for several efficacy measures
used on the double-blind trial comparing the outcome for rapid-cycling patients
maintained on placebo or lamotrigine. Interestingly, time to intervention for a
new mood episode proved relatively insensitive, but percentage remaining stable
without relapse through the 6-month follow-up period, time to drop-out, change
from baseline severity, and change from baseline Global Assessment Scale score
were useful in distinguishing between lamotrigine and placebo.
The most compelling of these measures, percentage remaining stable without
relapse, becomes highly relevant to course of illness, in large part because the
follow-up was carried out for 6 months. Beyond the sense of clinical relevance, it is
noteworthy that survival curves for both active and placebo-treated subjects in
most maintenance studies nearly always begin with an initial period of sharp
decline lasting 6“18 weeks. Therefore, study designs with follow-up of duration
shorter than 6 months are statistically disadvantageous.
Outcome criteria, such as percentage minimally symptomatic (meeting CMF
criteria for recovered or recovering), correspond to ˜˜stable without relapse,™™ but
may be insensitive to the beneficial effects of treatments that reduce the frequency
but do not eliminate cycling.
382 G. Sachs and M. Graves

Demonstration of decreased cycle rates might be possible using the continuous-
phase counting strategy above or using the categorical determination of zero, one,
or more than one phase change to compare the percentage of months with zero
phase changes. The duration of longest well period and quality-of-life measures
may also be promising efficacy measures. Each of these represents in itself a
composite outcome assessment, which avoids the problem of misinterpretation
of improvement on a mania or depression scale as improvement when it actually
represents affective switch. Whenever mood-rating scales are used, concurrent
measurement should be made for both depression and mood elevation.

The complexity of bipolar disorder and its subtypes need not discourage clinical
trials. Simple investigational strategies can facilitate the conduct of clinical trials
for mixed episodes and rapid cycling. Recommendations for studies of treatment
for mixed episodes include constructing a trial design for mixed episode subject
only, requiring the presence of mixed features for at least 4 weeks prior to
randomization, and use of composite outcome measures. For rapid cycling, the
development of standard operating procedures and definitions for prospective
assessment can reduce the complex problem of phase counting to a reliable
categorical determination (0, 1, >1). Recommendations offered include random-
izing subjects on the basis of prospectively assessed active cycling and determining
response to treatment over periods of at least 6 months.


Current rapid cycling
1. Patient meets the criteria for bipolar disorder and has had four episodes or
more in the preceding 12 months
2. Patient has experienced four episodes or two complete cycles within the preceding
12 months. Longest remission over the past 6 months does not exceed 12 weeks

History of rapid cycling
1. Patient meets criteria for bipolar disorder
2. Patient has had at least four episodes or two complete cycles in any 12-month

Secondary rapid cycling
1. Patient meets criteria for bipolar disorder
383 Investigational strategies

2. The 12-month period during which the patient satisfied the definition for rapid
cycling includes episodes attributable to secondary factors such as antidepres-
sant medication, substance abuse, travel across time zones, and sleep apnea
3. The subject would no longer meet criteria for rapid cycling if those phases
attributable to secondary factors were no longer counted

Primary rapid cycling
1. Patient meets criteria for bipolar disorder
2. Patient has experienced a period of rapid cycling characterized by at least four
episodes or two complete cycles within a 12-month period
3. At least two or more episodes were phases having occurred 6 months or more
after discontinuing the exposure to all identifiable cycle-promoting factors

Defining a phase shift
1. Phase change: the appearance of a new mood state with duration of 48 h or that
meets the DSM-IV criteria for an episode
2. As a continuous measure, the 48-h rule limits the range of phase changes per
month to between zero and 15. Even so, it can be problematic to reach
consensus on the total number of phase changes. Consensus is much easier to
reach when the number of phases is collapsed to one of three categories: none,
one, or more than one


Dr Sachs™ work is supported in part by the Stanley Medical Research Institute.


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Page numbers in italic refer to figures. Page numbers in bold denote entries in tables.
adolescents see children and adolescents aripiprazole 355
adoption studies 278 controlled studies for bipolar disorder 365
mood disorders 286“7 Aristotle 161
age at onset Asclepiades 6
mixed episode 21 association studies 278
rapid-cycling disorder 28 mood disorders 289“90
agitated depression 12, 13, 34 review of empirical evidence 290
forms 34, 35 asthenia, historical perspective 6
Akiskal, Hagop 16 attention-deficit hyperactivity disorder (ADHD)
classification of mixed states comorbidity with bipolar disorder 269
type B-I 16 compared with bipolar disorder 239
type B-II 16 atypical antidepressants 180“2
type B-III 17 atypical antipsychotics 353“4
alcohol abuse see also antipsychotics
mixed states 16, 17, 330 bipolar disorder in children and adolescents 248
rapid-cycling disorder 28, 68, 69 bipolar I and bipolar II disorders 100
amfetamines 330 controlled studies for bipolar disorder 354“5
anticonvulsants, use in agitated depression 179 aripiprazole 365
antidepressants clozapine 356
agitated depression 179 methodology 355“6
bipolar disorders 70 olanzapine 358“63
bipolar I and bipolar II disorders 100 quetiapine 363“4
combination therapy with lithium 342“3 risperidone 356“8
mixed states 339“41 ziprasidone 364
antipsychotics use in mania 362, 363, 365“6
see also atypical antipsychotics atypical bipolar mood disorder
cortisol levels 336“7 difficulties in conducting trials 369“72
depression in mania 337 bipolarity index 371
mania 336 follow-up 372
prophylaxis of bipolar disorder 338“9 treatment 369, 382
anxiety disorders 174 atypical psychoses 216
comorbidity with bipolar affective disorders 267“8 Aurelius, Cornelius Celsus 4, 6
anxiety“happiness psychosis 213
Aretaeus of Cappadocia 4, 6, 37 benzodiazepines, use in agitated depression 179
melancholia 159 bipolar I and bipolar II disorders 88“90, 101

387 Index

prepubertal bipolar disorder 239
clinical course and outcome 91“5, 93
clinical manifestations 238
suicide risk 92, 95
consequences 241
family history 244
age at onset 90“1
genetic epidemiology
differential features 91, 92
age of onset 289
epidemiological studies 90
family studies 287“8
gender differences 90
twin studies 288“9
pathophysiology 95
longitudinal course 242“4
family studies and genetics 95“6
bipolar disorder in high school students 243
neurochemical studies 98
prevalence 237“8
neuroimaging 96“7
rapid-cycling disorder 66, 67
neurophysiology 98
top-down studies 244“5
treatment 99“100
high-risk studies 246
antidepressants 100
treatment 245“8
atypical antipsychotics 100
chlorpromazine 354
carbamazepine 99
Churchill, Winston 327
lamotrigine 100
Cincinnati criteria 47, 48
lithium 99
Claude, Henri 190
olanzapine 100
clonazepam, use in agitated depression 179
quetiapine 100
Clouston, T. S. 163
risperidone 100
topiramate 100
controlled studies for bipolar disorder 356
bipolar schizoaffective mixed states see
mixed states 23
schizoaffective mixed states
prophylaxis of bipolar disorder 338
bipolar spectrum of disorders 109“11
cocaine 330
cumulative prevalence rates 110
˜˜crack™™ cocaine 331
definitions 113
Cologne Study 17, 20, 22
future perspectives 37
frequency of mixed episodes 193, 194
bipolarity index 371
´´ schizoaffective mixed states 187, 192“4
bouffee delirante 211, 215“16
combined depression (CD) 111


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