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17


Investigational strategies: treatment of
rapid cycling, mixed episodes, and atypical
bipolar mood disorder
Gary Sachs and Mandy Graves
Massachusetts General Hospital, Partners Bipolar Treatment Center, Boston, MA, USA




The psychiatric literature includes relatively few adequately powered controlled
double-blind clinical trials reporting results for bipolar disorders. The majority of
these randomized clinical trials report results for treatment of acute mania in
hospitalized bipolar I (BP-I) patients. The majority of bipolar patients are, how-
ever, not BP-I and manic states are relatively infrequent. Why are there so few
published controlled treatment studies dealing with common clinical problems
like rapid cycling, mixed episodes, and atypical bipolar disorder?
Rapid cycling, mixed episodes, and atypical bipolar mood disorder each chal-
lenge clinical researchers in distinctly different ways. This chapter explores the
issues as they relate to study design in general and offers suggestions for study
methodology.
The first consideration is the conceptual dissimilarity of the terms rapid cycling,
mixed episodes, and atypical bipolar disorder. These terms correspond to three
distinct organizational levels used in the Diagnostic and Statistical Manual of
Mental Disorders, 4th edn (DSM-IV) mood-disorder nosology and represent the
concepts of course specifier, acute episode, and subtype of bipolar (American
Psychiatric Association, 1994). Study designs for each require attention to sample
selection, outcome measures, and an analysis plan matched to the appropriate
level in the organizational hierarchy of the DSM-IV mood-disorder classification.


Difficulties in conducting clinical trials for atypical bipolar disorder
The DSM-IV bipolar mood disorder category is subtyped into BP-I, BP-II,
cyclothymia, and bipolar disorder not otherwise specified. The latter encompasses
all forms of ˜˜atypical bipolar disorder™™ which do not meet criteria for one of the
three defined subtypes. There are, as yet, no treatments that are indicated for any of
these disorders per se. Various regulatory authorities have granted indications
Cambridge University Press, 2005.
#
370 G. Sachs and M. Graves


specifically for treatment of single acute manic episodes and prophylaxis, but there is
neither treatment for bipolar disorder itself nor any of its subtypes. Several practical
obstacles make it difficult to carry out clinical trials that aim at the disorder or its
subtypes. The term ˜˜atypical bipolar disorder™™ could be defined in many ways, but
little research has been done to validate any particular definition. Whether or not
research focused on atypical bipolar disorder adopted a definition akin to that used
by the DSM-IV, the variance implied by this term creates a statistical challenge.
Heterogeneous diagnostic categories, like atypical bipolar disorder, are a disadvan-
tageous target for clinical trials because combining dissimilar conditions under a
single heading increases variance. Clinical trialists able to surmount this formidable
obstacle confront a series of additional daunting dilemmas such as what outcome
measure is appropriate in determining outcome for a longitudinal illness and what
duration of study might be sufficient to measure such an outcome confidently.
There are other important problems related to subtyping bipolar disorder. The
DSM-IV relies primarily on the characteristics and consequences of episodes of
mood elevation to assign subtypes. For instance, the classification BP-I is given
when the most extreme episode meets criteria for mania. Subtyping might, how-
ever, be based on other characteristics such as age of onset, course of illness,
biological markers, and response to treatment.
Categorical approaches to subtyping are as yet not well validated and any
lifetime diagnosis assigned to a living patient must be regarded as subject to
change. Furthermore there is no evidence of sharp distinctions between subtypes.
Figure 17.1, the bipolarity index under study in the Systematic Treatment
Enhancement Program for Bipolar Disorder (STEP-BD), scores five dimensions
of bipolarity and was developed to provide a continuous measure (0“100) where
a score of 20 on each dimension is assigned for unambiguous characteristics
considered most consistent with the classic form of BP-I illness. This scale offers
a continuous measure of bipolarity that can be determined separately from formal
diagnostic subtype.
Despite the difficulties in evaluating subtypes of bipolar illness, some notable
successes suggest the potential value of subtyping bipolar disorders. Subtyping of
bipolar illness by the sequence of phases or episode pattern has been shown to
predict response to lithium (Koukopoulos et al., 1980; Grof et al., 1987; Haag et al.,
1987; Maj et al., 1989). This promising technique may merit wide usage, if its
reliability and validity can be formally established.
The 11-year follow-up carried out by Alda et al. (1998) for 559 subjects
previously diagnosed with unipolar depression demonstrated differences in self-
report measures of mood lability, energy activity, and daydreaming between the
3.9% of subjects who developed full manic episodes (BP-I) and the 8.6% who
experienced hypomanias only (BP-II).
371 Investigational strategies


BIPOLARITY INDEX
For each of the items below, circle the score next to the characteristic that best describes the patient.
Characteristics™ scores range from 0 (no evidence of bipolar disorder) to 20 (most convincing characteristic of bipolar disorder).
I. Episode Characteristics
• Documented acute mania or mixed episode with prominent euphoria, grandiosity, or expansiveness and no significant general medical or known
20 secondary etiology


15 Clear - cut acute mixed episode or dysphoric or irritable mania with no significant general medical or known secondary etiology.
• Clear - cut hypomania with no significant general medical or known secondary etiology.

10 Clear - cut cyclothymia with no significant general medical or known secondary etiology.
• Clear - cut mania secondary to antidepressant use.
• Clear - cut hypomania secondary to antidepressant use.
• Episodes with characteristic sxs of hypomania, but sxs, duration, or intensity are subthreshold for hypomania or cyclothymia.
5
• A single MDE with psychotic or atypical features (Atypical is 2 of the following sxs: hypersomnia, hyperphagia, leaden paralysis of limbs)
• Any postpartum depression.
• Any recurrent typical unipolar major depressive disorder.
2
• History of any kind of psychotic disorder (i.e., presence of delusions, hallucinations, ideas of reference, magical thinking).

0 No history of significant mood elevation, recurrent depression, or psychosis.
st
II. Age of Onset (1 affective episode/syndrome)


20 15 to 19 years

15 before age 15 or between 20 and 30

10 30 to 45 years

5 after age 45

0 No history of affective illness (no episodes, cyclothymia, dysthymia, or BP NOS).
III. Course of Illness/Associated Features

20 Recurrent, distinct manic episodes separated by periods of full recovery.
• Recurrent, distinct manic episodes with incomplete inter - episode recovery.
15
• Recurrent distinct hypomanic episodes with full inter - episode recovery.
• Comorbid substance abuse.

10 Psychotic features only during acute mood episodes.
• Incarceration or repeated legal offenses related to manic behavior (e.g., shoplifting, reckless driving, bankruptcy).
• Recurrent unipolar MDD with 3 or more major depressive episodes.
• Recurrent, distinct hypomanic episodes without full inter - episode recovery.
• Recurrent medication non - compliance.
5
• Comorbid borderline personality disorder, anxiety disorders, or eating disorders, or history of ADHD.
• Engagement in risky behaviors that pose a problem for patient, family, or friends.
• Behavioral evidence of perimenstrual exacerbation of mood symptoms.
• Baseline hyperthymic personality (when not manic or depressed).
• Marriage 3 or more times (including remarriage to the same individual).
2
• In two or more years, has started a new job and changed jobs after less than a year.
• Has more than two advanced degrees.

0 None of the above.
IV. Response to Treatment

20 Full recovery within 4 weeks of therapeutic treatment with mood stabilizing medication.
• Full recovery within 12 weeks of therapeutic treatment with mood stabilizing medication or relapse within 12 weeks of discontinuing tx.
15
• Affective switch to mania (pure or mixed) within 12 weeks of starting a new antidepressant or increasing dose.
• Worsening dysphoria or mixed symptoms during antidepressant treatment subthreshold for mania.

10 Partial response to one or two mood stabilizers within 12 weeks of therapeutic treatment.
• Antidepressant - induced new or worsening rapid - cycling course.
• Treatment resistance: lack of response to complete trials of 3 or more antidepressants.
5
• Affective switch to mania or hypomania with antidepressant withdrawal.

2 Immediate near complete response to antidepressant withdrawal.


0 None of the above, or no treatment.
V. Family History

20 At least one first degree relative with documented bipolar illness.
• At least one second degree relative with documented bipolar illness.
15
• At least one first degree relative with documented, recurrent unipolar MDD and behavioral evidence suggesting bipolar illness.

• First degree relative with documented, recurrent unipolar MDD or schizoaffective disorder.
10 • Any relative with documented bipolar illness or recurrent unipolar MDD and behavioral evidence suggesting bipolar illness.
• First degree relative with documented substance abuse.
5
• And relative with possible bipolar illness.
• First degree relative with possible recurrent unipolar MDD.
2
• First degree relative with diagnosed related illness: anxiety disorders, eating disorders, ADD / ADHD.


0 None of the above, or no family psychiatric illness.


Total score (0 “ 100)
________



Fig. 17.1 Bipolarity index: a continuous measure sunmarizing five dimensions of mood disorder
relative to classic characteristics of bipolar I disorder.
372 G. Sachs and M. Graves


52%




37:1
31%

BPII

BPI 10%

1.4%
BPI
BPII
% weeks % weeks
Depression Manic spectrum

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