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16


The use of atypical antipsychotic agents
in the treatment of diagnostic subgroups
of bipolar disorder: mixed and pure
states, psychotic and non-psychotic
Robert W. Baker1, Leslie M. Schuh1 and Mauricio Tohen2
1
Lilly Research Laboratories, Indianapolis, IN, USA
2
Lilly Research Laboratories, Indianapolis, IN, and Harvard Medical School, Belmont, MA, USA




Introduction
There are many challenges in treating bipolar disorder, including confronting
marked variability in symptoms between patients, as well as highly differing
symptomatic presentations within an individual patient™s course of illness.
Diversity of presentation and course is potentially quite important to prognosis
and treatment selection, though the relevance has not been consistently well
defined in empirical research. This chapter reviews controlled findings regarding
the impact of variant bipolar presentations to predicting treatment response with
atypical antipsychotic agents.
Classic bipolar I disorder consists of euthymic periods punctuated by episodes
of mania or major depression. Interindividual variability is manifest in differing
severity, length, and frequency of manic and depressive episodes and the degree of
symptom relief occurring between acute episodes. There are, of course, many
variations on the classic pattern, such as the concurrent dysphoric and manic
symptoms of mixed states, subsyndromal presentations, or the markedly frequent
episodes of rapid cycling. Bipolar disorder is also commonly complicated by
psychiatric comorbidity, such as psychosis, as well as substance abuse or physical
disorders. Not surprisingly, patients with bipolar disorder have increased mortal-
ity from suicide, accidents, substance-abuse-related causes, and various medical
diseases (Baldessarini, 2002).
Variant presentations may be more difficult to treat than classic bipolar depres-
sion or mania. First, these presentations often broaden the range of target symptoms

Cambridge University Press, 2005.
#
354 R. W. Baker et al.


requiring treatment, including, for example, psychotic symptoms or the pivotal
need to slow cycling in rapid cyclers. Such variant presentations may help to explain
the polypharmacy that is typical of bipolar disorder treatment. Second, treatment
for one symptom may aggravate others, such as dysphoria secondary to adminis-
tration of some antipsychotic medications (Koukopoulos et al., 1980; Krakowski
et al., 1997) or manic or hypomanic symptoms promoted by antidepressant treat-
ment (Tohen et al., 2002a). Third, variant course may be a marker for relatively
treatment-resistant patients (e.g., rapid cycling) or for an independent complication
such as substance abuse or dependence. Finally, variant illness presentations may
respond differently to particular psychotropic treatments, such as apparent poor
response of patients with dysphoric mania to lithium (Swann et al., 1997). In fact,
the clinical benefit of identifying bipolar subtypes is amplified when such identifica-
tion can help to guide treatment decisions, such as evidence related to atypical
antipsychotic agents, as discussed below.
An expanded repertoire of psychotropic treatments for bipolar disorder is
needed, preferably accompanied by clinical trial data to guide clinicians in match-
ing medications to individual patients. In the case of atypical antipsychotic
medications, some findings are available regarding their use in patients with
rapid-cycling bipolar disorder, as well as mania complicated by depression or
psychosis. These findings are the principal focus of this chapter.


Controlled studies of atypical antipsychotic medications in bipolar disorder
For several decades, antipsychotic medications have been widely used for patients
with bipolar disorder, especially in the manic phase of illness. Conventional agents,
such as chlorpromazine, have a well-established efficacy for acute mania, but their
usefulness is limited by other considerations. Antipsychotic agents may have
unidirectional antimanic properties, tending to accelerate switch to depression
or to cause dysphoria even in those without a primary mood disorder (Morgan,
1972; Garfinkel et al., 1980; Koukopoulos et al., 1980; Tohen and Zarate, 1998;
Tohen et al., 2002a). Moreover, antimanic properties may not be accompanied by
prophylaxis against subsequent episodes (Goodwin and Jamison, 1990); chlor-
promazine, for example, appeared inferior to lithium in double-blind relapse
prevention studies (Goodwin and Jamison, 1990). Finally, extrapyramidal side-
effects and risk of tardive dyskinesia are important limitations to the use of
dopamine-antagonists in bipolar disorder, especially because patients with
mood disorders appear to have heightened sensitivity to these side-effects
(Nasrallah et al., 1988; Khanna et al., 1992; Brotman et al., 2000), and because
alternate treatments are available. Atypical antipsychotic agents may differ from
each other in presence or degree of association with extrapyramidal side-effects,
355 Use of atypical antipsychotic agents


but each appears to carry less overall risk of extrapyramidal side-effects than
benchmark conventional antipsychotic agents such as haloperidol (Seeman and
Trallerico, 1999; Glazer, 2000a, b, c; Stanniland and Taylor, 2000; Kapur and
Seeman, 2001). Consequently, atypical antipsychotics may, as a group, offer
some improvements over older agents for treating patients with bipolar disorder,
just as they have for schizophrenia. The differences or similarities across the
atypical agents remain unclear; certainly they are not homogeneous in several
neuropharmacological actions of potential relevance to mood, such as effects on
receptors or neurotransmitter release of catecholamines, acetylcholine, glutamate,
or gamma-aminobutyric acid. Further, as discussed below, clinical evaluation for
the other agents is lagging behind olanzapine. Therefore, it is too soon to deter-
mine whether the agents have similar efficacy to conventional neuroleptics and to
each other for acute mania. Even less is known about relative impacts for diag-
nostic subgroups and whether, in addition to olanzapine, any will be useful across
phases of bipolar disorder, or, like conventional neuroleptics, be relevant mostly to
acute mania.
Starting in the late 1990s, a flurry of clinical trials have tested atypical anti-

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