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Introduction
Since the Diagnostic and Statistical Manual of Mental Disorders, 4th edn (DSM-IV:
American Psychiatric Association, 1994) recognized the existence of rapid cycling as
a specific pattern of presentation, there has been increased interest in studying this
treatment-refractory variant of bipolar disorder (Bauer et al., 1994). Prior to recent
years, only open naturalistic studies had been conducted on populations of patients
with rapid-cycling bipolar disorder. More recent data have suggested that this
variant of illness is not always refractory to conventional treatment (Baldessarini,
et al., 2000). In particular, the data suggest that the management of hypomania and
mania accompanying this variant of illness is uncomplicated and that lithium is
frequently quite effective in managing this phase of the illness (Dunner et al., 1976).
However, it is now recognized that it is the management of the depressed phase
that poses the greatest challenge to our pharmacotherapeutic armamentarium
(Calabrese et al., 2001). The frequent recurrence of treatment-refractory depression
is emerging as the greatest unmet need in the clinical management of patients with
rapid-cycling bipolar disorder, and particularly those comorbid presentations with
alcohol and drug abuse (Ketter and Calabrese, 2002). What follows is an update of
the research conducted in the past 2 years that has aimed to clarify different aspects
of rapid-cycling bipolar disorder, refine the tools of its diagnosis and management,
and discover new pharmacotherapeutic interventions and strategies.
In a chapter of the ˜˜preceding book™™ (Marneros and Angst, 2000) Bipolar
Disorders. 100 Years After Manic-Depressive Insanity, we gave an extensive over-
view of many aspects of rapid cycling (Calabrese et al., 2000a). In this book, we
cover the efforts and results made after the publication of the above-mentioned
book. However, in order to complete the chapters, we will now give a summary of
certain aspects of our previous paper, and then expand on this information by
providing the new data.

Cambridge University Press, 2005.
#
62 O. Elhaj and J. R. Calabrese



Family genetics
In the above-mentioned paper (Calabrese et al., 2000a), the following was reported
concerning family history and genetics: family studies of rapid-cycling bipolar
disorder show no difference in family loading for bipolar disorder as compared
with non-rapid-cycling patients, nor does rapid cycling cluster in families of rapid
cyclers. Nurnberg et al. (1988) first evaluated the inheritance of rapid cycling.
Twenty-nine of 195 bipolar/episodic schizoaffective patients were judged to be
rapid cyclers (15%). The age-corrected risk of major affective disorder was 23.5%
in 179 relatives of rapid cyclers and 31% in 189 relatives of matched non-rapid
cyclers, suggesting that rapid cycling is not genetic and does not aggregate within
families. This result was replicated by Coryell et al. (1992) and Lish et al. (1993).
Coryell et al. collected information through family history and family study methods
for 268 relatives of 45 rapid cyclers and 1273 relatives of bipolar non-rapid cyclers.
More extensive data were obtained for 111 relatives of rapid cyclers and 397 relatives
of non-rapid cyclers who were also re-evaluated prospectively and at 6 years after
their initial interview. Neither data set revealed evidence suggesting that rapid cycling
had bred true in their cohort. Lish et al. (1993) used the Family History Research
Diagnostic Criteria to interview 165 rapid cyclers, non-rapid cyclers, or individuals
with recurrent unipolar depressive disorder about the psychiatric history of 812 adult
first-degree relatives. Rapid cyclers were younger and more likely to be female than
non-rapid cyclers, but the relatives of rapid cyclers did not differ significantly from
those of non-rapid cyclers in the prevalence of bipolar disorder, unipolar disorder,
rapid-cycling bipolar disorder, or substance abuse. However, there was a non-
significant trend for the relatives of rapid-cycling bipolar patients to have more
substance abuse than relatives of non-rapid-cycling patients. These three studies
appear to argue convincingly against any specific inheritance of rapid cycling as a
discrete course modifier. However, it remains a possibility that early-onset rapid
cycling, as opposed to late-onset, might be discretely inherited.
Only very recently have genetic abnormalities begun to be examined in rapid
cycling. One anecdotal report has noted the presence of the same chromosomal
aberration, a pericentric inversion of chromosome 9, in a bipolar II father
and daughter (McCandless et al., 1998). The same group of investigators first
demonstrated an association between ultradian rapid cycling and low activity of
catechol-O-methyltransferase (COMT), and extended this finding to bipolar patients
with either a current or a lifetime history of rapid cycling (Kirov et al., 1998). They
hypothesized that variation in the COMT gene modifies episode frequency.
Concurrently, Veit et al. (1998) presented new data suggesting that COMT activity
is subject to variability in humans, that this activity is associated with episode
frequency, and that low activity is primarily due to a G“A transition at codon 158.
63 Rapid-cycling bipolar disorder


Psychiatric patients with psychiatric illness in velocardiofacial syndrome (a genetic
condition caused by a microdeletion of chromosome 22q11, which includes the
COMT gene) were studied. Of 8 patients studied, 100% were found to have
COMTmet polymorphism on the complementary chromosome 22. It was hypothe-
sized that, since the blockade of catecholamine reuptake by tricyclic antidepressants
and the blocking of breakdown by monoamine oxidase inhibitors have been asso-
ciated with the induction of mania, homozygosity for COMT158met predisposes to
rapid cycling, and possibly represents a risk factor in the use of antidepressants as well.
This study examined the frequency of COMT 158met in 60 rapid cyclers. Of the 60
ultrarapid cyclers enrolled, four had been genotyped at the time of this publication,
and all four were homozygous for COMT158met (the low-activity allele), supporting
the hypothesis that the presence of this allele may alter the course of bipolar disorder.
In addition to the above-mentioned data, attempts to explore any genetic
correlation with susceptibility to rapid-cycling bipolar disorder have continued
(Jones and Craddock, 2001; Cusin et al., 2001). Some of the genes of particular
interest include those encoding the serotonin transporter, monoamine oxidase
A (MAOA) and COMT (Jones and Craddock, 2001). Cusin et al. (2001) reported
results suggesting that the serotonin transporter gene-linked functional poly-
morphic region (5-HTTLPR) variants may confer susceptibility toward rapid-
cycling mood disorders. They retrospectively studied a sample of inpatients
affected by recurrent and rapid-cycling mood disorders. The serotonin transporter
gene-linked functional polymorphic region (5-HTTLPR) and the (A218C) tryp-
tophan hydroxylase (TPH) gene variant were determined using a polymerase
chain reaction-based technique. For 5-HTTLPR polymorphism, they genotyped
435 inpatients affected by major depressive (n ¼ 153), bipolar (n ¼ 213), and
rapid-cycling (n ¼ 69) mood disorders and 456 controls. For TPH, they genotyped
399 inpatients (mood disorder, n ¼ 132; bipolar, n ¼ 203; rapid-cycling, n ¼ 64)
and 259 controls. Random regression model analysis was used to investigate the
longitudinal time course of the illness. It was found that 5-HTTLPR and TPH
polymorphisms were not associated with a mood-disorder time course. However,
the researchers observed an excess of 5-HTTLPR* long alleles among rapid-cycling
subjects compared with both controls (P ¼ 0.018) and remitting mood disorders
(P ¼ 0.006). TPH frequencies did not differ between mood-disorder subtypes. Even
though the results of this study were not definitive, the large sample of subjects lent
it credibility. More studies are needed to duplicate or clarify these results.


Pathophysiology
Findings from neuroimaging studies continue to enrich our understanding of the
pathophysiology of mood disorders generally and rapid-cycling bipolar disorder
64 O. Elhaj and J. R. Calabrese


particularly (more on this topic can be found in Chapter 14). Brain involvement is
currently thought to include both cortical and subcortical areas (Benabarre et al., 2001;
Ketter et al., 2001; Schreiner et al., 2001). Ketter et al. (2001) studied the effects of
mood and subtype on cerebral glucose metabolism in treatment-resistant bipolar
disorder. Forty-three medication-free, treatment-resistant, predominantly rapid-
cycling bipolar disorder patients and 43 age- and gender-matched healthy control
subjects had cerebral glucose metabolism assessed using positron emission tomo-
graphy and fluorine-18-deoxyglucose. The results indicated that, when compared to
control subjects, depressed bipolar disorder patients had decreased global, absolute
prefrontal, and anterior paralimbic cortical, and increased normalized subcortical
(ventral striatum, thalamus, right amygdala) metabolism. Degree of depression
correlated negatively with absolute prefrontal and paralimbic cortical, and positively
with normalized anterior paralimbic subcortical metabolism. Increased normalized
cerebelloposterior cortical metabolism was seen in all patient subgroups compared to
control subjects, independent of mood state, disorder subtype, or cycle frequency.
It was noted that, in bipolar depression, a pattern of prefrontal hypometabolism
consistent with previous observations in primary unipolar and secondary depression
was observed, suggesting that this is part of a common neural substrate for depression
independent of etiology. In contrast, the presence of cerebelloposterior cortical
normalized hypermetabolism seen in all bipolar subgroups (including euthymic)
suggests a possible congenital or acquired trait abnormality. However, the degree to
which these findings in treatment-resistant, predominantly rapid-cycling patients
pertain to community samples remains to be established. More studies with larger
sample size are needed to generalize these interesting findings.
The potential relationship between the rapid-cycling pattern of bipolar disorder
and the circadian rhythm continues to draw attention. Schreiner et al. (2001)
described (in a case report) the sleep and sleep“wake cycle of an 81-year-old
patient with de novo ultrarapid-cycling bipolar disorder. Mood was self-rated
daily over a period of 10 weeks. Additionally, polysomnographic and motor
activity recordings were performed during a drug-free baseline period. The
researchers noted that both depressive and hypomanic episodes had an average
duration of about 30 h. They concluded that the affective cycle was thus indepen-
dent from the sleep“wake cycle. When mood shifts occurred during night time,
sleep was different in nights following depression than in nights following hypo-
mania. Positron emission tomography revealed a moderate bilateral frontal hyper-
metabolism in the hypomanic phase and yielded normal findings for the
depressive stage. In contrast to what is usually expected in ultrarapid-cycling
bipolar disorder, this case demonstrated, according to the authors, an unusual
sleep-unrelated cycle duration in the oldest reported patient so far. However, the
generalizability of this case report™s findings would still be limited.
65 Rapid-cycling bipolar disorder


On the other hand, Weske et al. (Weske et al., 2001; Voderholzer et al., 2002)
reported the neurobiological findings in another patient with 48-h rapid-cycling
bipolar affective disorder. Alternating reduction and prolongation of sleep dura-
tion during manic and depressive days were found, as well as differences in the
amount of rapid-eye-movement sleep. Cortisol secretion was regularly increased
during depressive days. Regarding thyroid-stimulating hormone (TSH) secretion,
the circadian rhythm was absent on depressive days. However, the glucose meta-
bolic rate, as measured by positron emission tomography, did not differ on manic
and depressive days.
In an attempt to study any electrophysiological correlation with mood pattern,
Kudo et al. (2001) conducted a comparative analysis of 13 patients with epilepsy.
Ten of these patients had fluctuating mood disturbances, and eight had rapid
cycling of mood episodes. The researchers reported that an epileptogenic zone in
the frontal and temporal lobes seems to play an important role in the mood
episodes of the majority of patients with epilepsy.



Epidemiology, phenomenology, and comorbidity
While most researchers continue to consider rapid-cycling bipolar disorder as a
distinct and more challenging subtype of bipolar disorder in adults and children
(Findling and Calabrese, 2000, Sachs et al., 2000b, Calabrese et al., 2001; Findling
et al., 2001, Ketter and Calabrese, 2002; American Psychiatric Association, 2002),
a few still argue that in 20% it more likely represents a transient complication of
the long-term course of bipolar disorder (Akiskal et al., 2000).
On the other hand, the depressive phase continues to be the hallmark of this
subtype and presents a challenge for the patient and the clinician (Calabrese et al.,
2001, 2002). Perugi et al. (2000) published the results of a systematic retrospective
investigation of 320 patients with established bipolar I disorder. They examined
the past course on the basis of polarity at onset (depressive, mixed, and manic),
and found that depressive onsets were the most common, accounting for 50%,
followed by mixed and manic onsets in about equal proportions. In general, the
polarity of episodes over time reflected polarity at onset. Those with depressive
onset had significantly higher levels of rapid cycling, as well as suicide attempts,
but were significantly less likely to develop psychotic symptoms. Mixed onsets,
too, had high rates of suicide attempts, but differed from depressive onsets in
having significantly more chronicity yet negligible rates of rapid cycling at follow-
up evaluation. Because cases with depressive onset had received significantly
higher rates of psychopharmacologic treatment, the authors concluded that their
data were compatible with the hypothesis that antidepressants may play a role in
66 O. Elhaj and J. R. Calabrese



Table 3.1 Current episode type and number of previous episodes

Depresssive mania Rapid cycling

No Yes No Yes

Manic 11 71 41 94 02

24 21 22 16
>11

40, P < 10À6
2 1.3, P ¼ 0.25

Depressive 4 42 31 58 04

30 27 33 14
>4

2 0.3, P ¼ 0.6 8.9, P < 0.003




the induction of rapid cycling. They suggested that their data support the existence
of distinct longitudinal patterns within bipolar I disorder, which in turn appear to
be correlated with the polarity at onset. In particular, rapid-cycling and mixed
states emerge as distinct psychopathologic processes. These data further confirm
the notion of rapid cycling as a distinct pattern of bipolar disorder.
Swann et al. (2000) indicated that, in their study of inpatients in parallel
groups “ double-blind comparison of lithium, divalproex, or placebo “ there
was a tendency for subjects with four or more previous depressive episodes to be
women (25 of 57 were women versus 20 of 70 with three or fewer episodes,
2 ¼ 3.2, P ¼ 0.07). They also reported a highly significant increase in the occur-
rence of rapid-cycling bipolar disorder in subjects with a history of more than eight
manic episodes or four depressive ones (Table 3.1).
Reports on the prevalence of rapid cycling continue to show that significant
proportions of patients with bipolar disorder suffer from a rapid-cycling course.
Suppes et al. (2001) indicated that a prevalence rate higher than 24% is reported
for rapid-cycling bipolar disorder when minimum duration criteria are dropped
and patients with ultrafast rapid cycling are included. This notion of changing
prevalence rates depending on the inclusion criteria of rapid cycling draws the
attention back again to the potential need to revise the current nomenclatures and
their definitions (Maj, 2001).
The phenomenology of rapid-cycling bipolar disorder in children has received
much attention (Findling and Calabrese, 2000; Findling et al., 2001; Chang and
Ketter, 2001; Geller et al., 2001; Schraufnagel et al., 2001). Mostly, the findings
indicated the high prevalence of rapid cycling in this population, as well as its poor
prognosis.
67 Rapid-cycling bipolar disorder


Bringing attention to the high prevalence of rapid cycling among children with
bipolar disorder, Findling et al. (2001) studied 90 youths between the ages of 5 and
17 years meeting full diagnostic symptom criteria for bipolar disorder I (BP-I).
Researchers found that the clinical presentation of BP-I was similar in children and
adolescents. BP-I was found to be a cyclic disorder characterized by high rates of
rapid cycling (50%) with almost no interepisodic recovery. These data suggest that
the presentation of juvenile BP-I is a cyclic and valid clinical condition with
manifestations on a continuum with the later-onset forms of this illness.
Geller et al. (2001) reported the results of a study about 1-year recovery and

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