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Mania (n = 155) Mixed state (n = 143)
Fig. 2.3 Rates of mixed temperament (co-occurrence of at least three hyperthymic and three
depressive temperamental traits) in patients with pure mania and mixed state. Data from
Perugi et al. (1997).

temperaments coexist in a mixed-irritable form. Indeed, using a ˜˜mixed™™ thresh-
old of temperamental traits “ patients meeting the criteria of at least three or more
of both types “ we found that the MS group had a higher rate than the manic group
of such ˜˜mixed temperamental™™ traits (Fig. 2.3).
The EPIMAN study (Akiskal et al., 1998) validated the significantly higher rate
of hyperthymic temperament in classic mania, in contrast with the significantly
higher rate of depressive temperament in the mixed manic form; in addition, some
mixed manic patients could be characterized as cyclothymic. The fact that these
two temperaments have significantly higher female prevalence in the community
(Placidi et al., 1998) might explain the female preponderance of MS in clinical
populations. The instability generated from the concomitance of cyclothymic
traits on the one hand and mania on the other might explain the extreme affective
turmoil of these patients.
The relationship between affective temperaments and subtypes of mania has been
further investigated by Perugi et al. (2001c). In 155 patients with manic episode
according to DSM-IIIR criteria, those characterized by ˜˜euphoric“grandiose,™™
˜˜paranoid“anxious,™™ and ˜˜accelerated“sleepless™™ symptomatology were most likely
to belong to the hyperthymic temperament; those with more ˜˜depressive™™ symp-
toms had the highest rate of depressive temperament, and ˜˜irritable-agitated™™
features were high on both temperaments. These findings are consistent with the
56 G. Perugi and H. S. Akiskal

Table 2.6 Relationships between temperamental dispositions and affective episodes

Temperament Depression Mania

Hyperthymic Agitated Euphoric“paranoid
Depressive Inhibited Dysphoric“mixed
Cyclothymic Atypical“anxious Irritable“unstable“labile

Table 2.7 Relationships between temperamental dispositions and long-term complications
of manic-depressive illness

Temperament Bipolar II Bipolar I

Hyperthymic Rapid-cycling Chronic mania
Depressive Residual symptomatology Chronic mixed state
Cyclothymic Borderline features Continuous cycling (deteriorative)

hypothesis that the presence of different affective temperaments influences the
phenomenology of mania. Hyperthymic temperament seems to underlie the excited
pole with euphoric“accelerated-paranoid phenomenology; by contrast, the depres-
sive temperament seems to mute the expression of mania into a depressive“manic
phenomenology. Finally, patients with a constellation of the traits of both tempera-
ments seem to emerge as irritable“agitated manics with more severe symptomatol-
ogy and treatment refusal.
The foregoing findings and considerations suggest the model reported in
Table 2.6:
(1) The hyperthymic temperament underlying major depression produces
agitated depressive MS and, combined with mania, gives rise to pure
(2) The depressive temperament produces inhibited melancholic depression as
well as mixed mania (which, of all mixed states, probably best deserves the
designation of ˜˜dysphoric mania™™).
(3) The cyclothymic temperament underlies atypical depression or unstable“
labile mixed state.
As regards the long-term complications of manic depressive illness (Table 2.7),
we propose that the hyperthymic temperament is related to the development of
rapid cycling in bipolar II and chronic mania in bipolar I, the depressive tempera-
ment to residual symptomatology and chronic mixed states, and the cyclothymic
temperament to ˜˜borderline features™™ and/or to a deteriorating course of contin-
uous cycling.
57 Longitudinal perspective of mixed states

MS does not represent a mere superposition of affective symptoms of opposite
polarity, but a complex ˜process™ of temperamental, affective, and other processes.
Affective instability, fluctuation, lability, irritability, and diurnal variation “ all
sustained over a period of weeks “ emerge as the core phenomenologic features of
mixed bipolar states; perplexity, psychotic experiences, and grossly disorganized
behavior seem to arise from this protracted instability. Such instability in turn
appears to be the clinical expression of the neurophysiological dysregulation
believed to underlie manic depression (Delay, 1961; Goodwin and Jamison,
1990). MS might be considered the most eloquent expression of this dysregulation.
Hence the difficulties in clinical management and the high suicide potential
(Strakowski et al., 1996; Goldberg et al., 1998).
The foregoing phenomenologic considerations, which suggest considerable
broadening of the unstable terrain of mixed bipolar states beyond those of DSM-
IV, have important clinical implications. Although DSM-IV disqualifies phar-
macologic induction of mixed episodes from its definition of bipolar MSs, many
clinical investigators (Post and Kopanda, 1976; Himmelhoch, 1979;
Koukopoulos et al., 1992) have commented on how antidepressants, alcohol,
and stimulants could contribute to the genesis of MSs; regrettably, MSs in the
setting of such contributing factors are currently excluded from the MS rubric in
DSM-IV. The proper clinical recognition of depressive MSs would thus help in
the cause of preventing these patients from taking such drugs (Cassano et al., 1983;
Akiskal, 1994; Koukopoulos and Koukopoulos, 1999). Hypothetically, tempera-
mental dysregulation might underlie the exquisite sensitivity of these patients to
such substances (Akiskal, 1994). Such trait factors as depressive and hyperthymic
temperaments, when opposite to the polarity of superimposed affective episodes,
might in turn underlie the affective instability of mixed bipolar states.
Cyclothymic temperament appears to be more relevant to the labile instability of
bipolar II.
The proper identification of a depressive MS has critical implications for clinical
practice. These conditions might be confused with a number of other psychiatric
disorders, including unipolar agitated depression, delusional depression, schizo-
phrenia, borderline personality disorder, and organic mental disorder
(Himmelhoch et al., 1976; Secunda et al., 1985; Koukopoulos et al., 1992;
Akiskal and Mallya, 1987). Therefore, it would be important to distinguish MSs
from these conditions so that treatments (e.g., antidepressants) that might worsen
their symptomatology would be avoided, and treatments that might be particu-
larly effective (e.g., anticonvulsants, atypical antipsychotics, and electroconvulsive
therapy) would not go underutilized.
58 G. Perugi and H. S. Akiskal

Mixed states have re-emerged as a new focus of research in affective disorders,
and future investigations from other centers will be important in extending the
findings and conceptual advances described herein. Only one study (Cassidy et al.,
2001) has been published on the stability of MS over prospectively examined
follow-up of interepisode duration of 6 months. Therefore, prospective studies
will be particularly informative in future research on MS.


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Rapid-cycling bipolar disorder
Omar Elhaj1 and Joseph R. Calabrese2
Case Western Reserve University, University Hospitals of Cleveland, Cleveland, OH, USA
Case Western Reserve School of Medicine and University Hospitals of Cleveland, Cleveland, OH, USA


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