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Manual, 3rd edn revised (DSM-IIIR) criteria; ˜˜chronicity™™ refers to duration of at least 2 years; and
˜˜rapid-cycling™™ is to be used as a qualifier if the patient has had four or more episodes (of whatever
type) per year.

Toward a broader definition of mixed mania
As discussed, in the contemporary literature, bipolar MSs have been defined on the
basis of a combination of manic with depressive symptoms, varying primarily on
the basis of the minimum number of depressive symptoms required. In a col-
laborative study between the Department of Psychiatry at the University of Pisa
and the International Mood Center at the University of California San Diego
(Perugi et al., 1997), we developed a more specific set of MS criteria based on the
concepts of Kraepelin and the Vienna school (Table 2.4). These criteria include
psychotic and non-psychotic forms. Clinical, temperamental, and familial char-
acteristics of 143 patients so defined were compared with those of a group of 118
patients who met DSM-IIIR criteria for mania. The major finding of this study was
that MS as defined by DSM-III-R criteria identified only half of all mixed states
(Fig. 2.1). This subgroup conforms to the concept of dysphoric mania, which is the
prototype of MS in the current literature (Post et al., 1989; McElroy et al., 1992).
Kraepelin (1899) had described this entity as depressive-anxious mania. Our data
50 G. Perugi and H. S. Akiskal

mixed states

Hysterical psychosis
Mixed states and borderline states

Schizophreniform and
schizoaffective disorder
mixed state


Dysphoric mania
Fig. 2.1 The relationships of Kraepelinian, Vienna, and Pisa“San Diego mixed states (shaded area) to
Diagnostic and Statistical Manual, 4th edn (DSM-IV) mixed state and related entities.

also document the existence of at least two other forms of MS. The first one
(accounting for 26% of our patients) is best characterized as mania with fatigue
and indecisiveness. The second mixed bipolar form (17% of our patients) is best
described as agitated psychotic depression with pressure of speech and flight of
ideas. These two mixed subgroups, which do not meet DSM-IIIR criteria for
mixed bipolar episode, were well described by Kraepelin (1899) as, respectively,
˜˜inhibited-unproductive mania™™ and ˜˜excited depression with flight of ideas.™™
The results of the Pisa“San Diego collaborative study are in agreement with the
suggestions made by McElroy et al. (1992) that an MS can exist with full syndromal
mania and less than syndromal depression. In line with suggestions by Kraepelin
(1899), Weygandt (1899), Akiskal and Mallya (1987), and Koukopoulos et al.
(1992), we further delineated a mixed depressive state which consists of full
syndromal depression and less than syndromal mania.
The descriptions that we adopted from Kraepelin (1899) and the Vienna school
(Berner et al., 1993) seem to be more inclusive than those proposed in DSM-IV
and ICD-10 (Fig. 2.1). Indeed, utilizing these criteria we can redefine as MS a
substantial proportion of manic and major depressive episodes according to DSM
criteria. Some of the clinical pictures that could be defined as MS according to our
criteria are probably covered under the non-affective psychoses and borderline
personality disorder in DSM-IV and ICD-10. The validity of our broadly defined
subtypes of bipolar MS is supported by the fact that their family history and course
characteristics are essentially indistinguishable from those of the core dysphoric
mixed-mania group (Perugi et al., 1997). Moreover, our criteria appear useful in
detecting an MS even as a first episode. In fact, although the most frequent polarity
51 Longitudinal perspective of mixed states

Table 2.5 Differences between depressive mixed state and bipolar depression

Fewer number of episodes
Less cyclic course (no rapid cycling)
More likely to show mixed state at first episode
More previous mixed episodes
Longer duration of the current episode
Less interepisodic remission
More incongruent psychotic features
More agitation, irritable mood, pressured speech, and flight of ideas

Data from Perugi et al. (2001b).

of onset in our patient population was a depressive episode, MS represented the
onset of mood disorder in more than 40% of MS index patients. In this respect,
ICD-10 seems unduly restrictive in requesting at least one past affective episode.

Depressive mixed states
The depressive forms of MS are not included in the current official classificatory
systems and, until recently, were largely neglected in the current literature. In order to
characterize depression with mixed features, better we compared familial, demo-
graphic, clinical, and course characteristics of 32 patients with depressive MS accord-
ing to Pisa criteria and those of 36 patients with major bipolar depression (Perugi
et al., 2001b). The two groups had close similarities in clinical and sociodemographic
characteristics, including age, gender distribution, marital status, schooling, residence,
age at onset, age of first treatment, age of first hospitalization, percentage of chronicity
of the index episode, lifetime suicide attempts, and premorbid temperamental dis-
positions. First-degree family history for bipolar illness and other mental disorders was
also similar, except that for major depression, which was significantly more common
among the relatives of depressive MSs. These findings were in part foreshadowed in a
previous Pisa study of MSs from the female unit at our institute (Dell™Osso et al.,
1991), where an excess of depressive familial background had been observed in the
entire sample (that had not been divided into depressive and manic MS).
Depressive-MS patients can be distinguished from non-mixed bipolar depres-
sives by the fact that they have fewer episodes of longer duration, and frequently
begin their illness with a mixed episode (Table 2.5). Furthermore, as described by
Keller et al. (1986), the prognosis of MSs in terms of interepisodic symptoma-
tology is worse than in non-mixed depression. Concerning the symptomatolo-
gical picture, incongruous psychotic features were more common in depressive
MS compared to bipolar pure depressive patients. This observation is consistent
52 G. Perugi and H. S. Akiskal

with the view that MS does not represent a mere superposition of affective
symptoms of opposite polarity (Himmelhoch, 1979; Berner et al., 1983;
Akiskal and Mallya, 1987; Koukopoulos et al., 1992; Perugi et al., 1997; Akiskal
et al., 1998). Long-lasting affective instability emerges as the core phenomen-
ological features; from this protracted instability seems to arise perplexity,
psychotic experiences, and grossly disorganized behavior. This conclusion is
further substantiated by the HAM-D symptomatological profile where MS
patients report more cognitive disorders, agitation, and paranoid symptoms
with less motor retardation, somatic symptoms, and sexual disturbances com-
pared with bipolar pure depressives.
In agreement with previous clinical observations (Akiskal and Mallya, 1987;
Koukopoulos et al., 1992), the symptomatological profile of depressive MS is one
of agitated, mostly psychotic depression with irritable mood, pressured speech,
and flight of ideas. Akiskal and Mallya (1987) had reported that 25 patients
referred for treatment-resistant depression displayed subacute or chronic MSs,
apparently induced by tricyclic antidepressants; these mixed depressive states were
characterized by dysphoria, severe agitation, refractory anxiety, unendurable
sexual excitement, intractable insomnia, suicidal obsessions and impulses, and
˜˜histrionic™™ demeanor; they improved with antidepressant discontinuation
and initiation of lithium or carbamazepine. Koukopoulos et al. (1992) found that
45 patients with bipolar disorder suffering from a ˜˜mixed depressive syndrome™™ who
met DSM-IIIR criteria for major depression, but not for mania, deteriorated when
treated with antidepressants, experiencing increased agitation, insomnia and, in
some cases, suicidal impulses; these same patients responded to low-dose neurolep-
tics, lithium, anticonvulsants, and electroconvulsive therapy. Koukopoulos and
Koukopoulos (1999) have subsequently written a scholarly review on the clinical
rationale for the validity of the concept of agitated depression as an MS.

Bipolar II and unipolar depressive mixed states
The literature reviewed thus far pertains largely to mixed mania and agitated
depression observed among hospitalized and/or psychotic patients. We will now
consider depressive MS among outpatients with bipolar II and unipolar depres-
sion, which is even less studied. The high prevalence of hypomanic features in
depressed bipolar II and unipolar outpatients has recently been reported by
Benazzi (2000) and Benazzi and Akiskal (2001). The prevalence of full syndromal
hypomania among 70 outpatients with major depression was low (2.8%), but
three or more concurrent hypomanic symptoms were reported in 28.5% of the
sample. About half (48.7%) of bipolar II patients had three or more concurrent
hypomanic symptoms during major depression. Irritable mood, talkativeness, and
53 Longitudinal perspective of mixed states

distractibility were significantly more common in bipolar II than in unipolar
patients; racing thoughts were highly prevalent in both unipolar and bipolar II.
Among the (hypo)manic symptoms reported in depressive MS, flight of ideas,
racing thoughts, and distractibility belong to the same dimension of psychic
excitement. Increased mental activity (daydreaming, mental ruminations) has
been reported as one of the fundamental features of bipolar II ˜˜depression™™
(Akiskal et al., 1995; Perugi et al., 1998). Other hypomanic symptoms such as
euphoria and grandiosity, by definition, are too rare in depression to be utilized for
the selection of patients with depressive MSs, whereas irritability and restlessness
might be somewhat non-specific.
According to Akiskal and Benazzi (2003), unipolar depressives with depressive
MS might be classified into the bipolar spectrum, and must be considered
˜˜pseudo-unipolar.™™ The bipolar nature of these clinical pictures should, however,
be further confirmed. No prospective longitudinal studies explored whether
intraepisodic hypomanic symptoms during a depressive episode predict a diag-
nostic switch from unipolar depression to bipolar disorder. Clinical observations
suggest that unipolar depressive MS may not adequately respond to antidepres-
sants, and that the use of antidepressants for unipolar depressives with intra-
episodic manic symptoms may be causative in treatment resistance or lead to cycling
(Akiskal and Mallya, 1987; Koukopoulos et al., 1992). Well-designed controlled
trials with antidepressants versus mood stabilizers and/or other antimanic agents
should be conducted comparing unipolar depressives with and without intra-
episode excitatory symptoms.

Long-term aspects of mixed states
The literature on clinical and course characteristics of MS from Kraepelin
through the last decade of the past century has been masterfully reviewed by
McElroy et al. (1992). Alcohol abuse and neuropsychiatric conditions are com-
mon in MSs (Himmelhoch et al., 1976). MS has been best characterized in female
inpatients (Dell™Osso et al., 1991; Perugi et al., 1997; Akiskal et al., 1998), often
arising from a course of illness with more depressive than manic episodes and
with a tendency to repeat over time (Perugi et al., 2000). The available data
further suggest that MS patients, in comparison with mania and bipolar depres-
sives, more frequently begin their illness with a mixed episode and have fewer
episodes of longer duration (Perugi et al., 1997). The fact that MS is often the
first episode in the course of the illness seems to indicate that it cannot be
considered an end-stage or ˜˜malignant™™ denouement of the illness. Moreover,
MS and rapid cycling seem to be two independent manifestations of manic-
depressive illness (Perugi et al., 2000).
54 G. Perugi and H. S. Akiskal





Chronic episodes

Mania (n = 155) Depression (n = 165) Mixed state (n = 143)
Fig. 2.2 Rates of chronic episodes (length < 2 years) in bipolar patients. Data from Perugi et al.

The rate of chronic episodes, defined as a duration of the current episode lasting
more than 2 years, seems to be higher in MS than in mania and major depression
(Perugi et al., 2000; Fig. 2.2). Frequent chronic evolution was reported by
Kraepelin (1899), in his original description, as a specific clinical feature of MS.
Furthermore, as described by Keller et al. (1986) and Perugi et al. (2001b), the
prognosis of MSs in terms of interepisodic symptomatology is worse than that of
non-mixed episodes.
In considering the frequent coexistence of MS with long-lasting subaffective
symptomatology, the role of temperamental disposition in the development of MS
is a relevant factor (Akiskal, 1992). Affective temperaments, as conceived in the
classical psychiatric literature (Kraepelin, 1899; Kretschmer, 1936) and more
recently formulated (Akiskal et al., 1979), refer to subaffective trait expressions
that represent the earliest subclinical trait phenotypes of affective disorders, and
which persist as the subthreshold interepisodic phase of these disorders. The
identification of depressive, hyperthymic, cyclothymic, and irritable temperamen-
tal attributes has important implications not only for the classification of mood
disorders, but also for their prevention, treatment, and prognosis.
We will now consider more fully the implications of the provocative hypothesis
that derives MS from a temperament opposite to the polarity of the affective
episode (Akiskal, 1992). Dell™Osso et al. (1991, 1993) have reported data in partial
support of this hypothesis. In our study (Perugi et al., 1997), mania seems to arise
from a hyperthymic background; by contrast, MS seems to arise from a depressive
or hyperthymic disposition and, more tentatively, when traits of the two
55 Longitudinal perspective of mixed states




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