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Emerging concepts of mixed states:
a longitudinal perspective
Giulio Perugi1 and Hagop S. Akiskal2
University of Pisa, Pisa, Italy
University of California at San Diego and Veterans Administration Medical Center, La Jolla, CA, USA

Mixed state (MS) refers to an affective condition in which depressive and manic
symptoms are simultaneously present. It may manifest as a transitional condition,
bridging one phase of the illness with another, or may exist as an independent
clinical attack. In the latter case, along with mania and depression, MS represents a
major phase of manic-depressive illness; however, it is often misdiagnosed because
of its pleomorphic symptomatological presentation, as well as underdiagnosed
because of inadequate diagnostic delimitation. There is no terminological uni-
formity in the literature, and there is a regrettable tendency to use terms such as
˜˜mixed state,™™ ˜˜mixed mania,™™ ˜˜depression during mania,™™ and ˜˜dysphoric mania™™
interchangeably. In this chapter, we critically review the empirical literature on
different definitions of MS, focusing on their clinical validity. In doing so, we
devote special attention to the evolution of MS in the overall course of manic-
depressive illness.

Definition of bipolar mixed states
In the original description of MS given by Kraepelin (1899) and by his pupil
Weygandt (1899), one or more of the main psychopathological features of mania
(mood, cognition, psychomotor activity) were replaced by one or more of the
main features of depression, and vice versa. This approach led Kraepelin to
postulate six putative subtypes: (1) depression with flight of ideas; (2) excited
depression; (3) depressive-anxious mania; (4) unproductive mania; (5) inhibited
mania; and (6) manic stupor. In addition, Kraepelin described some specific
characteristics of MS, such as the tendency to become chronic and the frequent
presence of psychotic features (Table 2.1).
More recently, Berner et al. (1983, 1993) provided operational criteria (Vienna
research criteria) for MS based on the ˜˜dynamic™™ concept proposed by Janzarik
(1959). ˜˜Dynamic™™ in this context indicates a dimension of psychic life, biologically
Cambridge University Press, 2005.
46 G. Perugi and H. S. Akiskal

Table 2.1 Clinical features of mixed states

Opposite symptoms (in the domains of mood, thought, and psychomotility)
Psychotic symptoms (mimicking dementia praecox)
Course (periodicity, better prognosis than dementia praecox)
Personal and family history (manic-depressive illness)
Length of episode (more chronic than mania or depression) according to Kraepelin (1899)
and Weygandt (1899)

Table 2.2 Vienna criteria for stable mixed state according to Berner et al. (1993)

A. Appearance of persisting changes in affectivity, emotional resonance, or drive following a
period of habitual functioning:
1. Depressed, anxious, euphoric, expansive or hostile mood
2. Emotional resonance either lacking in or limited to depressive, manic, hostile, or
anxious responses
3. Persistent presence of a drive state contradictory to the mood state and/or the emotional
B. Biorhythmic disturbances:
1. Diurnal variations of affectivity, emotional resonance, or drive
2. Sleep disturbances (interrupted, prolonged, or shortened sleep or early awakening)

determined, deriving from an intimate mixture of the individual™s drive and emo-
tions. In an MS, the affective oscillations would be the result of dysregulation in this
process, giving rise to perplexity, indecisiveness, perceptual disturbances, and a sense
of external interference and depersonalization (Table 2.2). These characteristics are
specific to bipolar MS and cannot be derived from the mere combination of
depressive and manic symptomatology. The Vienna criteria thereby delineate a
mixed affective subtype with sustained instability characterized by the ˜˜persistent
presence of a drive state contradictory to the mood state and/or the emotional
resonance™™ (Berner et al., 1993, p. 164). This formulation emphasizes the emotional
instability of the MS, a feature shared with rapid cycling.
Diagnostic and Statistical Manual of Mental Disorders, 3rd edn revised (DSM-
III-R: American Psychiatric Association, 1987) basically defined MS as the sum of
manic and major depressive symptoms co-occurring over 1 week or longer, either
as the intermixing of the two opposite syndromes or their ultrarapid alternation
every few days. DSM-IV (American Psychiatric Association, 1994) essentially
retained the former pattern and, wisely, excluded the latter. There are several
problems with the DSM-IV concept of MS. First, the criteria do not consider
47 Longitudinal perspective of mixed states

cases in which expansive and depressive elements are combined without fully
satisfying the criteria for one or the other type of episode. Second, DSM-IV
stipulates an exclusion criterion that mixed symptomatology is ˜˜not due to the
direct physiological effects of a substance or a general medical condition™™ (DSM-
IV, p. 333). To evaluate if a mixed episode is a direct consequence of brain damage,
substance abuse and/or toxicity may be rather difficult; moreover, these conditions
are frequently reported in the personal history of patients with MS (Post and
Kopanda, 1976; Himmelhoch, 1979).
Tenth Revision of the International Classification of Diseases (ICD-10: World
Health Organization, 1992) gives a less strict definition, including, en passant, the
possibility of MS consisting of major depression plus hypomania (rather than full-
blown mania). But, like the DSM concept, it requires that ˜˜the diagnosis of mixed
bipolar disorder should be made only if the two sets of symptoms are both
prominent for the greater part of the current episode™™ (ICD-10, p. 119). In
addition, ICD-10 requires at least one past affective episode for the diagnosis of
MS, and therefore does not recognize that mixed symptomatology frequently
represents the first expression of a bipolar mood disorder.
In the last part of the past century, most research on MS has been focused on
manic states coexisting with some depressive features. These conditions are gen-
erally defined as ˜˜dysphoric mania™™ and variously considered as a subtype of
mania (Murphy and Beigel, 1974), a more severe manic state (Post et al., 1989),
or a transitional state between mania and depression (Bunney et al., 1972). In
the same period, the agitated depressive forms of MS, originally delineated by
Kraepelin (1899) and Weygandt (1899), and consisting of intrusions of psycho-
motor restlessness, hypersexuality, and racing thoughts into depression (Akiskal
and Mallya, 1987; Koukopoulos et al., 1992) have been relatively neglected. We
will consider both forms of MS in this chapter. We will also consider the hypoth-
esis that derives MSs from the intrusion of a temperament into an episode of
opposite polarity (Akiskal, 1992), i.e., depressive temperament into mania (manic
mixed state) and hyperthymic temperament into major depression (depressive
mixed state).

Dysphoric mania
We will first describe clinical research on dysphoric mania. A large literature
(Bauer et al., 1994; McElroy et al., 1995; Perugi et al., 1997; Swann et al., 1997;
Akiskal et al., 1998) is now available indicating that the DSM-IV threshold for
syndromal depression during mania is too restrictive, and suggesting that few
depressive symptoms would suffice in validating the clinical diagnosis of mixed
mania. The McElroy et al. (1992) operationalization of mixed mania (Table 2.3)
48 G. Perugi and H. S. Akiskal

Table 2.3 Cincinnati criteria for mixed mania according to McElroy et al. (1992)

A. A full manic syndrome by DSM-IIIR criteria
B. Simultaneous presence of at least three associated depressive symptoms
C. Simultaneous presence is defined as manic and depressive symptoms occurring at the same
time or alternating extremely rapidly, within minutes
D. Manic and depressive symptoms are simultaneously present for at least 24 h

DSM-IIR, Diagnostic and Statistical Manual of Mental Disorders, 3rd edn revised (American
Psychiatric Association, 1987).

conforms to the concept of dysphoric mania, i.e., mania plus at least three non-
manic depressive symptoms. Utilizing this definition, some distinctive features of
mixed mania compared with pure mania have been found: greater prevalence in
females, more past MS episodes, higher probability of an MS at onset, and higher
rate of comorbidity with obsessive-compulsive disorder (McElroy et al., 1995).
A similar definition of MS was used in the clinical Epidemiology of Mania
(EPIMAN) study, which was conducted in four centers in France, involving
over 100 patients (Akiskal et al., 1998). Because patients were entered into the
study on the basis of meeting full criteria for index manic episodes, the rates for
strictly defined DSM-IV mixed states were low (6.7%). But using a cut-off of
two or more depressive symptoms, 37% could be characterized as dysphoric
manic. As expected, these patients scored more than 10 on the modified
Hamilton-D (HAM-D) scale. Depressed mood and suicidal thoughts had the
best predictive diagnostic value for mixed mania. An important finding of this
study was that mixed manic patients, compared with those with pure mania,
had a higher percentage of depressive temperamental traits. Such data argue
that mixed mania can be defined categorically by two or more depressive
symptoms, psychometrically on the basis of HAM-D > 10, or dimensionally
on the basis of depressive (dysthymic) temperamental traits. The latter finding
supports the hypothesis that MSs arise when an affective episode is super-
imposed on a temperament of opposite polarity (Akiskal, 1992). Data along
these lines have also been reported in the Pisa“San Diego collaborative study
(Perugi et al., 1997, to be more fully discussed later in this chapter) and the Halle
study (Brieger et al., 2003).
The optimum number of depressive symptoms during mania in characterizing
MS has varied in the literature. McElroy et al. (1992) proposed a cut-off of 53,
Akiskal et al. (1998) 52, and Swann et al. (1997) 51 depressive symptoms in
the midst of mania for the diagnosis of MS. Defining this cut-off is not a mere
nosological exercise, because even one depressive symptom during mania seems to
predict low response to lithium and good response to divalproex (Swann et al., 1997).
49 Longitudinal perspective of mixed states

Table 2.4 Pisa“San Diego criteria for mixed state based on Perugi et al. (1997)

A. A state of sustained (at least 2 weeks) emotional instability and/or perplexity in which
depressive and manic symptoms are simultaneously present in a fluctuating manner.
Opposite extreme manifestations in at least two of the following five areas should be
present at the same time:
1. Mood (anxious“sad versus euphoric“irritable)
2. Thought flow (slowing versus racing)
3. Thought content (depressive versus expansive)
4. Perceptual disturbance (depressive versus expansive)
5. Motility (retardation versus acceleration)
B. At least two of the following:
1. Labile or hypersyntonic, i.e., heightened emotional resonance
2. Low threshold for anger“hostility, especially impulse dyscontrol
3. Major shifts in sexual drive from habitual baseline
4. Marked sleep disturbances
5. Diurnal variations of at least one of the items listed under A
C. Adequate interpersonal relationships and affective responses in the premorbid and/or
interepisodic phases

The mixed state so defined could, in addition, be characterized as ˜˜non-psychotic™™ or ˜˜psychotic™™
(in which case further specified as mood-congruent or-incongruent) by Diagnostic and Statistical


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