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can occupy the entire episode or at least the greater part of its duration. Usually, it is the
later episodes that have the tendency to change to long-lasting mixed states. The course is
in many aspects somewhat more chronic than that of the pure manic or depressive episodes,
but in other ways, the prognosis regarding the recovery of the episode is exactly the same
(Weygandt, 1899, p. 63).

Weygandt explained the manifestation of mixed states as follows:

It is relevant to consider that the two symptom lines, i.e. euphoric mood, psychomotor
excitability and flight of ideas, on the one hand, and depressive mood, psychomotor inhibition
and thought inhibition, on the other hand, are not stable. But the disorders are characterized by
instability in the domain of mood, psychomobility and thought, and this is a characteristic of the
whole circular or manic-depressive insanity (Weygandt, 1899, p. 5).

The mixture of the three opposite pairs of symptoms mentioned above could
give rise “ according to Weygandt “ to the six possible types of mixed states
previously mentioned but occasionally, and only for a short period, perhaps
more than six. Three of the six types are most relevant: ˜˜We are forced by reasons
of practical psychiatry, because we are opposed to speculation, to distinguish and
describe only three groups of mixed states as the most relevant; they are the most
frequent and have the longest duration . . . manic stupor . . . agitated depres-
sion . . . and unproductive mania . . . ™™(Weygandt, 1899, p. 20). He used the
remaining two-thirds of his book to describe only these three types of mixed
states, not the other three possible types, which he mentioned but did not name
(pp. 20“36). In 1913, Kraepelin gave extensive descriptions of all six types of
mixed states (Table 1.2).
According to Koukopoulos and Koukopoulos (1999), Weygandt was the first
to introduce the term ˜˜agitated depression™™ (agitierte Depression) in his book,
although in fact the syndrome had been described by Frank Richarz (melancholia
agitans) more than 40 years earlier (1858). Weygandt himself quoted Richarz™s
paper in his book (pp. 41, 42). Koukopoulos and Koukopoulos™ paper contains a
very interesting discussion on the origin and diagnostic placement of agitated
depression. The authors argue that agitated depression is in fact a form of mixed
state, as Kraepelin and Weygandt assumed. According to the opinion of Akiskal
and Pinto (2000), the term ˜˜hyperthymic depression™™ can more closely be asso-
ciated with mixed states than the term ˜˜agitated depression.™™
Kraepelin thought that the first three types of mixed states (˜˜depressive or
anxious mania,™™ ˜˜excited or agitated depression,™™ and ˜˜mania with thought
poverty™™) were based on the three fundamental symptoms of mania, namely flight
of ideas, euphoria, and hyperactivity (Fig. 1.7). A depressive or anxious mania can
arise if two of the three basic symptoms of mania, namely flight of ideas and
hyperactivity, are present, but euphoria is replaced by depressive mood. If,
14 A. Marneros and F. K. Goodwin




Fig. 1.7 The modus of manifestation of mixed states of manic-depressive insanity (according to
Kraepelin, 1913).




additionally, the symptom flight of ideas changes to inhibition of thought, only the
hyperactivity remains as a manic symptom and, thus, ˜˜excited™™ or ˜˜agitated
depression™™ can arise. Mania with thought poverty occurs if poverty of thought
is associated with the manic symptom euphoria and perhaps also hyperactivity.
The basis of the next three types of mixed states “ according to Kraepelin “ is
the fundamental symptomatology of depression, namely ˜˜inhibition of thought,™™
˜˜depressive mood,™™ and ˜˜weakness of volition.™™ ˜˜Manic stupor™™ (which for
Weygandt is the most important type of mixed state and for Kraepelin the most
convincing) arises when depressive mood is replaced by ˜˜euphoria,™™ but depressive
thoughts and lack of will or abulia persist. ˜˜Depression with flight of ideas™™ comes
into being when the poverty of thoughts is replaced by flight of ideas, while the two
other basic symptoms of depression (depressive mood and abulia) continue. If, in
addition to flight of ideas, depressive mood changes to euphoria, ˜˜inhibited mania™™
arises. Kraepelin separated inhibited mania from manic stupor because flight of
ideas is absent in manic stupor, but present in inhibited mania.
15 Beyond major depression and euphoric mania


Kraepelin distinguished two groups of mixed states: (1) transitional forms,
a stage in between, when depression changes to mania and vice versa; and
(2) autonomic forms, a disorder on its own. Between these two groups relevant
differences exist. The autonomic group is characterized by Kraepelin as the most
unfavorable form of manic-depressive insanity. The course is longer, with a
tendency to chronicity, and the individual episodes are longer than in other
types of manic-depressive insanity (Kraepelin, 1899, 1904, 1913; Weygandt,
1899) “ findings that were confirmed 100 years later. Also confirmed by some
modern studies are the findings of Kraepelin and Weygandt:
(1) Females are more frequently represented in groups of mixed states.
(2) Using broad definitions, more than two-thirds of patients with manic-
depressive illness have a mixed state (usually a transitional form) at least
once. Even when using narrow definitions, approximately 20% of them
experience mixed states (as many modern authors have also found, for
example, see Winokur et al., 1969; Himmelhoch et al., 1976a, b; Akiskal and
Puzantian, 1979; Goodwin and Jamison, 1990; Marneros et al., 1991a, b,
1996a, b; Akiskal, 1992; Himmelhoch, 1992; McElroy et al., 1995, 1997;
Swann et al., 1995, 1997; Akiskal and Pinto, 2000)
But even during the period after Kraepelin, in which the relevance of mixed states
faded in scientific literature, many influential psychiatrists, such as Johannes Lange
(1928) in Germany and Campbell (1953) in the English-speaking countries,
continued to emphasize the relevance of mixed states.
J. D. Campbell, in his book Manic-Depressive Disease: Clinical and Psychiatric
Significance, which was published exactly at the beginning of the psychopharma-
cological revolution, but before its consequences, namely in 1953, emphasized the
conceptual significance of mixed states in a way very similar to Kraepelin and
Weygandt:

The mixed type of manic-depressive psychosis epitomizes the entire cyclothymic process, in that
it contains the symptoms characteristic of the various phases. Whether it is a sustained reaction
or represents a phase of metamorphosis between the major forms, the mixed type emphasizes
the underlying similarities between the depressive and hypomanic, the fact that the manic and
depressive reactions may be superimposed, and that the same individual possesses the potenti-
alities for either form.



The renaissance of mixed states
The renaissance of mixed states began in the USA at the end of the 1970s and the
beginning of the 1980s as a consequence of the pharmacological revolution in
psychiatry, especially through the contributions of Winokur et al. (1969), Kotin
and Goodwin (1972), Himmelhoch et al. (1976a, b), Akiskal et al. (1979), Akiskal
16 A. Marneros and F. K. Goodwin


(1981, 1992, 1997), Secunda et al. (1987), Goodwin and Jamison (1990),
Himmelhoch (1992), McElroy et al. (1992, 1995, 1997, 2000), Swann et al.
(1995), and Akiskal and Pinto (2000). The cooperation between the groups of
Akiskal and Cassano led to the Memphis“San Diego“Pisa study on mixed states
(Dell™Osso et al., 1991). The work of Cassano et al. (1992) as well as that of the
Perugi group in Pisa (end of 1997), Koukopoulos and Koukopoulos (1999),
Koukopoulos et al. (1992, 1995) in Italy, and Bourgeois and colleagues in France
(1995) supported this renaissance.
An interesting enrichment was introduced by Hagop Akiskal (Akiskal, 1981,
1992; Akiskal and Mallya, 1987; Akiskal and Pinto, 2000). He suggested a mixing of
manic or depressive symptoms with cyclothymic, hyperthymic, or depressive
temperament. The seed of this idea can be found in Griesinger (1845, p. 205),
adapted later by Kraepelin (1913). The mixing of symptoms and temperament can
give rise, in Akiskal™s view, to three different types of mixed states:
(1) Type B-I: ˜˜depressive temperament þ psychosis™™
(2) Type B-II: ˜˜cyclothymic temperament þ depression™™
(3) Type B-III: ˜˜hyperthymic temperament þ depression™™
The Pisa“Memphis collaborative study (Dell™Osso et al., 1991) on the tempera-
ment and course of mood disorders of over 200 classical B-I manic-depressive
patients suggests that B-I mixed states are typically psychotic, often mood-
incongruent, and seem to arise from a depressive temperament. The clinical
picture is in conformity with Kraepelin™s classic description of a mixed state where
depression and mania coexist more or less syndromally. Its distinctive features
derive from the simultaneous occurrence of numerous signs and symptoms of the
two syndromes: crying, euphoria, racing thoughts, grandiosity, hypersexuality,
suicidal ideation, irritability and anger, psychomotor agitation, severe insomnia,
persecutory delusions, auditory hallucinations, and confusion (Akiskal and
Puzantian, 1979). Alcohol abuse, a not infrequently associated finding, can be a
contributory cause or a complication. B-I mixed states thus overlap with schi-
zoaffective conditions (Marneros and Tsuang, 1986) and with what in franco-
´´
phone psychiatry is labelled as bouffees delirantes.
B-II mixed states are typically non-psychotic and consist of cyclothymic intru-
sions into a retarded depression (Akiskal, 1981). That is, the unstable cyclothymic
background (Akiskal et al., 1979) serves to change the clinical phenomenology of
the depression. Thus, depressed mood, hyperphagia, hypersomnia, fatigue, and
low self-esteem can be mixed with racing thoughts “ which may manifest in spurts
of creativity, such as writing verses “ jocularity, angry outbursts, tension, rest-
lessness, impulsive hypersexuality, other evidence of uninhibited behavior, gam-
bling, or dramatic suicide attempts. Abuse of stimulants (including caffeine) and
of sedatives“hypnotics (including alcohol), either as sensation-seeking or attempts
17 Beyond major depression and euphoric mania


at self-treatment, are common comorbid conditions. These cases are then mis-
taken for borderline personality disorder, as shown by the University of Tennessee
research on over 200 probands studied to date (Akiskal and Pinto, 2000).
B-III mixed states are increasingly seen following the overzealous treatment of
retarded, seemingly unipolar depressions arising from a stable hyperthymic tem-
peramental background without hypomanic episodes. As reported by Akiskal and
Mallya (1987), based on a series of 25 cases, the end results of multiple anti-
depressant trials in these patients could manifest as follows: unrelenting dysphoria
and irascibility; agitation against a background of retardation; extreme fatigue
with racing thoughts; panic and insomnia; suicidal obsessions and impulses;
unendurable sexual excitement; histrionic countenance, yet genuine expressions
of intense suffering. Here, too, abuse of stimulants and alcohol is commonly
observed. These patients are often misdiagnosed as being agitated depressives
when symptoms are severe, or neurotic depressives when they are moderate in
intensity. It is here, according to Akiskal, that lithium ˜˜augmentation™™ works best.
(Lithium alone might work as well.) This highly refractory group of patients,
whose temperament is seriously compromised by the protracted ˜˜depression,™™
presents a major therapeutic challenge (Akiskal, 1992).
Another aspect of the evolution of the concept of mixed states is their extension
into the group of schizoaffective disorders. Marneros et al. have described the
frequency, clinical characteristics, and prognostic value of ˜˜schizoaffective mixed
episodes™™ (Marneros, 1989; Marneros et al., 1986, 1988a“c, 1989a“c, 1991a, b,
1996a, b, 2000). It seems that mixed states in schizoaffective disorders are not rare:
33% of bipolar schizoaffective patients in the Cologne study had at least one
schizomanic“depressive mixed episode during an average duration of illness of
25 years (Marneros et al., 1991a, b, 1996a, b). Unfortunately, however, no other
systematic investigations on this topic have been carried out with the exception of
the Halle Bipolarity Longitudinal Study (HABILOS), the preliminary findings of
which we present in this book.
The HABILOS showed that 32.2% of patients with bipolar schizoaffective
disorder have at least one mixed episode showing no significant difference from
the frequency of the pure bipolar affective disorder (Fig. 1.8). Additionally, the
study shows that schizoaffective mixed states are apparently the most severe type of
bipolar disorders in general (see Chapter 8).
It can be concluded that mixed states are well established. Diagnostic and
Statistical Manual of Mental Disorders, 3rd edn (DSM-III) (American Psychiatric
Association, 1980), DSM-III-R (American Psychiatric Association, 1987), and
DSM-IV (American Psychiatric Association, 1994), as well as Tenth Revision of
the International Classification of Diseases (ICD: World Health Organization,
1991) include definitions and diagnostic criteria. The modern definitions of
18 A. Marneros and F. K. Goodwin


Bipolar affective Bipolar schizoaffective
(n = 100) (n = 177)
Mixed Mixed
25.0% 32.2%




Non-mixed Non-mixed
NS
75.0% 67.8%

Fig. 1.8 Frequency of patients with mixed course in the Halle Bipolarity Longitudinal Study
(HABILOS). NS, not significant.



mixed states are similar to those of Kraepelin and Weygandt, who distinguished
between narrow (coexistence of the full symptomatology of a manic and a depres-
sive episode) and broad definitions (˜˜cardinal™™ depressive symptoms in manic
episodes, and vice versa). The modern definitions can be divided into three
groups:
(1) Broad definitions: the presence of single depressive symptoms within a manic
episode is considered sufficient for diagnosis of a mixed episode.
(2) Narrow or strict definitions: only the coincidence of the full symptomatology
of a manic and a depressive episode allows for the diagnosis of a mixed
episode. This category corresponds to the diagnostic criteria of ICD-10
(Table 1.3) and DSM-IV (Table 1.4).
(3) Moderate definitions: according to moderate definitions, the coincidence of
the full syndromes of mania and melancholia is not necessary. However, the
presence of either the depressive or manic syndrome is not sufficient. These
definitions demand prominent depressive symptoms within a manic syn-
drome, or vice versa. The Cincinnati, Pisa, and Vienna criteria belong to
this category (Berner et al., 1983; McElroy et al., 1992; Perugi et al., 1997).
McElroy et al. (2000) pointed out that numerous modern phenomenological
studies, including factor-analytic studies, have confirmed the occurrence of
depressive symptoms in mania, and have provided support for the hypothesis
that mixed mania (mania with depressive features) may be distinct from pure or
euphoric mania (mania without depressive features). Moreover, these studies
suggest that systems used to define mixed states should be broad and dimensional,
as well as categorical, rather than overly narrow. As Goodwin and Jamison (1990)
wrote, ˜˜in general, it is best to consider the depressive spectrum and the manic
spectrum as independent and capable of interacting in a variety of combinations
19 Beyond major depression and euphoric mania



Table 1.3 Demographics of rapid cycling (RC) versus non-rapid (NRC) bipolar disorder (BP-II)
(according to Kilzieh and Akiskal, 1999)

n Age % Female % BP-II

Study RC NRC RC NRC RC NRC RC NRC % RC

Dunner and Fieve (1974) 33 215 29 30 71 47 40 36 13
Koukopoulos et al. (1980) 87 347 70 57 82 43 20
Cowdry et al. (1983) 24 19 45 41 83 53* 56
Nurnberger et al. (1988) 29 29 86 53* 41 28 15
Wehr and Goodwin (1979) 51 19 30 27 92 44* 47 47
Coryell et al. (1992) 45 198 26 25 71 50* 36 18* 18
Lish et al. (1993) 45 44 39 82 64*
Maj et al. (1994) 37 74 43.3 37.7* 65 51.4 40.5 24.3 13.6
Bauer et al. (1994) 120 119 39.3 37.8 70 50.4 45 37.8

*P  0.05.

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