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de/ kai/ o)rghloi/ prosgi/gnontai a)lo/gwj, ou) tini/ e)p= ai)/tih du/squmoi, a)/grupnoi, e)k tw=n
u(/pnwn e)kqorubou/menoi.
The symptoms [of melancholia] are not unclear: [the melancholics] are either quiet or
dysphoric, sad or apathetic. Additionally, they could be angry without reason and
suddenly awake in panic (van Kappadokien, 1847).

Also, he described a phenomenological polymorphism of mania in Chapter 6 of
his first book On the Causes and Symptoms of Chronic Diseases as follows:

Kai/ oi(=si me/n h(donh/ v) mani/h, gelw=si, pai/zousi, o)rxeu/ontai nukto/† kai/ h(me/rh†,
kai/ e)† a)gorh/n a)mfado/n kai/ e)stemme/noi kote/, o(/kw† e)c a)gwni/h† nikhfo/roi, e)ci/asi.
a)/lupo† toi=si pe/la† h( i)de/h. Metece/teroi de/ u(po/ o)rgh=† e)kmai/nontai . . . i)de/ai de/
mu/riai. Toi=si me/n ge eu)fu/esi te kai/ eu)maqe/si a)stronomi/h a)di/daktoj, filosofi/h
au)toma/th, poi/hsi† dh=qen a)po/ mouse/wn.
Some patients with mania are cheerful “ they laugh, play, dance day and night, and
stroll through the market, sometimes with a garland on their head, as if they had won
a game: these patients do not worry their relatives. But others fly into a rage . . . The
manifestations of mania are countless. Some manics, who are intelligent and well
educated, deal with astronomy, although they never studied it, with philosophy, but
autodidactically, they consider poetry a gift of muses (van Kappadokien, 1847).

The problem of the polymorphism of mania is also reflected in the writings of the
Roman physician Caelius Aurelianus trying to describe the etymology of the word
˜˜mania™™. In his book On Acute Diseases. (Chapter 5), Caelius Aurelianus, a
member of the Methodist school and student of the Soranus of Ephesos, gave at
least six possible etymologies of the word ˜˜mania.™™ The fact that he was able to do
so demonstrated the many meanings of the term. He wrote:

The school of Empedocles holds that one form of madness consists of a purification of the soul,
and the other of an impairment of the reason resulting from a bodily disease or indisposition. It
is this latter form that we shall now consider. The Greeks call it mania because it produces great
mental anguish (Greek ania); or because there is an excessive relaxing of the soul or mind, the
Greek word for ˜˜relaxed™™ or ˜˜loose™™ being manos; or because the disease defiles the patient, the
Greek word ˜˜to defile™™ being lymaenein; or because it makes the patient desirous of being alone
and in solitude, the Greek word ˜˜to be bereft™™ and ˜˜to seek solitude™™ being monusthae; or
because the disease holds the body tenaciously and is not easily shaken off, the Greek word for
˜˜persistence™™ being monia; or because it makes the patient tough and enduring, Greek hypome-
neticos™™ (Caelius Aurelianus, translated by Drabkin, 1950).
6 A. Marneros and F. K. Goodwin


The first descriptor of manic-depressive illness as one entity “ one disease with
two opposite symptomatological constellations “ was Aretaeus of Cappadocia
(Marneros, 1999, 2001; Angst and Marneros, 2001; Marneros and Angst, 2000).
His descriptions of the boundless developments of melancholia into mania led to
the thinking that there is not only a ˜˜switch™™ but also a ˜˜mixture™™ of symptoms.
In his books: On the Aetiology and Symptomatology of Chronic Diseases
and The Treatment of Chronic Diseases, he wrote: Doke/ei te/ de/ moi mani/hj ge
e)/mmenai a)rxh/ kai/ me/roj h( melagxoli/h : ˜˜I think that melancholia is the begin-
ning and a part of mania™™ and: ˜˜oi( de/ mai/nontai, au/)cv th=j nou/sou ma=llon,
h) a)llagv= pa/qeoj ™™: ˜˜The development of mania is really a worsening of the
disease [melancholia], rather than a change into another disease.™™ And some
sentences later: ˜˜Hn de e)c a)qumi/hj a/llote kai/ a)llote dia/xusij ge/nhtai, h(donh/
) /
prosgi/gnetai e)pi/ toi=si plei/stoisi! oi( de/ mai/nontai™™: ˜˜In most of them
[melancholics], the sadness became better after various lengths of time and
changed into happiness; the patients then develop a mania.™™
Ideas similar to those of Hippocrates and Aretaeus of Cappadocia were also
presented by many other classical Greek and Roman physicians, such as
Asclepiades (who established Greek medicine in Rome), Aurelius Cornelius
Celsus (who translated the most important Greek medical authors into Latin),
Soranus of Ephesos and his scholar Caelius Aurelianus (who extensively recorded
the views of his teacher on phrenitis, mania, and melancholia), and later Galenus
of Pergamos. All of these physicians focused their interest on mental disorders,
especially melancholia and mania (Alexander and Selesnick, 1966; Fischer-
Homberger, 1968).

From Heinroth to the psychopharmacological revolution
As Koukopoulos and Koukopoulos (1999) pointed out, the nosologists of the
eighteenth century, such as Lorry, Boissier de Sauvages, and William Cullen, have
already classified among the melancholias such forms as melancholia moria,
melancholia saltans, melancholia errabunda, melancholia silvestris, melancholia
furens, and melancholia enthusiastica, which are in fact ˜˜mixed™™. But the scientific
description really began in the 19th century (Marneros, 2001).
Perhaps the first psychiatrist to systematically describe mixed states was the
German professor of psychiatry Johann Christian August Heinroth (1773“1843).
He was the first professor of ˜˜Mental Medicine™™ at a German university (Leipzig).
In his textbook Disorders of Mental Life (1818) he classified mental disorders into
three voluminous categories:
The first category comprised the exaltations (hyperthymias). The second cate-
gory embraced the depressions (asthenias), and the third category, the mixed
states of exaltation and weakness (hypo-asthenias) (Heinroth used the
7 Beyond major depression and euphoric mania



Table 1.1 Mixture of exaltation and depression according to Heinroth, 1818

Hyper-asthenias

First group: mixed mood disorders (animi morbi complicati)
1. Ecstasis melancholica
2. Melancholia moria
3. Melancholica furens
4. Melancholia mixta catholica

Second group: mixed mental disorders (morbi mentis mixti)
1. Paranoia anoa
2. Paranoia anomala
3. Paranoia anomala maniaca
4. Paranoia anomala catholica

Third group: mixed volition disorders (morbi voluntatis mixti, athymia)
1. Panphobia, melancholia hypochondriaca
2. Athymia melancholica
3. Athymia paranoica
4. Athymia melancholico-maniaca




German word ˜˜Mischung™™, which can be translated as ˜˜mixture™™). This last
category of mixed states was divided into mixed mood disorders (animi morbi
complicati), mixed mental disorders (morbi mentis mixti), and mixed volition
disorders (morbi voluntatis mixti), as shown in Table 1.1. It is evident that
mainly in the categories ˜˜mixed mood disorders™™ and ˜˜mixed volition disorders,™™
mixed affective and schizoaffective disorders according to modern definitions
are involved.
In addition to the above-mentioned mixed states, Heinroth described the pure
forms of exaltation (hyperthymias), including melancholia erotica and melancholia
metamorphosis. Melancholia saltans, however, is defined by Heinroth as a form of
mania (Fig. 1.3).
The French psychiatrist Joseph Guislain described in his book Treatise on
Phrenopathias or New System of Mental Disorders (1838) a category of mixed states
named ˜˜joints of diseases.™™ To this category, he allocated ˜˜grumpy depression,™™
˜˜grumpy exaltation,™™ and ˜˜depression with exaltation and foolishness,™™ which also
included ˜˜depression with anxiety.™™ The first type, especially, features long epi-
sodes and an unfavorable prognosis (Guislain, 1838).
But the real author of what we today call mixed states is Emil Kraepelin (Fig. 1.4).
He distilled, conceptualized, and categorized previous knowledge regarding mixed
8 A. Marneros and F. K. Goodwin




Fig. 1.3 Johann Christian August Heinroth (1773“1843).




Fig. 1.4 Emil Kraepelin (c. 1900).
9 Beyond major depression and euphoric mania



Table 1.2 The development of Kraepelin™s concept of ˜˜mixed states™™

1893 1899 1904 1913

1. ˜˜Manic 1. ˜˜Manic state 1. ˜˜Furious mania™™ 1. ˜˜Depressive or anxious
stupor™™ with inhibition™™ (zornige Manie) mania™™ (depressive oder
¨ ¨
(manischer (manische Zustande angstliche Manie)
2. ˜˜Depressive
Stupor) mit Hemmung) excitation™™ (depres- 2. ˜˜Excited depression™™
2. ˜˜Depressive states sive Hemmung) (erregte Depression)
with excitation™™ 3. ˜˜Unproductive 3. ˜˜Mania with thought
¨
(depressive Zustande mania with poverty™™ (ideenarme
mit Erregung) thought poverty™™ Manie)
(unproduktive 4. ˜˜Manic stupor™™
gedankenarme (manischer Stupor)
Manie)
5. ˜˜Depression with flight
4. ˜˜Manic stupor™™ ¨
of ideas™™ (ideenfluchtige
(manischer Stupor) Depression)
5. ˜˜Depression with 6. ˜˜Inhibited mania™™
flight of ideas™™ (gehemmte Manie)
(Depression mit
Ideenflucht)
6. ˜˜Manic inhibition™™
(manische
Hemmung)


¨
states, as well as other mental disorders. Kraepelin used the term Mischzustande
(mixed states) or Mischformen (mixed forms) for the first time in the fifth edition
of his textbook (1896, p. 634), although, already in 1893, he had described the
˜˜manic stupor™™ (1 year after Kraepelin™s description of manic stupor, Dehio
referred to it during the 1894 meeting of ˜˜South-western German Alienists™™). He
practically completed their theoretical conceptualization in the sixth edition
(1899, pp. 394“399), although their final categorization and nomenclature came
with the eighth edition in 1913 (Table 1.2).
In the same year that Kraepelin™s sixth edition (1899) was published, Wilhelm
Weygandt (pupil and colleague of Kraepelin in Heidelberg) published the first
¨ ¨
book on mixed states in psychiatric literature: Uber die Mischzustande des
manisch-depressiven Irreseins (On the Mixed States of Manic-Depressive Insanity;
see Fig. 1.5).
Since Weygandt referred to the sixth edition of Kraepelin™s handbook as a
source, it can be assumed that Kraepelin™s handbook was published earlier in the
year or that Weygandt was familiar with his teacher™s manuscript. Kraepelin did
10 A. Marneros and F. K. Goodwin




Fig. 1.5 The first book in psychiatric literature on mixed states (Weygandt, 1899).
11 Beyond major depression and euphoric mania




Fig. 1.6 Wilhelm Weygandt (1870“1939).



not use the term ˜˜mixed states™™ per se in 1893; rather he noted that ˜˜the cases are
mixed™™ (pp. 366“7). But even before the first use of the term ˜˜mixed states™™ in
1896, Kraepelin described ˜˜manic stupor™™ (1893, pp. 366“7), later characterized by
him as the most convincing type of mixed state (1899, p. 396). In the final
description of mixed states (eighth edition of the handbook in 1913,
pp. 1284“303), Kraepelin defined six types (Table 1.2).
Although Kraepelin, as the one who clarified and systematized previous observa-
tions, is undoubtedly the definer of the concept, the work of Wilhelm Weygandt
(Fig. 1.6) makes it difficult to distinguish the respective roles of the two men with
regard to the development of the final concept. It is, however, beyond any doubt
that the clarification of former views, the systematic descriptions, and theoretical
formulations are the work of Kraepelin. Mixed states belonged to the core of
Kraepelin™s ˜˜manic-depressive insanity™™ (Koukopoulos and Koukopoulos, 1999;
Marneros, 1999; Marneros and Angst, 2000; Angst and Marneros, 2001). However,
12 A. Marneros and F. K. Goodwin


it can be assumed that the final clinical description, the categorization, and the
systematic gathering of data on the topic is the common work of both men.
¨ ¨
In his slim, 63-page monograph Uber die Mischzustande des manisch-depressiven
Irreseins (1899), Weygandt gives a very plastic description of mixed states in a style
very similar to that of Kraepelin. A year before the publication of his monograph,
Weygandt presented his findings during the 29th meeting of the South-western
German Alienists, held in Heidelberg on 27 November 1898. Weygandt™s con-
tribution was cited pedantically, including the exact time of the session (from
˜˜1.15 p.m. to 3.45 p.m.™™); perhaps a sign that it was the first oral presentation on
the subject of mixed states during a scientific conference. In his presentation
(published a year later, in 1899), Weygandt spoke about many possible types of
mixed states, three of which (˜˜manic stupor,™™ ˜˜agitated depression,™™ and
˜˜unproductive mania™™) he considered the most important (Weygandt, 1899).
Weygandt wrote in his book:

It is very common, both in the manic and in the depressive episodes of manic-depressive or
circular insanity, for there to be not only periods of time which are mostly without symptoms,
but also, often, hours or days when the symptoms switch to the opposite pole. So, during a
manic episode, euphoria can suddenly change into a deeply depressive mood, while the other
symptoms of exaltation, such as hyperkinesia and hyperactivity, distractibility and excitability,
logorrhea, and flight of ideas, persist; or after a month-long depression, suddenly a smile can be
observed on the face of the patient and the depressive mood can change for hours or days into a
high or manic mood, but without any change in psychomotor behavior, in the inhibition or,
sometimes, in the severe stupor. Less common, but actually frequent enough if observation is
careful, is a temporary change in psychomotor behavior while the affective aspects of the psychosis
continue without any change; the patients remain euphoric, but the manic excitability changes
into a psychomotor inhibition. Instead of tireless hyperactivity, the patients stay in bed, show
slowness of movement and little or no mutism. In patients with the phenomenological picture of
depression with stupor, one can sometimes observe a change to mild excitability, agitation and an
urge to speak lasting for hours or days, while the depressive mood continues.
Additionally, we have to consider one more pair of opposite symptoms, because this is the
only way that we can touch all the relevant points in their totality. Similar to the euphoric mood
and the psychomotor excitability for mania are also morbid changes in the domain of thinking,
the flight of ideas.
...
In depressive episodes, instead of flight of ideas, one sees thought inhibition.
These states, very well known, but because of their short duration, usually less noted, are a mix of
manic and depressive episodes of circular insanity (Weygandt, 1899, pp. 1“2).

Weygandt concluded:
The co-existence of the main symptoms of both typical episodes of manic-depressive insanity,
mostly only of short duration, is extraordinarily frequent: in some cases, the mixed states
13 Beyond major depression and euphoric mania

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