<<

. 28
( 68 .)



>>

In the eighth edition (Kraepelin, 1913), Kraepelin subsumed involutional mel-
ancholia into manic-depressive insanity, accepting the results of the catamnestic
investigation carried out by his student Dreyfus (1907) on Kraepelin™s same
patients in Heidelberg. In essence, Dreyfus showed that involutional melancholia
was a mixed state of manic-depressive insanity. In his foreword to Dreyfus™s
Melancholia, Kraepelin wrote with evident regret: ˜˜Nevertheless, it is to be foreseen
that the old clinical form of Melancholia, one of the oldest in psychiatry, will
completely disappear because it contains mainly manic-depressive features.™™ What
he could not have foreseen was that, by the end of the twentieth century, agitated
depression, which had replaced melancholia, in all likelihood would also lose its
status as a mixed state.
In the following decades, the concept of melancholia was replaced in European
psychiatry by the concept of endogenous depression and in the USA by the concept of
depressive reaction according to Meyer™s (1951) idea of reaction types. Under the
impact of DSM-III (American Psychiatric Association, 1980), the term major depres-
sion replaced worldwide the terms of melancholia, endogenous depression, and
161 Agitated depression: spontaneous and induced


depressive reaction. The term involutional melancholia remained in use for a long time,
and it was still present in DSM-II (American Psychiatric Association, 1968). It was
abandoned as the name of a separate entity in DSM-III, and the term melancholia was
relegated to a subclassification at the fifth digit: major depressive episode with mel-
ancholia: ˜˜a term from the past in this manual used to indicate a typically severe form
of depression that is particularly responsive to somatic therapy.™™ This subclassifica-
tion may be seen as an effort to preserve the oldest term in psychiatry. Certainly the
syndrome described here would have been called melancholia simplex in the past, but
it does not bring out the dramatic picture of anxiety, fear, rage, and delusional ideas
that have traditionally been associated with the term melancholia and are still seen in
clinical practice today. The term melancholia would have better suited the form
described as major depressive episode with psychotic features.
Another key shift in DSM-III was the introduction of the term bipolar disorder
in place of manic-depressive illness. In this regard, the authors fully share Jamison™s
(1995) view:

the word ˜˜bipolar™™ seems to me to obscure and minimize the illness it is supposed to repre-
sent . . . and it minimizes the importance of mixed manic and depressive states, conditions that
are common, extremely important clinically, and lie at the heart of many of the critical
theoretical issues underlying this particular disease.




Mixed affective states and agitated depression
Many authors clearly described mixed affective states well before Kraepelin,
including Lorry (1765), mania melancholica; Heinroth (1818), melancholia
mixta catholica, melancholia furens; Guislain (1852), melancholie maniaque;
and Griesinger (1845), melancholia with persistent excitement of the will.
Kraepelin conceptualized and described mixed states in a systematic way. He
made them the cornerstone of the manic-depressive entity. In conceiving the
manic-depressive mixed states, Kraepelin started from the excitement or depres-
sion of the three domains of psychic life: (1) the intellect (train of thought rather
than its contents); (2) mood; and (3) volition, expressed in psychomotor
activity.
Distinguishing between the foregoing three domains of psychic life has been a
constant idea in western culture and stems both from Plato™s (1994) three elements
of the soul “ rational, emotional, and appetitive “ and from Aristotle™s (1970)
psychic powers (faculties) “ rational, sensory, and appetitive. Via the equivalent
faculties of Kant (1800) “ the rational, the sense of pleasure or pain, and the
appetitive faculty “ these distinctions have had a great influence on psychiatry and
162 A. Koukopoulos et al.


the understanding and classification of psychic disorders as well as the conception
of mixed manic disorders in particular, as discussed later.
In the fifth edition of his textbook (1896), Kraepelin introduced the concept of
mixed states and described manic stupor. In the sixth edition (Kraepelin, 1899), he
presented the entity of manic-depressive insanity and described the mixed states:
mania with inhibition of thought, manic stupor, querulous mania, states of
transition, and depression with flight of ideas. In the seventh edition (Kraepelin,
1904), he introduced among the mixed states depressive agitation and mania with
poverty of ideas.
In the eighth edition of his textbook (Kraepelin, 1913), starting from mania,
which consists of flight of ideas, exalted mood, and hyperactivity, Kraepelin
described depressive or anxious mania. Flight of ideas is evident in the speech of
the patient, who continuously spins out thoughts and often shows a real passion
for writing. The mood is anxiously despairing and is manifested in great rest-
lessness and senseless pressure of activity. Ideas of sin and persecution or
hypochondriacal delusions are frequently present. The degree of excitement in
this condition is such that the noun mania seems appropriate, and, given the
prominence of anxiety, the adjective anxious seems more suitable than depressive.
This syndrome certainly comes close to the old melancholia agitata. The next
mixed state is excited depression (erregte Depression) with inhibition of thought,
great restlessness, and anxious and despondent mood. The difference between
these two syndromes is the presence of flight of ideas in the first and inhibition in
the second.
Although the previous two mixed forms originate, according to Kraepelin, from
a manic state, the third one originates from a state of depression and is called
depression with flight of ideas: ˜˜in a usual picture of depression, inhibition of
thought may be replaced by flight of ideas . . . They cannot hold fast their thoughts
at all; constantly things come crowding into their heads.™™ Kraepelin also states: ˜˜in
such cases we have to do with the appearance of a flight of ideas which only on
account of the inhibition of external movements of speech is not recognizable. The
patients are almost mute and are rigid in their whole conduct and are of cast-down
and hopeless mood.™™ As discussed later, in many cases there is, in fact, no
inhibition at all. The patient moves and talks freely and complains about crowded
thoughts, whereas the mood is despondent. These two Kraepelinian mixed states
seem similar to the present agitated depression, which is discussed later. Kraepelin
explained the coexistence of manic and depressive symptoms with the hypothesis
that the three areas of psychic function (mood, thought, and volition) do not
evolve in a synchronous way in mixed states. The frequent occurrence of mixed
states during periods of transition between two opposite phases lends support to
this hypothesis.
163 Agitated depression: spontaneous and induced


In 1888, Clouston from Edinburgh described excited motor melancholia, a term
that stresses the excitatory nature of the agitation. In 1899, a monograph appeared
on Mixed States of Manic Depressive Insanity by Kraepelin™s pupil Weygandt, based
on a study carried out in Heidelberg. He focused on only three types of mixed
state: manic stupor, unproductive mania, and agitated depression (agitirte
Depression) with depressed mood, psychomotor excitement, and flight of ideas.
This is the first time to the authors™ knowledge that the term agitated depression
was used. Weygandt pointed out the similarity with agitated forms of involutional
melancholia and, similar to Lange (1928), Specht (1908), and Thalbitzer (1908),
considered melancholia agitata a mixed state of manic-depressive insanity, in
contrast to Wernicke™s (1906) school of thought, which viewed it as a form of
anxiety psychosis.
Stransky, in 1911, wrote in Aschaffenburg™s handbook that the anxiety of
melancholia agitata, or depression with anxious excitation, does not contain
mixed elements. He also remarked that inhibition of thought is not always present
in manic stupor, and motor inhibition does not affect facial expressiveness. He did
not consider dysphoric mania a mixed state because the basic mood is an expan-
sive one.
In 1928, Lange discussed mixed states and noted that classic, pure clinical
pictures of mania or depression are rarely found. He recognized melancholia
agitata as a mixed state. Among the mixed states, he described a form that he
named excitable depression (anregbare Depression), marked by inner anxiety and
lack of motor agitation. Some patients present with inhibition of thought, and
some have flight of ideas. If they are somehow stimulated, these patients show
motor agitation and exaggerated expressive movements. Lange pointed out that
in many patients depressive mood and motor inhibition coexist with hyperactivity
of thought.
Interest in mixed states was waning by the 1920s. In 1923, Jaspers wrote that the
issue of mixed states ˜˜did not have any further development, and this was very
natural since elements of understanding psychology had been considered as
objective components and factors of psychic life.™™ Schneider (1962) was more
hasty: ˜˜We no longer believe in manic-depressive mixed states. Anyway, what may
look like this is a change or a switch, if it pertains to Cyclothymia at all.™™
On purely psychopathologic grounds, without any knowledge of the underlying
neuropathologic alterations, it is difficult to make significant progress in this field.
The present interest in mixed states is due to the adverse effects of antidepressants
and the beneficial effects of lithium, anticonvulsant mood stabilizers, and atypical
antipsychotics.
At present, agitated depression has lost its status as a mixed state, not only in the
DSM system, but also in the view of most psychiatrists worldwide. Apart from the
164 A. Koukopoulos et al.


impact of the conceptual shifts that are mentioned subsequently, another reason
may be the great efficacy of ECT in both agitated and retarded depression. The
nosologic differences between the two forms were probably overshadowed by the
similar therapeutic outcome. ECT is as effective (Gruber et al., 2000) or more
effective in agitated depression than on any other form of depression
(Koukopoulos et al., 1995). ECT is effective in both mania and depression
(Small, 1985). With the widespread use of antidepressants, coupled with the
diminishing use of ECT, the different response of agitated and psychotic depres-
sion has become increasingly clear. Agitated depression was considered a subtype
of major depressive disorder in the Research Diagnostic Criteria (RDC: Spitzer
et al., 1978) but was not carried over in DSM-IIIR (American Psychiatric
Association, 1987) or DSM-IV (American Psychiatric Association, 1994).
In the criteria of major depressive episode, agitation is listed as the fifth
symptom: ˜˜psychomotor agitation or retardation nearly every day (observable
by others, not merely subjective feelings of restlessness or being slowed down)™™
(American Psychiatric Association, 1994). This seems as if agitation and retard-
ation are equivalent symptoms.
Over the course of more than 2000 years, the disease entity melancholia has
become the syndrome agitated depression and now a symptom, agitation, of a
depressive episode. This evolution has had an enormous impact on therapeutic
approaches to depression. The kind of treatment is determined by the diagnosis of
a disease or a syndrome and less by a symptom. Thus, major depressive episodes
with or without agitation are treated in the same way, and the result is disastrous in
many cases of agitated depression. Both symptoms and course worsen.
A significant inverse symmetry may be seen in the evolution that occurred with
the concept of depression. In the beginning, it was a symptom that could be
present in many conditions. Ziehen (1902) objected to the term manic-depressive
insanity on the grounds that Kraepelin had conflated a disease, mania, with a
symptom, depression, and he proposed, as many others did, the term manic-
melancholic insanity. Then, in the entity manic-depressive insanity, depression
became a syndrome, the depressive phase of the illness. Today, depression is
understood as a morbid entity and every physician is entitled to offer antidepres-
sant treatment to nearly all patients with despondent mood diagnosed as meeting
the DSM-III criteria for a major depressive episode with or without agitation.
Agitated depression is not considered a mixed state in DSM-IV or in ICD-10. Most
psychiatrists (World Health Organization, 1992) today consider it a form of
depression with anxiety.
In recent years, a growing number of psychiatrists (Himmelhoch et al., 1976a;
Koukopoulos et al., 1989; Dell™Osso et al., 1991; Akiskal, 1992; Koukopoulos et al.,
1992; Swann et al., 1993; Bourgeois et al., 1995; Perugi et al., 1997; Benazzi, 2000)
165 Agitated depression: spontaneous and induced


have expressed disenchantment with the official view, proposing agitated depres-
sion as a mixed form of affective disorders. The DSM system opposes this view
because agitated depressives do not simultaneously meet the criteria for mania and
major depression. Schatzberg (1998) finds
a number of key differences in the seeming overlap of symptoms: manic or mixed patients
demonstrate a decreased need for sleep while agitated depressives complain of insomnia. The
bipolar patient has increased thinking and increased speech, while agitated depressives have
especially depressive ruminations and decreased speech. The increased motor activity of the
agitated depressive is purposeless and unpleasant, while in bipolar patients it is often aimed at
some grandiose goal.

One could object that the state of depression inevitably modifies the excitatory
symptoms and vice versa. The DSM system not only conceives a mixed state as an
overlap of manic and depressive symptoms, but also requires the rare simultan-
eous presence of a full manic and a full depressive syndrome. The symptoms of
agitated depression are of a different kind, as their response to treatment demon-
strates. The current interest in this topic stems from the clinical observation that
antidepressant drugs exacerbate agitation, insomnia, anxiety, and suicidal ideas in
these patients (Koukopoulos et al., 1992).


The parallelism between drive, mood, and thought
Normal human behavior, and especially behavior during affective episodes, has
created the impression that good mood is allied with good drive and fluent
thinking and vice versa. Hypomania with euphoric mood with hyperactivity,
and depression with retardation are typical examples of this parallelism. Cullen
(1785b), who ascribed the state of excitement and state of collapse (asthenia,
depression) to changes in nervous power, remarked that ˜˜these different states
of the brain are expressed in the body by strength or debility, alacrity or sluggish-
ness; and in the mind by courage or timidity, gaiety or sadness.™™
This bipolarity is certainly a clinical reality, but the mixture of elements of
excitement with elements of depression (inhibition) creates clinical pictures called
mixed states. These elements manifest themselves as symptoms and the clinical
pictures are syndromic sets of symptoms. As Goodwin and Jamison (1990) state,
˜˜mixed states can be broadly defined as the simultaneous presence of depressive
and manic symptoms.™™ Nevertheless, physicians cannot help associating them
with an underlying, analogous physiopathologic alteration that they try to modify
by treatment. Part of the problem lies in the term depression, which probably
displaced melancholia because it was thought to convey the meaning of a state of
mood rather than that of a disease entity. Clinicians and laypersons automatically
166 A. Koukopoulos et al.


relate such a state of depressed mood to lower activity of the nervous system, as
Cullen did, and physicians today prescribe antidepressants to most patients who
look and behave depressed, just as they prescribe antimanic medication for those
who behave in an excited way. This concept of depression being caused by lower
nervous activity is also borne out by the medical terms and popular expressions for
despondent mood in most languages: like the Latin depressio, the German nieder-
¨
gedruckt, the English downcast or down in the dumps, the French abattement, the
`
Spanish abatido, and the Italian essere giu, they all imply being low. Nosology and
therapy of the so-called functional psychoses can be based only on their phenomen-
ology, course, and outcome. The extensive use of effective psychotropic drugs,
however, sheds new light and provides meaningful information on the underlying
neurophysiologic conditions.
There is important clinical evidence, in fact, that excitatory brain processes may
cause despondent mood, anxiety, and symptoms of inhibition. Stages II and III of
mania, as described by Carlson and Goodwin (1973), with their dysphoric mood,
panic, and hopelessness, are a perfect example of a condition that phenomeno-
logically looks like a mixed state but neurophysiologically is a purely manic state,
and useful treatments are exclusively antimanic.
The same applies to dysphoric mania, which is still considered a mixed state
(Secunda et al., 1987; Post et al., 1989; McElroy, 1997). The useful treatments are
antimanic ones, and typically, under their effect, euphoria replaces dysphoria
before the patient becomes euthymic or depressed. A similar phenomenon may
occur between excitement and psychomotor inhibition. In manic stupor, there is
no inhibition of thought, as Kraepelin believed. The patient does not speak, but
when he or she recovers, the patient discloses that there were so many thoughts in
his or her head racing so fast that the patient could not utter them. Also in the few
cases of mania with poverty of ideas that the authors have seen, the patients have
reported that their heads were so full of thoughts that they could not express them
or hold a conversation. As with mood in dysphoric mania, here too the inhibitory
symptoms are solely due to an increase in the levels of excitement, and treatment is
exclusively antimanic. Should they really be considered mixed states?
The case of agitated depression is different. As discussed subsequently, elements
of clear excitement are bound together with authentic depressive elements. It is

<<

. 28
( 68 .)



>>