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7


Agitated depression: spontaneous and
induced
Athanasios Koukopoulos, Gabriele Sani, Matthew J. Albert,
Gian Paolo Minnai, and Alexia E. Koukopoulos
Centro Lucio Bini, Center for the Treatment and Research of Affective Disorders, Rome, Italy




Sometimes it is more ˜˜inward anxiety and trembling,™™ a painful tension; some-
times it is an anxious restlessness, which finds an outlet in the most varied gestures,
in states of violent excitement, and in heedless attempts at suicide. These moods
are most frequently found in the periods of transition between states of depression
and mania; they are, therefore, probably most correctly regarded as mixed states of
depression and manic excitability (Kraepelin, 1913).
The inner unrest is the constant thing, while the motor unrest is variable (Lewis,
1934).


Introduction
The greatest shortcoming of psychiatry is the near complete lack of knowledge
of the pathophysiological processes underlying our clinical entities. Kahlbaum
(1863) was the first to distinguish clearly between symptomatic clinical pictures
and the disease process that was responsible for them. Kraepelin took this concept
a step further and based the idea of the disease process (Vorgang) on the conditions
under which the disease starts, its course, and outcome. This method of clinical
psychiatry achieved the separation of manic-depressive illness from dementia
praecox. But the real identity of the pathophysiological process underlying the
clinical entities still remains obscure. Our psychiatric nosology is entirely based on
phenomenology and course.
We do, however, have important tools at our disposal, which are the psychoactive
drugs. The response to these drugs not only indicates the pharmacological action
of the drug itself but also provides important clues about the nature of the
neuropathologic process upon which the drug acts. Thus far we have not fully
profited from these responses to enhance our understanding of clinical entities
and improve our nosology. On the contrary, clinical entities are taken as firm
Cambridge University Press, 2005.
#
158 A. Koukopoulos et al.


points of reference and the response of a clinical syndrome to a drug is used to
qualify the action of that drug. For instance, if a number of depressed patients
improve on lithium or carbamazepine we conclude that these drugs have anti-
depressant properties. We do not question the nature of the processes that underlie
what we call depression according to our present nosology. Further, if a depressed
patient becomes agitated on antidepressants, it is labeled an adverse reaction
instead of considering it a potentially normal reaction of an excited or excitable
neuronal substratum: that we are in fact treating a mixed state. It does not occur to
us that in some cases what presents itself with depression of mood, anhedonia,
anxiety and other ˜˜depressive™™ symptoms may be linked to, or caused by, excitatory
processes.
A century and a half ago W. Griesinger had this intuition without the help of
modern psychopharmacology:

By using the expression ˜˜psychic depressive states™™ we did not mean to imply that the basic
nature of these states is inactivity and weakness and suppression (depression) of the psychic or
cerebral processes that underlie them. We have much more reason to assume that very intense
states of irritation of the brain and excitation of the psychic processes are very often the cause of
such states; but the end result of these (psychic and cerebral) states as far as mood is concerned is
a state of depression or psychic suffering. (Griesinger, 1861).

Agitated depression and psychotic depression are crucial issues today because their
nosological position as depressive states does not correspond to their response to
antidepressant treatments, which on the contrary may increase or induce agita-
tion, insomnia, and suicidal or other violent acts. Agitated melancholia and
agitated depression used to be considered mixed affective states but the
Diagnostic and Statistical Manual of Mental Disorders (DSM: American
Psychiatric Association, 1968, 1980, 1987, 1994) and ICO-10: International
Statistical Classification of Diseases and Related Health Problems (World Health
Organization, 1992) systems do not consider them as such. The main reason for
this was probably the very good response of these conditions to electroconvulsive
therapy (ECT). With the introduction of tricyclic antidepressants and selective
serotonin reuptake inhibitors, the poor response, in contrast to the beneficial
response of non-agitated and non-psychotic depressions, became clear. Actually,
antidepressant drugs may exacerbate these conditions, as we discuss in this
chapter, and as is well known among clinicians.


Melancholia agitata
From classical antiquity to the end of the nineteenth century, melancholia was
described in various forms, many of which would today be considered mixed
159 Agitated depression: spontaneous and induced


affective states. The first and one of the best descriptions of agitated melancholia is
found in Diseases II by Hippocrates (1988):
Anxiety: the patient feels something like a thorn stinging his innards. He flees from light and from
people, loves the dark and he is caught by panic . . . he is terrified and sees frightening visions,
dreadful nightmares and sometimes dead people. The disease attacks most people in spring.

Aretaeus (1735) stated that melancholics suffer from ˜˜violent rage and sadness and
awful dejection.™™ The nosologists of the eighteenth century, such as Boissier de la
Croix de Sauvages (1768) and Cullen (1785a), classified among the melancholias
such forms as melancholia phrontis, melancholia moria, melancholia saltans, mel-
ancholia errabunda, melancholia silvestris, melancholia furens, and melancholia
enthusiastica.
Heinroth (1818) abandoned the intellectualistic conception of melancholia and
¨
considered it a disease of the mood (Gemuth). In his classification of the morbid
conditions of the soul, he placed melancholia metamorphosis among states of
exaltation (hypersthenia), whereas among the manias he listed melancholia saltans.
Among the mixtures of exaltation with weakness (hyperasthenia), he cited ecstasis
melancholica, melancholia furens, mania melancholica, and athymia melancholico-
maniaca (timidity with melancholia and rage).
Griesinger (1845) considered melancholia a disease of the affects (intense,
altered emotional states), distinguishing them into two major classes: (1) the
expansive, affirmative ones, such as happiness, joy, and hope; and (2) the depres-
sive, negative ones, such as dejection, sadness, and fear. He placed rage in an
intermediate position between the two kinds of affect. Griesinger described,
among the states of mental depression, melancholia in the strict sense, melancholia
with destructive tendencies, and melancholia with persistent excitement of the
will. As noted earlier, he had the great insight that processes of cerebral excitation
may be the cause of psychic pain and depression. Griesinger saw the cause of
melancholia in a state of hyperesthesia, and Kahlbaum (1863) saw the cause in a
state of hyperthymia. As Schmidt-Degenhardt (1983) points out, there is an
evident contrast with the concept of depression, which implies suppression or
weakening of brain processes.
The first to use the term melancholia agitans was Richarz in 1858 in his
remarkable work On the Nature and Treatment of Melancholia with Excitement
(Melancholia Agitans), in which he differentiates ˜˜racing thoughts™™ of agitated
melancholia from the flight of ideas of mania. He introduced the term melancholia
agitans instead of melancholia activa because it better suited the aimless rest-
lessness of the patient. More commonly termed as melancholia agitata, it was
widely employed in the second half of the nineteenth century, and it was later
replaced by Angstmelancholie and eventually agitated depression.
160 A. Koukopoulos et al.


With the introduction in 1851 of folie circulaire by Falret (1851), a significant
number of melancholias became a component of a more complex disease entity
and lost their nosologic independence. This nosographic evolution eventually led
to the creation of manic-depressive insanity by Kraepelin in 1899 and the definitive
substitution of the concept of melancholia with that of depression. Many psych-
iatrists had proposed substituting the term melancholia, which had become too
vague, with other terms such as tristimania, proposed by Rush (1830), lypemania
by Esquirol (1838), dysthymia by Flemming (1844), and vecordia melaena by
Kahlbaum (1863).
In the first edition (1883) of his textbook, Kraepelin placed melancholia activa
among the excited states and distinguished it from melancholia periodica, which is
in any case marked by delirious or delusional ideas and anxious agitation. Only
melancholia of circular insanity, marked by psychic and physical inhibition, corres-
ponds to the clinical picture of the present disorder major depression. In the second
(Kraepelin, 1887) and third (Kraepelin, 1889) editions, Kraepelin distinguished
between melancholia activa, very agitated, and melancholia simplex. In the fourth
edition, published in 1893, he replaced melancholia activa with Angstmelancholie,
to emphasize better the component of anxiety in this condition. In the fifth edition
(Kraepelin, 1896), he introduced melancholia of the age of involution: ˜˜with the
name of melancholia we designate all pathological anxious depressions of older
age which do not represent parts in the course of other psychic disorders.™™ The
clinical picture also comprised delusions, especially of guilt but also of persecu-
tion, and hypochondriacal ideas. The similarity with the old melancholia agitata is
evident. Kraepelin included Angstmelancholie in involutional melancholia.

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