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inactivity, the despair, the undirected and groundless rage, and the violent suicidal
impulses, all the essential elements of classic melancholia and of the more mund-
ane agitated depression of today, seem to be caused by that ominous, dark force.
The long-standing western tradition that has always associated the colour black
with melancholy and depression is probably linked to this force within the patient.
This force is so violent that it cannot be anything but manic in nature. It improves
rapidly under the effect of neuroleptic drugs, whereas it can worsen dramatically
under the effect of antidepressants, especially if given without neuroleptics or
discrete doses of benzodiazepines or anticonvulsant drugs. ECT is the most
effective treatment (Koukopoulos et al., 1992; Gruber et al., 2000). A young
woman called her agitated depression black mania, a term also used by Jamison
(1995). Why this manic energy, rather than improving drive and mood, instead
annihilates psychic life, must be due to the depression itself and a tentative
explanation is offered below.

Role of temperament
Many hypotheses have been advanced to explain the genesis of mixed states.
Kraepelin™s (1904) idea of the unsynchronized transition between the two phases
and the consequent hypothesis of the patient being ˜˜trapped in the switch process™™
may be accepted for transitional mixed states but not for the permanent ones. The
most important mixed states either start as such or they become mixed under the
effect of treatment. Himmelhoch et al. (1976a, b) advance the hypothesis of a
double bipolar and unipolar heredity to explain the manic elements in a state of
depression. McElroy (1997) thinks that the agitation may be driven by hypomania.
Akiskal (1992; Akiskal et al., 1998) advances the ground-breaking hypothesis
that mixed states arise from the intrusion of an affective episode into an opposite
affective temperament or one with a high degree of chronic instability, such as the
cyclothymic temperament. Thus, dysphoric mania results from the intrusion of a
manic episode in a depressive temperament, and depressive mixed states arise
from the intrusion of a depressive state into a hyperthymic (hypomanic) tempera-
ment. Marneros (2001) also agrees with this interpretation.
The authors™ view is similar to that of Akiskal. The premorbid temperament of
depressed patients with motor or psychic agitation is marked by a high degree of
excitability, emotional reactivity, and energetic drive. Many hyperthymic people
and all cyclothymic and irritable people have such features, especially women, who
make up the vast majority of agitated depressive patients. People with such
temperaments react intensely to stimuli in general and particularly to emotionally
charged ones. They tend to have passionate love affairs, deeply felt disappoint-
ments, intense reactions to pleasure or frustration, deep artistic and religious
174 A. Koukopoulos et al.

experiences, and powerful fits of anger when irritated. The escalation of anger
from initial irritation to outright rage typifies their reactive processes under stress
or emotional stimuli. Their temperamental energy intensifies their emotions, and
the emotions fire their energy. The authors™ hypothesis is the following: when a sad
or stressful event provokes a depressive reaction, or a seasonal or endogenous
depression occurs in such a person, the psychic reaction is intense and exacerbates
the depression itself. In turn, the emotional reaction heightens and unleashes this
energy, which produces manic symptoms, such as restlessness and racing
thoughts, while it also triggers anxiety and aggravates the depressive psychic
pain. This tight interweaving of manic traits and depressive states of agitated
depression makes it an authentic mixed state.

The nature and definition of agitated depression
Agitated depression should not be considered a depressive syndrome in which
some manic or hypomanic symptoms coexist. No such symptoms can be present
in agitated depression or in agitated mixed states in general. They are certainly
symptoms of an excitatory nature, but there is nothing manic or hypomanic in
depressive mixed states if we accept expansiveness as the essential feature of mania
or hypomania. The cardinal symptom of agitated depression is psychic agitation
with or without motor agitation and this agitation torments the patient and
inhibits every activity and every pleasure. Even the racing thoughts are very
different from the manic flight of ideas. The flight of ideas is expressed in speech
and even facilitates, together with expanded emotion, literary creativity. Racing
thoughts of agitated depression are not verbalized and are very tormenting to the
point that some patients wish to die just to stop them. Kraepelin™s conception of
mixed states was the coexistence of manic and depressive symptoms. Nevertheless,
in all the forms of agitated depression he described, from melancholia activa of
1883 to the evolutional melancholia and the excited depression of 1913, he
emphasized the inner motor agitation of the patient. Since psychic agitation is
very intense also in patients with motor agitation and even in psychotic agitated
depression there is often a tormenting, inner agitation, it should be considered as
the fundamental symptom of all these depressive mixed states.
But what is this agitation from the psychopathological point of view? Kraepelin
and all the authors at the turn of the nineteenth century defined it with the term
anxiety, Angst. On the other hand, agitation is synonymous with anxiety in lay and
psychiatric language. Day reviews and highlights the ambiguities of the term
agitation (Day, 1999). In the Hamilton scale for depression, psychic agitation
has the meaning of psychic anxiety. Furthermore, patients suffering from agitated
depression express their suffering in terms of anxiety and anxious fears. Patients,
175 Agitated depression: spontaneous and induced

however, specially endowed with powers of introspection describe a type of
psychic agitation in a totally different way from anxiety. They describe it as an
ominous force that agitates them and is more physical, more somatic, coming
more from their body than from their psyche. They cannot cope with it. A woman
explained her desire to die just in order to escape her body “ she could not live
inside it any longer. The old theme of black and darkness reappears. The same
woman said that ˜˜everything was dark and I was in a very narrow dark place where
I could not live. It was something physical, very physical,™™ she insisted. Other
patients describe it as a physical, tremendous energy that makes them feel like
exploding, their heads or chests bursting or imploding. Often these painful sensa-
tions are felt in the epigastrium. Such an agitation cannot be caused by anything
less than excitatory processes. Indeed, it calms down with typical or atypical
neuroleptics and is exacerbated by antidepressants.
But why does it inhibit all mental activities? Probably because the excitation
emerges in the midst of a major depression. One seems to be seeing the reaction of
very energetic temperaments to the depressive event. People with such tempera-
ments are overreactive in general to all environmental and psychic events. No
event is more traumatic than depression. On the other hand, agitated depressions
are often triggered by life events which may be more or less important but to which
they react immediately in a disproportionate manner. In a certain sense, their
reaction to antidepressants may also be viewed as disproportionate and it could be
considered as an exaggerated neuronal reaction. This reaction is indeed not only
very intense and dramatic to the patient but often manifests itself within hours of
the first intake of the antidepressant drug. Equally dramatic and swift is also the
benefit given by the appropriate sedative. We saw three cases where the agitated
syndrome disappeared within 24 h after the intake of small doses of neuroleptics
and benzodiazepines and another three after olanzapine. One day we will certainly
have adequate means to measure neuronal activity and reactivity. Affective tem-
peraments can be viewed as an overall expression of different degrees of nervous
activity and reactivity.
That something permanently distinct exists in patients with agitated depression
has been posited by many authors who propose that agitated depression is a
distinct clinical entity. One of the arguments is that these patients have had in
their lives other episodes of agitated or psychotic depression. This observation is
correct. But these patients at other times have simple depressions or manias or
hypomanias. It therefore clearly belongs to the manic-depressive spectrum, but
certainly is distinct as a syndrome from simple major depression. Its peculiarity as
a syndrome is the mixed nature of the phenomenology and the underlying
pathology. What creates the permanent predisposition throughout life is the
temperament of these patients together with their susceptibility to depression.
176 A. Koukopoulos et al.

The temperamental reactions of all persons are often similar in type but they are
not constant. Other factors contribute, such as life situation and age. Old age has
often been recognized as the age at which agitated and anxious depressions are more
frequent. Involutional melancholia is an atypical example. The relationship between
affective disorders and age is certainly very complex. The perimenopausal years, for
example, are a time of increased emotional lability and reactivity. The mean age at
onset of agitated depression in our sample was 45.9 for men and 44.9 for women.

Diagnostic criteria of agitated depression
Full depressive syndrome and inner unrest are both essential elements of this
syndrome. The presence of motor agitation is sufficient to make the diagnosis,
as in the RDC criteria, because it also confirms the presence of psychic agitation.
The absence of motor agitation creates the diagnostic problem of distinguishing
anxiety from the particular inner unrest of agitated depression. In order to clarify
the differential diagnosis between anxiety and inner agitation, pending more
systematically validated criteria, we used a set of criteria different from that
proposed in our previous paper (Koukopoulos, 1999). Along with major depres-
sion and inner agitation, at least three of the following symptoms must be present:
(1) racing or crowded thoughts
(2) irritability or an unprovoked feeling of rage
(3) absence of signs of retardation
(4) talkativeness
(5) dramatic descriptions of suffering or frequent spells of weeping
(6) mood lability and marked emotional reactivity
(7) early insomnia
Such symptoms are of an excitatory, not depressive, nature and indicate the absence
of inhibition. Early insomnia is often sustained by racing or crowded thoughts. These
criteria were, however, validated by the external criterion of the effect of antidepres-
sant treatments. A total of 113 cases had simple depressions that became agitated
(with at least three of the above symptoms) when treated with antidepressants.

Patients and method
During the years 1990“1999 we have examined and treated 212 (152 women; 72%)
patients suffering from agitated depression as defined above. All met DSM-IIIR
criteria for major depression. Sixty-seven cases presented with agitated depression
(non-psychotic) with psychomotor agitation. The others suffered from minor
agitated depression (77 cases), as defined above, and psychotic agitated depression
(68 cases). Transient agitated depressive states were not included. A minimum of
177 Agitated depression: spontaneous and induced

Table 7.2 Nosologic diagnosis of 212 patients according to sex and polarity

Male Female Total %

Bipolar I 20 36 56 27
Bipolar II 15 51 66 31
Unipolar depression 12 56 68 32
MxD 14 8 22 10

MxD, first episode of agitated (mixed) depression.

2 weeks™ duration was required. All these patients were examined, evaluated, and
treated by the authors at the Centro Lucio Bini in Rome. The previous course of the
disorder, treatments, and present condition were evaluated with all available medical
records and with the cooperation of at least one family member. Table 7.2 shows the
distribution of these patients by gender and polarity of their previous course; the age
at first affective episode was 31.9 for women and 37.6 for men; the age at index
episode of agitated depression was 44.9 for women and 44.5 for men. One hundred
and eleven patients had had earlier episodes of agitated depression. The age at onset
of the first episode of agitated depression as first affective episode was 44.5 years.
The mean Hamilton-D score was 23.8 (range 14“39) for all patients; 27.2 (range
17“39) for patients with psychotic agitated depression; 25.3 (range 16“36) for
cases with agitated depression (non-psychotic) with psychomotor agitation; and
20.0 (range 14“32) for patients with minor agitated depression.
The mean duration of the episodes of agitated depression was 4.6 months (range
1“48 months).

Spontaneous and induced agitated depression
The episode started as an agitated depression in 99 (47%) cases. In the other 113
(53%) cases, the episode started as a simple depression without symptoms of
agitation, and later it turned into an agitated depression. The mean duration of the
simple depression was 4.7 months (1“36 months). The shift from simple to
agitated depression occurred in association with various treatments, mainly anti-
depressants, but also other treatments with stimulant effect (Table 7.3). The onset
of agitated depression took place either immediately or within a few days to a few
weeks. The great majority of agitated depressions emerged during treatment with
tricyclic antidepressants (58 cases), selective serotonin reuptake inhibitors (45
cases), other antidepressants (27 cases), and seven cases during maintenance
treatment with antidepressants. The small number of cases (four) associated
with monoamine oxidise inhibitors is probably due to the limited use of these
178 A. Koukopoulos et al.

Table 7.3 Treatments associated with onset of agitated depression

Tricyclic antidepressants 58
Selective serotonin uptake inhibitors 45
Monoamine oxidase inhibitors 4
Other antidepressants 27
Steroids 6
Levothyroxine 4
Caffeine 4
Lithium withdrawal 4
Neuroleptic withdrawal 2
Maintenance antidepressants 7

agents in Italy, but the possibility that these agents may be less agitating cannot be
ruled out. Six cases were associated with steroids, four with levothyroxine, four with
excessive caffeine intake, four with lithium withdrawal, and two with neuroleptic
withdrawal. Eighty-three women (55% of all women) and 30 men (50% of all men)
became agitated in association with the above-mentioned treatments. The previous
course of these 113 patients was: bipolar I (BP) for 27 patients, BP-II for 47 patients,
unipolar depression for 34 patients and five were first affective episodes. If we
compare them to the total numbers of the different groups, we find that 48% of
the BP-I, 71% of the BP-II, and 50% of the unipolar patients had induced agitated
depressions. The preponderance of BP-II patients is to be noted. The age at onset of
the mixed episode was 48.4 years for the induced group and 41.7 years for the
spontaneous group. The duration of the mixed episode was 4 months for the
induced group and 5.4 months for the spontaneous group. There was no difference
between the spontaneous and induced groups with regard to severity or outcome.
Among our 212 agitated depressions, 68 (47 women and 21 men) also had
psychotic symptoms. As psychotic symptoms we considered hallucinations,
delusions, both congruent and non-congruent (true delusions and not mere
fears or doubts), and the presence of a state of mental confusion and grossly
disturbed behavior. Of these patients, 22 (32%) were spontaneous, i.e., the psy-
chotic symptoms emerged spontaneously and not in association with pharmaco-
logical treatment. In the other 46 patients, the psychotic symptoms emerged in
association with antidepressant treatment. Of these 46 patients, 30 patients had a
BP-I course (54% of all BP-I patients), 14 had a course of BP-II (21% of all BP-II
patients), 19 had a previous course of recurrent depression (28% of all unipolar
patients), and five were first affective episodes of psychotic depression. It should be
underlined that all the 14 BP-II patients who had a psychotic agitated depression
were induced by antidepressants.
179 Agitated depression: spontaneous and induced

Latent agitated depression
There are cases of depression that, though without manifest psychic or motor
agitation and not delusional, rapidly become agitated after the institution of
antidepressant drug treatment. All antidepressants can induce this effect in
certain patients but the most rapid triggering is seen with selective serotonin


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