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reuptake inhibitors. Probably the cases of suicidal or other violent acts attributed
to selective serotonin reuptake inhibitors in recent years may be due to the
agitation induced by the drugs in patients who were already agitated or prone
to agitation, and not due to adverse pharmacological reactions. Reading the
clinical descriptions of these cases, it is clear that the suicidal ideas have emerged
from a state of agitated depression (Teicher et al., 1990; Healy, 1994), the
psychomotor component of which is often seen as akathisia (Drake and
Ehrlich, 1985). We propose the term latent agitated depression for these depres-
sions prone to agitation. How can they be identified? According to our observa-
tions, the most reliable signs are:
1. total lack of inhibition in speech and movement
2. rich description of their depressive suffering
3. early or middle insomnia rather than late insomnia
These signs are not of absolute value but may suffice to suspect a latent agitated
depression and make one more cautious with treatment. One should start with an
antimanic, antianxiety medication, or, if antidepressants are used in the beginning,
a sedative should be added. In any case, sedative treatment is the best protection
against suicide, as Fawcett et al. (1993) emphasize.

In the majority of our depressed patients, the emergence of psychotic features,
motor agitation, or intense psychic agitation was associated with antidepressant
treatments or was exacerbated by them. The basic rule for their treatment,
therefore, was to suspend antidepressants if they were being administered or
not to administer them until psychotic symptoms and agitation had subsided.
The best results are obtained by initiating treatment with old or new neurolep-
tics, benzodiazepines, anticonvulsants, and lithium. Perhaps the most rapid
effect is achieved by a combination of neuroleptics and benzodiazepines.
Haloperidol and clonazepam are equally effective. In cases of minor agitated
depression, even lower doses of haloperidol and clonazepam, such as 2 mg, may
be effective in as little as 48 h. In more resistant cases, higher doses are required.
ECT is rapidly effective. Table 7.4 shows the treatments given to the patients who
fully recovered.
180 A. Koukopoulos et al.

Table 7.4 Treatments associated with full improvement of mixed depression
episodes (n ¼ 120)

Electroconvulsive therapy 51
Neuroleptic 40
Antiepileptics 40
Lithium 38
Olanzapine 22
Benzodiazepines 30

One hundred and twenty patients (57%) fully recovered. Forty-two patients (20%)
showed partial improvement demonstrated by a mean Hamilton-D score of 11
(range 9“15). Fifty (23%) patients did not improve significantly and four of these
patients committed suicide.

Treatment with olanzapine
We have found olanzapine to be particularly effective in the treatment of agitated
depression. Thirty-three patients were treated with olanzapine at a mean daily
dose of 5.5 mg (range 2.5“15 mg). Twenty-two patients (67%) recovered fully, five
(15%) recovered partially, and six (18%) did not improve. The therapeutic delay
of olanzapine was short, with a mean of 7.65 days (range 1“30 days; SD ¼ 6.67).
Three cases improved substantially within 24 h.
Olanzapine was administered alone in nine cases. In the remaining cases
benziodiazepines or anticonvulsants were added. Our observations about the
effectiveness and speed of action of olanzapine in similar cases confirm earlier
reports (Parker, 2002). Parker and Malhi (2001) advance the hypothesis that
atypical antipsychotics may have an antidepressant effect, particularly in
treatment-resistant melancholic depression, and suggest the term atypical anti-
depressants. We maintain, as explained above, that the antidepressant effect is due
to the antimanic action of these agents in cases of depression of a mixed nature.

Agitated depression followed by simple depression
In many cases the resolution of the psychic agitation also swiftly brings to an end
the depressive symptoms. In other cases, especially those with motor agitation or
psychotic features, a phase of simple, more or less inhibited depression follows.
181 Agitated depression: spontaneous and induced

This has also been observed by other authors (Glassman et al., 1975; Spiker et al.,
1985). We treated this pure depressive phase with antidepressant drugs. In this
pure depressive phase, any antidepressant treatment may be effective. The tradi-
tional amitriptylin seems the most suitable because it is the least likely to trigger
agitation. In our view the mixed depressive phase followed by a simple depression
corresponds to the pattern of manic-depressive cycle starting with mania and
followed by depression. There, too, the manic phase is treated with antimanic
agents and the depression is susceptible only to antidepressant treatments.
Agitated depression was followed by simple depression in 64 cases (30%). In
their previous course, these patients were bipolar I (n ¼ 20), bipolar II (n ¼ 17),
unipolar depression (n ¼ 22), and five cases were first episode agitated depression.
We hold that it is no coincidence that 28% of bipolar patients present the same
cycle pattern consisting of mania followed by depression, which in most cases is of
a simple or clearly inhibited type (Kukopoulos et al., 1980).
Many clinicians, on an empirical basis, have always treated these patients first
with neuroleptics and then with antidepressants and many authors, starting with
Klein and Davis (1969), have recommended this line of treatment. ECT is even
more effective in mixed depressive states than in non-mixed depressions. The less
frequent use of ECT in recent years (in Italy, unfortunately, for political and not
medical reasons), coupled with the widespread use of antidepressants, has wor-
sened the condition of these seriously ill patients, who often suffer longer duration
of episodes, longer hospitalization, and higher risk of suicide.
It may be argued that the treatment of the agitated phase with neuroleptics and
other antimanic agents favors the onset of a depressive phase, but this is also true
for the typical mania“depression cycle where it is clear that neuroleptics only
accentuate the natural evolution of the manic“depressive cycle, i.e., the depression,
more or less severe, that follows the manic phase. ECT, with its antidepressant and
antimanic action and its particular effectiveness in mixed depressive states, had
cloaked the essential difference between mixed and simple depression. But as far as
response to treatment is concerned, the same thing happened with the frequently
biphasic course of agitated and psychotic depression. Glassman et al. (1975) made
the first observation of a simple depression following a psychotic depression after
neuroleptic treatment in 1975, though their interpretation was different from
ours. ECT sweeps away mixed and simple depression in the course of the same
series of sessions, and this is conceivable. But what reveals the singular nature of
mixed depressive states is the fact that, often, after one to three ECT sessions, the
whole syndrome resolves abruptly. We have seen complete recovery after only one
ECT. This outcome seems analogous to that obtained in milder cases after a few
days of neuroleptic“benzodiazepine treatment and especially with olanzapine
treatment. This rapid response is hard to explain but it demonstrates that
182 A. Koukopoulos et al.

excitatory and depressive phenomena do not simply coexist but are interdepen-
dent in their emergence and evolution, and are probably caused by the same
pathophysiological alteration. An additional explanation could be that, once the
excitatory phenomena have subsided, the highly energetic temperament of these
patients quickly overrides the depression, obviating the need for antidepressant
treatment. In other cases depression sets in and antidepressant treatment is
necessary for weeks or months. This biphasic evolution of many cases of agitated
depression may be the basis of the doubts and hesitations of many clinicians about
its treatment (Erfurth et al., 2001).

Agitated depression should be considered a mixed affective state given its phe-
nomenology and response to treatments. Antidepressants worsen the condition of
these patients and, in many cases, induce agitation or psychosis in cases with
otherwise simple depression. The authors propose new diagnostic criteria for
agitated depression and introduce the term minor agitated depression for the
cases with psychic agitation without motor agitation or psychotic symptoms.
Three forms of agitated depression (mixed depression) are described: (1) psycho-
tic agitated depression; (2) agitated depression with psychomotor agitation; and
(3) minor agitated depression. All these forms may be induced or aggravated by
antidepressants and improve with mood-stabilizing and antipsychotic treatments,
as well as ECT.


Akiskal, H. S. (1992). The distinctive mixed states of bipolar I, II, and III. Clin. Neuropharmacol.,
15 (suppl. 1), 632A“3A.
Akiskal, H. S., Hantouche E. G., Bourgeois, M. L. et al. (1998). Gender, temperament, and the
clinical picture in dysphoric mixed mania: findings from a French national study (EPIMAN).
J. Affect. Disord., 50, 175“86.
American Psychiatric Association (1968). Diagnostic and Statistical Manual of Mental Disorders.
Washington, DC: American Psychiatric Association.
American Psychiatric Association (1980). Diagnostic and Statistical Manual of Mental Disorders.
Washington, DC: American Psychiatric Association.
American Psychiatric Association (1987). Diagnostic and Statistical Manual of Mental Disorders.
Washington, DC: American Psychiatric Association.
American Psychiatric Association (1994). Diagnostic and Statistical Manual of Mental Disorders.
Washington, DC: American Psychiatric Association.
Aretaeus Cappadox (1735). De Causis et Signis Morborum. Lugduni Batavorum: Janssonios
183 Agitated depression: spontaneous and induced

Aristotle (1970). On the Soul. London: Harvard University Press.
Benazzi, F. (2000). Depressive mixed states: unipolar and bipolar II. Eur. Arch. Psychiatry Clin.
Neurosci., 250, 249“53.
Boissier de la Croix de Sauvages, F. (1768). Nosologia Methodica sistens Morborum Classes: juxta
Sydenhami Mentem et Botanicorum Ordinem. Amstelodami: Tournes.
Bourgeois, M., Verdoux, H., Mainard, C. H. et al. (1995). Dysphoric mania and mixed states.
Encephale, 21, 21“32.
Braden, W. and Qualls, C. B. (1979). Racing thoughts in depressed patients. J. Clin. Psychiatry,
40, 336“9.
Carlson, G. A. and Goodwin, F. K. (1973). The stages of mania. A longitudinal analysis of the
manic episode. Arch. Gen. Psychiatry, 28, 221“8.
Clouston, T. S. (1888). Clinical Lectures on Mental Diseases. London: J. & A. Churchill.
Cullen, W. (1785a). Synopsis Nosologiae Methodicae: Exhibens Clariss, Virorum
Sauvagesii, Linnaei, Vogelii, Sagari, et MacBridii, Systemata Nosologica. Edinburgh: William
Cullen, W. (1785b). Institutions of medicine for the use of the students in the University of
Edinburgh. Edinburgh: Charles Elliot, T. Cadell.
Day, R. K. (1999). Psychomotor agitation: poorly defined and badly measured. J. Affect. Disord.,
55, 89“98.
Dell™Osso, L., Placidi, G. F., Nassi, R. et al. (1991). The manic-depressive mixed state: familial,
temperamental and psychopathologic characteristics in 108 female inpatients. Eur. Arch.
Psychiatry Clin. Neurosci., 240, 234“9.
Drake, R. E. and Ehrlich, J. (1985). Suicide attempts associated with akathisia. Am. J. Psychiatry,
142, 499“501.
Dreyfus, G. L. (1907). Die Melancholie, ein Zustandsbild des manisch-depressiven Irreseins. Jena:
G. Fischer.
Erfurth, A., Michael, N., Grunze, H., et al. (2001). Diagnosis and treatment of bipolar depression.
Psychiatr. Fenn., 32 (suppl. 1), 33“43.
´´ ´ ´
Esquirol, E. (1838). Des Maladies Mentales Considerees sous les Rapports Medicale, Hygienique et
´ ´ `
Medico-legal. Paris: J.-B. Bailliere.
Falret, J. P. (1851). Marche de la folie. Gazette ds H.p, Paris, 14 January, 24.
Fawcett, J., Clark, D. C., Busch, K. A. et al. (1993). Assessing and treating the patient at risk for
suicide. Psychiatr. Ann., 23, 244“54.
Flemming, C. F. (1844). Ueber Classification der Seelentoerungen. Allg. Ztschr. Psychiatr., 1,
Frances, A., Brown, R. P., Koesis, J. H. et al. (1981). Psychotic depression: a separate entity? Am.
J. Psychiatry, 138, 831“3.
Glassman, A. H., Kantor, S. J., Shostak, M. et al. (1975). Depression, delusions, and drug
response. Am. J. Psychiatry, 132, 716“19.
Goodwin, F. K. and Jamison, K. R. (1990). Manic-Depressive Illness. New York: Oxford
University Press.
Griesinger, W. (1845). Pathologie und Therapie der psychischen Krankheiten. Stuttgart: Adolf
Krabbe Verlag.
184 A. Koukopoulos et al.

Griesinger, W. (1861). Pathologie und Therapie der psychischen Krankheiten. Stuttgart: Adolf
Krabbe Verlag.
Gruber, N. P., Dilsaver, S. C., Shoaib, A. M. et al. (2000). ECT in mixed affective states: a case
series. J. Ect., 16, 183“8.
Guislain, J. (1852). Traite sur les Phrenopathies. Gand: Hebbelynck.
Healy, D. (1994). The fluoxetine and suicide controversy: a review of the evidence. CNS Drugs, 1,
Heinroth, J. C. A. (1818). Lehrbuch der Stroerungen des Seelenlebens. Leipzig: Vogel.
Himmelhoch, J. M., Coble, P., Kupfer, K. J. et al. (1976a). Agitated psychotic depression
associated with severe hypomanic episodes: a rare syndrome. Am. J. Psychiatry, 133, 765“71.
Himmelhoch, J. M., Mulla, D., Nell, J. F. et al. (1976b). Incidence and significance of mixed
affective states in a bipolar population, Arch. Gen. Psychiatry, 33, 1062“6.
Hippocrates (1988). Diseases II, para 72. Cambridge, MA: Harvard University Press.
Jamison, K. R. (1995). An Unquiet Mind. New York: A. A. Knopf.
Jaspers, K. (1923). Allgemeine Psychopathologie: fur Studierende, Arzte und Psychologen. Berlin:
Verlag von J. Springer.
Kahlbaum, K. L. (1863). Die Gruppierung der psychischen Krankheiten und die Eintheilung der
Seelenstoerungen. Danzig: Kafemann.
Kant, I. (1800). Anthropologie in pragmatischer Hinsicht. Konigsberg: F. Nicolovius.
Klein, D. F., and Davis, J. M. (1969). Treatment of affective disorders. In Diagnosis and Drug
Treatment of Psychiatric Disorders, D. F. Klein and J. M. Davis, eds, pp. 304“5. Baltimore, MD:
Williams and Wilkins.
Klein, D. F. and Liebowitz, M. R. (1982). Hysteroid dysphoria. Am. J. Psychiatry, 139, 1520“1.
Koukopoulos, A. (1999). Agitated depression as a mixed state and the problem of melancholia.
Psychiatr. Clin. North Am., 22, 547“64.
Koukopoulos, A., Girardi, P., Proietti, R. et al. (1989). Diagnostic and therapeutic considera-
tions on agitated depression understood as a mixed affective state. Minerva Psichiatr., 30,
Koukopoulos, A., Faedda, G., Proietti, R. et al. (1992). Mixed depressive syndrome. Encephale,
18, 19“21.
Koukopoulos, A., Pani, L., Serra, G. et al. (1995). Anxious-excited depression: a mixed affective
syndrome. Encephale, 21, 33“6.
Kraepelin, E. (1883). Psychiatrie. Leipzig: JA Barth.
Kraepelin, E. (1887). Psychiatrie, 2nd edn. Leipzig: JA Barth.
Kraepelin, E. (1889). Psychiatrie, 3rd edn. Leipzig: JA Barth.
Kraepelin, E. (1893). Psychiatrie, 4th edn. Leipzig: JA Barth.
Kraepelin, E. (1896). Psychiatrie, 5th edn. Leipzig: JA Barth.
Kraepelin, E. (1899). Psychiatrie, 6th edn. Leipzig: JA Barth.
Kraepelin, E. (1904). Psychiatrie, 7th edn. Leipzig: JA Barth.
Kraepelin, E. (1913). Psychiatrie, 8th edn. Leipzig: JA Barth.
Kukopulos, A., Reginaldi, D., Laddomada, P. et al. (1980). Course of the manic-depressive
cycle and changes caused by treatment. Pharmakopsychiatr. Neuropsychopharmakol., 13,
185 Agitated depression: spontaneous and induced

Lange, J. (1928). Die endogenen und reaktiven Gemuetserkrankungen und die manische-
depressive Konstitution. In Handbuch der Geisteskrankheiten, O. Bumke, ed., p. 111. Berlin:


. 31
( 68 .)