European Psychiatry 19 (2004) 85–90

www.elsevier.com/locate/eurpsy

Original article

Toward a validation of a new definition of agitated depression as a bipolar

mixed state (mixed depression)
F. Benazzi a,b,*, A. Koukopoulos c, H.S. Akiskal d
a
Outpatient Psychiatry Center, Via Pozzetto 17, Castiglione di Cervia, 48010 Ravenna, Italy
b
Department of Psychiatry, National Health Service, Forli, Italy
c
Centro Lucio Bini, outpatient private practice, Rome, Italy
d
International Mood Center, University of California, San Diego CA, USA

Received 15 July 2003; received in revised form 28 August 2003; accepted 11 September 2003

Abstract

Purpose. – As psychotic agitated depression is now a well-described form of mixed state during the course of bipolar I disorder, we sought
to investigate the diagnostic validity of a new definition for agitated (mixed) depression in bipolar II (BP-II) and major depressive disorder
(MDD).
Materials and methods. – Three hundred and thirty six consecutive outpatients presenting with major depressive episodes (MDE) but
without history of mania were evaluated with the Structured Clinical Interview for DSM-IV when presenting for the treatment of MDE. On the
basis of history of hypomania they were assigned to BP-II (n = 206) vs. MDD (n = 130). All patients were also examined for hypomania during
the current MDE. Mixed depression was operationally defined by the coexistence of a MDE and at least two of the following excitatory signs
and symptoms as described by Koukopoulos and Koukopoulos (Koukopoulos A, Koukopoulos A. Agitated depression as a mixed state and the
problem of melancholia. In: Akiskal HS, editor. Bipolarity: beyond classic mania. Psychiatr Clin North Am 1999;22:547–64): inner psychic
tension (irritability), psychomotor agitation, and racing/crowded thoughts. The validity of mixed depression was investigated by documenting
its association with BP-II disorder and with external variables distinguishing it from unipolar MDD (i.e., younger age at onset, greater
recurrence, and family history of bipolar disorders). We analyzed the data with multivariate regression (STATA 7).
Results. – MDE plus psychic tension (irritability) and agitation accounted for 15.4%, and MDE plus agitation and crowded thoughts for
15.1%. The highest rate of mixed depression (38.6%) was achieved with a definition combining MDE with psychic tension (irritability) and
crowded thoughts: 23.0% of these belonged to MDD and 76.9% to BP-II. Moreover, any of these permutations of signs and symptoms defining
mixed depression was significantly and strongly associated with external validators for bipolarity. The mixed irritable-agitated syndrome
depression with racing-crowded thoughts was further characterized by distractibility (74–82%) and increased talkativeness (25–42%); of
expansive behaviors from the criteria B list for hypomania, only risk taking occurred with some frequency (15–17%).
Conclusions. – These findings support the inclusion of outpatient-agitated depressions within the bipolar spectrum. Agitated depression is
validated herein as a dysphorically excited form of melancholia, which should tip clinicians to think of such a patient belonging to or arising
from a bipolar substrate. Our data support the Kraepelinian position on this matter, but regrettably this is contrary to current ICD-10 and
DSM-IV conventions. Cross-sectional symptomatologic hints to bipolarity in this mixed/agitated depressive syndrome are virtually absent in
that such patients do not appear to display the typical euphoric/expansive characteristics of hypomania—even though history of such behavior
may be elicited by skillful interviewing for BP-II. We submit that the application of this diagnostic entity in outpatient practice would be of
considerable clinical value, given the frequency with which these patients are encountered in such practice and the extent to which their
misdiagnosis as unipolar MDD could lead to antidepressant monotherapy, thereby aggravating it in the absence of more appropriate treatment
with mood stabilizers and/or atypical antipsychotics.
© 2004 Elsevier SAS. All rights reserved.

Keywords: Bipolar II disorder; Unipolar; Depressive mixed state; Mixed depression; Agitated depression; Excited melancholia

* Corresponding author.
E-mail address: f.benazzi@fo.nettuno.it (F. Benazzi).

© 2004 Elsevier SAS. All rights reserved.

doi:10.1016/j.eurpsy.2003.09.008
86 F. Benazzi et al. / European Psychiatry 19 (2004) 85–90
1. Introduction
In the field of mood disorders, mixed states still have an
unclear place and different definitions. DSM-IV [10] in-
cludes only a bipolar I mixed state, in which full criteria of
mania and major depressive episode (MDE) must be concur-
rently present. Patients meeting the latter strict definition are
not common in clinical practice [6,23]. Less strict definitions
of mixed (dysphoric) mania require only few depressive
symptoms during a manic episode [6,23]. The depressive
pole of mixed states (MDE and concurrent manic/hypomanic
symptoms) is understudied [5]. Kraepelin [28] defined a
mixed state as a combination of opposite symptoms of mood,
thought, and activity and included two depressive mixed
states: agitated depression and depression with flight of
ideas. In his view, it was enough to have one of the three
components of the affective states (psychomotor activity,
mood and thinking) in a polarity opposite to the other two to
have a mixed state. It is for this reason, and also based on the
follow-up study of his student Dreyfus, that Kraepelin [28]
classified agitated melancholia as a mixed state.
Mixed states might result from the combination of an
affective episode with an opposite affective temperament
[4,6,29]. Depressive mixed states might be associated with
BP-II and cyclothymic or hyperthymic temperament, and
mixed mania might be associated with bipolar I and dysthy-
mic temperament [5,6]. But formal diagnostic systems define
mixed states on the basis of the simultaneous presence of
manic and depressive syndromes. Recent studies have gone
beyond the narrow DSM-IV definition of a mixed state,
which is limited to depression during mania. The work of the
senior author [3,7] described BP-II depressive mixed state
(MDE plus such hypomanic symptoms as racing thoughts,
sexual excitement, irritability and psychomotor agitation);
Perugi et al. [29] described bipolar I depressive mixed state;
Dayer et al. [20] proposed a definition of mixed states in
which a dysphoric syndrome was the fundamental dimen-
sion; and we [9,14,16] described BP-II depressive mixed
state as the combination of MDE and at least two or three
hypomanic symptoms (the most common being irritability,
distractibility, racing/crowded thoughts, increased talkative-
ness and psychomotor agitation). In light of these consider-
ations, it is noteworthy that even in patients not selected on
the basis of mixed state status, irritability, distractibility and
racing thoughts were the most common manic/hypomanic
symptoms across the bipolar spectrum outpatients [14].
In the DSM-IV, psychomotor agitation and irritability can
be found in the diagnostic criteria and text description of both
manic/hypomanic episodes and MDE, while racing thoughts
are found only in manic/hypomanic episodes. The inclusion,
within the DSM-IV, of typical manic/hypomanic symptoms
(psychomotor agitation and irritability) within opposite epi-
sodes may reflect uncertainty about classification or the im-
plicit possibility of mixed states occurring within the context
of disorders other than bipolar I. In the authors’ view, depres-
sive mixed states belongs to the bipolar spectrum
[3,5,7,9,27]. Others [35,36] contend that agitated, especially
psychotic agitated depression, is distinct from bipolar mixed
states, and must be classified as a unipolar major depressive
disorder (MDD). Judging from a recent international “con-
sensus” conference [8], which among others deliberated on
what constitute valid bipolar diagnostic subtypes, agitated
depressions—indeed the entire concept of depressive mixed
states—did not receive a favorable “vote.” It would appear
that agitated depression is still classified as a unipolar MDD
by a considerable majority of psychiatrists.
Koukopoulos and Koukopoulos [27] have proposed a new
definition for agitated depression. Mixed depression, as they
call it, is based on the coexistence of a MDE and at least two
of the following excitatory symptoms: (1) inner tension, (2)
psychomotor agitation, and (3) racing/crowded thoughts.
This definition has yet to be validated. Agitated mixed states,
often of psychotic proportion, have been well-documented in
the course of bipolar I disorder [30,34]. This is relatively easy
to recognize because of past history of mania. The diagnostic
problem in agitated depression is more difficult in BP-II—
where ascertainment of history of hypomania requires skill-
ful interviewing—and in unipolar MDD, where history of
hypomania is by definition absent. Given that BP-II MDE is
prevalent (30–60%) among depressed outpatients
[3,8,13,17,18,26], the delineation of agitated depression in
this population is of considerable interest—especially be-
cause they appear, on the basis of new data [31], to be highly
suicide-prone.
The aim of the present study was to test the diagnostic
validity of the Koukopoulos and Koukopoulos’ definition
[27] of mixed depression, by studying its association with
variables typically distinguishing bipolar disorders from uni-
polar MDD. The specific variables we investigated were:
earlier age at onset, high recurrences, and family history of
bipolar disorders based on the rich literature on bipolar vali-
dators [2,8,25]. We further sought its association with the
diagnosis of BP-II.
2. Methods and materials
2.1. Patients and study setting
Three hundred and thirty-six consecutive outpatients, pre-
senting voluntarily for treatment of MDE over a two-year
period, were included in this study. Excluded were patients
who had received psychotropic medication other than benzo-
diazepines in the past 2 weeks, those with active alcohol and
substance abuse, as well as those with severe personality
disorders. The study setting, FB’s outpatient practice, is a
collaborative effort [9,17] with the International Mood Cen-
ter of the University of California at San Diego, CA, USA.
This is a private setting, which is more representative of
mood disorder patients in Italy than the national health ser-
vice or university centers where one usually encounters the
most severe mood patients.
 F. Benazzi et al. / European Psychiatry 19 (2004) 85–90
2.2. Interview procedures
Patients were interviewed by FB during the first visit
(cross-sectional assessment) with the Structured Clinical In-
terview for DSM-IV Axis I Disorders-Clinician Version
(SCID-CV [22], as modified by Benazzi and Akiskal [17]),
and the Global Assessment of Functioning (GAF) scale [10].
Hypomanic episodes were not severe enough to have caused
marked impairment of functioning (ruling out manic symp-
toms and mixed mania, as only 6.2% of patients had the
DSM-IV minimum number of symptoms required for the
diagnosis of hypomania). No patient had DSM-IV rapid
cycling or cyclothymic disorder. Any history of mania/
hypomania was always investigated soon after making the
diagnosis of MDE, and before the assessment of all the other
study variables, thereby avoiding a possible bias related to
knowledge of the presence of indicators of bipolarity (see
below). History of 4-day minimum threshold for hypomania
for BP-II diagnosis [10] was not followed. Instead, at least
2 days of hypomania were required for BP-II diagnosis, on
the basis of a recent international consensus [8], our own
clinical data [1,15], and epidemiological findings [11]. Bipo-
lar II defined by the 2-day threshold for hypomania has been
found to have a high diagnostic stability during long-term
follow-up [19]. Most of the BP-II patients in the present
study had more than one hypomanic episode (increasing the
reliability of BP-II diagnosis [8]). Often, family members or
close friends supplemented the clinical information during
the interview (increasing the reliability of the diagnosis), as
BP-II patients often do not see hypomania as a disorder, and
may not easily remember positive events (as hypomanias
often are), due to the negative cognitive bias of depression
[8].
To assess the presence of hypomanic signs and symptoms
during the index MDE, we systematically applied the
SCID-CV [22]. Such hypomanic signs and symptoms were
required to have lasted at least 1 week, to have appeared
during the index MDE, and had to be present during the
index MDE at the time of the interview.
2.3. Assessing and validating agitated depressive mixed
state
The present sample in FB’s private practice has been the
subject of other analyses by us on methodological, differen-
tial, diagnostic, atypical and depressive mixed state features
[9,17] of BP-II vs. MDD. Our focus here on an expanded
sample is on the more specific question of testing agitated
depression as a mixed bipolar subtype. Koukopoulos and
Koukopoulos [27] definition of agitated depression as mixed
depression was our starting point: major depressive episode;
and at least two of the following signs and symptoms: motor
agitation, psychic agitation or intense inner tension, and
crowded thoughts. These signs and symptoms partly fol-
lowed DSM-IV [10] and SCID-CV [22] definitions. Irritabil-
ity was taken as an observable indicator of intense inner
87
tension. The SCID-CV [22] has the limitation of having a
structured question only for the manic irritable mood (“are
you so irritable that you find yourself shouting at people, or
starting fights or arguments, or yelling at people you do not
really know”), while it does not have a structured question for
hypomanic irritable mood. Questions for hypomanic irritable
mood were then taken from the Hypomania Interview Guide,
Current Assessment Version [38]. The following questions
were included: “Have you been feeling unusually irritable in
the past week, have you been annoyed by little things, have
you found yourself arguing more than usual, argumentative,
hard to get along with, noticed or remarked by others, and
uncharacteristic for you.” A positive answer to at least three
of these questions was taken as a sign of irritability. Like-
wise, racing thoughts and psychomotor agitation definitions
followed DSM-IV/SCID-CV [10,22]. Crowded thoughts
was based on Koukopoulos and Koukopoulos’ definition
[27], requiring that the patient complains about his/her head
being full of thoughts that he/she is unable to stop; we have
elsewhere reported [9] that crowded thoughts are better un-
derstood by patients than racing thoughts. We thus tested a
definition of mixed depression with either of the two follow-
ing signs and symptoms: (psycho)motor agitation, psychic
tension/irritability, and crowded/racing thoughts. We tested
all the permutations of these signs and symptoms with the
MDE. The independent variables we used to validate this
definition of mixed depression were the following: family
history of bipolar disorders, age at onset of the first MDE,
number of MDE recurrences and BP-II disorder.
The variables of the sample (from studies comparing bipo-
lar and unipolar [2,9,25]) were gender, age, age at onset of
the first MDE, MDE recurrences, axis I comorbidity, index
MDE severity measured by GAF, index DSM-IV psychotic,
melancholic, and atypical features, depression chronicity
(chronic MDE, and MDE without full interepisode recovery,
lasting more than 2 years from index MDE, reported in the
table as MDE symptoms for more than 2 years), MDE and
hypomanic symptoms, and family history of bipolar disor-
ders.
Family history was investigated with the structured Fam-
ily History Screen [37], an instrument for collecting lifetime
psychiatric history on first-degree relatives (median sensitiv-
ity 67.6%, specificity 87.6%).
2.4. Statistical analyses
Multivariate regression (STATA Statistical Software, Re-
lease 7, Stata Corporation, College Station TX, USA, 2001)
was used to test associations between different definitions of
mixed depression and study variables. Multivariate regres-
sion differs from multiple regression in that several depen-
dent variables are jointly regressed on the same independent
variables, calculating the joint significance of all the equa-
tions. P values were two-tailed, and the chosen probability
level was 0.01, to reduce risk of Type I error [33].
88 F. Benazzi et al. / European Psychiatry 19 (2004) 85–90

3. Results Table 4
Multivariate regression of MDE with intense psychic tension/irritability
(PT/I) and racing/crowded thoughts (R/CT) vs. variables typically associa-
The features of our patients are presented in Table 1. MDE ted with bipolar disorders, and vs. bipolar II diagnosis
with intense inner tension (indicated by irritability), and
Variable F DF P PT/I: t R/CT: t
racing and/or crowded thoughts was present in 38.6%
Bipolar II diagnosis 21.7 2, 334 0.000 5.2 4.6
(130/336) of patients: 23.0% from a MDD, 76.9% from Age at onset first MDE, 8.4 2, 334 0.000 –3.1 –3.0
BP-II, baseline. MDE with intense inner tension/irritability years
and psychomotor agitation was present in 15.4% (52/336) of ≥5 MDEs 2.4 2, 334 0.091 1.7 –0.9
patients, and MDE with psychomotor agitation and Bipolar family history 5.3 2, 334 0.005 2.1 2.8
racing/crowded thoughts in 15.1% (51/336). MDE with all
three signs and symptoms, i.e., intense inner tension (irrita- Table 5
bility), psychomotor agitation and racing/crowded thoughts, Multivariate regression of MDE with intense psychic tension/irritability
(PT/I), psychomotor agitation (PA), and racing/crowded thoughts (R/CT)
was present in 12.5% (42/336) of patients. Multivariate re- vs. variables typically associated with bipolar disorders, and vs. bipolar II
gression (Tables 2–5) showed that all the combinations of diagnosis
symptoms of Koukopoulos and Koukopoulos’ proposed di- Variable F DF P PT/I: t PA: t R/CT: t
agnostic criteria for mixed depression were significantly and Bipolar II diagnosis 18.0 3, 334 0.000 5.2 4.5 4.6
strongly associated with nearly all the characteristic features Age at onset first MDE, 6.1 0.000 –3.1 –2.0 –3.0
of bipolar disorders: younger age at onset, MDE recurrences, years
BP-II lifetime, and bipolar family history. ≥5 MDEs 3.9 0.009 1.7 2.8 –0.9
Bipolar family history 6.2 0.000 2.1 3.5 2.8

Table 1
Sample features (n = 336) Table 6
Frequency of criteria B hypomanic symptoms during the MDE (major
Variable: mean (S.D.) (%) depressive episode) defined by three permutations of psychic
Unipolar MDD 38.6 tension/irritability (PT/I), racing/crowded thoughts (R/CT), and psychomo-
Bipolar II 61.3 tor agitation (PA)
Females 64.2 Variables (%) PT/I + R/CT PT/I + PA R/CT + PA
Age, years 43.9 (15.0) Distractibility 73.8 76.9 82.3
Age at onset first MDE, years 26.7 (13.0) More talkativeness 24.6 42.3 41.1
Duration of illness, years 17.3 (13.1) Risky behavior 15.3 17.3 15.6
GAF 50.8 (8.9) Increased goal-directed 3.0 3.8 5.8
>2 years index MDE symptoms 44.6 activity
Axis I comorbidity 52.0 Reduced need for sleep 1.1 3.8 1.9
≥5 MDEs 74.4 Flight of ideas 0.0 0.0 0.0
Index psychotic features 8.3 Grandiosity 0.0 0.0 0.0
Index melancholic features 16.6
Index atypical features 39.2
Bipolar (type I + type II) family history 44.9 Table 6 shows the frequency of criterion B hypomanic
N hypomanic symptoms during MDE 2.3 (1.4) signs and symptoms in the three different permutations by
which patients could meet the criteria for mixed depression.
Table 2 The most common of these signs and symptoms were dis-
Multivariate regression of MDE with psychomotor agitation (PA) and tractibility (73.8–82.3%) and increased talkativeness (74.6–
racing/crowded thoughts (R/CT) vs. variables typically associated with 41.1%). Expansive symptoms were rare, risky behavior be-
bipolar disorders, and vs. bipolar II diagnosis
ing the only one with a rate above 15% (15.3–17.3%).
Variable F DF P PA: t R/CT: t
Bipolar II diagnosis 19.1 2, 334 0.000 4.5 4.6
Age at onset first MDE, years 6.1 2, 334 0.002 –2.0 –3.0
4. Discussion
≥5 MDEs 4.8 2, 334 0.008 2.8 –0.9
Bipolar family history 8.8 2, 334 0.000 3.5 2.8
Our results validate the Koukopoulos and Koukopoulos’
Table 3
definition of agitated depression as a mixed state [27], show-
Multivariate regression of MDE with intense psychic tension/irritability ing that it was associated with variables, which typically
(PT/I) and psychomotor agitation (PA) vs. variables typically associated distinguish bipolar disorders from unipolar MDD, including
with bipolar disorders, and vs. bipolar II diagnosis bipolar family history. Familiarity is the most important
Variable F DF P PT/I: t PA: t diagnostic validator [32]. Moreover, the majority belonged to
Bipolar II diagnosis 20.1 2, 334 0.000 5.2 4.5 the BP-II category. Different combinations of the symptoms
Age at onset first MDE, years 5.9 2, 334 0.002 –3.1 –2.0 suggested in the diagnostic criteria of mixed depression
≥5 MDEs 4.6 2, 334 0.010 1.7 2.8 tested with multivariate regression were significantly and
Bipolar family history 7.2 2, 334 0.001 2.1 3.5
strongly associated with bipolar predictor variables, further
 F. Benazzi et al. / European Psychiatry 19 (2004) 85–90
supporting Kraepelin’s historical reassignment of agitated
depression as mixed state.
The frequency of mixed (agitated) depression in the
present sample of BP-II and unipolar outpatients was 38.6%,
supporting the clinical importance of mixed depression in
outpatient clinical practice. This rate may be related to the
high frequency of BP-II patients in our sample. The high
frequency of BP-II patients in the present sample is not
unusual, as many studies have recently shown that the fre-
quency of BP-II in MDE outpatients is much higher (up to
60%) than previously reported [3,8,12,26], because of sys-
tematic interviewing by trained clinicians about past hy-
pomanic episodes supplemented by information from key
informants [21].
The frequency of mixed depression in the present study
sample (up to 38.6%) has importance for the treatment of
depression. Clinicians have observed that antidepressants
may be associated with mixed depression by increasing psy-
chomotor agitation, insomnia, racing/crowded thoughts, and
suicidal behavior, while antipsychotics and mood stabilizers
often improve the condition [7,27]. Given the potentially
negative results of antidepressants in bipolar [24], and par-
ticularly those with mixed states [7], we suggest on the basis
of clinical considerations that the optimal treatment of mixed
depression could be a combination of antidepressants and
mood stabilizers, with antidepressants added when mood
stabilizers and/or atypical antipsychotics have treated the
excitatory symptoms; given that BP-II mixed state may not
infrequently respond well to mood stabilizers and/or antipsy-
chotics, an alternative might be not to use antidepressants at
all.
Although the study was conducted in the practice of a
single practitioner who was not blind to the validators used,
the systematic structured interview of a very large sample
tended to reduce any clinical biases. We find comfort in the
fact that agitated depression has been validated in a recent
study in Italian [30] and German [34] samples of bipolar I
patients. Although our findings provide persuasive evidence
to reclassify most outpatients with agitated depressions as
belonging to bipolar mixed states, they leave open the possi-
bility that a minority of such patients could still belong to
unipolar MDD. Koukopoulos’ specific definition of mixed
depression must be tested in the inpatient or daycare hospital
setting as well, although whatever data [30,34] exists from
alternative criteria for agitated depression from such settings
does support their inclusion in the bipolar spectrum.
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