1. health and fitness
2. disorders
3. mental disorder
4. depression

Available online at www.sciencedirect.com
Comprehensive Psychiatry xx (2011) xxx – xxx
www.elsevier.com/locate/comppsych
Depression across mood disorders: review and analysis in
a clinical sample
Daniel Souerya , Leonardo Zaninottob , Raffaella Calatib , Sylvie Linottec ,
Julien Mendlewicza , Othman Sentissid , Alessandro Serrettib,⁎
a
Laboratoire de Psychologie Medicale, Université Libre de Bruxelles and Psy Pluriel, Centre Europeén de Psychologie Medicale, 1180 Brussels, Belgium
b
Institute of Psychiatry, University of Bologna, 40123 Bologna, Italy
c
FNRS, Universite' Libre de Bruxelles, 1050, Belgium
d
Département de Psychiatrie, Hôpitaux Universitaires de Genève, Faculté de Médecine de Genève, Geneve, Switzerland
Abstract
Objectives: In this article we aimed to: (1) review literature concerning the clinical and psychopathologic characteristics of Bipolar (BP)
depression; (2) analyze an independent sample of depressed patients to identify any demographic and/or clinical feature that may help in
differentiating mood disorder subtypes, with special attention to potential markers of bipolarity.
Methods: A sample of 291 depressed subjects, including BP -I (n = 104), BP -II (n = 64), and unipolar (UP) subjects with (n = 53) and without (n =
70) BP family history (BPFH), was examined to evidence potential differences in clinical presentation and to validate literature-derived markers of
bipolarity. Demographic and clinical variables and, also, single items from the Hamilton Depression Rating Scale (HDRS), the Montgomery-Asberg
Depression Rating Scale (MADRS), and the Young Mania Rating Scale (YMRS) were compared among groups.
Results: UP subjects had an older age at onset of mood symptoms. A higher number of major depressive episodes and a higher incidence of
lifetime psychotic features were found in BP subjects. Items expressing depressed mood, depressive anhedonia, pessimistic thoughts, and
neurovegetative symptoms of depression scored higher in UP, whereas depersonalization and paranoid symptoms' scores were higher in BP.
When compared with UP, BP I had a significantly higher incidence of intradepressive hypomanic symptoms. Bipolar family history was
found to be the strongest predictor of bipolarity in depression.
Conclusions: Overall, our findings confirm most of the classical signs of bipolarity in depression and support the view that some features,
such as BPFH, together with some specific symptoms may help in detecting depressed subjects at higher risk for BP disorder.
© 2011 Elsevier Inc. All rights reserved.
1. Introduction
The coming of diagnostic manuals, with their polaritybased categorical model, has progressively obscured the
Conflicts of interest. None to declare.
Role of funding source. This work was supported by a research grant
from the National Found for Scientific Research, Belgium-Fonds National
de la Recherche Scientifique. Convention N° 3.4553.01. It was also
supported by an unrestricted grant from Janssen-Cilag.
Contributors. Daniel Souery designed the study and wrote the protocol.
Leonardo Zaninotto managed the literature searches and analyses. Raffaella
Calati undertook the statistical analysis, and Leonardo Zaninotto and
Alessandro Serretti wrote the first draft of the manuscript. Sylvie Linotte,
Othman Sentissi, and Julien Mendlewicz contributed to the improving of the
manuscript in various stages. All authors contributed to and have approved
the final manuscript.
⁎ Corresponding author. Tel.: +39 051 6584233; fax +39 051 521030.
E-mail address: [email protected] (A. Serretti).
0010-440X/$ – see front matter © 2011 Elsevier Inc. All rights reserved.
doi:10.1016/j.comppsych.2011.01.010
traditional dimensional concept of manic-depressive illness.
Early classical authors, such as Kraepelin [1] and Weygandt
[2], had placed more emphasis on recurrence rather than on
polarity of mood symptoms. It was with the classification by
Kleist [3] and Leonhard [4] and with the research by Angst
[5] and Perris [6] that the Unipolar (UP)–Bipolar (BP)
distinction gained its place in current nosology.
However, over the past 3 decades, some theoretical
studies have hypothesized that the current diagnostic
systems may be less suitable than the traditional spectrum
model in classifying mood disorders [7-12]. By requiring
the presence of both full-syndrome hypomanic and major
depressive episodes (MDEs), they fail to include symptoms
or signs that are mild and do not meet threshold criteria.
Some authors [13] have claimed that there is a substantial
proportion of UP patients whose mood disorder shows BP
affinity and that such patients occupy a large terrain
2
D. Souery et al. / Comprehensive Psychiatry xx (2011) xxx–xxx
between the extremes of classic unipolarity and bipolarity.
The concept of bipolar spectrum disorder (BSD) [7,14,15]
was developed to include a range of BP conditions that
would otherwise be misdiagnosed as UP depression. It has
been hypothesized that up to 50% of patients with recurrent
depression may be misclassified as having a UP disorder
rather than a BSD [16-18].
Misdiagnosing a BP patient as a UP depressed may have
many important consequences, such as inappropriate medications, poorer prognosis, and more health care resource
utilization. Indeed, antidepressant monotherapy is supposed
to cause more frequent mood episodes [19], treatment
resistance [20], destabilization of mood [21], rapid cycling
[22,23], and increased suicidal risk [24,25] in BP patients.
Thus, in recent years, there has been an increasing interest in
defining the phenomenology of BP depression [26,27], and
several practical guidelines have been developed to help
clinicians to reduce the risk of mistreatment [28-30].
In this sense, a definition of BP depression necessarily
depends on a comparison with UP depression, because their
therapeutic and prognostic pathways are significantly
different. As a consequence, most studies on BP depression
have been implicitly inspired by the polarity-based categorical model, as they usually compare BP- to UP-depressed
patients as homogeneous and distinct groups [31-44]. These
studies do not consider that some signs of bipolarity (eg,
subthreshold manic symptoms) may be represented in the
depressive phase of different mood disorders in a dimensional pattern. Only a few recent studies compare the
phenomenology of BP and UP depression, considering also
symptoms below the threshold of diagnostic manuals [4552]. Moreover, heterogeneity among samples of UP patients
and lack of control for differences in severity of depression
or age at onset may be other potential sources of divergent
findings in some studies comparing BP to UP depression.
To fill this gap, in this article we aimed to: (1) review
literature concerning the clinical and psychopathologic
characteristics of BP depression, when compared to UP
depression; (2) analyze an independent sample of depressed
patients to identify any demographic and/or clinical features
that may help in differentiating mood disorder subtypes, with
special attention to potential markers of bipolarity.
anxiety [31,36,43,60] have all been associated with UP
depression (Table 1). In this part of the article, we aimed to
give a more extensive overview of those features that may
serve as potential clues for bipolarity in depression.
An electronic literature search was performed to find
studies investigating differences between BP and UP
depression. Some prospective studies, including UP subjects
who will later convert to BP disorder, were also examined to
identify possible predictors of switching. Because literature
on this topic is extremely vast and heterogeneous, we
considered only those aspects that can be potentially detected
on a diagnostic interview and through the most common
rating scales for mood symptoms, such as the Hamilton
Depression Rating Scale (HAM-D) [61], the MontgomeryAsberg Depression Rating Scale (MADRS) [62], and the
Young Mania Rating Scale (YMRS) [63].
PubMed database was searched for articles published in
English until May 2010 by using any combination of the
terms bipolar, unipolar, major, and depression with
psychopathology, symptoms, or diagnosis. Other combinations were with terms such as psychomotor, mixed, atypical,
psychotic, onset, familiarity, and comorbidity. References
from retrieved articles were also screened to identify any
Insomnia
BP-I
BP-II
NS
2. Review of the literature
Atypical features
↑
↑ (BP-I)
↑ (BP-II)
NS
[102,104]
[43,48]
[171,48,49,73,50,51,172]
[105]a, [41,107]
Mixed features
↑
↑ (BP-II)
[71,50,173]
[174,73,172,175]
Psychotic features
↑ (BP-I)
Table 1
Clinical features of BP vs UP depressions
Clinical features
BP
UP
Studies
Somatic anxiety
BP-I
↑
↑
[31]
[44]
[33,54]
↑
↑
NS
[31,43]
[36], [60]a
[44]
↑
↑ (BP-I)
↑ (BP-II)
NS
[31,32]
[54,42,43]
[50]
[6,39,67,74]
NS
Psychic anxiety
Retardation
Appetite/weight loss
2.1. Defining the clinical presentation of BP depression
Although over the past 3 decades many studies have tried
to define BP depression [31,33,35-37,39,42-44,53-58],
currently, there are no accepted diagnostic criteria for it.
The most consisting evidence on bipolarity in depression
concerns the features of psychomotor activity, the presence
of mixed or atypical features, and the prevalence of
psychotic symptoms [34,42,43,48,54,59]. On the other
hand, initial insomnia [36,43,44,50], weight and appetite
loss [35,40], somatic complaints [31,44,55], and psychic
BP-I
↑
NS
↑
[35,40]
↑
↑
[36,43,44]
[50]
[40]
↑a
[34,43,59]
[60,176,37,139]
[42,36]
[38,31]
NS indicates nonsignificant differences.
a
Unipolar subjects who will later convert to BP disorder.
D. Souery et al. / Comprehensive Psychiatry xx (2011) xxx–xxx
3
Table 2
Sample size and measures used in the main studies
BP
UP
n
n
41
1087b
Clinical
Chart review
[104]
[177]
26 (I)
29
104
SADS; RDC
605
79
904
39
HAM-D; Zung Depression
Rating Scale; SCL-90
SADS
ADDS
CORE
HAM-D, CORE
293
SCL-90R; SAS-SR; ADDS
26
122
[37]
[38]
41
161
[59]
122 (I)
[60]
[41]
[42]
[43]
[102]
231 (I)
30
83
39
25
8
28
139
12
27
96 (II)
27 (II)
n
70 (I)
14
32
27
n
[71]
[73]
[35]
[36]
66 (II)
UP
[174]
[40]
[74]
[48]
[107]
25
13
15
19
6 (I)
17 (II)
a
BP
Bunney-Hamburg 15
Clinical
HAM-D
Clinical
HAM-D; Global Depression
Rating (self); MAACL
Clinical
PSE
[31]
[32]
[33]
[34]
[54]
[39]
Measure
65
40
107
708
690
SCID-CV; GAF
SCAN
SCID-CV; GAF
SCID 1.0; OPCRIT; HAM-D
SCID; SADS; GAF
25 (II)
187 (II)
863
126
10 (II)
37
50
[175]
348 (II)
254
[51]
348 (II)
254
25 (II)
379 (II)
863
271
1074
256
AMDP system
SCID-CV; GAF;
Family History Screen;
Hypomania Interview Guide
Clinical
SCID; Symptom
Questionnaire; CGI-BP,
Anger Attacks Questionnaire
SCID-CV; Family History Screen;
Hypomania Interview Guide
SCID-CV; GAF; Family History
Screen; Hypomania Interview Guide
AMDP system
SCID; Hypomania Interview Guide
MADRS; HAM-A
HAM-D; Rosenthal Atypical
Depression Scale; MVAS-BP
[173]
[172]
[44]
[50]
103 (II)
Measure
40
863 (I)
59
70 (I)
164 (II)
141 (II)
477
196 (II)
MAACL indicates Multiple Affect Adjective Checklist; PSE, Present State Examination; SADS, Schedule for Affective Disorders and Schizophrenia;
RDC, Research Diagnostic Criteria; SCL-90, Symptom Checklist 90; ADDS, Atypical Depression Diagnostic Scale; CORE, Consortium for Research in
ECT rating scale for psychomotor disturbances; SAS-SR, Social Adjustment Scale–Self-Report version; SCID-CV, Structured Clinical Interview for
DSM-IV, Clinician Version; GAF, Global Assessment of Functioning; SCAN, Schedules for the Clinical Assessment in Neuropsychiatry; OPCRIT,
Operational Criteria for Psychotic Illness Checklist; AMDP, Association for Methodology and Documentation in Psychiatry; CGI-BP, Clinical Global
Impression-BP subjects; MVAS-BP, Multi-Visual Analog Scale of Bipolarity; HAM-A, Hamilton Anxiety Rating Scale.
a
Which measures changes in the patient's behavior.
b
Divided into primary UP depression and secondary UP depression.
additional study. For all publications, the entire article was
evaluated to detect pertinent references. For studies comparing samples of BP and UP patients, sample sizes and used
measures were extracted (Table 2). Most articles were widely
heterogeneous in their theoretical background, outcome
measures, inventories, sample size, and selection of BP
patients (BP-I, BP-II or, sometimes, only BP).
We schematically divided the diagnostic validators for BP
depression into 2 main categories: (a) internal validators,
including psychopathologic characteristics of depression that
have been most widely associated with bipolarity; and (b)
external validators, concerning additional characteristics,
such as the clinical correlates and the course of illness. For
the first category, we considered only those features for
which there were at least 2 articles with the symptompolarity association running in the same direction (Table 1).
2.2. Internal validators
2.2.1. Psychomotor activity
Traditionally, psychomotor activity has always represented an important distinctive element for mood polarity.
The original position of Kraepelin [1] and Weygandt [2]
paid a significant attention to the combination of opposite
symptoms of mood, thought and activity to define
mood polarity.
The extreme variability of symptoms, which may range
from depressive stupor to agitated psychosis, makes it
difficult to define a characteristic picture of psychomotor
activity in BP depression. Psychomotor retardation with
hypersomnia [43,64,65] may be more characteristic of the
“pure” depressive phase of the illness, whereas psychotic,
agitated-irritable depression may be more connected to
mixed states [66]. Some studies have reported a higher
prevalence of psychomotor retardation in both BP-I and BPII patients [31,42,50,54]. Conversely, in UP depression,
some authors [31,53] found higher activity levels, whereas
others [67] found no significant differences. Other studies
[6,33,39,54,55,68] reported discrepant findings.
These inconsistencies may depend on 2 main reasons: (1)
sometimes in UP subjects, agitation can coexist with
retardation [69]; (2) a major depressive state may present
with subthreshold manic symptoms [70,71]. To disentangle
this complex situation, it has been proposed to consider that
4
D. Souery et al. / Comprehensive Psychiatry xx (2011) xxx–xxx
it is acceleration and not agitation that must be opposed to
retardation [72]. However, a clearer definition of psychomotor changes in BP depression also depends on whether
mixed features are permitted (and on the established
threshold for mixed states) and, also, on which type of BP
disorder (BP-I or BP-II) is compared to UP depression
[50,73,74]. Despite a lack of consistency, most authoritative
clinical descriptions, for example, by Goodwin and Jamison
[12], continue to describe psychomotor retardation as being
more prevalent in BP-depressed patients.
2.2.2. Mixed depression
The diagnosis of mixed depression has been supported by
several recent studies in BP-I, BP-II, and UP samples
[66,71,75-80]. More than the strict definition of DSM-IV-TR
(Diagnostic and Statistical Manual of Mental Disorders,
Fourth Edition, Text Revision) for mixed states, which seems
to be not common in clinical practice [81,82], a dimensional
definition of mixed depression (or depressive mixed state)
was found to have better diagnostic validity [71,83,84]. A
definition requiring MDEs plus 3 or more intra-MDE
subthreshold manic symptoms (eg, irritability, distractibility,
or racing/crowded thoughts) was the most strongly validated
definition [75, 85-87].
The construct of mixed depression has been traditionally
associated with bipolarity. Recently, it has also been
validated by usual BP disorder validators [88-90] and by
factor analysis [75,83,91]. Interestingly, Benazzi [45] and
Benazzi and Akiskal [92] found a sort of “dose-response”
relationship between hypomania scores in depression and the
extent of BP family history (BPFH), suggesting that UP with
BPFH and BP-II are on the same spectrum rather than
representing separate categories.
2.2.3. Psychotic features
Despite few inconsistent findings [31,38], BP depression
may be characterized by a higher incidence of psychotic
features [34,36,42,43,59,93]. Furthermore, an important
prospective follow-up study found that most of UP subjects
who converted to BP-I were more likely to have been
psychotic or hospitalized at the index depressive assessment
[60]. However, most studies only compared BP subjects to
UP depressed, without distinguishing BP-I and BP-II, even if
this characteristic seems to be more consistently related to
the depressive phase of BP-I disorder [34,43,59].
2.2.4. Atypical features
In BP depression, a greater prevalence of atypical
features or reverse neurovegetative symptoms, such as
hypersomnia or hyperphagia, was reported by most studies
[35,37,43,73,94-98], but not all [41]. A prospective study
has also demonstrated that atypical depression more than
expected progresses into a BSD [99]. More atypical
symptoms have also been detected in BP-II than in UPdepressed patients [43,50,51,95,99-104]. Not all investigators have found such differences [41,105-108], but negative
studies usually involved small and/or unbalanced samples
[12]. As for mixed features, Akiskal and Benazzi [51,52]
found a robust association between atypical symptoms and
BPFH, suggesting that these features also may serve as a
bridge between UP and BP-II disorders.
2.3. External validators
2.3.1. Familiarity
Bipolar disorder has an estimated heritability of 59% to
87% [109]. Although exploring familiarity is more difficult
for BP-II than for BP-I disorder, BP-II disorder also seems to
run in families with specific aggregation patterns [92,110113]. Other several associated clinical phenomena, such as
psychosis [114,115], comorbidities [115,116], and suicidality [117], and some characteristics of the course of illness,
such as rapid cycling [118], age of onset [119,120], and
episode frequency [121] may come together in BP families.
Moreover, BP and UP disorders seem also to run together in
families, as BP patients frequently have UP family members
and vice versa [122,123]. Furthermore, UP patients with
BPFH seem to present significantly lower age at onset, more
recurrences, and an atypical pattern (all BP features) [89,90].
2.3.2. Comorbidities
Many studies have evidenced differences in the incidence
rate of comorbid disorders between UP and BP patients.
Empirical data suggest that UP patients may have more
anxiety disorders in general [124-126], whereas evidence
from population-based studies (Epidemiologic Catchment
Area and National Comorbidity surveys) shows that panic
disorder comorbidity is significantly greater among individuals with BP disorder [127-130]. Some studies have also
pointed to a specific genetic relationship between BP
disorder and panic disorder [116,131]. Other results from
large clinical samples suggest that generalized anxiety
disorder and obsessive-compulsive disorder are more
frequent in BP disorder than in UP disorder [130,132,133].
Finally, BP patients may also present with higher rates of
substance use [12,134] than UP patients.
2.3.3. Course of illness
Traditionally, BP disorder has been reported to have an
earlier age at onset than recurrent major depressive disorder
[135]. A close association has been shown among early
onset, high recurrence, and both individual [136,137] and
family traits of bipolarity [138]. Thus, early-onset (and
highly recurrent) UP depression is supposed to be at higher
risk of shifting to BP disorder [17,60,139]. This finding may
be very important for its therapeutic implications
[12,140,141]. Bipolar disorder seems to present a higher
number of lifetime depressive episodes [44,142,143], more
severe diurnal mood variations [144], higher variability of
mood symptoms across and within episodes (especially in
BP-II) [4,36,50,56], and faster development of full-blown
depressive symptoms [145]. Conversely, UP subjects seem
to be characterized by longer duration of episodes
[33,43,146] and by an unvarying quality of mood symptoms
D. Souery et al. / Comprehensive Psychiatry xx (2011) xxx–xxx
[36,43]. There is also some evidence about a greater severity
[44,147] of mood symptoms in UP subjects, although on this
topic findings are contrasting [148,149].
3. Original study
3.1. Methods
Patients were recruited within the center “Psy Pluriel,”
Centre Européen de Psychologie Médicale (outpatients
only), and the Department of Psychiatry of Erasme
Hospital (in- and outpatients) in Brussels, between March
2004 and March 2009, in the context of the COPE-Bipolar.
COM (Clinical Outcome and Psycho Education for Bipolar
Disorder.Clinical Outcome Measures Section) program
(started in December 2003 and now ongoing). The
COPE.COM for Bipolar Disorder is a software program
that allows assessment of mood disorder patients by using
structured examination tools and immediate data capture. It
is composed of 10 “modules,” each of them dedicated to
essential elements of UP and BP disorders, such as
sociodemographic characteristics, familiarity, diagnosis,
treatment, and quality of life and functioning.
Clinical interviews were carried out by specifically trained
psychiatrists. Lifetime diagnosis, course of illness, and
comorbidities of patients were assessed based on the MiniInternational Neuropsychiatric Interview [150]. Further information was gathered from the patient's relatives. Psychiatric
familial antecedents have been screened without the use of
structured interviews, investigating for each patient, (1) familial
history of recurrent major depressive disorder and BP disorder
in first- and second-degree relatives; (2) familial history of other
psychiatric disorders in first-degree relatives; (3) familial
history of suicide and suicidal attempts in first- and seconddegree relatives. Diagnoses of familial antecedents were not
blind to proband diagnosis. Severity of mood symptoms was
assessed using the HAM-D [61], MADRS [62], and YMRS
[63] rating scales. For each scale all the items were available.
The accuracy and completeness of the collected clinical
information have been independently tested by 2 researchers.
All raters were trained for the use of instruments with good
interrater reliability (κ N 0.8).
Patients were included if they met DSM-IV criteria for a
diagnosis of mood disorders (BP-I, BP-II, UP) according to the
Mini-International Neuropsychiatric Interview [150]. Individuals with mental retardation, dementia, neurologic disorder,
or severe organic disease were excluded. Written informed
consent was obtained from all participants in the study.
A total of 554 patients were examined for demographic
and clinical variables. Patients were divided into BP-I (n =
222), BP-II (n = 133), and UP (n = 199) mood disorder
subtypes. Furthermore, UP subjects were subdivided based on
the presence of BPFH into UP with BPFH (n = 81) and UP
without BPFH (n = 118). From this sample, depressed
subjects (n = 291) were extracted. Depression was defined by
a cutoff score of 13 at the HAM-D to include also patients
5
with milder forms of depression [151]. The final sample
included 104 BP-I (35.7%), 64 BP-II (22%), 53 UP with
BPFH (18.2%), and 70 UP without BPFH (24.1%).
Both HAM-D and MADRS items were compared among
diagnostic groups by using analysis of covariance, with the total
score of the rating scale as the covariate. Although the use of a
rating scale for mania in depressed patients may be questionable,
we also decided to compare YMRS items among groups to
detect any potential difference in the presence of hypomanic
symptoms. HAM-D and YMRS total scores were used as
covariates. For analysis of covariance, the HAM-D items were
also pooled into the following factors: core (items 1, 2, 7, 8, 10,
and 13), sleep (items 4, 5, and 6), activity (items 7 and 8),
psychic anxiety (items 9 and 10), somatic anxiety (items 11, 12,
and 13), and delusion (items 2, 15, and 20) [100,152-154].
Although there have been several reports on the factor analysis
of the MADRS [153,155-159], the results have been inconsistent, so items were not pooled into a factor model. Demographic
and illness characteristics were compared by using a χ2 test for
categorical data and an analysis of variance for continuous
measures. Whenever indicated, post hoc analyses (least
significant difference test) were performed to discriminate
individual effects. Finally, a logistic regression model was
performed to determine the best predictors of BP depression vs
UP depression, to find potential markers of bipolarity. The
variables included in the models were those which were found to
be significantly associated with diagnosis on univariate and
covariate analyses.
We defined statistical significance at P = .05. The sample
had sufficient power (0.80) to detect a small-medium effect
size (F = 0.19), that, as an example, corresponds to a 1.1
score at the HAM-D total score between UP and BP-I
patients. “Statistica” package (StatSoft. Statistica for Windows, 1995, StatSoft Italia srl) was used for the analyses.
4. Results
4.1. Demographic and clinical characteristics
In our sample (n = 291), BP-I patients had the strongest
representation (35.7%), equally divided between inpatients and
outpatients. The ratio of inpatients was higher in the UP and UP
with BPFH subsamples (69.6% and 70.6%, respectively). No
difference among groups was found for sex, mean age, civil
status, level of education, and professional status.
The most significant difference emerged for familiarity
(Table 3). Unipolar patients with BPFH exhibited a higher
probability of having a positive family history for UP
depression, suicide, and other psychiatric disorders. No
differences were found in the number of family members
affected by BP disorder between BP-I and BP-II.
Regarding the course of illness, duration of the current
depressive episode was longer in UP than in BP-I subjects
(P = .03). Unipolar also had an older age at onset and an
older age at the first MDE than the other groups. A higher
number of lifetime MDEs (F = 4.03; P = .008) was found in
6
D. Souery et al. / Comprehensive Psychiatry xx (2011) xxx–xxx
Table 3
Demographic features, course of illness, and clinical characteristics of the current mood episode (MDE)
Total, 291 subjects
Age (y)
Sex
Civil status
BP-I, n = 104
(35.7%)
n (%)/mean (SD)
44.9 (14.4)
Male
42 (40.4%)
Single
38 (36.5%)
Married
46 (44.2%)
Separated/widowed
20 (19.2%)
Education
Primary/no education
8 (7.8%)
(n = 289) Secondary
70 (68.0%)
University
25 (24.3%)
Profession Student/employed
78 (75.0%)
(n = 290) Unemployed/retired
26 (25.0%)
Origin
Inpatients
52 (50.5%)
(n = 287)
Familiarity UP
86 (82.7%)
77 (74.0%)
BPa
Suicide
36 (34.6%)
Other
73 (70.2%)
Severity
Severe
81 (81.0%)
(n = 266) Moderate
13 (13.0%)
Mild
6 (6.0%)
Features
Melancholic (n = 287)
65 (63.1%)
26 (30.6%)
Seasonalb
Psychotic (lifetime)
57 (54.8%)
Psychotic (current)
17 (16.4%)
140.4 (396.0)
Current episode (d)
(n = 273)c
Age at onset (n = 274)d 21.6 (12.3)
7.5 (4.2)
No. of lifetime MDE
(n = 285)e
23.2 (12.6)
Age at first MDE
(n = 266)f
13.6 (54.8)
Hospitalization
lifetime (wk)g
Age first hospitalization 32.4 (13.5)
(n = 97)
BP-II, n = 64
(22.0%)
n (%)/mean (SD)
UP/BPFH, n = 53
(18.2%)
n (%)/mean (SD)
UP, n = 70
(24.1%)
n (%)/mean (SD)
χ2/F
df
P
44.4 (13.2)
21 (32.8%)
16 (25.0%)
38 (59.4%)
10 (15.6%)
3 (4.8%)
47 (74.6%)
13 (20.6%)
47 (73.4%)
17 (26.6%)
24 (37.5%)
45.3 (12.7)
22 (41.5%)
22 (41.5%)
20 (37.7%)
11 (20.8%)
7 (13.2%)
33 (62.3%)
13 (24.5%)
42 (80.8%)
10 (19.2%)
36 (70.6%)
49.0 (16.6)
17 (24.3%)
19 (27.1%)
32 (45.7%)
19 (27.1%)
6 (8.6%)
51 (72.9%)
13 (18.6%)
45 (64.3%)
25 (35.7%)
48 (69.6%)
1.52 3.287
5.97 3
.2090
.1128
9.13 6
.1663
4.13 6
.6596
4.52 3
.2109
19.69 3
.0002
53 (82.8%)
47 (73.4%)
26 (40.6%)
46 (71.9%)
51 (83.6%)
10 (16.4%)
–
30 (46.9%)
22 (41.5%)
19 (29.7%)
8 (12.5%)
160.0 (191.7)
52 (98.1%)
53 (100%)
31 (58.5%)
41 (77.4%)
28 (70.0%)
11 (27.5%)
1 (2.5%)
28 (54.9%)
9 (23.7%)
13 (24.5%)
4 (7.6%)
180.5 (259.2)
51 (72.9%)
–
20 (28.6%)
37 (53.9%)
44 (67.7%)
19 (29.2%)
2 (3.1%)
40 (58.0%)
11 (22.5%)
4 (5.7%)
3 (4.3%)
266.2 (474.4)
13.79
0.01
12.59
10.12
3
1
3
3
.0032
.9314
.0056
.0176
12.51 6
.0516
21.6 (11.5)
8.0 (4.2)
20.9 (11.6)
6.1 (4.2)
26.0 (13.7)
6.0 (4.2)
2.34 3.270
4.03 3.281
.0733
.0079
22.6 (12.9)
20.9 (11.6)
26.7 (13.9)
2.07 3.262
.1052
7.8 (29.7)
13.7 (24.5)
6.7 (5.7)
1.07 3.287
.3609
32.1 (11.0)
30.6 (11.9)
36.2 (13.5)
0.89 3.93
.4486
4.35
5.38
48.63
7.05
1.71
3
.2259
3
.1459
3
b.0001
3
.0702
3.269 .1650
a
The comparison was made only between BP subjects.
Excluded subjects with less than 2 lifetime MDEs.
c
Post hoc: UP more than BP-I (P = .03).
d
Post hoc: UP more than BP-I (P = .02); UP more than BP-II (P = .05); UP more than UP/BPFH (P = .03).
e
Adjusted for age at onset. Post hoc: BP-I more than UP (P = .02); BP-II more than UP/BPFH (P = .01); BP-II more than UP (P = .005); BP-I more than UP/
BPFH (P = .04).
f
Adjusted for age at onset. Post hoc: UP more than BP-I (P b .0001); BP-I more than UP/BPFH (P = .01); UP more than BP-II (P b .0001); UP more than
UP/BPFH (P b .0001).
g
Adjusted for the presence of lifetime psychotic features.
b
BP subjects, independently from age at onset. Moreover, BPI showed the highest rate of lifetime psychotic features (χ2 =
48.63; P b .0001). Unexpectedly, we could not detect any
difference in comorbidity among groups (Table 4), but
we hypothesize that this may depend on a higher severity
of UP subjects.
The same analyses were also performed on the original
sample (n = 554), where results about course of illness and
age at onset run in the same direction. In detail, BP-II and UP
subjects, respectively, exhibited the highest (n = 7.62) and
the lowest (n = 5.75) number of lifetime MDEs (F = 3.53;
P = .01). Moreover, UP with BPFH presented an earlier
onset of illness (F = 5.61; P = .0009), a younger age at the
first MDE (F = 4.63; P = .003), and a younger age at the first
hospitalization (F = 3.68; P = .01) than the other groups.
4.2. Symptom presentation
Multivariate comparisons of HAM-D factors and MADRS
items were performed, and all analyses were adjusted for
overall depressive severity (results are shown in Table 5). The
scores expressing “depressed mood” (HAM-D item 1 and
MADRS items 1 and 2) were significantly higher for UP than
for BP patients. Other items expressing depressive anhedonia
and “pessimistic thoughts” (MADRS items 8 and 9) or
neurovegetative symptoms of depression (HAM-D item 16
D. Souery et al. / Comprehensive Psychiatry xx (2011) xxx–xxx
7
Table 4
Comorbidities of mood disorder subtypes
Total, 291 subjects
BP-I, n = 104 (35.7%) BP-II, n = 64 (22.0%) UP/BPFH, n = 53 (18.2%) UP, n = 70 (24.1%) χ2
df P
Anxiety disorders
Panic disorder/agoraphobia (n = 290)
Social phobia (n = 290)
OCD (n = 284)
PTSD
Substance use disorders
Alcohol abuse/dependence
Other substances
Eating disorders (n = 290)
73 (70.2%)
52 (50.0%)
19 (18.3%)
13 (12.9%)
7 (6.7%)
27 (26.0%)
27 (26.0%)
8 (7.7%)
2 (1.9%)
3
3
3
3
3
3
3
3
3
41 (64.1%)
24 (38.1%)
12 (19.1%)
12 (19.1%)
6 (9.4%)
14 (21.9%)
8 (12.5%)
8 (12.5%)
2 (2.1%)
34 (64.2%)
20 (37.7%)
5 (9.4%)
4 (8.0%)
4 (7.6%)
10 (18.9%)
7 (13.2%)
4 (7.6%)
2 (3.9%)
47 (67.1%)
28 (40.0%)
10 (14.3%)
13 (18.6%)
12 (17.1%)
14 (20.0%)
13 (18.6%)
4 (5.7%)
5 (7.1%)
0.92
3.55
3.66
1.61
6.54
1.38
6.22
2.20
3.23
.8195
.3141
.3004
.6581
.0880
.7094
.1014
.5320
.3578
OCD indicates obsessive-compulsive disorder; PTSD, post-traumatic stress disorder.
Table 5
Psychopathologic features of mood disorder subtypes
HAM-D total score
CORE (items 1, 2, 7, 8, 10, and 13)a
Sleep (items 4, 5, and 6)
Activity (items 7 and 8)
Psychic anxiety (items 9 and 10)b
Somatic anxiety (items 11, 12, and 13)c
Delusion (items 2, 15, and 20)
Item 1 (depressed mood)d
Item 8 (retardation)e
Item 11 (somatic anxiety)f
Item 16 (weight loss)g
Item 17 (insight)h
Item 19 (depersonalization/derealization)i
Item 20 (paranoid symptoms)j
MADRS total score
MADRS item 1 (apparent sadness)k
MADRS item 2 (reported sadness)l
MADRS item 3 (inner tension)m
MADRS item 4 (reduced sleep)n
MADRS item 5 (reduced appetite)o
MADRS item 7 (lassitude)p
MADRS item 8 (inability to feel)q
MADRS item 9 (pessimistic thoughts)r
MADRS item 10 (suicidal thoughts)
BP-I, mean (SD)
BP-II, mean (SD)
UP/BPFH, mean (SD)
UP, mean (SD)
F
df
P
21.6 (5.6)
10.45 (2.92)
2.34 (1.61)
3.63 (1.64)
2.93 (1.35)
3.18 (1.59)
2.68 (1.60)
2.08 (0.92)
1.22 (0.91)
1.50 (0.96)
0.40 (0.70)
0.35 (0.55)
0.64 (1.06)
0.34 (0.66)
20.3 (4.6)
10.14 (2.56)
2.25 (1.52)
3.45 (1.55)
2.53 (1.21)
3.22 (1.31)
2.56 (1.41)
2.09 (0.75)
1.14 (1.01)
1.59 (0.90)
0.50 (0.71)
0.20 (0.41)
0.22 (0.60)
0.28 (0.55)
20.7 (5.3)
10.83 (2.72)
2.15 (1.55)
3.91 (1.87)
2.70 (1.25)
2.75 (1.80)
2.77 (1.48)
2.17 (1.05)
1.57 (0.99)
1.26 (0.92)
0.38 (0.69)
0.38 (0.60)
0.38 (0.79)
0.26 (0.68)
22.1 (5.7)
10.92 (2.84)
2.60 (1.59)
3.60 (1.63)
2.76 (1.24)
3.46 (1.55)
2.47 (1.35)
2.43 (0.81)
1.27 (0.93)
1.71 (0.89)
0.69 (0.86)
0.49 (0.53)
0.31 (0.75)
0.11 (0.47)
1.59
1.45
0.48
1.24
0.93
1.99
1.63
2.21
2.79
2.54
2.31
2.85
3.89
2.50
3.286
3.286
3.286
3.286
3.286
3.286
3.286
3.286
3.286
3.286
3.286
3.286
3.286
3.286
.1920
.2294
.6972
.2611
.4249
.1155
.1823
.0863
.0408
.5656
.0766
.0377
.0095
.0598
25.2 (8.5)
2.89 (1.41)
3.21 (1.36)
2.90 (1.25)
2.28 (1.59)
1.37 (1.52)
3.02 (1.40)
2.13 (1.53)
2.58 (1.39)
1.80 (1.53)
25.0 (7.0)
2.91 (1.08)
3.09 (1.11)
2.88 (0.98)
2.41 (1.43)
1.44 (1.47)
3.09 (1.16)
1.84 (1.45)
2.25 (1.18)
2.16 (1.60)
24.6 (7.8)
3.32 (1.34)
3.08 (1.36)
2.42 (1.41)
2.21 (1.76)
1.19 (1.59)
3.38 (1.47)
2.08 (1.53)
2.53 (1.50)
1.72 (1.59)
28.4 (8.8)
3.43 (1.20)
3.69 (1.17)
3.06 (1.30)
2.76 (1.42)
1.89 (1.59)
3.23 (1.12)
2.34 (1.41)
2.96 (1.12)
2.09 (1.58)
3.14
3.92
0.74
2.29
0.50
0.54
2.58
0.78
1.73
1.65
3.286
3.286
3.286
3.286
3.286
3.286
3.286
3.286
3.286
3.286
.0256
.0091
.5287
.0784
.6812
.6574
.0537
.5087
.1602
.1770
For HAM-D, only items with differences across groups were represented.
a
Post hoc: UP more than BP-II (P = .03).
b
Post hoc: BP-I more than BP-II (P = .04).
c
Post hoc: UP more than UP with BPFH (P = .003).
d
Post hoc: UP more than BP-I (P = .005); UP more than BP-II (P = .02).
e
Post hoc: UP with BPFH more than BP-I (P = .02); UP with BPFH more than BP-II (P = .01).
f
Post hoc: UP more than UP with BPFH (P = .003); BP-II more than UP with BPFH (P = .03).
g
Post hoc: UP more than BP-I (P = .01); UP more than UP with BPFH (P = .02).
h
Post hoc: UP more than BP-II (P = .002).
i
Post hoc: BP-I more than UP (P = .007); BP-I more than BP-II (P = .0008); BP-I more than UP with BPFH (P = .05).
j
Post hoc: BP-I more than UP (P = .02).
k
Post hoc: UP more than BP-I (P = .0001); UP more than BP-II (P = .0008); UP with BPFH more than BP-II (P = .01); UP with BPFH more than BP-I
(P = .005).
l
Post hoc: UP more than BP-I (P = .0005); UP more than BP-II (P = .0001); UP more than UP with BPFH (P = .0001).
m
Post hoc: UP more than UP with BPFH (P = .001); BP-II more than UP with BPFH (P = .02); BP-I more than UP with BPFH (P = .007).
n
Post hoc: UP more than BP-I (P = .03); UP more than UP with BPFH (P = .03).
o
Post hoc: UP more than BP-I (P = .007); UP more than BP-II (P = .04); UP more than UP with BPFH (P = .002).
p
Post hoc: UP with BPFH more than BP-I (P = .04).
q
Post hoc: UP more than BP-II (P = .01).
r
Post hoc: UP more than BP-I (P = .02); UP more than BP-II (P = .0001); UP more than UP with BPFH (P = .03).
8
D. Souery et al. / Comprehensive Psychiatry xx (2011) xxx–xxx
Fig. 1. Least squares mean scores from individual baseline HAM-D selected items, adjusted for total HAM-D score (*P b .05; **P b .005).
and MADRS items 4 and 5) also scored higher in UP than in
BP patients. Moreover, items referring to psychomotor
retardation (HAM-D item 8 and MADRS item 7) were
higher for UP with BPFH than for BP subjects, whereas the
paranoid item (HAM-D item 20) scores were higher for BP-I
than for UP patients (Figs. 1 and 2).
YMRS items were also compared among groups, using
YMRS and HAM-D total scores as covariates (Fig. 3).
Significant differences were found on items 4 (“decreased
sleep”) and 7 (“thought disorder”) (Table 6). Need for sleep
was more reduced in BP-I and UP with BPFH. Interest-
ingly, when compared with UP, BP-I scored significantly
higher on all items. Only on items expressing decreased
sleep (item 4), “aggressive-disruptive behavior” (item 9),
and “insight” (item 11) UP with BPFH emerged with
higher scores.
Clinical features and rating scale items were then
incorporated as predictors in a logistic regression model
with diagnosis (BP vs UP) as the outcome variable
(predictors are presented in Table 7). A final comprehensive
model was then performed to include all variables that were
significantly associated with bipolarity in the previous
Fig. 2. Least squares mean scores from individual baseline MADRS selected items, adjusted for total MADRS score (*P b .05; **P b .005).
D. Souery et al. / Comprehensive Psychiatry xx (2011) xxx–xxx
9
Fig. 3. Least squares mean scores from individual baseline YMRS items, adjusted for total YMRS and total HAM-D score (*P b .05; **P b .005).
models. In our sample, the strongest indices of bipolarity
appeared to be a positive family history for BP disorder and a
higher incidence of psychotic features (lifetime). Conversely, MADRS items 1 (“apparent sadness”) and 9 (“pessimistic
thoughts”) were significantly associated with UP diagnosis.
The exclusion from the model of UP patients with a single
MDE did not significantly affect the level of significance.
5. Discussion
Our results seem to point out some clinical and
psychopathologic variables, which may serve as diagnostic
clues for bipolarity in depression [12,160,161]. A different
clinical and symptomatic profile of depression among mood
disorder subtypes has been evidenced, where the 2 extremes
Table 6
Psychopathologic features of mood disorder subtypes (YMRS items)
a
YMRS item 1 (elevated mood)
YMRS item 2 (increased motor activity)b
YMRS item 3 (sexual interest)c
YMRS item 4 (decreased sleep)d
YMRS item 5 (irritability)e
YMRS item 6 (speech)f
YMRS item 7 (thought disorder)g
YMRS item 8 (content)h
YMRS item 9 (aggressive behavior)i
YMRS item 10 (appearance)j
YMRS item 11 (insight)k
a
b
c
d
e
f
g
h
i
j
k
BP-I, mean (SD)
BP-II, mean (SD)
UP/BPFH, mean (SD)
UP, mean (SD)
F
df
P
0.32 (0.66)
0.44 (0.82)
0.21 (0.73)
0.50 (0.90)
1.14 (1.47)
0.71 (1.54)
0.37 (0.64)
0.20 (0.64)
0.17 (0.55)
0.29 (0.59)
0.36 (0.82)
0.09 (0.29)
0.19 (0.53)
0.05 (0.21)
0.27 (0.62)
0.70 (1.06)
0.31 (0.96)
0.05 (0.21)
0.06 (0.35)
0.03 (0.25)
0.06 (0.24)
0.11 (0.48)
0.08 (0.33)
0.17 (0.47)
0.06 (0.30)
0.58 (0.97)
0.75 (1.39)
0.23 (0.72)
0.15 (0.53)
0.15 (0.66)
0.21 (0.72)
0.21 (0.49)
0.40 (0.91)
0.01 (0.12)
0.07 (0.39)
–
0.37 (0.76)
0.53 (0.91)
0.09 (0.41)
0.01 (0.12)
0.03 (0.24)
0.04 (0.27)
0.13 (0.41)
0.04 (0.20)
0.94
0.40
2.06
0.27
1.20
2.70
0.22
1.30
0.80
2.40
0.94
3.286
3.286
3.286
3.286
3.286
3.286
3.286
3.286
3.286
3.286
3.286
.0627
.4138
.7168
.0440
.8000
.3110
.0480
.8774
.2831
.5654
.0730
Post hoc: BP-I more than UP (P b .0001); BP-I more than UP with BPFH (P b .0001); BP-I more than BP-II (P b .0001).
Post hoc: BP-I more than UP (P b .0001); BP-I more than UP with BPFH (P = .0003); BP-I more than BP-II (P = .0003).
Post hoc: BP-I more than UP (P = .001); BP-I more than UP with BPFH (P = .03); BP-I more than BP-II (P = .01).
Post hoc: BP-I more than BP-II (P = .03); UP with BPFH more than BP-II (P = .01).
Post hoc: BP-I more than UP (P b .0001); BP-I more than UP with BPFH (P = .01); BP-I more than BP-II (P = .002).
Post hoc: BP-I more than UP (P b .0001); BP-I more than UP with BPFH (P = .0003); BP-I more than BP-II (P = .002).
Post hoc: BP-I more than UP (P b .0001); BP-I more than UP with BPFH (P = .0004); BP-I more than BP-II (P b .0001); UP with BPFH more than UP (P = .03).
Post hoc: BP-I more than UP (P = .01); BP-I more than BP-II (P = .04).
Post hoc: BP-I more than UP (P = .04); BP-I more than BP-II (P = .03); UP with BPFH more than BP-II (P = .02); UP with BPFH more than UP (P = .03).
Post hoc: BP-I more than UP (P = .01); BP-I more than BP-II (P = .0005).
Post hoc: BP-I more than UP (P b .0001); BP-I more than BP-II (P = .002); UP with BPFH more than UP (P = .0001); UP with BPFH more than BP-II (P = .002).
10
D. Souery et al. / Comprehensive Psychiatry xx (2011) xxx–xxx
Table 7
Multiple logistic regression model for BP vs UP depression
Regression and variable
Odds ratio
95% CI
P
0.29-1.47
0.71-1.07
2.04-7.05
0.08-1.18
0.73-6.61
0.53-1.82
0.93-1.03
1.04-1.20
0.99-1.10
1.01-1.02
.3042
.2013
b.0001
.0854
.1625
.9537
.4099
.0021
.1224
b.0001
Model 2: BP vs UP depression: adjusted HAM-D items
HAM-D 1 (depressed mood)
0.66
0.36-1.22
HAM-D 8 (retardation)
0.80
0.46-1.39
HAM-D 11 (somatic anxiety)
1.14
0.63-2.04
HAM-D 16 (weight loss)
0.70
0.34-1.41
HAM-D 17 (insight)
0.27
0.10-0.73
HAM-D 20 (paranoid symptoms) 2.87
1.04-7.94
.1856
.4229
.6637
.3164
.0091
.0411
Model 3: BP vs UP depression: adjusted MADRS items
MADRS 1 (apparent sadness)
0.71
0.55-0.93
MADRS 2 (reported sadness)
0.91
0.67-1.25
MADRS 3 (inner tension)
0.91
0.73-1.12
MADRS 4 (reduced sleep)
0.84
0.68-1.05
MADRS 5 (reduced appetite)
0.86
0.60-1.23
MADRS 7 (lassitude)
0.69
0.52-0.91
MADRS 8 (inability to feel)
0.96
0.70-1.32
MADRS 9 (pessimistic thoughts)
0.72
0.55-0.95
Total MADRS
0.96
0.95-0.98
.0115
.5745
.3649
.1274
.4033
.0094
.8161
.0184
.0002
Model 1: BP vs UP depression: clinical variables
Familiarity UP
0.66
No. of affected relatives (UP)
0.88
Familiarity BP
3.79
Familiarity suicide
0.31
No. of affected relatives (suicide)
2.19
Familiarity other
0.98
Onset
0.98
No. of lifetime MDE
1.12
Age at first MDE
1.04
Lifetime psychotic features
1.02
Model 4: BP vs UP depression: adjusted YMRS items
YMRS 1 (elevated mood)
3.45
0.12-103.30
YMRS 2 (increased motor
2.14
0.07-63.47
activity)
YMRS 3 (sexual interest)
3.06
0.10-92.61
YMRS 4 (decreased sleep)
1.60
0.05-47.23
YMRS 5 (irritability)
1.82
0.06-53.87
YMRS 6 (speech)
2.06
0.07-60.93
YMRS 7 (thought disorder)
2.11
0.07-64.34
YMRS 8 (content)
2.08
0.07-61.80
YMRS 9 (aggressive behavior)
1.43
0.05-42.44
YMRS 10 (appearance)
1.93
0.07-57.27
YMRS item 11 (insight)
1.70
0.06-50.04
Model 5: BP vs UP depression: significant variables
Familiarity BP
3.54
2.02-6.22
No. of lifetime MDE
1.06
0.99-1.34
Lifetime psychotic features
1.02
1.01-1.02
HAM-D 17 (insight)
0.49
0.17-1.44
HAM-D 20 (paranoid symptoms) 0.63
0.19-2.08
MADRS 1 (apparent sadness)
0.37
0.19-0.71
MADRS 7 (lassitude)
0.62
0.36-1.08
MADRS 9 (pessimistic thoughts)
0.44
0.24-0.80
Total MADRS
0.98
0.94-1.01
.4735
.6604
.5188
.7858
.7282
.6759
.6668
.6703
.8361
.7020
.7588
b.0001
.0774
b.0001
.1950
.4419
.0026
.0927
.0072
.1785
CI indicates confidence interval.
of the spectrum, UP and BP-I, show the most divergent
features. Finally, a subgroup of patients, UP subjects with
BPFH, seems to be characterized by a significantly higher
risk of developing a BP disorder [37,60].
Our data on family history are in line with previous
studies reporting differences for family psychiatric history
among mood disorder subtypes [59,162,163]. As in BP
disorder, in the group of UP subjects with BPFH, other
associated clinical conditions, such as psychosis [114,115],
comorbidities [115,116], and suicidality [117], may come
together in families.
Regarding the course of illness, in our sample, BP-I and
BP-II had a similar age at onset [165,166], while UP
subjects had an older age at onset of mood symptoms
[12,163,164] and an older age at the first MDE [142]. BP
patients, in general, showed a higher number of previous
lifetime MDEs [44,142,143]. Interestingly, in the original
sample (n = 554), UP subjects with BPFH were
characterized by the earliest age at onset and the earliest
age at the first hospitalization, further supporting the
hypothesis of a distinctive pattern of risk for this subgroup
of patients [138]. Indeed, early-onset (and highly recurrent)
UP depression is supposed to be at higher risk of shifting to
bipolarity [17,60,139].
Unexpectedly, we could not find any difference in the
comorbidity rate among groups, but we hypothesize that this
may depend on a higher severity of UP subjects, whose
prevalence among inpatients suggests a more serious course
of illness. Indeed, it has been reported that only a subsample
of individuals with recurrent major depression receives
psychiatric treatment [167], as patients may only seek
treatment for the most persistent or most severe of their
episodes. This characteristic most probably apply to the
patients included in our study. To further support this
hypothesis, there was no difference in age at first
hospitalization or total duration of hospitalization (lifetime)
between BP and UP subjects [166].
Examining the pattern of symptoms, items expressing
“depressed mood” scored significantly higher in UP than in
BP patients [44]. On the other hand, we found an association
between HAM-D item 19 (“depersonalization/derealization”) and BP-I diagnosis, which is in line with previous
reports [56,168] and which may support the recent
hypothesis of Mula et al [169] that affective depersonalization may be higher in BP than in UP subjects. Conversely, in
our sample, UP subjects exhibited higher scores on
anhedonia (as measured by MADRS).
We could not support the higher incidence of psychomotor
retardation [6,36,39,54,68] or atypical [43,73,96-98] or
melancholic [42,43] features in BP depression. Nevertheless,
we found that insomnia and reduced appetite were more
strongly associated with UP depression [40,44], indirectly
supporting the association between at least 2 atypical
depressive features and BP depression [44]. A higher incidence
of lifetime psychotic features was significantly associated with
BP-I disorder. However, psychosis is one of the features that
distinguish mania from hypomania, so we cannot rule out the
possibility that this difference may depend on manic rather
than on depressive episodes. Interestingly, mood-incongruent
paranoid symptoms were prevalent among BP-I subjects,
D. Souery et al. / Comprehensive Psychiatry xx (2011) xxx–xxx
whereas higher scores on the “pessimistic thoughts" item,
including mood-congruent delusional symptoms of depression
(guilt), were more common in UP subjects.
Our multivariate analyses of YMRS items support the
view that mixed depression may be more common than
expected [71,83,84]. BP-I depressed patients may present
with some hypomanic “intrusions” within their depressive
symptoms, the most common being irritability, distractibility, racing/crowded thoughts, increased talkativeness, and
psychomotor agitation [75,85-87]. UP subjects with BPFH
also expressed higher scores on some items, further
suggesting that this group may have more than one point
in common with BP disorder [88-90].
Finally, excluding the higher incidence of psychotic
features (lifetime), which can be potentially altered by the
incidence of psychotic manic episodes, a positive family
history for BP disorder was found to be the most important
predictor for bipolarity in depression.
A strength point of our study is that participants came
from general clinical population, including both inpatients
and outpatients. Most of our findings are easily detectable
on a diagnostic interview and with the most common
rating scales for mood symptoms. Moreover, in our
comparison with UP depression, we considered both BP-I
and BP-II disorders.
The major limitation of our study, which may affect the
validity and generalizability of some findings, is that raters
were not blind to diagnosis. Another limitation may be the
fact that some UP subjects, particularly those with BPFH,
may be subsequently rediagnosed as affected by BP disorder
[56,60]. However, the mean age of UP subjects in our sample
was beyond the peak period of risk for a manic episode
[170]. Moreover, the exclusion of first-episode subjects from
the regression model did not significantly alter our results.
The disparity between BP and UP inpatients may be another
limit, as the reported differences on symptoms may be
affected by the higher severity of UP patients. Nevertheless,
no differences were found among groups on severity of
current mood episode and on interepisode remission rate,
and all the individual differences that we found on symptom
presentation were adjusted for overall depressive severity.
Finally, the use of a rating scale for mania in a sample of
depressed patient may be questionable, but it should be said
that, to date, there are no available validated instruments for
evaluating the hypomanic dimension of depression.
Overall, our findings support the view that BP-I disorder
is different from the remaining subtypes, whereas BP-II
disorder is closer to UP. UP subjects with BPFH have shown
to have more points in common with BP than with UP
patients, thus supporting the view that family history may be
one of the most important variables for predicting evolution
into BP disorder. Indeed, UP subjects reporting a family
history positive for BP disorder as well as for other
psychiatric disorders and suicide may be considered at a
significantly increased risk for BP disorder. In addition to the
traditional indices of bipolarity, some individual symptoms
11
(“apparent” or “reported” depressed mood, reduced appetite,
reduced sleep, depersonalization, paranoid symptoms, and
pessimistic thoughts) may help distinguishing UP from BP
disorder, this approach being particularly applicable in the
initial identification of depressed patients at high risk for BP
disorder. Moreover, the identification of subpopulations of
subjects defined by homogeneous clinical features may be a
key element in genetic research or pharmacologic studies
where homogeneity is crucial.
Acknowledgment
The authors are grateful to Prof DW Black for making
available his original article for the preparation of this review.
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