Depression across mood disorders: review and analysis in a clinical sample
Transcription
Depression across mood disorders: review and analysis in a clinical sample
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. 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