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ScienceDirect Comprehensive Psychiatry 55 (2014) 799 – 806 www.elsevier.com/locate/comppsych

Phenomenological subtypes of severe bipolar mixed states: a factor analytic study Giulio Perugi a,⁎, Pierpaolo Medda a , Alan C. Swann b , Joao Reis c , Salvatore Rizzato a , Mauro Mauri a a

Clinica Psichiatrica, Dipartmento di Medicina Sperimentale, University of Pisa, Pisa, Italy Department of Psychiatry, The University of Texas Health Science Center, Houston, TX, USA c Serviço de Psiquiatria e Saúde Mental, Hospital de Santa Maria – CHLN, Lisboa, Portugal – Faculdade de Medicina de Lisboa, Universidade de Lisboa b

Abstract Objective: The correct identification of bipolar mixed states (MS) has important implications for clinical practice. The aim of the study was to define the multidimensional psychopathological structure of severe MS. To our knowledge, no factor analytical studies including only patients with MS, have been conducted before. Methods: In the first week of hospitalization, we evaluated by HAM-D-17, YMRS, BPRS and CGI, 202 Bipolar I inpatients with MS according to DSM-IV criteria referred for an ECT trial. A Principal-component analysis followed by Varimax rotation was performed on the 24-item BPRS. The relationships among different symptomatological subtypes and other clinical characteristics were explored. Results: Six interpretable factors were extracted: Psychotic-positive symptoms, Mania, Disorientation-Unusual Motor Behaviour, Depression, Negative Symptoms and Anxiety. On the basis of the highest z-scores, we found 6 “dominant” BPRS factor groups, that were statistically distinct and without significant overlap in the main symptomatological presentation. Only 29 (14.4%) of our patients could be described as “Dominant Manic” and 48 (23.8%) as “Dominant Depressive”; most importantly 125 (61.9%) were neither predominatelymanic nor predominately-depressive. Variables including age, number of previous episodes, suicidal behavior and HAM-D and YMRS scores significantly differentiated the subtypes. Conclusion: At least in the most severe forms, MS appears to represent more than the superposition of affective symptoms of opposite polarity. Anxiety, perplexity, psychotic experiences, motor disturbances and grossly disorganized behavior seem to arise from protracted intra-episodic instability and presence of a drive state influencing the mood state and the emotional resonance. © 2014 Elsevier Inc. All rights reserved.

1. Introduction Mixed state (MS) refers to an affective condition in which depressive and manic symptoms are simultaneously present. It may manifest as a transitional condition bridging one phase of the illness with another, or it may exist as an independent episode. In the latter case, along with mania and depression, MS represents a major phase of Bipolar Disorder; however, it is often misdiagnosed because of its pleomorphic symptomatological presentation [1] as well as

⁎ Corresponding author at: Clinica Psichiatrica Università Di Pisa, Via Roma 67, 56100, Pisa, Italy. Tel.: +39 335435387; fax: +39 502219787. E-mail address: [email protected] (G. Perugi). 0010-440X/$ – see front matter © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.comppsych.2014.01.012

under-diagnosed because of inadequate diagnostic delimitation [2,3]. Definitions of mixed states, especially those with prominent depression, are not well established. There is no terminological uniformity in the literature, and there is a tendency to use such terms as “mixed state,” “mixed mania”, “depression during mania,” and “dysphoric mania” interchangeably. DSM-IV and DSM IV-TR adopted a pragmatic but restrictive, descriptive approach, requiring full syndromal mania and depression for the diagnosis of MS. In the last 30 years, a rebirth of interest in MS produced studies of mixed mania [4] (mania plus less than syndromal depression) and, more recently, mixed depression [5] (major depression plus less than syndromal mania). This approach addressed depressive and manic episodes separately, regarding mixed state as subtypes of manic or depressive episodes,

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rather than in terms of specific features or episode components. Manic episodes with or without sub-syndromal depression differ in treatment response, severity of anxiety and course characteristics [6–9]. Although they were not addressed in DSM-IV, mixed hypomanic episodes [10] and depressive episodes with concurrent hypomanic symptoms may be common [11–13]. In some patients hypomanic or manic symptoms can be present only during depressive episodes [11,13–15]. As concerns symptomatological features, MS have generally been studied as subtypes of manic or depressive episodes. Symptoms characterizing mixed manic episodes include increased mood lability and irritability, less grandiosity, euphoria, pressure of speech, and decreased need for sleep compared to non-mixed episodes [16]. Dysphoric mood, anxiety, excessive guilt, and suicidality are depressive symptoms associated with mixed-manic episodes [17]. In terms of severity of depression and anxiety, mixed manic episodes were similar to agitated depressive episodes, with more severe agitation, irritability, and cognitive impairment [18]. Irritable mood, distractibility, racing thoughts/flight of ideas, agitation and increased talking are hypomanic symptoms described in mixed depressive episodes [11,19]. Severity of depressive symptoms appears similar in depressive episodes with or without concurrent manic symptoms [13,20]. Anxiety, negative evaluation of self, increased energy, visible hyperactivity, and racing thoughts has been associated with MS, regardless of dominant polarity [21]. Non-affective symptoms, including anxiety or psychosis, could be very common in MS and their role in depressive and manic syndromes may differ. Anxiety scores are correlated with depression scores in mania [21,22] and were minimal in non-mixed mania [18,21]. More recently anxiety has been considered a core symptom of mixed manic episodes [23]. On the contrary anxiety seems to be present in depression, regardless of the presence of mixed features [18]. In bipolar depression, severity of anxiety correlates with manic [21] as well as depressive symptoms [20,21]. In a recent study, conducted on 187 bipolar I inpatients hospitalized for DSM-IV-TR acute depressive, manic or mixed episodes, principal factor analysis was performed on 24-item Brief Psychiatric Rating Scale (BPRS 4.0) [24]. The analysis revealed five factors corresponding to “psychosis”, “euphoric mania”, “mixity”, “dysphoria” and “inhibited depression”. The mixity factor showed relative independence from “mood symptoms”, since it was mainly characterized by a set of symptoms like anxiety, tension, suicidality, and motor hyperactivity that suggest an “anxious-agitated arousal”. Severity of psychosis is not generally increased in mixed versus non-mixed mania [25]. Factorial analyses have delineated a psychotic manic subtype that is distinct from depressive mania [17,26,27]. As with mania, factor analysis of symptoms in bipolar depressive episodes yields a psychosis/delusions factor [28]. Prevalence of psychotic symptoms is lower in depression than in mania, so psychotic

symptoms correlate with manic symptoms severity in bipolar depressive episodes [20], as well as with the degree to which affective symptoms are mixed [21]. Psychotic features were more likely to be mood-incongruent in mixed than in nonmixed bipolar depression [1]. Finally in MS, sustained affective instability has been characterized by the "persistent presence of a drive state contradictory to the mood state and/or the emotional resonance" [29] and associated with specific symptoms such as cognitive and motor indecisiveness, emotional perplexity, perceptual disturbances, and a sense of external interference and depersonalization [30]. These characteristics have been considered common in MS [31], and cannot be derived from the superposition of depressive and manic symptomatology and are difficult to be operationalized in a combinatory model. In the present study we have conducted a factor analysis of BPRS symptoms systematically assessed in a large sample of Bipolar I patients with treatment-resistant MS referred for ECT trial. To our knowledge, this is the first analysis to include only patients with MS diagnosed according to DSM-IV criteria. We also explored the relationships between the symptomatological subtypes of MS, identified by means of principal component factor analysis, and other clinical features of mood disorders. Our hypotheses were that 1) in severe mixed states, driverelated “non-affective” symptoms are prominent regardless of manic or depressive symptoms; and 2) the symptomatological presentation might be related to demographic and clinical features.

2. Methods The study involved 202 Bipolar I patients with treatmentresistant MS, who had received ECT between January 2006 and July 2011 at the Department of Psychiatry of the University of Pisa. The sample comprised 81 males (40.1%) and 121 females (59.9%), with age between 21 and 81 years (mean 44.1, sd = 0.5); 70 (34.7%) were married, 104 (51.5%) single and 28 (13.9%) widowed or divorced. Most of the patients were employed (106, 52.5%), 27 (13.4%) were students, 28 (13.9%) were housewives, and 67 (33.2%) were unemployed or retired. All subjects met the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), for a mixed episode. The diagnoses were made by 2 senior psychiatrists (P.M, M.M.) and were confirmed by the administration of the M.I.N.I. (Mini International Neuropsychiatric Interview-Italian version 5.0.1). When questions arose, all diagnostic information was reviewed for consensus agreement and, if necessary, patients were recontacted for further clarification. All subjects gave their written informed consent to receive ECT and to participate to this study, and the study was approved by the Ethics Review

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Board of the University of Pisa being all the procedures in accordance with the Helsinki Declaration of 1975. All patients were hospitalized in the psychiatric unit, were non-responders to pharmacological treatment and had received one or more medication trials before being proposed to ECT. Non-response was defined as the presence of persisting mixed state despite 1 trial of at least 16 weeks with 2 or more mood stabilizers and/or typical or atypical antipsychotics and/or antidepressants in variable doses depending on the symptom pattern. Information to establish treatment resistance was based upon a review of outpatient and inpatient medical records and upon the reports of the patient, family members and prescribing psychiatrists. The patients were evaluated in the first week of hospitalization prior to ECT, using Hamilton Rating Scale for Depression-17 items (HAM-D-17), Mania Rating Scale (MRS), Brief Psychiatric Rating Scale (BPRS) and Clinical Global Improvement (CGI). All the scales were administrated by a psychiatrist (P.M.) with substantial experience in the assessment and treatment of bipolar patients. In the absence of a specific scale for psychotic symptoms, the variation in psychotic symptomatology was approximated using BPRS psychosis cluster score: hostility, suspiciousness, hallucinations, unusual thought content and conceptual disorganization (item 6, 9, 10, 11 and 15 – maximum score 35). 2.1. Statistical analyses Principal component factor analysis (PCA) was performed on the 24-item BPRS scale. We introduced the items as quantitative variables and R-matrix (Varimax rotation) was obtained by calculating the correlation coefficients for each pair of variables. We excluded multicollinearity. We checked for the determinant of correlation (N.00001). The appropriateness of the analysis was evaluated by looking at the Kaiser-Meyer-Olkin (KMO) and Bartlett’s test of sphericity (p b .05). Factors were considered with Eigenvalues N1.0 and confirmed by the scree-plot cut-off point. Once factors were extracted, we assumed loadings N.40 for a given variable to be significant. Factor scores were calculated with a regression method, where factor loadings were adjusted and expressed as z-scores (mean = 0 and standard deviation = 1). To test for normality of distribution of the total sample and scores of each factor, we used the Kolmogorov–Smirnov test. In order to analyze the relationships among the qualitatively different symptomatological subtypes of MS and other clinical characteristics, we grouped the subjects into different subtypes on the basis of the highest z-scores obtained for each BPRS factor (dominant BPRS factor). This procedure gives the opportunity to classify groups of subjects on the basis of the most statistically abnormal symptomatological aspect. In this way is possible to resolve the problem of identifying a cut-off for including patients into the different identified groups. To verify how distinct the subtypes are, how much overlap exists between different

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groups and how many cases fell close to multiple category we analyzed for each dominant group the mean z-scores across the factors. We also performed a discriminant analysis utilizing the scores of the 6 factors to predict the membership to a dominant group. We compared symptomatological and clinical variables among the various dominant BPRS factor groups by means of one-way ANOVA followed by the Tukey test, and Kruskal-Wallis followed by Dunn’s procedure for multiple group comparisons when appropriate. Significance was set at a Bonferroni’s corrected level of p N .0043, however, given the exploratory nature this study, we decided to comment also differences at p b .05 level (two tailed). Statistical analyses were performed using the Statistical Package for Social Sciences (SPSS, 20.0 version for MAC).

3. Results 3.1. Factor analyses of BPRS The results of the factor analysis for BPRS items are in Table 1. Six factors were extracted with eigenvalues between 1.8 and 3.3, explaining 63.98% of the total variance. Based on rotated factor loadings, factors were characterized as: Factor 1, Psychotic positive symptoms (high loadings of suspiciousness, hallucinations, unusual thought content, bizarre behavior, conceptual disorganization); Factor 2, Mania (hostility, elated mood, grandiosity, uncooperativeness, excitement, motor hyperactivity); Factor 3, Disorientation–Unusual Motor Behaviour (neglect, disorientation, motor retardation, uncooperativeness and mannerisms and posturing); Factor 4, Depression (anxiety, depression, suicidality, guilt, tension without elated mood); Factor 5, Negative Symptoms (blunted affect, emotional withdrawal and motor retardation) and Factor 6, Anxiety (anxiety, somatic concern and motor retardation). 3.2. Dominant Factor Groups On the basis of the highest z-scores obtained for each BPRS factor (dominant BPRS factor), we classified the subjects into 6 groups. The dominant “Positive-Psychotic Symptoms” group comprised 41 subjects (20.3%), the dominant “Mania” group 29 (14.4%), the dominant “Disorientation-Unusual Motor Behavior” group 14 (6.9%), the dominant “Depression” group 48 (23.8%), the dominant “Negative Symptoms” group 37 (18.3%), and the dominant “Anxiety” group 33 (16.3%). Mean z-scores and CI 95% across factors are reported in Table 2. The six groups were sufficiently distinct and did not show any significant overlap. Only for group 3, dominant “Disorientation-Unusual Motor Behavior”, we observed positive mean z-score for factor 6 “anxiety” other than factor 3. This finding was confirmed by the discriminant analysis, which revealed a percentage of correctly classified ‘grouped’ cases of 91.1%, and very few cases fell close to multiple categories.

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Table 1 Results of factor analysis of the BPRS item scores of 202 bipolar I patients with mixed states. Loadings over 0.4 are distinguished as significant. BPRS

Somatic concern Anxiety Depression Suicidality Guilt Hostility Elated mood Grandiosity Suspiciousness Hallucinations Unusual thought content Bizarre behavior Self-neglect Disorientation Conceptual Disorganization Blunted affect Emotional withdrawal Motor retardation Tension Uncooperativeness Excitement Distractibility Motor hyperactivity Mannerisms and Posturing Eigenvalue Explained variance (%) total 63.98% Interpretation

Factor groups 1

2

3

4

5

6

.046 .123 -.198 -.049 -.026 .044 .126 .094 .736 .793 .801 .663 .340 .371 .660 .056 .284 -.005 .062 .199 .072 .308 .129 .170 3.3 13.75 Psychotic positive symptoms

.007 -.114 -.290 .000 -.009 .718 .577 .593 .111 .033 .016 .336 -.148 .005 .127 -.211 -.004 -.189 .180 .516 .781 .300 .645 .003 3.0 12.32 Mania

-.066 -.152 .307 .041 .244 .110 -.181 -.149 .035 .141 .144 .202 .612 .663 .377 -.026 -.031 .585 -.063 .570 .021 .299 -.026 .718 2.6 10.70 Disorientation–Unusual Motor Behaviour

.091 .599 .542 .752 .506 .172 -.468 -.309 .078 -.079 -.073 .014 .229 -.010 .049 -.002 -.039 -.166 .705 .154 .011 -.195 .202 .094 2.6 10.57 Depression

-.014 -.161 .229 .018 .129 .182 .004 -.048 .282 .117 .183 -.162 -.027 -.177 -.298 .757 .808 .412 -.220 -.039 -.293 -.322 -.370 -.008 2.2 9.07 Negative Symptoms

.812 .468 .383 -.338 .117 .256 .042 -.146 .086 -.066 -.012 .009 -.159 .331 .238 -.119 .077 .408 .089 -.018 -.038 .303 -.207 -.211 1.8 7.58 Anxiety

3.3. Associations among the “dominant” BPRS factor groups and other variables Demographic and clinical variables were compared among 6 Dominant BPRS Factor Groups (Table 3). Age was significantly higher in Groups 6 and 3 than Groups 1, 2 and 5; age at onset was higher in Group 6 than in Group 5 and duration of the illness was longer in Group 3 than in Group 1, but the differences did not reach a Bonferroni’s corrected level of significance (respectively p = .013 and p = .043). As concerns to gender distribution, males were more represented in Groups 2 and 5 than in Groups 1, 3 and 4. These differences did not reach a Bonferroni’s corrected level of significance (p = .02). Number of episodes was significantly higher in Group 6 than in Groups 1, 2 and 5 and number of hospitalizations was higher (p = .02) in Group 6 than in Group 5. Number of previous suicide attempts was higher in Group 4 than in all other groups, but the difference did not reach a Bonferroni’s corrected level of significance. The duration of the current episode is not statistically different across the Factor Groups (p = .07); Group 3 reported the lowest mean duration. In our sample the comorbidity rate of Panic Disorder/ Agoraphobia was higher (p = .04) in Group 3 (50.0%) and 6 (57.6%) than in Groups 1 (26.8%) and 2 (24.1%). The rates

of comorbidity for Social Phobia, Obsessive-Compulsive Disorder, Anorexia Nervosa, Bulimia, Alcohol and Substance misuse were not significantly different across the 6 factor groups. Regarding symptom severity, mean CGI-Severity scores were not statistically different among the 6 Groups. The total BPRS score was higher (p = .02) for the Group 3 compared with Group 4 and Group 5. For BPRS Psychotic Symptoms, the mean score of Group 1 was significantly higher than Group 5 and 6; Group 4 reported the lowest score. The HAM-D total score was significantly higher in Group 3, 4, 5, 6 than Group 1 and 2. As expected the mean total score of YMRS was significantly higher in groups 1 and 2 than in the other groups. 4. Discussion Consistent with our hypotheses, this study of severely ill, treatment-resistant patients in bipolar mixed states found that: 1) factor analysis revealed two factors that were independent of depressive or manic symptoms, and 2) phenomenological subtypes differed in clinical and illnesscourse characteristics. In discussing these findings, we will also address the nature of the study sample and features of

−0.52 (−1.00/-0.06) 0.00 (−0.68/0.68) −0.38 (−0.69/-0.06) −0.37 (−0.91/0.18) -.030 (−0.49/-0.01) −0.41(−0.56/-0.05) −0.37 (−0.65/-.10) −0.39 (−0.64/-0.14) −0.25 (−0.14/0.14)

0.96 (0.80/1.11) −0.23 (−0.49/0.01) −0.20 (−0.45/0.06) b.0001. 4 N 1,2,3,5,6 −0.26 (−0.46/-0.06) 1.30 (1.03/1.57) −0.11 (−0.40/0.17) b.0001 5 N 1,2,3,4,6 −0.44(−0.91/0.08) −0.22 (−0.60/-0.29) 1.63 (−0.40/-0.03) b.0001 6 N 1,2,3,4,5

2 N 1.3,4,5,6 3 N 1,2,4,5,6 b.0001 b.0001 −0.21 (−0.37/-0.04) −0.32 (−0.51/-0.13) −0.16 (−0.51/0.19) −0.24 (−0.37/-0.11) −0.03 (−0.27/0.21) 0.06 (−0.28/0.40) 1.64 (1.29/1,98) −0.15 (−0.68/0.38) −0.22 (−0.43/-0.01) 2.19 (1.07/3.31) −0.45 (−0.64/-0.25) -.032 (−0.49/-0.16)

1 N 2,3,4,5,6 b.0001 −0.31 (−0.67/0.04) -.41 (−0.62/-0.20) −0.07 (−0.32/0.18) −0.11 (−0.92/0.69) −0.17 (−0.54/0.21) 0.95 (0.71/1.19)

Factor 1 – Positive Psychotic Symptoms Factor 2 – Mania Factor 3 - Disorientation- Unusual Motor Behaviour Factor 4 – Depression Factor 5 – Negative Symptoms Factor 6 – Anxiety

Group 3 DisorientationGroup 4 Group 5 Negative Group 6 Unusual Motor Behaviour Depression (n = 48) Symptoms (n = 37) Anxiety (n = 33) (n = 14) Group1 Positive Psychotic Group 2 symptoms (n = 41) Mania (n = 29)

BPRS Factor z-scores mean (C.I.)

Table 2 Mean (Confidence Interval) of z-scores across BPRS factors in Different Dominant Groups.

Dominant Factor Groups

p

Group Comparisons

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the clinical evaluations that differentiate this study from previous investigations of mixed states. Factor analysis indicated that orthogonal combinations of 6 different psychopathological dimensions: PsychoticPositive Symptoms, Mania, Disorientation–Unusual Motor Behaviour, Depression, Negative Symptoms and Anxiety characterized MS in our patients. This multidimensional structure is generally consistent with the current model of MS that propose a combination of typical Manic and Depressive symptoms associated with non-mood symptoms such as psychosis and anxiety [3]. Interestingly, in our sample, was possible to identify two non-mood characterized by Disorientation-Unusual Motor Behaviour, that seem to be related to the presence of symptoms such as emotional perplexity and cognitive and motor indecisiveness, and Negative Symptoms, characterized by blunted affect and emotional withdrawal. On the basis of the highest score obtained for each BPRS factor only 29 (14,4%) of our patients can be described as “Dominant Manic”, while about 48 (23,8%) should be considered as “Dominant Depressive”. It is likely that in our patients, referred for an ECT trial, depressive MS might be overrepresented. Most importantly 125 (61,9%) were neither predominately-manic nor predominately-depressive. Interestingly dominant Psychotic Symptoms and Anxiety characterize respectively about 20% and 15% of the patients. This finding is consistent with previous observations indicating the clinical relevance of these dimensions in MS [17]. Finally a substantial minority of our patients reported “Negative Symptoms” (18%) and “Disorientation-Unusual Motor Behavior” (7%), as dominant symptomatological features. The presence of these phenomenological characteristics in severe, treatment resistant mixed states, confirm previous clinical observations [1,29,31,32], and it could hardly be described as a combination of manic and depressive symptoms. In our sample, we clearly detected four groups of bipolar mixed patients that were dimensionally characterized by the presence of anxiety, psychosis, disorientation-unusual motor behavior and negative symptoms as clinically prevalent elements. The DSM-IV definition of mixed state as well as the DSM-5 “mixed features” specifier for mania and depression may not be effective in capturing these features of severe MS [33,34] It is possible that the combinatory model might be more appropriate for the definition of less severe MS, in which mood symptoms are prominent and clearly identifiable. Actually it has been successfully applied to patients selected for pharmacological trials [3]. In the most severe MS, characterized by psychosis, severe emotional, perceptual and motor disturbances the association with depressive and manic features could be not easily recognized. The results of the present study seem to indicate the need of specific diagnostic criteria for the definition of such a prominent symptomatological aspects not directly derivable from the mere combination of mania and depression. Comparisons between demographic and clinical variables among the 6 BPRS factor groups indicated that late age and

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Table 3 Demographic and Clinical variables in 6 groups determined by dominant BPRS factor scores among 202 bipolar I patients with Mixed State. Dominant Factor Groups Group1 Psychotic Group 2 positive symptoms Mania (n = 41) (n = 29) Age (years), mean (sd) 39.6 (8.10) Age at onset, mean (sd) 24.1 (9.00) Duration of the illness 15.5 (5.74) (years), mean (sd) Gender (Male), n (%) 12 (29.3) Number of episodes, mean (sd) 4.3 (1.92) Number of hospitalization, 3.4 (2.08) mean (sd) Number of suicide attempts, .3 (0.89) mean (sd) Duration of Current Episode 11.6 (16.82) (months), mean (sd) Comorbidity, n (%) Panic Disorder/Agoraphobia 11 (26.8) Social Phobia 1 (2.4) Obsessive-Compulsive 8 (19.5) Disorder Anorexia Nervosa 0 (0.0) Bulimia 0 (0.0) Alcohol misuse 4 (9.8) Substance misuse 2 (4.9) Symptomatological Variables, mean (sd) CGI-Severity 6.1 (0.40) BPRS, total score 62.8 (12.73) BPRS psychotic symptoms 18.0 (4.51) HAMD-18, total score 19.5 (4.58) Young mania, Total score 19.3 (6.21)

Group 3 Disorientation- Group 4 Unusual Motor Depression Behaviour (n = 14) (n = 48)

41.5 (12.67) 50.7 (14.18) 22.8 (7.20) 25.3 (13.36) 18.7 (10.39) 25.4 (10.78)

Group 5 Negative Symptoms (n = 37)

Group 6 Anxiety (n = 33)

p

Group comparisons

44.9 (12.84) 40.4 (10.93) 52.0 (16.80) b.0001 6, 3 N 1, 2, 5 25.7 (11.40) 20.8 (8.09) 29.9 (13.35) .013 6N5 19.2 (11.28) 19.5 (8.82) 22.1 (13.61) .043 3N1

16 (55.2) 4.7 (2.59) 3.5 (2.64)

4 (28.6) 5.6 (2.31) 4.4 (2.65)

15 (31.2) 6.0 (3.62) 3.6 (2.26)

22 (59.5) 4.4 (2.49) 2.8 (2.03)

12 (36.4) 7.2 (4.11) 4.9 (3.69)

.02 5, 2 N 1, 3, 4 b.0001 6 N 1, 2, 5 .02 6N5

.2 (0.64)

0.9 (1.21)

1.1 (1.39)

0.3 (0.75)

0.4 (0.90)

7.4 (7.10)

5.4 (4.45)

11.5 (11.91)

9.1 (8.42)

6.2 (5.32)

b.0001 4 N 1, 2, 3, 5, 6 ns -

7 (24.1) 0 (0.0) 4 (13.8)

7 (50.0) 1 (7.1) 1 (7.1)

22 (45.8) 0 (0.0) 6 (12.5)

14 (37.8) 1 (2.7) 7 (18.9)

19 (57.6) 0 (0.0) 4 (12.1)

.04 ns ns

3, 6 N 1, 2, 3 -

0 (0.0) 1 (3.4) 1 (3.4) 5 (17.2)

0 (0.0) 1 (7.1) 0 (0.0) 1 (7.1)

0 (0.0) 0 (0.0) 2 (5.4) 1 (2.7)

0 (0.0) 0 (0.0) 1 (3.0) 1 (3.0)

ns ns ns ns

-

5.9 (0.39) 60.1 (11.04) 13.2 (4.97) 23.0 (4.12) 15.6 (6.57)

6.0 (0.39) 61.9 (17.65) 13.0 (6.59) 24.8 (4.71) 12.8 (6.5)

ns .02 b.0001 b.0001 b.0001

3 N 4,5 1 N 5,6 N 4 3,4,5,6 N 1,2 1,2 N 3,4,5,6

6.0 (0.50) 64.2 (13.64) 13.7 (6.98) 17.7 (5.26) 21.7 (6.23)

5.9 (1.77) 70.9 (19.40) 14.9 (8.65) 24.5 (4.93) 15.8 (8.10)

late age at onset were significantly associated with the Dominant Anxiety subtype; Disorientation-Unusual Motor Behavior was also associated with late age at the moment of the evaluation and length of the illness. From our data it is not possible to distinguish the effects of age and/or of prolonged illness with multiple episodes. As concerns gender distribution, males were significantly more represented in Mania and Negative Symptoms dominant subtypes than in the other groups. Other reports found both similar [1] and different [35] gender distribution in mixed mania. It is likely that these discrepancies reflect differences in sample selection. Dominant Anxiety patients reported the highest number of episodes and hospitalizations. This finding is consistent with other reports in mixed patients characterized by severe anxiety [25]. As expected, number of previous suicide attempts was higher in the depressive subtype than in all other groups. The combination of hopelessness with impulsivity and activation in mixed depression has been described as a risk factor for suicidal behavior [14]. Although the Disorientation-Unusual Motor Behavior group reported the shortest mean duration of the current episode, the difference was not statistically significant (p = .07). It is possible that disorientation, motor and perceptual disturbances may characterize more acute forms of MS.

3 4 2 2

(6.2) (8.3) (4.2) (4.2)

6.0 (0.36) 57.4 (8.60) 10.3 (4.79) 24,5 (3.52) 15.0 (6.33)

In our sample the comorbidity rates with other mental disorders were generally low and similar in the different symptomatological subtypes, with the exception of Panic Disorder/Agoraphobia. This latter comorbidity was present in about 1/3 of the sample and was more represented in dominant Disorientation–Unusual Motor Behavior and Anxiety subtypes than in the other groups, involving more than half of the cases in these 2 subtypes. Panic anxiety has been reported as frequently associated with mixed mania in several studies [36,37]. The low rate of comorbid alcohol and substance abuse was not expected according to the literature [38,39] and could be due to the possibility that patients with such comorbidity are less likely to be referred for ECT. Another possibility is that substance-related comorbidity [22,40] may increase risk for MS in less severely ill individuals, while in those with more severe forms, MS occurs even without factors like substance use. Concerning the global severity of the symptomatology measured by CGI, all the subtypes were considered severely ill, a finding largely expected in a sample of patients with acute MS referred for ECT trial. Disorientation-Unusual Motor Behavior subtype reported a significantly higher total BPRS score than the other groups, indicating a more extended and pervasive symptomatology. As expected Positive Psychotic Symptoms and Manic subtypes reported

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lower HAM-D and higher YMRS total score than the other groups. This finding is consistent with previous literature reporting a correlation between psychotic features and severity of manic symptomatology in MS [20]. In line with the original definition of Kraepelin [32], our data support the existence of multiple depressive and manic symptomatological subtypes of severe bipolar MS. These subtypes showed clinically relevant differences in terms of age, number of previous episodes, suicidal behavior and HAM-D and YMRS scores. Further studies are necessary in order to explore possible differences in terms of response to different treatment options such as lithium, anticonvulsive mood-stabilizing and antipsychotic drugs or ECT. There are several limitations in this study. First the sample size, despite a congruent number of subjects for item, was relatively small. A strength of the present investigation is that clinical and diagnostic evaluations were based on a semistructured interview conducted by psychiatrists trained in mood disorders and involved in the treatment of the patients. For this reason, it was not possible for them to be blind to the BPRS ratings. We submit that the systematic nature of our investigation minimizes any biases that could arise from non-blind methodology. Another major limitation inherent to all the studies exploring affective symptomatology in naturalistic samples is that different medications and different stages of recovery from the illness might confound symptom assessment. We attempted to limit this problem by evaluating all our patients in the first week of hospitalization, before the first ECT trial. Finally, the fact that our sample was referred for ECT may have influenced the selection of individuals with particularly severe symptomatology, resistant to pharmacological treatment and not representative of the full spectrum of MS. However, these patients represent an extremely rigorously defined group of MS patients In conclusion, at least in the most severe forms, MS appears to represent more than a superposition of affective symptoms of opposite polarity. Anxiety, perplexity, psychotic experiences, motor disturbances and grossly disorganized behavior seem to arise from protracted instability and presence of a drive state influencing the mood state and/or the emotional resonance [29]. The foregoing phenomenologic considerations suggest a considerable broadening of the unstable terrain of bipolar MS beyond those of DSM-IV and DSM-5 proposals. The proper identification of MS has critical implications for clinical practice. When not characterized by prevalent manic or depressive features, these conditions might be confused with a number of other psychiatric disorders, including borderline personality disorder, delusional depression, schizophrenia, and organic mental disorder [3,31,41,42]. Therefore, it would be important to distinguish mixed states from these conditions so that treatments (e.g., antidepressants), which might worsen their symptomatology, would be utilized with due caution and treatments that might be particularly effective (e.g., mood stabilizers and ECT) would not go underutilized.

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