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A reevaluation of the possibility and characteristics in bipolar mania with mixed features: A retrospective chart review
Psychiatry Research 215 (2014) 335–340
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A reevaluation of the possibility and characteristics in bipolar mania with mixed features: A retrospective chart review In Hee Shim, Young Sup Woo, Tae-Youn Jun, Won-Myong Bahk n Department of Psychiatry, Yeouido St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea
art ic l e i nf o
a b s t r a c t
Article history: Received 15 May 2013 Accepted 4 November 2013 Available online 12 November 2013
The aim of the present study was to reevaluate the feasibility of diagnosing a mixed features behind bipolar mania and to elucidate the clinical characteristics, treatment response, and course of the illness throughout a 12-month follow-up. The subjects (n ¼171) were inpatients diagnosed with bipolar I disorder, manic, between 2003 and 2010 and were classified into three groups: “mania” (n ¼67), “mania with probable mixed features” (n ¼ 79), and “mania with definite mixed features” (n ¼25). Diagnoses were in accordance with the Cincinnati criteria, which include the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision characteristics for a major depressive episode, except for agitation and insomnia. The charts of subjects were retrospectively reviewed for demographic and clinical characteristics prior to the index episode, clinical data regarding the index episode, and treatment courses over a 12-month follow-up period. Subjects in the mania with definite mixed features were more likely to be young at admission, to be female, to have a familial affective loading, and to have a history of suicidality relative to the mania. The results of the present study suggest the need for regular assessment of symptoms associated with both polarities during an episode in routine practice. & 2013 Elsevier Ireland Ltd. All rights reserved.
Keywords: Bipolar disorder Mixed feature Mixed mania Cincinnati criteria Clinical characteristics
1. Introduction An understanding of the mixed state in bipolar disorder is generally considered important when defining what constitutes an episode of the disorder and when examining the relationship between episodes and illness course characteristics. Mixed features may be associated with a clinical course and treatment response that differ from exclusively depressive or manic states (Swann et al., 2013). Perugi and Akiskal (2005) suggested that a mixed state does not represent a mere superimposition of affective symptoms of opposite polarity but rather a complex process of temperamental, affective, and other components. In this sense, the mixed state might be considered the clearest expression of neurophysiological dysregulation. Despite increasing awareness of the importance of the mixed state in bipolar disorder, the under-diagnosis or delayed diagnosis and consequent undertreatment of mixed-state episodes still occurs in clinical settings. Efforts to investigate the mixed state have resulted in its increasingly clear definition. In the modern taxonomy of the International Statistical Classification of Diseases and Related
n Correspondence to: Department of Psychiatry, Yeouido St. Mary's Hospital, College of Medicine, The Catholic University of Korea, #62 Yeouido-Dong, Youngdeungpo-Gu, Seoul 150-713, South Korea. Tel.: þ 82 2 3779 1250; fax: þ 82 2 780 6577. E-mail address: [email protected] (W.-M. Bahk).
0165-1781/$ - see front matter & 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.psychres.2013.11.002
Health Problems-10 (ICD-10) (World Health Organization, 1993), a mixed state refers to the co-existence or rapid alternation of prominent depressive symptoms and manic/hypomanic symptoms for at least 2 weeks. The Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR) (American Psychiatric Association, 2000) requires that a person meet the criteria for a full-blown manic episode and a depressive syndrome almost every day for at least 1 week. However, these criteria have not yet been fully elucidated. The definitions of a mixed state from both the DSM-IV-TR and the ICD-10 are too restrictive and are rarely satisfied in a clinical situation, resulting in the exclusion of many patients who may be clinically considered to be experiencing such a state. Moreover, studies evaluating the onset, clinical characteristics, course, and outcome of the mixed state have yet to completely clarify its features. At this point in time, a new categorical approach to the mixed state is necessary for clinical practice. It has been proposed that a new definition and set of characteristics be created for the mixed state that will integrate an approach that conceptualizes the co-existence of manic and depressive symptoms (Dayer et al., 2000). Thus, the diagnosis of a full DSM-IV-TR manic syndrome associated with dysphoria and some depressive symptoms or a full DSM-IV-TR depressive syndrome associated with irritability, agitation, and some manic symptoms would be possible. Recent studies (McElroy et al., 1992; Swann et al., 1997; Akiskal et al., 1998a, 1998b) have suggested that the preliminary operational diagnostic
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criteria for mixed mania should include all of the DSM-IV-TR criteria for a major depressive episode, except for agitation and insomnia, in conjunction with primary mania. For a diagnosis of a mixed state in bipolar disorder, McElroy et al. (1992) advocated the criterion of more than three depressive symptoms combined with primary mania, whereas Akiskal et al. (1998a, 1998b) and Swann et al. (1997) respectively suggested that the presence of more than two, or one depressive symptom, is sufficient. The present study was conducted to reclassify patients hospitalized for bipolar I disorder, manic episode, in accordance with the Cincinnati criteria (McElroy et al., 1992), the narrowest set of criteria for mixed mania. Subjects were categorized into three groups: mania (no depressive symptoms); mania with probable mixed features (one or two depressive symptoms); and mania with definite mixed features (Z3 depressive symptoms). The aim of the present study was to reevaluate the feasibility of diagnosing a mixed features underlying primary mania and to elucidate the clinical characteristics, treatment response, and course of illness associated with this state throughout a 12-month follow-up.
2. Methods 2.1. Subjects This chart review was conducted at Yeouido St. Mary's Hospital, College of Medicine at The Catholic University of Korea in Seoul, Korea. All patients hospitalized at this institution had been diagnosed by clinical interview with an Axis I disorder by a board-certified psychiatrist in accordance with the DSM-IV-TR. All subjects in this study met the DSM-IV-TR criteria for bipolar I disorder, manic, during the period of 2003–2010. The following inclusion criteria were used: (1) patients were diagnosed using the DSM-IV-TR as currently having a manic episode, non-mixed; and (2) patients were between the ages of 15–75 years. Exclusion criteria consisted of insufficient data, a severe comorbid medical condition that could contribute to mood symptoms, organic brain lesion that may influence mood symptoms, an episode of substance-induced mood disorder, a comorbid psychiatric disorder such as personality disorder, schizophrenia, schizoaffective disorder, anxiety disorder, or dementia, and a change in the diagnosis during the follow-up period. The charts of 306 subjects diagnosed with bipolar I disorder, manic, were analyzed at baseline, and 135 cases were excluded based on the abovementioned criteria. Thus, 171 inpatients diagnosed with bipolar I disorder, manic, were enrolled in the study and categorized into three groups: mania, mania with probable mixed features, and mania with definite mixed features. The classification was performed in accordance with the stringent Cincinnati criteria (McElroy et al., 1992) for a mixed state, which include the DSM-IV-TR criteria for a major depressive episode (except for agitation and insomnia): depressed mood, markedly diminished interest or pleasure, weight gain or increase in appetite, hypersomnia, psychomotor retardation, fatigue or loss of energy, worthlessness or excessive or inappropriate guilt, helplessness or hopelessness, and recurrent thoughts of death, recurrent suicidal ideation, or a specific plan for committing suicide. Of the 171 patients who were included in the analysis, 147 who were followed for more than 12 months after discharge were included in the analysis over a 12-month follow-up period.
2.2. Assessments The charts of the subjects were reviewed for demographic and clinical characteristics including age of onset, age at first treatment, age at admission, sex, marital status, family history of mood disorder, number of hospitalizations, number of episodes, number of depressive episodes, number of manic episodes, number of hypomanic episodes, number of mixed episodes, lifetime number of psychotic features, and suicidality. Suicidality was defined as recurrent suicidal ideation, a specific plan for suicide, or recurrent suicide attempts. Index episode was a term used to define the manic episode that led to the hospitalization of the patient due to severe symptoms from 2003 to 2010. If a patient experienced more than one hospitalization during the whole study period, only the data from the last admission were analyzed. Clinical data in the index episode included duration of the episode, patient medications (change of medications, total number of medications, number of mood stabilizers, and number of antipsychotics), suicidality, and psychotic features. To identify mixed features, patients were monitored for opposite-polarity symptoms such as depressive symptoms (according to the DSM-IV-TR criteria for a major depressive episode, excluding agitation and insomnia (McElroy et al., 1992)) in addition to emotional
intensity and affective instability, which contribute to a mixed state (Henry et al., 2010). Two independent (Y.S.W. and W.M.B.) who were not informed about the purpose of the study independently evaluated the medical records for clinical data over a 12-month follow-up period. During the follow-up period, the number of episodes, number of manic episodes, number of depressive episodes, number of hypomanic episodes, number of mixed episodes, number of hospitalizations, the re-hospitalization rate and the duration from discharge to rehospitalization, psychotic features, suicidality, inter-episode remission, and rapid cycling were retrospectively evaluated. 2.3. Statistical analysis Statistical analyses were carried out using SAS for Windows (version 9.2). Statistical methods consisted of Chi-square tests or Fisher's exact test with Bonferroni's correction for comparisons of categorical variables and analysis of variance (ANOVA) for continuous variables. Post hoc analysis using Tukey's procedure was used to calculate mean differences and to determine significant differences among means. To identify the factors associated with mixed features, a multinomial logistic regression analysis was conducted; independent variables included demographic information, clinical characteristics, and clinical data from the index episode including depressive symptoms (according to the DSM-IV major depressive episode criteria, excluding agitation and insomnia, the Cincinnati criteria (McElroy et al., 1992)); the dependent variable was group assignment, including the mania group (patients not meeting the criteria for mixed mania), the mania with probable mixed features group (patients with one or two of these criteria), and the mania with definite mixed features group (patients with Z 3 of these criteria). A P-value of 0.05 was considered statistically significant, and when Bonferroni's correction for comparisons of categorical variables was used, P-values of 0.017 were considered statistically significant. 2.4. Ethics The study was conducted according to the Declaration of Helsinki, and approval to conduct this chart review was obtained from the Institutional Review Board. Because this was a retrospective study and the data were obtained by routine psychiatric examination and treatment, the board judged that an informed consent was unnecessary.
3. Results 3.1. Demographic and clinical characteristics prior to the index episode The distribution of patients meeting the criteria for Bipolar I disorder, manic, is shown in Table 1. Of the patients included in the final analysis, 67 (39.1%) had no depressive symptoms during their manic episode (mania group), 79 (46.3%) exhibited one or two associated depressive symptoms (mania with probable mixed features group), and 25 (14.6%) exhibited three or more depressive symptoms (mania with definite mixed features group). Several significant differences in demographic and clinical characteristics were identified, including age of onset, age at first treatment, age at admission, sex, family history of mood disorder (more specifically, family history of depressive disorder), lifetime number of psychotic features, and suicidality. Sex was significantly different among the three groups (P ¼0.001) with the mania with probable mixed features group including more women compared to the mania group (70.9% vs. 40.3%; P o0.001). The mean age of onset (P¼ 0.002), mean age at first treatment (P¼ 0.002), and mean age at index hospitalization (P ¼0.001) were significantly different among the three groups. The mania with probable mixed features group had a younger mean age at onset (25.9 79.6 vs. 30.1 712.2 years; P ¼0.040), younger mean age at first treatment (26.3 79.8 vs. 30.47 12.1 years; P¼ 0.045), and younger mean age at admission (35.2 712.0 vs. 41.8712.4 years; P ¼0.002) than the mania group. The mania with definite mixed features group also had a younger mean age at onset (22.2 7 4.4 vs. 30.1 712.2 years; P¼ 0.003), younger mean age at first treatment (22.2 74.4 vs. 30.47 12.1 years; P¼ 0.002), and younger mean age at admission (33.2 79.4 vs. 41.8712.4 years; P ¼0.006) than the mania group.
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Table 1 Demographic and clinical characteristics prior to the index episode.
Age (years) Onset 1st treatment At admission Sex (Male), n (%) Married, n (%) Family history, n (%) Mood disorder Bipolar disorder Depressive disorder Total episodes Manic episodes Depressive episodes Hypomanic episodes Mixed episodes Number of hospitalization Number of psychotic features Suicidality, n (%)
M (N ¼67)
PM (N ¼ 79)
DM (N ¼25)
Significance (M vs. PM vs. DM)
Significance (M vs. PM)
Significance (M vs. DM)
Significance (PM vs. DM)
30.17 12.2 30.4 7 12.1 41.8 7 12.4 40 (59.7) 40 (59.7)
25.9 79.6 26.3 79.8 35.2 7 12.0 23 (29.1) 37 (46.8)
22.2 7 4.4 22.2 7 4.4 33.27 9.4 8 (32.0) 13 (52.0)
0.002n 0.002n 0.001n 0.001n 0.299
0.040n 0.045n 0.002n o0.001nn N.A.
0.003n 0.002n 0.006n 0.018 N.A.
0.250 0.235 0.759 0.783 N.A.
9 (13.4) 4 (6.0) 5 (7.5) 4.2 7 2.3 2.9 7 1.8 1.17 1.2 0.17 0.3 07 0.2 3.4 7 2.5 1.3 72.0
19 (24.1) 8 (10.1) 13 (16.5) 4.2 73.6 3.3 73.3 0.8 71.2 0 07 0.1 3.17 2.7 1.6 7 2.2
10 (40.0) 1 (4.0) 10 (40.0) 4.5 7 3.2 3.5 7 3.1 17 1.3 0 0.1 70.3 4.1 73.4 2.9 7 3.5
0.021n 0.489 0.001n 0.257 0.629 0.423 0.211 0.222 0.257 0.022n
0.104 N.A. 0.100 N.A. N.A. N.A. N.A. N.A. N.A. 0.722
0.005nn N.A. 0.001nn N.A. N.A. N.A. N.A. N.A. N.A. 0.017n
0.121 N.A. 0.013nn N.A. N.A. N.A. N.A. N.A. N.A. 0.062
8 (11.9)
9 (11.4)
11 (44.0)
o 0.001n
0.918
0.001nn
0.001nn
M: mania group, PM: mania with probable mixed features, DM: mania with definite mixed features. P-values are results of Chi-square or Fisher's exact tests (categorical variables) and ANOVA (continuous variables) between groups, Post-hoc analysis using Tukey's procedure was used. n
Po 0.05, Bonferroni's correction for comparisons of categorical variables. Po 0.017, N.A. not applicable.
nn
Table 2 Clinical data in index episode.
Duration of index episode Change of medication, n (%) Number of medications Number of mood stabilizers Number of antipsychotics Psychotic features, n (%) Suicidality, n (%)
M (N¼ 67)
PM (N ¼ 79)
DM (N ¼25)
Significance (M vs. PM vs. DM)
Significance (M vs. PM)
Significance (M vs. DM)
Significance (PM vs. DM)
1.5 7 0.8 24 (35.8) 4.2 7 1.6 1.5 7 0.8 1.1 70.3 37 (55.2) 0
1.4 7 0.5 34 (43.0) 4.2 71.6 1.4 7 0.6 1.2 7 0.5 46 (58.2) 4 (5.1)
1.3 70.5 8 (32.0) 4.17 1.7 1.2 70.7 1.0 70.3 17 (68.0) 7 (28.0)
0.302 0.513 0.927 0.250 0.068 0.541 o 0.001n
N.A. N.A. N.A. N.A. N.A. N.A. 0.125
N.A. N.A. N.A. N.A. N.A. N.A. o0.001nn
N.A. N.A. N.A. N.A. N.A. N.A. 0.004nn
M: mania group, PM: mania with probable mixed features group, DM: mania with definite mixed features group. P-values are results of Chi-square or Fisher's exact tests (categorical variables) and ANOVA (continuous variables) between groups, Post-hoc analysis using Tukey's procedure was used. n
Po 0.05, Bonferroni's correction for comparisons of categorical variables. Po 0.017, N.A. not applicable.
nn
No significant differences were found between the mania with probable mixed features group and the mania with definite mixed features group in terms of age of onset, age at first treatment, and age at admission. Familial affective loading (P ¼0.021) and family history of depressive disorders (P ¼0.001) were significantly different among the three groups. Familial affective loading (40% vs. 13.4%; P ¼0.005) and familial depressive disorders (40% vs. 7.5%; P ¼0.001) were more common in the mania with definite mixed features group compared with the mania group. Patients in the mania with definite mixed features group also more had frequent family histories of depressive disorders than did those in the mania with probable mixed features group (40.0% vs. 16.5%; P ¼0.013), whereas there were no differences between the other groups. The lifetime number of psychotic features was significantly different among the three groups (P¼ 0.022), being more common in the mania with definite mixed features group than in the mania group (2.97 3.5 vs. 1.372.0; P ¼0.017). Suicidality was also significantly different among the three groups (Po 0.001) and was greater in the mania with definite mixed features group than in the mania group (44.0% vs. 11.9%; P ¼0.001) and the mania with probable mixed features group (44.0% vs. 11.4%; P¼ 0.001).
3.2. Clinical data in index episode Characteristics of the clinical data for each group during the index episode are summarized in Table 2. There were no significant differences in the duration of index episode, change of medications (mood stabilizers or antipsychotics), the total number of medications, mood stabilizers, or antipsychotics, or psychotic features. Suicidality was significantly different among the groups (P o0.001), with higher rates in the mania with definite mixed features group compared with the mania group (28.0% vs. 0%; Po 0.001) and the mania with probable mixed features group (28.0% vs. 5.1%; P ¼0.004). Fig. 1 depicts the loads of the nine items associated with Cincinnati depressive symptoms (McElroy et al., 1992) for manic subjects with either mania with probable mixed features or mania with definite mixed features. The highest frequencies of symptoms were observed for depressed mood or labile mood (88% and 82.3%, respectively), markedly diminished interest or pleasure (64% and 21.5%, respectively), helplessness or hopelessness (56% and 3.8%, respectively), and fatigue (44% and 5.1%, respectively). Each of these symptoms showed significantly different frequencies in the mania
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100 Probable mixed mania group (N=79)
Percent of patients (%)
90 80
Definite mixed mania group (N=25)
70 60 50 40 30 20 10 0
Fig.1. Specific Cincinnati depressive symptoms during the index episode.
Table 3 Final model of multinomial logistic regression between groups. M vs. PM Significance
Age at admission Sex (female) Family history of mood disorder Suicidality
0.013n o 0.001n 0.021n 0.637
M vs. DM a
OR
0.949 4.594 3.310 1.372
95% C.I. for OR Lower
Upper
0.911 2.121 1.195 0.368
0.989 9.948 9.168 5.113
Significance
0.032n 0.006n 0.011n 0.019n
PM vs. DM a
OR
0.936 5.600 5.907 6.947
95% C.I. for OR Lower
Upper
0.881 1.652 1.504 1.367
0.994 18.983 23.193 35.295
Significance
0.632 0.733 0.301 0.022n
ORb
0.986 1.219 1.785 5.063
95% C.I. for OR Lower
Upper
0.932 0.390 0.596 1.269
1.044 3.808 5.343 20.201
M: mania group, PM: mania with probable mixed features group, DM: mania with definite mixed features group. n
a b
Po 0.05. Relative to mania group. Relative to mania with probable mixed features group.
Table 4 Course of illness over a 12 months follow-up period.
Number of episodes Manic Depressive Hypomanic Mixed Number of hospitalization Re-hospitalization, n (%) Duration from discharge to re-hospitalization (month) Psychotic features, n (%) Suicidality, n (%) Inter-episode remission, n (%) Rapid cycling, n (%)
M (N ¼ 57)
PM (N ¼67)
DM (N ¼ 23)
Significance (M vs. PM vs. DM)
Significance (M vs. PM)
Significance (M vs. DM)
Significance (PM vs. DM)
0.5 7 0.8 0.2 7 0.4 0.3 7 0.7 0.17 0.2 07 0.1 0.2 7 0.5 26 (45.6) 6.7 7 3.7
0.4 7 0.7 0.2 7 0.4 0.3 7 0.5 0 0 0.2 7 0.5 29 (43.3) 8.5 7 7.8
0.7 70.8 0.17 0.3 0.5 70.7 0.17 0.3 07 0.2 0.3 70.4 9 (39.1) 9.7 712.8
0.227 0.750 0.381 0.277 0.288 0.776 0.868 0.778
N.A. N.A. N.A. N.A. N.A. N.A. N.A. N.A.
N.A. N.A. N.A. N.A. N.A. N.A. N.A. N.A.
N.A. N.A. N.A. N.A. N.A. N.A. N.A. N.A.
7 (12.3) 2 (3.5) 50 (87.7) 1 (1.8)
6 (9.0) 2 (3.0) 65 (97.0) 0
3 (13.0) 1 (4.3) 16 (69.6) 1 (4.3)
0.786 40.999 0.001n 0.146
N.A. N.A. 0.079. N.A.
N.A. N.A. 0.100 N.A.
N.A. N.A. 0.001nn N.A.
M: mania group, PM: mania with probable mixed features group, DM: mania with definite mixed features group. P-values are results of Chi-square or Fisher's exact tests (categorical variables) and ANOVA (continuous variables) between groups, Post-hoc analysis using Tukey's procedure was used. n
Po 0.05, Bonferroni's correction for comparisons of categorical variables. Po 0.017, N.A. not applicable.
nn
I.H. Shim et al. / Psychiatry Research 215 (2014) 335–340
with definite mixed features group compared with the mania with probable mixed features group except for depressed mood or labile mood (P¼0.559), hypersomnia (P¼0.029), and psychomotor retardation (P¼ 0.148). Depressed mood or labile mood (82.3% vs. 0%, Po0.001) and markedly diminished interest or pleasure (21.5% vs. 0%, Po0.001) were significantly different between the mania with probable mixed features group and the mania group. The multinomial logistic regression included all significant variables and revealed several independent correlates of bipolar I disorder, mixed. The final regression model evaluating the three groups is presented in Table 3. Subjects with mania with definite mixed features were more likely to be young at admission (OR ¼0.936, 95% CI 0.881–0.994), to be female (OR ¼5.600, 95% CI 1.652–18.983), to have familial affective loading (OR ¼5.907, 95% CI 1.504–23.193), and to have a history of suicidality (OR¼ 6.947, 95% CI 1.367–35.295) compared with the mania group. 3.3. Course of illness over a 12-month follow-up period The number of episodes, rate of re-hospitalization and duration of stay in re-hospitalized patients, psychotic features, suicidality, inter-episode remission, and rapid cycling in each group during the 12-month follow-up are shown in Table 4. Fifty-seven patients (38.8%) had mania, 67 (45.6%) had mania with probable mixed features, and 23 (15.6%) had mania with definite mixed features. The inter-episode remission rate was significantly different among the three groups (P ¼0.001) and was lower in the mania with definite mixed features group than in the mania with probable mixed features group (69.6% vs. 97.0%; P ¼0.001).
4. Discussion The objective of this study was to reevaluate the possibility of a mixed features diagnosis in patients hospitalized for bipolar I disorder, manic, and to elucidate the clinical characteristics, treatment response, and course of illness for these patients throughout a 12-month follow-up period. Based on this analysis, it appears that a mixed features was under- or undiagnosed in 15% of cases, consistent with the rate of 20.8% undiagnosed mixed state manic patients in a previous study (Jon et al., 2006). Also similar to previous studies, the prevalence rates of dysphoric mania among acutely manic patients with bipolar disorder ranged from 9% to 23.2% in this study (Vieta and Morralla, 2010). The current study also found that patients diagnosed with a mixed features were younger at onset, younger age at first treatment, and younger at admission than were those diagnosed with pure manic states. These results are in close agreement with the results reported by Gonzalez-Pinto et al. (2011). Depressive symptoms in a mixed manic episode were commonly manifested as depressed mood or labile mood, markedly diminished interests or pleasure, helplessness, and fatigue, whereas other depressive symptoms showed a broadly similar distribution. The results of the present study are similar to those of a previous study. Depressive symptoms associated with mixed manic episodes in this study included dysphoric mood, anxiety, excessive guilt, and suicidality (Cassidy et al., 1998). The results of the present study agree well with the previous study in the high prevalence of psychotic symptoms (Gonzalez-Pinto et al., 2004). Similar to Perugi et al. (1997), the present study found that subjects with mixed symptoms experienced fewer inter-episode remissions. An important finding in the present study is the association of a mixed features with young age at admission, being female, having a high familial affective loading, and suicidality. This confirms earlier reports indicating that patients in broadly defined mixed states are more likely to be women
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(Suppes et al., 2005), tend to have high familial affective loading (Moorhead and Scott, 2000), and have a higher risk for suicide than patients whose history includes non-mixed manic episode (Pacchiarotti et al., 2011). However, these findings also contradict those of earlier studies in some respects. In the present study, no significant difference in the number of total episodes was found among the three groups, whereas Pacchiarotti et al. (2011) found that patients with mixed manic states had more lifetime episodes of illness than did those without mixed states. It is important to consider several differences between these studies, such as design and clinical characteristics. Pacchiarotti et al. (2011) applied a more restrictive set of criteria, namely those of DSM-IV-TR (American Psychiatric Association, 2000), which have a lower concordance with the Cincinnati criteria (McElroy et al., 1992) than with the ICD-10 (World Health Organization, 1993) for patients in a mixed state (Vieta and Morralla, 2010). Moreover, in that study, lifetime neuropsychiatric history was subdivided into past or current manic episodes only (purely manic), past or current manic and mixed episodes, and past or current mixed episodes only (purely mixed). Second, patients in the present study had an older mean age of onset and a lower rate of previous depressive and hypomanic episodes than did those in the study by Pacchiarotti et al. (2011). These differences may be due to recall bias in that patients and their family members may have had difficulty remembering past depressive or hypomanic episodes. Although the finding that those with a mixed-state diagnosis had more lifetime episodes of illness than those without mixed states is commonly accepted, various studies have used different study designs and inclusion criteria to diagnose the mixed state. Furthermore, some studies have found that manic patients had a significantly greater mean number of episodes than did mixed patients (Perugi et al., 1997). Much more research remains to be done regarding the number of total episodes in a mixed state. The current findings suggest that mixed features may be dimensionally characterized by a combination of manic episodes in conjunction with two or three depressive symptoms, and that this combination may result in significant differences in the course of the illness and its clinical characteristics (McElroy et al., 1992; Akiskal et al., 1998a, 1998b). Actually, mixed feature specifier in DSM-5 also support categorical diagnoses with dimensional approaches, in the case of mania or hypomania, the specifier will require the presence of at least three symptoms of depression in concert with the episode of mania/hypomania (Wittchen et al., 2010). Thus, these results may be reflected in manic episode with mixed features in DSM-5, although these need to be assessed on the light of the new DSM-5 criteria because of minor differences of clinical symptoms. This study demonstrates that patients with mixed features tend to be diagnosed with a manic or depressive episode rather than the less clearly defined mixed episode. Thus, these findings may be a positive contribution to the literature concerning the diagnosis and treatment of undiagnosed mixed features. Interestingly, the results of the present study indicate that family history of depressive disorder is more often associated with a mixed features than is family history of bipolar disorder. Mixed mania was linked closely with a heavy familial loading for depressive disorder that was approximately double the hereditary loading for bipolar disorder (Dell'Osso et al., 1991). The results of some studies assume that mixed states more commonly arise from a background of depressive temperament, which may add a dysphoric component to the manic episodes, compared with purer bipolar episodes that seem to arise from a hyperthymic temperament (Akiskal et al., 2003). Several limitations should be considered in the interpretation of these data. First, this was a retrospective study. The possibility
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of recall bias and reviewer bias needs to be considered in that some symptoms, features, and sub-threshold episodes might have been underestimated. Second, this study has a relatively small sample size, which might have had a negative effect on the results. Third, this study did not include a structured interview. Although a clinical interview would not focus on the issues studied here, it may have provided a general detailed understanding of the illness, which may eventually have provided important information. Taken together, the results of the present study suggest that regular assessment of symptoms associated with both polarities during a hypomanic, manic, or depressed episode should be recommended in routine practice to understand a patient's clinical course and response to treatment. Much more research remains to be done on definitions, clinical characteristics, and effective treatment for mixed features.
Acknowledgment The authors had no conflicts of interest in conducting this study or preparing the manuscript. The English in this document has been checked by at least two professional editors, both native speakers of English. For a certificate, please see: http://www.textcheck.com/certificate/SesO1U References Akiskal, H.S., Azorin, J.M., Hantouche, E.G., 2003. Proposed multidimensional structure of mania: beyond the euphoric–dysphoric dichotomy. Journal of Affective Disorders 73, 7–18. Akiskal, H.S., Hantouche, E.G., Bourgeois, M.L., Azorin, J.M., Sechter, D., Allilaire, J.F., Lancrenon, S., Fraud, J.P., Chatenet-Duchene, L., 1998a. Gender, temperament, and the clinical picture in dysphoric mixed mania: findings from a French national study (EPIMAN). Journal of Affective Disorders 50, 175–186. Akiskal, H.S., Placidi, G.F., Maremmani, I., Signoretta, S., Liguori, A., Gervasi, R., Mallya, G., Puzantian, V.R., 1998b. TEMPS-I: delineating the most discriminant traits of the cyclothymic, depressive, hyperthymic and irritable temperaments in a nonpatient population. Journal of Affective Disorders 51, 7–19. American Psychiatric Association, 2000. Diagnostic and Statistical Manual of Mental Disorders, 4th ed. American Psychiatric Association, Washington, DC. (Text Revision (DSM-IV-TR). Cassidy, F., Murry, E., Forest, K., Carroll, B.J., 1998. Signs and symptoms of mania in pure and mixed episodes. Journal of Affective Disorders 50, 187–201. Dayer, A., Aubry, J.M., Roth, L., Ducrey, S., Bertschy, G., 2000. A theoretical reappraisal of mixed states: dysphoria as a third dimension. Bipolar Disorders 2, 316–324.
Dell'Osso, L., Placidi, G.F., Nassi, R., Freer, P., Cassano, G.B., Akiskal, H.S., 1991. The manic-depressive mixed state: familial, temperamental and psychopathologic characteristics in 108 female inpatients. European Archives of Psychiatry and Clinical Neuroscience 240, 234–239. Gonzalez-Pinto, A., Aldama, A., Pinto, A.G., Mosquera, F., Perez de Heredia, J.L., Ballesteros, J., Gutierrez, M., 2004. Dimensions of mania: differences between mixed and pure episodes. European Psychiatry 19, 307–310. Gonzalez-Pinto, A., Barbeito, S., Alonso, M., Alberich, S., Haidar, M.K., Vieta, E., Tabares-Seisdedos, R., Zorrilla, I., Gonzalez-Pinto, M.A., Lopez, P., 2011. Poor long-term prognosis in mixed bipolar patients: 10-year outcomes in the Vitoria prospective naturalistic study in Spain. The Journal of Clinical Psychiatry 72, 671–676. Henry, C., M'Bailara, K., Lepine, J.P., Lajnef, M., Leboyer, M., 2010. Defining bipolar mood states with quantitative measurement of inhibition/activation and emotional reactivity. Journal of Affective Disorders 127, 300–304. Jon, D.I., Kim, K.R., Lee, E., Son, S.J., 2006. Re-evaluation for bipolar patients hospitalized for manic episode: possibility of diagnosing as a mixed episode. Journal of Korean Neuropsychiatric Association 45, 337–342. McElroy, S.L., Keck Jr., P.E., Pope Jr., H.G., Hudson, J.I., Faedda, G.L., Swann, A.C., 1992. Clinical and research implications of the diagnosis of dysphoric or mixed mania or hypomania. American Journal of Psychiatry 149, 1633–1644. Moorhead, S., Scott, J., 2000. Clinical characteristics of familial and non-familial bipolar disorder. Bipolar Disorders 2, 136–139. Pacchiarotti, I., Mazzarini, L., Kotzalidis, G.D., Valenti, M., Nivoli, A.M., Sani, G., Torrent, C., Murru, A., Sanchez-Moreno, J., Patrizi, B., Girardi, P., Vieta, E., Colom, F., 2011. Mania and depression. Mixed, not stirred. Journal of Affective Disorders 133, 105–113. Perugi, G., Akiskal, H.S., Micheli, C., Musetti, L., Paiano, A., Quilici, C., Rossi, L., Cassano, G.B., 1997. Clinical subtypes of bipolar mixed states: validating a broader European definition in 143 cases. Journal of Affective Disorders 43, 169–180. Perugi, G., Akiskal, H.S., 2005. Emerging concept of mixed states: a longitudinal perspective. In: Marneros, A., Goodwin, F.K. (Eds.), Bipolar Disorders, Mixed States, Rapid-cycling and Atypical Forms. Cambridge University Press. Suppes, T., Mintz, J., McElroy, S.L., Altshuler, L.L., Kupka, R.W., Frye, M.A., Keck Jr., P. E., Nolen, W.A., Leverich, G.S., Grunze, H., Rush, A.J., Post, R.M., 2005. Mixed hypomania in 908 patients with bipolar disorder evaluated prospectively in the Stanley Foundation Bipolar Treatment Network: a sex-specific phenomenon. Archives of General Psychiatry 62, 1089–1096. Swann, A.C., Bowden, C.L., Morris, D., Calabrese, J.R., Petty, F., Small, J., Dilsaver, S.C., Davis, J.M., 1997. Depression during mania. Treatment response to lithium or divalproex. Archives of General Psychiatry 54, 37–42. Swann, A.C., Lafer, B., Perugi, G., Frye, M.A., Bauer, M., Bahk, W.M., Scott, J., Ha, K., Suppes, T., 2013. Bipolar mixed states: an international society for bipolar disorders task force report of symptom structure, course of illness, and diagnosis. American Journal of Psychiatry 170, 31–42. Vieta, E., Morralla, C., 2010. Prevalence of mixed mania using 3 definitions. Journal of Affective Disorders 125, 61–73. Wittchen, H.-U., Höfler, M., Gloster, A.T., Craske, M.G., Beesdo-Baum, K., 2010. Options and dilemmas of dimensional measures for DSM-V: which types of measures fare best in predicting course and outcome?. In: Regier, D.A., Narrow, W.E., Kuhl, E.A., Kupfer, D.J. (Eds.), The Conceptual Evolution of DSM-5, American Psychiatric Publishing, Washington. World Health Organization, 1993. The ICD-10 Classification of Mental and Behavioral Disorders: Diagnostic Criteria for Research. World Health Organization, Geneva.
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Psychiatry Research journal homepage: www.elsevier.com/locate/psychres
A reevaluation of the possibility and characteristics in bipolar mania with mixed features: A retrospective chart review In Hee Shim, Young Sup Woo, Tae-Youn Jun, Won-Myong Bahk n Department of Psychiatry, Yeouido St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea
art ic l e i nf o
a b s t r a c t
Article history: Received 15 May 2013 Accepted 4 November 2013 Available online 12 November 2013
The aim of the present study was to reevaluate the feasibility of diagnosing a mixed features behind bipolar mania and to elucidate the clinical characteristics, treatment response, and course of the illness throughout a 12-month follow-up. The subjects (n ¼171) were inpatients diagnosed with bipolar I disorder, manic, between 2003 and 2010 and were classified into three groups: “mania” (n ¼67), “mania with probable mixed features” (n ¼ 79), and “mania with definite mixed features” (n ¼25). Diagnoses were in accordance with the Cincinnati criteria, which include the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision characteristics for a major depressive episode, except for agitation and insomnia. The charts of subjects were retrospectively reviewed for demographic and clinical characteristics prior to the index episode, clinical data regarding the index episode, and treatment courses over a 12-month follow-up period. Subjects in the mania with definite mixed features were more likely to be young at admission, to be female, to have a familial affective loading, and to have a history of suicidality relative to the mania. The results of the present study suggest the need for regular assessment of symptoms associated with both polarities during an episode in routine practice. & 2013 Elsevier Ireland Ltd. All rights reserved.
Keywords: Bipolar disorder Mixed feature Mixed mania Cincinnati criteria Clinical characteristics
1. Introduction An understanding of the mixed state in bipolar disorder is generally considered important when defining what constitutes an episode of the disorder and when examining the relationship between episodes and illness course characteristics. Mixed features may be associated with a clinical course and treatment response that differ from exclusively depressive or manic states (Swann et al., 2013). Perugi and Akiskal (2005) suggested that a mixed state does not represent a mere superimposition of affective symptoms of opposite polarity but rather a complex process of temperamental, affective, and other components. In this sense, the mixed state might be considered the clearest expression of neurophysiological dysregulation. Despite increasing awareness of the importance of the mixed state in bipolar disorder, the under-diagnosis or delayed diagnosis and consequent undertreatment of mixed-state episodes still occurs in clinical settings. Efforts to investigate the mixed state have resulted in its increasingly clear definition. In the modern taxonomy of the International Statistical Classification of Diseases and Related
n Correspondence to: Department of Psychiatry, Yeouido St. Mary's Hospital, College of Medicine, The Catholic University of Korea, #62 Yeouido-Dong, Youngdeungpo-Gu, Seoul 150-713, South Korea. Tel.: þ 82 2 3779 1250; fax: þ 82 2 780 6577. E-mail address: [email protected] (W.-M. Bahk).
0165-1781/$ - see front matter & 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.psychres.2013.11.002
Health Problems-10 (ICD-10) (World Health Organization, 1993), a mixed state refers to the co-existence or rapid alternation of prominent depressive symptoms and manic/hypomanic symptoms for at least 2 weeks. The Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR) (American Psychiatric Association, 2000) requires that a person meet the criteria for a full-blown manic episode and a depressive syndrome almost every day for at least 1 week. However, these criteria have not yet been fully elucidated. The definitions of a mixed state from both the DSM-IV-TR and the ICD-10 are too restrictive and are rarely satisfied in a clinical situation, resulting in the exclusion of many patients who may be clinically considered to be experiencing such a state. Moreover, studies evaluating the onset, clinical characteristics, course, and outcome of the mixed state have yet to completely clarify its features. At this point in time, a new categorical approach to the mixed state is necessary for clinical practice. It has been proposed that a new definition and set of characteristics be created for the mixed state that will integrate an approach that conceptualizes the co-existence of manic and depressive symptoms (Dayer et al., 2000). Thus, the diagnosis of a full DSM-IV-TR manic syndrome associated with dysphoria and some depressive symptoms or a full DSM-IV-TR depressive syndrome associated with irritability, agitation, and some manic symptoms would be possible. Recent studies (McElroy et al., 1992; Swann et al., 1997; Akiskal et al., 1998a, 1998b) have suggested that the preliminary operational diagnostic
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criteria for mixed mania should include all of the DSM-IV-TR criteria for a major depressive episode, except for agitation and insomnia, in conjunction with primary mania. For a diagnosis of a mixed state in bipolar disorder, McElroy et al. (1992) advocated the criterion of more than three depressive symptoms combined with primary mania, whereas Akiskal et al. (1998a, 1998b) and Swann et al. (1997) respectively suggested that the presence of more than two, or one depressive symptom, is sufficient. The present study was conducted to reclassify patients hospitalized for bipolar I disorder, manic episode, in accordance with the Cincinnati criteria (McElroy et al., 1992), the narrowest set of criteria for mixed mania. Subjects were categorized into three groups: mania (no depressive symptoms); mania with probable mixed features (one or two depressive symptoms); and mania with definite mixed features (Z3 depressive symptoms). The aim of the present study was to reevaluate the feasibility of diagnosing a mixed features underlying primary mania and to elucidate the clinical characteristics, treatment response, and course of illness associated with this state throughout a 12-month follow-up.
2. Methods 2.1. Subjects This chart review was conducted at Yeouido St. Mary's Hospital, College of Medicine at The Catholic University of Korea in Seoul, Korea. All patients hospitalized at this institution had been diagnosed by clinical interview with an Axis I disorder by a board-certified psychiatrist in accordance with the DSM-IV-TR. All subjects in this study met the DSM-IV-TR criteria for bipolar I disorder, manic, during the period of 2003–2010. The following inclusion criteria were used: (1) patients were diagnosed using the DSM-IV-TR as currently having a manic episode, non-mixed; and (2) patients were between the ages of 15–75 years. Exclusion criteria consisted of insufficient data, a severe comorbid medical condition that could contribute to mood symptoms, organic brain lesion that may influence mood symptoms, an episode of substance-induced mood disorder, a comorbid psychiatric disorder such as personality disorder, schizophrenia, schizoaffective disorder, anxiety disorder, or dementia, and a change in the diagnosis during the follow-up period. The charts of 306 subjects diagnosed with bipolar I disorder, manic, were analyzed at baseline, and 135 cases were excluded based on the abovementioned criteria. Thus, 171 inpatients diagnosed with bipolar I disorder, manic, were enrolled in the study and categorized into three groups: mania, mania with probable mixed features, and mania with definite mixed features. The classification was performed in accordance with the stringent Cincinnati criteria (McElroy et al., 1992) for a mixed state, which include the DSM-IV-TR criteria for a major depressive episode (except for agitation and insomnia): depressed mood, markedly diminished interest or pleasure, weight gain or increase in appetite, hypersomnia, psychomotor retardation, fatigue or loss of energy, worthlessness or excessive or inappropriate guilt, helplessness or hopelessness, and recurrent thoughts of death, recurrent suicidal ideation, or a specific plan for committing suicide. Of the 171 patients who were included in the analysis, 147 who were followed for more than 12 months after discharge were included in the analysis over a 12-month follow-up period.
2.2. Assessments The charts of the subjects were reviewed for demographic and clinical characteristics including age of onset, age at first treatment, age at admission, sex, marital status, family history of mood disorder, number of hospitalizations, number of episodes, number of depressive episodes, number of manic episodes, number of hypomanic episodes, number of mixed episodes, lifetime number of psychotic features, and suicidality. Suicidality was defined as recurrent suicidal ideation, a specific plan for suicide, or recurrent suicide attempts. Index episode was a term used to define the manic episode that led to the hospitalization of the patient due to severe symptoms from 2003 to 2010. If a patient experienced more than one hospitalization during the whole study period, only the data from the last admission were analyzed. Clinical data in the index episode included duration of the episode, patient medications (change of medications, total number of medications, number of mood stabilizers, and number of antipsychotics), suicidality, and psychotic features. To identify mixed features, patients were monitored for opposite-polarity symptoms such as depressive symptoms (according to the DSM-IV-TR criteria for a major depressive episode, excluding agitation and insomnia (McElroy et al., 1992)) in addition to emotional
intensity and affective instability, which contribute to a mixed state (Henry et al., 2010). Two independent (Y.S.W. and W.M.B.) who were not informed about the purpose of the study independently evaluated the medical records for clinical data over a 12-month follow-up period. During the follow-up period, the number of episodes, number of manic episodes, number of depressive episodes, number of hypomanic episodes, number of mixed episodes, number of hospitalizations, the re-hospitalization rate and the duration from discharge to rehospitalization, psychotic features, suicidality, inter-episode remission, and rapid cycling were retrospectively evaluated. 2.3. Statistical analysis Statistical analyses were carried out using SAS for Windows (version 9.2). Statistical methods consisted of Chi-square tests or Fisher's exact test with Bonferroni's correction for comparisons of categorical variables and analysis of variance (ANOVA) for continuous variables. Post hoc analysis using Tukey's procedure was used to calculate mean differences and to determine significant differences among means. To identify the factors associated with mixed features, a multinomial logistic regression analysis was conducted; independent variables included demographic information, clinical characteristics, and clinical data from the index episode including depressive symptoms (according to the DSM-IV major depressive episode criteria, excluding agitation and insomnia, the Cincinnati criteria (McElroy et al., 1992)); the dependent variable was group assignment, including the mania group (patients not meeting the criteria for mixed mania), the mania with probable mixed features group (patients with one or two of these criteria), and the mania with definite mixed features group (patients with Z 3 of these criteria). A P-value of 0.05 was considered statistically significant, and when Bonferroni's correction for comparisons of categorical variables was used, P-values of 0.017 were considered statistically significant. 2.4. Ethics The study was conducted according to the Declaration of Helsinki, and approval to conduct this chart review was obtained from the Institutional Review Board. Because this was a retrospective study and the data were obtained by routine psychiatric examination and treatment, the board judged that an informed consent was unnecessary.
3. Results 3.1. Demographic and clinical characteristics prior to the index episode The distribution of patients meeting the criteria for Bipolar I disorder, manic, is shown in Table 1. Of the patients included in the final analysis, 67 (39.1%) had no depressive symptoms during their manic episode (mania group), 79 (46.3%) exhibited one or two associated depressive symptoms (mania with probable mixed features group), and 25 (14.6%) exhibited three or more depressive symptoms (mania with definite mixed features group). Several significant differences in demographic and clinical characteristics were identified, including age of onset, age at first treatment, age at admission, sex, family history of mood disorder (more specifically, family history of depressive disorder), lifetime number of psychotic features, and suicidality. Sex was significantly different among the three groups (P ¼0.001) with the mania with probable mixed features group including more women compared to the mania group (70.9% vs. 40.3%; P o0.001). The mean age of onset (P¼ 0.002), mean age at first treatment (P¼ 0.002), and mean age at index hospitalization (P ¼0.001) were significantly different among the three groups. The mania with probable mixed features group had a younger mean age at onset (25.9 79.6 vs. 30.1 712.2 years; P ¼0.040), younger mean age at first treatment (26.3 79.8 vs. 30.47 12.1 years; P¼ 0.045), and younger mean age at admission (35.2 712.0 vs. 41.8712.4 years; P ¼0.002) than the mania group. The mania with definite mixed features group also had a younger mean age at onset (22.2 7 4.4 vs. 30.1 712.2 years; P¼ 0.003), younger mean age at first treatment (22.2 74.4 vs. 30.47 12.1 years; P¼ 0.002), and younger mean age at admission (33.2 79.4 vs. 41.8712.4 years; P ¼0.006) than the mania group.
I.H. Shim et al. / Psychiatry Research 215 (2014) 335–340
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Table 1 Demographic and clinical characteristics prior to the index episode.
Age (years) Onset 1st treatment At admission Sex (Male), n (%) Married, n (%) Family history, n (%) Mood disorder Bipolar disorder Depressive disorder Total episodes Manic episodes Depressive episodes Hypomanic episodes Mixed episodes Number of hospitalization Number of psychotic features Suicidality, n (%)
M (N ¼67)
PM (N ¼ 79)
DM (N ¼25)
Significance (M vs. PM vs. DM)
Significance (M vs. PM)
Significance (M vs. DM)
Significance (PM vs. DM)
30.17 12.2 30.4 7 12.1 41.8 7 12.4 40 (59.7) 40 (59.7)
25.9 79.6 26.3 79.8 35.2 7 12.0 23 (29.1) 37 (46.8)
22.2 7 4.4 22.2 7 4.4 33.27 9.4 8 (32.0) 13 (52.0)
0.002n 0.002n 0.001n 0.001n 0.299
0.040n 0.045n 0.002n o0.001nn N.A.
0.003n 0.002n 0.006n 0.018 N.A.
0.250 0.235 0.759 0.783 N.A.
9 (13.4) 4 (6.0) 5 (7.5) 4.2 7 2.3 2.9 7 1.8 1.17 1.2 0.17 0.3 07 0.2 3.4 7 2.5 1.3 72.0
19 (24.1) 8 (10.1) 13 (16.5) 4.2 73.6 3.3 73.3 0.8 71.2 0 07 0.1 3.17 2.7 1.6 7 2.2
10 (40.0) 1 (4.0) 10 (40.0) 4.5 7 3.2 3.5 7 3.1 17 1.3 0 0.1 70.3 4.1 73.4 2.9 7 3.5
0.021n 0.489 0.001n 0.257 0.629 0.423 0.211 0.222 0.257 0.022n
0.104 N.A. 0.100 N.A. N.A. N.A. N.A. N.A. N.A. 0.722
0.005nn N.A. 0.001nn N.A. N.A. N.A. N.A. N.A. N.A. 0.017n
0.121 N.A. 0.013nn N.A. N.A. N.A. N.A. N.A. N.A. 0.062
8 (11.9)
9 (11.4)
11 (44.0)
o 0.001n
0.918
0.001nn
0.001nn
M: mania group, PM: mania with probable mixed features, DM: mania with definite mixed features. P-values are results of Chi-square or Fisher's exact tests (categorical variables) and ANOVA (continuous variables) between groups, Post-hoc analysis using Tukey's procedure was used. n
Po 0.05, Bonferroni's correction for comparisons of categorical variables. Po 0.017, N.A. not applicable.
nn
Table 2 Clinical data in index episode.
Duration of index episode Change of medication, n (%) Number of medications Number of mood stabilizers Number of antipsychotics Psychotic features, n (%) Suicidality, n (%)
M (N¼ 67)
PM (N ¼ 79)
DM (N ¼25)
Significance (M vs. PM vs. DM)
Significance (M vs. PM)
Significance (M vs. DM)
Significance (PM vs. DM)
1.5 7 0.8 24 (35.8) 4.2 7 1.6 1.5 7 0.8 1.1 70.3 37 (55.2) 0
1.4 7 0.5 34 (43.0) 4.2 71.6 1.4 7 0.6 1.2 7 0.5 46 (58.2) 4 (5.1)
1.3 70.5 8 (32.0) 4.17 1.7 1.2 70.7 1.0 70.3 17 (68.0) 7 (28.0)
0.302 0.513 0.927 0.250 0.068 0.541 o 0.001n
N.A. N.A. N.A. N.A. N.A. N.A. 0.125
N.A. N.A. N.A. N.A. N.A. N.A. o0.001nn
N.A. N.A. N.A. N.A. N.A. N.A. 0.004nn
M: mania group, PM: mania with probable mixed features group, DM: mania with definite mixed features group. P-values are results of Chi-square or Fisher's exact tests (categorical variables) and ANOVA (continuous variables) between groups, Post-hoc analysis using Tukey's procedure was used. n
Po 0.05, Bonferroni's correction for comparisons of categorical variables. Po 0.017, N.A. not applicable.
nn
No significant differences were found between the mania with probable mixed features group and the mania with definite mixed features group in terms of age of onset, age at first treatment, and age at admission. Familial affective loading (P ¼0.021) and family history of depressive disorders (P ¼0.001) were significantly different among the three groups. Familial affective loading (40% vs. 13.4%; P ¼0.005) and familial depressive disorders (40% vs. 7.5%; P ¼0.001) were more common in the mania with definite mixed features group compared with the mania group. Patients in the mania with definite mixed features group also more had frequent family histories of depressive disorders than did those in the mania with probable mixed features group (40.0% vs. 16.5%; P ¼0.013), whereas there were no differences between the other groups. The lifetime number of psychotic features was significantly different among the three groups (P¼ 0.022), being more common in the mania with definite mixed features group than in the mania group (2.97 3.5 vs. 1.372.0; P ¼0.017). Suicidality was also significantly different among the three groups (Po 0.001) and was greater in the mania with definite mixed features group than in the mania group (44.0% vs. 11.9%; P ¼0.001) and the mania with probable mixed features group (44.0% vs. 11.4%; P¼ 0.001).
3.2. Clinical data in index episode Characteristics of the clinical data for each group during the index episode are summarized in Table 2. There were no significant differences in the duration of index episode, change of medications (mood stabilizers or antipsychotics), the total number of medications, mood stabilizers, or antipsychotics, or psychotic features. Suicidality was significantly different among the groups (P o0.001), with higher rates in the mania with definite mixed features group compared with the mania group (28.0% vs. 0%; Po 0.001) and the mania with probable mixed features group (28.0% vs. 5.1%; P ¼0.004). Fig. 1 depicts the loads of the nine items associated with Cincinnati depressive symptoms (McElroy et al., 1992) for manic subjects with either mania with probable mixed features or mania with definite mixed features. The highest frequencies of symptoms were observed for depressed mood or labile mood (88% and 82.3%, respectively), markedly diminished interest or pleasure (64% and 21.5%, respectively), helplessness or hopelessness (56% and 3.8%, respectively), and fatigue (44% and 5.1%, respectively). Each of these symptoms showed significantly different frequencies in the mania
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I.H. Shim et al. / Psychiatry Research 215 (2014) 335–340
100 Probable mixed mania group (N=79)
Percent of patients (%)
90 80
Definite mixed mania group (N=25)
70 60 50 40 30 20 10 0
Fig.1. Specific Cincinnati depressive symptoms during the index episode.
Table 3 Final model of multinomial logistic regression between groups. M vs. PM Significance
Age at admission Sex (female) Family history of mood disorder Suicidality
0.013n o 0.001n 0.021n 0.637
M vs. DM a
OR
0.949 4.594 3.310 1.372
95% C.I. for OR Lower
Upper
0.911 2.121 1.195 0.368
0.989 9.948 9.168 5.113
Significance
0.032n 0.006n 0.011n 0.019n
PM vs. DM a
OR
0.936 5.600 5.907 6.947
95% C.I. for OR Lower
Upper
0.881 1.652 1.504 1.367
0.994 18.983 23.193 35.295
Significance
0.632 0.733 0.301 0.022n
ORb
0.986 1.219 1.785 5.063
95% C.I. for OR Lower
Upper
0.932 0.390 0.596 1.269
1.044 3.808 5.343 20.201
M: mania group, PM: mania with probable mixed features group, DM: mania with definite mixed features group. n
a b
Po 0.05. Relative to mania group. Relative to mania with probable mixed features group.
Table 4 Course of illness over a 12 months follow-up period.
Number of episodes Manic Depressive Hypomanic Mixed Number of hospitalization Re-hospitalization, n (%) Duration from discharge to re-hospitalization (month) Psychotic features, n (%) Suicidality, n (%) Inter-episode remission, n (%) Rapid cycling, n (%)
M (N ¼ 57)
PM (N ¼67)
DM (N ¼ 23)
Significance (M vs. PM vs. DM)
Significance (M vs. PM)
Significance (M vs. DM)
Significance (PM vs. DM)
0.5 7 0.8 0.2 7 0.4 0.3 7 0.7 0.17 0.2 07 0.1 0.2 7 0.5 26 (45.6) 6.7 7 3.7
0.4 7 0.7 0.2 7 0.4 0.3 7 0.5 0 0 0.2 7 0.5 29 (43.3) 8.5 7 7.8
0.7 70.8 0.17 0.3 0.5 70.7 0.17 0.3 07 0.2 0.3 70.4 9 (39.1) 9.7 712.8
0.227 0.750 0.381 0.277 0.288 0.776 0.868 0.778
N.A. N.A. N.A. N.A. N.A. N.A. N.A. N.A.
N.A. N.A. N.A. N.A. N.A. N.A. N.A. N.A.
N.A. N.A. N.A. N.A. N.A. N.A. N.A. N.A.
7 (12.3) 2 (3.5) 50 (87.7) 1 (1.8)
6 (9.0) 2 (3.0) 65 (97.0) 0
3 (13.0) 1 (4.3) 16 (69.6) 1 (4.3)
0.786 40.999 0.001n 0.146
N.A. N.A. 0.079. N.A.
N.A. N.A. 0.100 N.A.
N.A. N.A. 0.001nn N.A.
M: mania group, PM: mania with probable mixed features group, DM: mania with definite mixed features group. P-values are results of Chi-square or Fisher's exact tests (categorical variables) and ANOVA (continuous variables) between groups, Post-hoc analysis using Tukey's procedure was used. n
Po 0.05, Bonferroni's correction for comparisons of categorical variables. Po 0.017, N.A. not applicable.
nn
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with definite mixed features group compared with the mania with probable mixed features group except for depressed mood or labile mood (P¼0.559), hypersomnia (P¼0.029), and psychomotor retardation (P¼ 0.148). Depressed mood or labile mood (82.3% vs. 0%, Po0.001) and markedly diminished interest or pleasure (21.5% vs. 0%, Po0.001) were significantly different between the mania with probable mixed features group and the mania group. The multinomial logistic regression included all significant variables and revealed several independent correlates of bipolar I disorder, mixed. The final regression model evaluating the three groups is presented in Table 3. Subjects with mania with definite mixed features were more likely to be young at admission (OR ¼0.936, 95% CI 0.881–0.994), to be female (OR ¼5.600, 95% CI 1.652–18.983), to have familial affective loading (OR ¼5.907, 95% CI 1.504–23.193), and to have a history of suicidality (OR¼ 6.947, 95% CI 1.367–35.295) compared with the mania group. 3.3. Course of illness over a 12-month follow-up period The number of episodes, rate of re-hospitalization and duration of stay in re-hospitalized patients, psychotic features, suicidality, inter-episode remission, and rapid cycling in each group during the 12-month follow-up are shown in Table 4. Fifty-seven patients (38.8%) had mania, 67 (45.6%) had mania with probable mixed features, and 23 (15.6%) had mania with definite mixed features. The inter-episode remission rate was significantly different among the three groups (P ¼0.001) and was lower in the mania with definite mixed features group than in the mania with probable mixed features group (69.6% vs. 97.0%; P ¼0.001).
4. Discussion The objective of this study was to reevaluate the possibility of a mixed features diagnosis in patients hospitalized for bipolar I disorder, manic, and to elucidate the clinical characteristics, treatment response, and course of illness for these patients throughout a 12-month follow-up period. Based on this analysis, it appears that a mixed features was under- or undiagnosed in 15% of cases, consistent with the rate of 20.8% undiagnosed mixed state manic patients in a previous study (Jon et al., 2006). Also similar to previous studies, the prevalence rates of dysphoric mania among acutely manic patients with bipolar disorder ranged from 9% to 23.2% in this study (Vieta and Morralla, 2010). The current study also found that patients diagnosed with a mixed features were younger at onset, younger age at first treatment, and younger at admission than were those diagnosed with pure manic states. These results are in close agreement with the results reported by Gonzalez-Pinto et al. (2011). Depressive symptoms in a mixed manic episode were commonly manifested as depressed mood or labile mood, markedly diminished interests or pleasure, helplessness, and fatigue, whereas other depressive symptoms showed a broadly similar distribution. The results of the present study are similar to those of a previous study. Depressive symptoms associated with mixed manic episodes in this study included dysphoric mood, anxiety, excessive guilt, and suicidality (Cassidy et al., 1998). The results of the present study agree well with the previous study in the high prevalence of psychotic symptoms (Gonzalez-Pinto et al., 2004). Similar to Perugi et al. (1997), the present study found that subjects with mixed symptoms experienced fewer inter-episode remissions. An important finding in the present study is the association of a mixed features with young age at admission, being female, having a high familial affective loading, and suicidality. This confirms earlier reports indicating that patients in broadly defined mixed states are more likely to be women
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(Suppes et al., 2005), tend to have high familial affective loading (Moorhead and Scott, 2000), and have a higher risk for suicide than patients whose history includes non-mixed manic episode (Pacchiarotti et al., 2011). However, these findings also contradict those of earlier studies in some respects. In the present study, no significant difference in the number of total episodes was found among the three groups, whereas Pacchiarotti et al. (2011) found that patients with mixed manic states had more lifetime episodes of illness than did those without mixed states. It is important to consider several differences between these studies, such as design and clinical characteristics. Pacchiarotti et al. (2011) applied a more restrictive set of criteria, namely those of DSM-IV-TR (American Psychiatric Association, 2000), which have a lower concordance with the Cincinnati criteria (McElroy et al., 1992) than with the ICD-10 (World Health Organization, 1993) for patients in a mixed state (Vieta and Morralla, 2010). Moreover, in that study, lifetime neuropsychiatric history was subdivided into past or current manic episodes only (purely manic), past or current manic and mixed episodes, and past or current mixed episodes only (purely mixed). Second, patients in the present study had an older mean age of onset and a lower rate of previous depressive and hypomanic episodes than did those in the study by Pacchiarotti et al. (2011). These differences may be due to recall bias in that patients and their family members may have had difficulty remembering past depressive or hypomanic episodes. Although the finding that those with a mixed-state diagnosis had more lifetime episodes of illness than those without mixed states is commonly accepted, various studies have used different study designs and inclusion criteria to diagnose the mixed state. Furthermore, some studies have found that manic patients had a significantly greater mean number of episodes than did mixed patients (Perugi et al., 1997). Much more research remains to be done regarding the number of total episodes in a mixed state. The current findings suggest that mixed features may be dimensionally characterized by a combination of manic episodes in conjunction with two or three depressive symptoms, and that this combination may result in significant differences in the course of the illness and its clinical characteristics (McElroy et al., 1992; Akiskal et al., 1998a, 1998b). Actually, mixed feature specifier in DSM-5 also support categorical diagnoses with dimensional approaches, in the case of mania or hypomania, the specifier will require the presence of at least three symptoms of depression in concert with the episode of mania/hypomania (Wittchen et al., 2010). Thus, these results may be reflected in manic episode with mixed features in DSM-5, although these need to be assessed on the light of the new DSM-5 criteria because of minor differences of clinical symptoms. This study demonstrates that patients with mixed features tend to be diagnosed with a manic or depressive episode rather than the less clearly defined mixed episode. Thus, these findings may be a positive contribution to the literature concerning the diagnosis and treatment of undiagnosed mixed features. Interestingly, the results of the present study indicate that family history of depressive disorder is more often associated with a mixed features than is family history of bipolar disorder. Mixed mania was linked closely with a heavy familial loading for depressive disorder that was approximately double the hereditary loading for bipolar disorder (Dell'Osso et al., 1991). The results of some studies assume that mixed states more commonly arise from a background of depressive temperament, which may add a dysphoric component to the manic episodes, compared with purer bipolar episodes that seem to arise from a hyperthymic temperament (Akiskal et al., 2003). Several limitations should be considered in the interpretation of these data. First, this was a retrospective study. The possibility
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of recall bias and reviewer bias needs to be considered in that some symptoms, features, and sub-threshold episodes might have been underestimated. Second, this study has a relatively small sample size, which might have had a negative effect on the results. Third, this study did not include a structured interview. Although a clinical interview would not focus on the issues studied here, it may have provided a general detailed understanding of the illness, which may eventually have provided important information. Taken together, the results of the present study suggest that regular assessment of symptoms associated with both polarities during a hypomanic, manic, or depressed episode should be recommended in routine practice to understand a patient's clinical course and response to treatment. Much more research remains to be done on definitions, clinical characteristics, and effective treatment for mixed features.
Acknowledgment The authors had no conflicts of interest in conducting this study or preparing the manuscript. The English in this document has been checked by at least two professional editors, both native speakers of English. For a certificate, please see: http://www.textcheck.com/certificate/SesO1U References Akiskal, H.S., Azorin, J.M., Hantouche, E.G., 2003. Proposed multidimensional structure of mania: beyond the euphoric–dysphoric dichotomy. Journal of Affective Disorders 73, 7–18. Akiskal, H.S., Hantouche, E.G., Bourgeois, M.L., Azorin, J.M., Sechter, D., Allilaire, J.F., Lancrenon, S., Fraud, J.P., Chatenet-Duchene, L., 1998a. Gender, temperament, and the clinical picture in dysphoric mixed mania: findings from a French national study (EPIMAN). Journal of Affective Disorders 50, 175–186. Akiskal, H.S., Placidi, G.F., Maremmani, I., Signoretta, S., Liguori, A., Gervasi, R., Mallya, G., Puzantian, V.R., 1998b. TEMPS-I: delineating the most discriminant traits of the cyclothymic, depressive, hyperthymic and irritable temperaments in a nonpatient population. Journal of Affective Disorders 51, 7–19. American Psychiatric Association, 2000. Diagnostic and Statistical Manual of Mental Disorders, 4th ed. American Psychiatric Association, Washington, DC. (Text Revision (DSM-IV-TR). Cassidy, F., Murry, E., Forest, K., Carroll, B.J., 1998. Signs and symptoms of mania in pure and mixed episodes. Journal of Affective Disorders 50, 187–201. Dayer, A., Aubry, J.M., Roth, L., Ducrey, S., Bertschy, G., 2000. A theoretical reappraisal of mixed states: dysphoria as a third dimension. Bipolar Disorders 2, 316–324.
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