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Prevalence rates and clinical implications of bipolar disorder “with mixed features” as defined by DSM-5
Journal of Affective Disorders 173 (2015) 120–125
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Research report
Prevalence rates and clinical implications of bipolar disorder “with mixed features” as defined by DSM-5 In Hee Shim a, Young Sup Woo b, Won-Myong Bahk b,n a b
Department of Psychiatry, Dongnam Institute of Radiological & Medical Sciences, Busan, Republic of Korea Department of Psychiatry, Yeouido St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
art ic l e i nf o
a b s t r a c t
Article history: Received 23 July 2014 Received in revised form 27 October 2014 Accepted 29 October 2014 Available online 10 November 2014
Background: We investigated the increase in the prevalence of bipolar disorder with mixed features following the replacement of DSM-IV-TR criteria with DSM-5 criteria. Additionally, we examined the clinical implications of the use of “with mixed features” as a specifier with bipolar disorder. Method: We retrospectively reviewed medical charts from 2003 to 2013. A total of 331 patients diagnosed with bipolar disorder using the DSM-IV TR were enrolled and categorized into four groups: manic/hypomanic with mixed features, manic/hypomanic without mixed features, depressed with mixed features, and depressed without mixed features. These classifications were made in accordance with the DSM-5 definition of bipolar disorder “with mixed features.” Changes in the prevalence, demographic and clinical characteristics were compared among the groups. Results: The prevalence rates of mixed features were significantly different when using the DSM-5 criteria vs. the DSM-IV-TR criteria. Patients with mixed features had a younger age of onset, younger age at hospitalization, more frequent hospitalizations for mixed episodes, and greater suicide risk compared with patients without mixed features. Limitations: Retrospective study may have resulted in under diagnosis of mixed states. Conclusions: An approximately three-fold greater risk for mixed features was observed in patients with bipolar disorder when using the DSM-5 criteria than when using the DSM-IV-TR criteria. The additional patients may represent patients with sub-syndromal mixed features and could indicate that patients with mixed features are underdiagnosed. & 2014 Elsevier B.V. All rights reserved.
Keywords: Bipolar disorder Clinical implication DSM-5 Mixed features Prevalence
1. Introduction Compared with patients with bipolar disorder who exhibit pure manic/hypomanic or depressive episodes, the presence of mixed mood states in bipolar disorder patients is associated with a more severe course of illness and a different set of clinical characteristics that include younger age of onset, more frequent occurrence of psychotic symptoms, major risk for suicide, higher rates of comorbidities, and longer time to achieve remission (Baldessarini et al., 2010; Shim et al., 2014; Undurraga et al., 2012). Clinical vigilance and cautious evaluation are required to properly diagnose and assess the occurrence of mixed states during a diagnostic interview. According to the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR) criteria, the diagnosis of a mixed episode applies only to patients with bipolar I disorder who exhibit the simultaneous presence of full manic and full depressive symptoms for at least
n
Corresponding author. Tel.: þ 82 2 3779 1250; fax: þ 82 2 780 6577. E-mail address: [email protected] (W.-M. Bahk).
http://dx.doi.org/10.1016/j.jad.2014.10.061 0165-0327/& 2014 Elsevier B.V. All rights reserved.
1 week (American Psychiatric Association, 2000). However, mixed episodes do not simply consist of the simultaneous or sequential occurrence of polar opposite affective symptoms but rather of complex, fluctuating, and unstable clinical features (Kruger et al., 2005). Thus, the DSM-IV-TR criteria for mixed states in bipolar disorder are too narrow and have a too high threshold; as a result, many patients who are actually suffering from these features may be excluded from this diagnosis. The DSM, Fifth Edition (DSM-5) definition of mixed states in bipolar disorder uses a more dimensional perspective that defines mixed features during an episode as a particular subtype of mood disorder (Micoulaud Franchi et al., 2013). The new specifier “with mixed features” that has been included in the DSM-5 may be applied to episodes of mania/hypomania in which depressive features are present and to episodes of depression in the context of major depressive disorder or bipolar disorder when features of mania/hypomania are present (American Psychiatric Association, 2013). These changes reflect a more liberal application of the “with mixed features” specifier to both polarities of bipolar disorder and will likely have an impact on the rate of diagnosis of bipolar disorder with mixed features, the strategies used to treat this
I.H. Shim et al. / Journal of Affective Disorders 173 (2015) 120–125
subtype, and clinical research regarding mood disorders. However, the effects and clinical implications associated with use of the DSM specifier “with mixed features”, including the presence of specific clinical characteristics have yet to be fully assessed. Therefore, the present study investigated the increase in prevalence rates of the diagnosis of bipolar disorder with mixed features based on DSM-5 criteria. Additionally, patients diagnosed with bipolar I, bipolar II, or bipolar disorder not otherwise specified (NOS) according to DSMIV-TR criteria were re-categorized into four groups based on the new DSM-5 criteria in order to examine the clinical implications of the “with mixed features” specifier on the demographic and clinical characteristics of patients with bipolar disorder.
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The index episode for each patient was defined as any mood episode that led to a hospitalization between 2003 and 2013. If a patient experienced more than one hospitalization during the study period, only the data from the most recent admission were analyzed. To identify a state with mixed features, the patients were monitored for symptoms of the opposite polarity of the primary mood episode. Additionally, patients with symptoms that met the full episode criteria for both polarities simultaneously, such as a mixed episode according to the DSM-IV-TR, were diagnosed as manic/hypomanic with mixed features. Two independent physicians (W.Y.S. and B.W.M.) who were blind to the purpose of the study separately evaluated the medical records of the patients for symptoms of the opposite polarity. 2.3. Statistical analysis
2. Patients and methods 2.1. Patients The medical charts of all participants included in the present study were retrospectively reviewed at Yeouido St. Mary's Hospital, College of Medicine at The Catholic University of Korea in Seoul, Korea. All patients hospitalized in this institution were diagnosed by a boardcertified psychiatrist using the clinical interview for Axis I disorders in accordance with DSM-IV-TR criteria for mood disorders. All subjects met the DSM-IV-TR criteria for bipolar I, bipolar II, or bipolar disorder, NOS, during the period from 2003 to 2013 as well as the following inclusion criteria: (1) a current diagnosis of bipolar disorder with any type of mood episode based on DSM-IV-TR criteria and (2) aged between 15 and 75 years. The exclusion criteria consisted of insufficient data, a severe comorbid medical or neurological condition that could contribute to mood symptoms, an organic brain lesion that could influence mood symptoms, a thought disorder (such as schizophrenia or schizoaffective disorder), a personality disorder as a principle diagnosis, or a cognitive disorder (such as dementia) that could confound the phenomenology of a mood episode. The charts of 371 inpatients diagnosed with bipolar I, bipolar II, or bipolar disorder, NOS, were initially assessed, and 40 cases were excluded based on the above criteria. Thus, a total of 331 patients were enrolled in the present study and categorized into four groups: manic/hypomanic with mixed features, manic/hypomanic without mixed features, depressed with mixed features, and depressed without mixed features. These classifications were performed in accordance with the DSM-5 definition of bipolar disorder and the “with mixed features” specifier, which is as follows: the full criteria are met for a manic/hypomanic or depressed episode and at least three symptoms of the opposite polarity are present. 2.2. Assessments All observed changes in terms of the prevalence and clinical implications of a diagnosis of bipolar disorder with mixed features based on the DSM-IV-TR definition vs. the DSM-5 definition were assessed. The charts of all patients were reviewed to estimate the prevalence rate of mixed features and demographic and clinical characteristics including age of onset, age at admission, sex, family history of mood disorder (especially family history of bipolar and depressive disorders), number of mood episodes (total number of mood episodes, number of depressed episodes, number of manic/ hypomanic episodes, and number of mixed episodes), number of hospitalizations for mood episodes (total number of hospitalizations for mood episodes, number of hospitalizations for depressed episodes, number of hospitalizations for manic episodes, and number of hospitalizations for mixed episodes), suicidality (defined as any suicide attempts during the patient's lifetime), rapid cycling, and psychotic features.
All statistical analyses were performed using SAS for Windows, version 9.3 (SAS Institute, Cary, NC, USA). Chi-square tests or Fisher's exact tests were used for categorical variables, and independent ttests or Mann–Whitney U-tests were used for continuous variables. Additionally, logistic regression analyses were used for categorical variables, and either analysis of covariance (ANCOVA) or the Wilcoxon rank–sum test (rank ANCOVA) was used for continuous variables, with clinical characteristics such as age at hospitalization included as covariates for adjustment. A p-value o0.05 was considered statistically significant, and a p-value between 0.05 and 0.10 was considered to indicate a trend toward statistical significance. 2.4. Ethics The present study was conducted according to the Declaration of Helsinki, and approval to conduct the chart review was obtained from the Institutional Review Board. Because this was a retrospective study and the data were obtained during routine psychiatric examinations and treatment, the board determined that informed consent was unnecessary.
3. Results 3.1. Demographic characteristics at the index episode The distribution of patients meeting the criteria for bipolar I, bipolar II, and bipolar disorder, NOS, with any mood episode according to the DSM-IV-TR is provided in Table 1. Of the 331 patients included in the final analysis, 266 (80.4%) were diagnosed with any mood episode without mixed features, 165 (49.8%) did not exhibit depressive symptoms during manic/hypomanic episodes (manic/hypomanic without mixed features), 101 (30.5%) did not exhibit manic/hypomanic symptoms during depressed episodes (depressed without mixed features), 65 (19.6%) were diagnosed with any mood episode with mixed features, 52 (15.7%) exhibited three or more depressive symptoms during manic/ hypomanic episodes (manic/hypomanic with mixed features), and 13 (3.9%) exhibited three or more manic symptoms during depressed episodes (depressed with mixed features). 3.2. The prevalence of mixed features The prevalence rate for mood episodes based on the DSM-IV-TR definition of mixed features and that for the DSM-5 “with mixed features” specifier is presented in Fig. 1. Based on DSM-IV-TR criteria, 59.5% of the mood episodes were manic/hypomanic, 34.4% were depressed, and 6.0% were mixed episodes. However, when using the DSM-5 definition and the “with mixed features” specifier, there was a threefold greater risk for mixed features in patients with bipolar disorder. In this case, 49.8% of mood episodes
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Table 1 Demographic and clinical characteristics at the index episode. Without mixed features N ¼266
Manic/ hypomanic without mixed features N ¼ 165 Age (years) Onset At hospitalization Sex (male), n (%) Family history, n (%) Mood disorder Bipolar Disorder Depressive disorder Number of mood episodes Depressed Manic/hypomanic Mixed Number of hospitalization Depressed Manic Mixed Suicidality, n (%) Rapid cycling, n (%) Psychosis, n (%) n
†
With mixed features N ¼ 65
Manic/ hypomanic with mixed features N ¼ 52
Depressed without mixed features N ¼ 101
Significance (without mixed features vs. with mixed features)
Significance (without mixed features vs. with mixed features in mania/hypomania)
Significance (without mixed features vs. with mixed features in depression)
Depressed with mixed features N ¼13
34.2 7 13.6 32.5 7 12.7 43.8 7 13.4 42.6 7 12.3 114 (42.9) 74 (44.8)
37.17 14.6 21.6 7 7.0 22.17 7.6 45.8 7 14.9 25.2 79.1 26.3 79.7 40 (39.6) 24 (36.9) 19 (36.5)
19.6 72.8 20.5 7 2.9 8 (61.5)
o 0.001n o 0.001n 0.384
o 0.001n o 0.001n 0.291
o0.001n o0.001n 0.937
66 (24.8) 29 (10.9) 42 (15.8) 5.3 7 4.5 1.9 7 2.5 3.3 7 3.8 0.17 0.4 3.3 7 2.8 1.1 71.7 2.2 7 2.7 07 0.2 19 (7.1) 6 (2.3) 95 (35.7)
30 (29.7) 15 (14.9) 19 (18.8) 5.5 7 4.2 3.4 7 2.8 2.0 7 2.1 0.1 70.6 2.7 7 2.6 2.0 7 2.0 0.6 7 1.5 07 0.2 14 (13.9) 4 (4.0) 15 (14.9)
3 (23.1) 1 (7.7) 2 (15.4) 3.9 7 2.2 2.5 7 1.4 1.5 7 1.2 0 1.1 70.3 1.0 7 0 0.17 0.3 0 7 (53.8) 1 (7.7) 1 (7.7)
0.747 0.220 0.751 0.871 0.656 0.592 0.120 0.362 0.972 0.154 o 0.001n 0.076† 0.977 0.152
0.764 0.567 0.410 0.894 0.364 0.655 o 0.001n 0.237 0.672 0.052† o 0.001n 0.053† 0.485 0.491
0.559 0.705 0.606 0.094† 0.294 0.633 0.217 o0.001n o0.001n 0.084† 0.195 0.836 0.786 0.273
36 (21.8) 14 (8.5) 23 (13.9) 5.2 7 4.7 1.17 1.8 4.1 74.4 07 0.1 3.6 7 3.0 0.5 7 1.0 3.1 72.8 07 0.1 5 (3.0) 2 (1.2) 80 (48.5)
15 (23.1) 3 (4.6) 13 (20.0) 4.17 3.4 1.3 7 1.7 2.6 72.3 0.2 70.6 2.4 72.3 0.5 70.7 1.7 7 2.1 0.2 70.5 13 (20.0) 3 (4.6) 32 (49.2)
12 (23.1) 2 (3.8) 11 (21.2) 4.2 73.6 1.17 1.7 2.9 72.4 0.2 70.6 2.7 72.5 0.4 70.7 2.17 2.1 0.2 70.5 6 (11.5) 2 (3.8) 31 (59.6)
Po 0.05. 0.05 r †P o 0.10.
were manic/hypomanic, 30.5% were depressed, 15.7% were manic/ hypomanic episodes with mixed features, and 3.9% were depressed episodes with mixed features. Thus, the prevalence rates of mixed features were significantly different when using the DSM-5 criteria vs. the DSM-IV-TR criteria (19.6% vs. 6.0%, respectively; po0.001). 3.3. Clinical characteristics at the index episode 3.3.1. The group without mixed features vs. the group with mixed features The comparison of the group without and the group with mixed features revealed several significant differences in demographic and clinical characteristics including age of onset, age at hospitalization, number of hospitalizations for a mixed episode, and suicidality. Patients with mixed features had a significantly younger age of onset (21.677.0 vs. 34.2 713.6 years; p o0.001), younger age at hospitalization (25.2 79.1 vs. 43.87 13.4 years; p o0.001), and more hospitalizations for a mixed episode (0.27 0.5 vs. 0 70.2; p o0.001) compared with patients without mixed features. Although there was a trend toward significance for patients with mixed features to have a higher rate of suicidality than patients without, this difference was not significant (20.0% vs. 7.1%, p¼ 0.076). 3.3.2. The group without mixed features vs. the group with mixed features among patients with primary mania/hypomania The comparison of the group without and the group with mixed features group among patients with manic/hypomanic episodes revealed that those with mixed features had a significantly younger age of onset (22.1 77.6 vs. 32.5 712.7; p o0.001), younger age at hospitalization (26.3 79.7 vs. 42.6 712.3; p o0.001), more mixed episodes (0.2 7 0.6 vs. 0 70.1; p o0.001), and more hospitalizations for mixed episodes (0.2 70.5 vs. 07 0.1;
po 0.001) compared with the manic/hypomanic group without mixed features. Although there was a tendency for manic/hypomanic patients with mixed features to have fewer hospitalizations for manic episodes compared with patients without mixed features, this difference was not significant (2.17 2.1 vs. 3.17 2.8; p¼ 0.052). Similarly, there was a tendency for the manic/hypomanic patients with mixed features to have a higher rate of suicidality compared with those without mixed features, but this difference was not significant (11.5% vs. 3.0%, p ¼0.053). 3.3.3. The group without vs. the group with mixed features among patients with primary depressive episodes The comparison of the group without and the group with mixed features among patients with depressive episodes revealed that the depressed patients with mixed features had a significantly younger age of onset (19.6 72.8 vs. 37.17 14.6 years; po 0.001), younger age at hospitalization (20.5 72.9 vs. 45.8 714.9 years; po 0.001), fewer hospitalizations (1.1 70.3 vs. 2.7 7 2.6; po 0.001), and fewer hospitalizations for depressive episodes (1.0 70 vs. 2.0 72.0; p o0.001) than did depressed patients without mixed features. Although there was tendency for depressed patients with mixed features group to experience fewer mood episodes than those without, this difference was not significant (3.972.2 vs. 5.5 74.2; p ¼0.094). Similarly, there was a tendency for depressed patients with mixed features to be hospitalized more often for manic episodes compared with depressed patients without mixed features, but this difference was not significant (0.17 0.3 vs. 0.6 71.5; p ¼0.084). 4. Discussion In the present study, the prevalence rates of mixed features in patients with bipolar disorder were compared using the DSM-IV-
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DSM -IV TR *Mixed
episode 6.0 %
Depressive episode 34.4 % Manic/hypomanic episode 59.5 %
DSM -5
Depressive episode 30.5 %
*With
Manic/hypomanic episode 49.8 %
mixed features 19.6 %
Manic/hypomanic, with mixed features15.7 %
Depressed, with mixed features 3.9 %
Fig. 1. The prevalence of mixed features during any mood episode in bipolar disorder using the DSM-IV-TR criteria vs. the DSM-5 criteria. *Po 0.05.
TR definition of a mixed episode and the DSM-5 definition of an episode associated with the “with mixed features” specifier. Additionally, the clinical characteristics associated with the new specifier “with mixed features” were compared, with a special focus on clinical implications. There was an approximately threefold greater risk for the presence of mixed features in patients with bipolar disorder when using the DSM-5 criteria than when using the DSM-IV-TR criteria. Patients with mixed features showed a younger age of onset, younger age at hospitalization, more frequent hospitalizations for mixed episodes, and greater risk of suicide compared with patients without mixed features. Additionally, manic/hypomanic patients with mixed features had a younger age of onset, younger age at hospitalization, more frequent mixed episodes, more frequent hospitalizations for mixed episodes, and a higher risk of suicide compared with manic/hypomanic patients without mixed features. Patients who were depressed with mixed features had a younger age of onset, younger age at hospitalization, less frequent mood episodes, and fewer hospitalizations for depressive or manic episodes than did depressed patients without mixed features. The prevalence rates of the subtypes with mixed features and without mixed features were dependent on the definition used. When the more restrictive DSM-IV-TR criteria (the simultaneous presence of full manic and full depressive syndromes for at least 1 week of bipolar I disorder) were used, 6.0% of patients in the present study were considered to have mixed episodes. However, when the DSM-5 criteria were applied together with the specifier “with mixed features”, there was a greater than threefold increase in the number of bipolar patients (19.6%) diagnosed with mixed features instead of pure manic/hypomanic or depressed episodes. Of all the patients included in the present study, approximately 20% were diagnosed with mixed features; 24% of patients in the manic/ hypomanic group exhibited mixed features, and 11% of patients in the depressed group exhibited mixed features. These results are consistent with those of prospective studies that reported that the
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prevalence of mixed manic states was 6.7–66% according to which definition was used (Cassidy et al., 2008) and with a cross-sectional study that relied on more restrictive criteria and clinicians' judgments that reported the prevalence was 9–23% (Vieta and Morralla, 2010). However, predominantly depressive mixed states have been less studied, but the reported rates vary between 20% and 70% depending on the use of a narrow or broad definition (Vieta and Valenti, 2013). It has been reported that increased use of a diagnoses, or diagnostic inflation, can occur with the introduction of new disorders and when diagnostic criteria are broadened (Malhi, 2013). The use of the new diagnostic criteria for a mixed episode and the subsequent increase in prevalence rates of mixed features among bipolar disorder patients have a number of clinical implications. First, the additional patients with mixed features that have been identified since the introduction of the new DSM-5 “with mixed features” specifier may reflect patients with sub-syndromal presentation of mixed features based on previous criteria. The literature related to the nosology of mixed features in bipolar disorder generally advocates dimensional approaches that require satisfaction of at least one to three criteria of the opposite polarity. Patients with the sub-syndromal presentation of mixed features demonstrated differences in clinical and treatment responses compared with patients without mixed features. Thus, the identification of additional patients with mixed features according to the updated DSM-5 definition affirms that the separation of these more severe subtypes of mood episodes from manic or depressive states alone is necessary in clinical settings. Second, under the new diagnostic criteria, patients with mixed features may be recommended for treatment of a distinct affective state rather than for a pure manic/ hypomanic or depressed episode. Patients with mixed features typically have a poor response to pharmacological treatment compared with patients with pure mood episodes, and combination therapy is often required to treat the former group of patients. However, second-generation antipsychotic monotherapy options for treating mixed features may become more common (Fountoulakis et al., 2012; González-Pinto et al., 2011). Moreover, there is no clear pharmacological treatment recommendation for depressed patients with mixed features, and evidence supporting the use of antidepressants as an adjunctive therapy for bipolar patients with mixed features is lacking (Rosa et al., 2010). Third, these new dimensional assessments and criteria will likely have a positive influence on clinical research that focuses on the unsolved issues associated with the mixed features of bipolar disorder such as biomarkers, pathophysiology, pharmacology, and the more accurate conceptualization of this disease. Henceforth, clinical research may favor more dimensionally oriented and less restrictive criteria and may investigate many of the sub-syndromal mixed features of bipolar disorder that were excluded by the narrower DSM-IV-TR definition. Thus, the increased number of patients with mixed features will be helpful for the identification of more obvious clinical research outcomes in this population. Additionally, the unification of diverse criteria by further clinical research will be beneficial when interpreting future research outcomes and comparing the various clinical characteristics and treatment responses found in previous research data. The novel classifications of bipolar disorder with mixed features and bipolar disorder without mixed features using the new quantitative measures (manic/hypomanic with three to six mixed features or depressed with three to seven mixed features) will also be helpful for statistical measurements, the quantification of severity, and stratified analyses investigating changes between mood disorder categories or severity levels (Vieta and Valenti, 2013). However, use of the DSM-5 “with mixed features” specifier may also have negative consequences. For example, the inclusion of milder or subsyndromal cases of mixed features may lead to an increase in the inclusion of false-positive patients in clinical trials and an increase in the placebo effect. Therefore, it may become more difficult to find a
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statistically significant difference when patient populations are defined using the lower thresholds in terms of diagnostic criteria (Butlen-Ducuing et al., 2012). The present findings correspond well those of an earlier study that found that Kraepelin's mixed states had greater underlying severity or affective instability, which drives the emergence of combined symptoms (Kraepelin, 1921). In other words, regardless of whether a mixed mood state is primarily depressed or primarily manic based on the individual characteristics of the patient, the course of illness and treatment outcome will be similar. In the present study, patients in the group with mixed features had a significantly younger age of onset and younger age at hospitalization compared with those in the group without mixed features. Moreover, the earlier age of onset for patients with mixed features was seen in both the manic/hypomanic group and the depressed group. These findings are similar to those reported by González-Pinto et al. (2011) who reported that mixed-episode patients were more likely to have a younger age at onset than were non-mixed patients. The early age of onset, as well as the poor outcomes, such as more frequent suicidal ideation or attempts and increased severity, in mixed-episode patients may be associated with a genetic liability in susceptible individuals with mixed features (Carter et al., 2003; Schurhoff et al., 2000). In the present study, suicidality during one's lifetime was more common in the group with mixed features than in the group without, and it was more common in patients who were manic/hypomanic with mixed features than in patients who were manic/hypomanic without mixed features. Patients with mixed mania and mixed depression were at an increased risk for suicidal behavior (Balazs et al., 2006; Dilsaver et al., 1994). When the number of mixed episodes and the number of hospitalizations for mixed episodes in the groups in the present study were compared, patients with mixed features experienced more frequent mixed episodes than did patients without mixed features. These differences may be due to the instability of mixed episodes, the more severe course of this subtype of bipolar disorder, and/or the psychopathological complexity that characterizes these episodes. Similarly, a history of mixed episodes was evident in patients who currently exhibited mixed symptoms (Cassidy et al., 2008), and it has been suggested that mixed states do not typically appear randomly but tend to recur consistently in susceptible individuals following inter-episode stability (Cassidy et al., 2002; Sato et al., 2004). The recurrent pattern of mixed symptoms is supported by the stability of mixed and non-mixed episodes throughout the course of the illness, which suggests that there may be various subtypes of bipolar disorder including manicprone, depression-prone, and mixed states. Additionally, although these data suggest that this relationship persists regardless of the dominant polarity of the mixed state, they contrast with the findings from the depressed group with mixed features in the present study. Thus, the number of episodes and the risk for subsequent recurrent episodes need to be clarified. Several limitations of the present study need to be considered when interpreting the findings. First, retrospective nature of the diagnoses based on chart review. This may have resulted in under diagnosis of mixed states and may have affected mixed depression more than mixed mania, given its later emergence as a topic of clinical attention. Second, substance- and/or medication-induced mood disorders, such as with antidepressant treatment, were not included in the present study. Based on the DSM-5 criteria for bipolar disorder, mood episodes induced by medication or electroconvulsive therapy may be diagnosed as bipolar disorder depending on the persistence of symptoms at a fully syndromal level beyond the normal physiological effects. Third, the limitation of the group to inpatients may have an over representation of mixed mania and also mixed depression given increase risk for suicide and possible increased past history of attempts. Taken together, the present findings demonstrate that the number of patients experiencing mixed features during any mood-related episode of bipolar disorder increased by more than threefold when
the DSM-5 criteria including the specifier “with mixed features” were used compared with when the DSM-IV-TR definition of a mixed episode was used. The additional patients identified using the DSM-5 criteria may represent patients with sub-syndromal and nonoverlapping mixed features and could indicate that patients with mixed features are underdiagnosed. These DSM-5-related changes will help to identify bipolar disorder patients with mixed features in clinical practice and further the understanding of the clinical course, clinical characteristics, and pharmacological treatment of this bipolar disorder subtype. Additionally, these changes will help to focus future research on various topics, including the development of an accurate definition of mixed features in patients with bipolar disorder.
Role of funding source Nothing declared.
Conflict of interest No conflict of interest declared.
Contributors Author In Hee Shim designed the study and wrote the protocol. Author In Hee Shim, Young Sup Woo, and Won-Myong Bahk managed the literature searches, summaries of previous related work. Author In Hee Shim undertook the statistical analysis and wrote the first draft of the manuscript. All authors contributed to and have approved the final manuscript. Acknowledgment The authors had no conflicts of interest in conducting this study or preparing the manuscript.
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Shim, I.H., Woo, Y.S., Jun, T.Y., Bahk, W.M., 2014. Mixed-state bipolar I and II depression: time to remission and clinical characteristics. J. Affect. Disord. 152– 154, 340–346. Undurraga, J., Baldessarini, R.J., Valenti, M., Pacchiarotti, I., Vieta, E., 2012. Suicidal risk factors in bipolar I and II disorder patients. J. Clin. Psychiatry 73, 778–782. Vieta, E., Morralla, C., 2010. Prevalence of mixed mania using 3 definitions. J. Affect. Disord. 125, 61–73. Vieta, E., Valenti, M., 2013. Mixed states in DSM-5: implications for clinical care, education, and research. J. Affect. Disord. 148, 28–36.
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Research report
Prevalence rates and clinical implications of bipolar disorder “with mixed features” as defined by DSM-5 In Hee Shim a, Young Sup Woo b, Won-Myong Bahk b,n a b
Department of Psychiatry, Dongnam Institute of Radiological & Medical Sciences, Busan, Republic of Korea Department of Psychiatry, Yeouido St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
art ic l e i nf o
a b s t r a c t
Article history: Received 23 July 2014 Received in revised form 27 October 2014 Accepted 29 October 2014 Available online 10 November 2014
Background: We investigated the increase in the prevalence of bipolar disorder with mixed features following the replacement of DSM-IV-TR criteria with DSM-5 criteria. Additionally, we examined the clinical implications of the use of “with mixed features” as a specifier with bipolar disorder. Method: We retrospectively reviewed medical charts from 2003 to 2013. A total of 331 patients diagnosed with bipolar disorder using the DSM-IV TR were enrolled and categorized into four groups: manic/hypomanic with mixed features, manic/hypomanic without mixed features, depressed with mixed features, and depressed without mixed features. These classifications were made in accordance with the DSM-5 definition of bipolar disorder “with mixed features.” Changes in the prevalence, demographic and clinical characteristics were compared among the groups. Results: The prevalence rates of mixed features were significantly different when using the DSM-5 criteria vs. the DSM-IV-TR criteria. Patients with mixed features had a younger age of onset, younger age at hospitalization, more frequent hospitalizations for mixed episodes, and greater suicide risk compared with patients without mixed features. Limitations: Retrospective study may have resulted in under diagnosis of mixed states. Conclusions: An approximately three-fold greater risk for mixed features was observed in patients with bipolar disorder when using the DSM-5 criteria than when using the DSM-IV-TR criteria. The additional patients may represent patients with sub-syndromal mixed features and could indicate that patients with mixed features are underdiagnosed. & 2014 Elsevier B.V. All rights reserved.
Keywords: Bipolar disorder Clinical implication DSM-5 Mixed features Prevalence
1. Introduction Compared with patients with bipolar disorder who exhibit pure manic/hypomanic or depressive episodes, the presence of mixed mood states in bipolar disorder patients is associated with a more severe course of illness and a different set of clinical characteristics that include younger age of onset, more frequent occurrence of psychotic symptoms, major risk for suicide, higher rates of comorbidities, and longer time to achieve remission (Baldessarini et al., 2010; Shim et al., 2014; Undurraga et al., 2012). Clinical vigilance and cautious evaluation are required to properly diagnose and assess the occurrence of mixed states during a diagnostic interview. According to the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR) criteria, the diagnosis of a mixed episode applies only to patients with bipolar I disorder who exhibit the simultaneous presence of full manic and full depressive symptoms for at least
n
Corresponding author. Tel.: þ 82 2 3779 1250; fax: þ 82 2 780 6577. E-mail address: [email protected] (W.-M. Bahk).
http://dx.doi.org/10.1016/j.jad.2014.10.061 0165-0327/& 2014 Elsevier B.V. All rights reserved.
1 week (American Psychiatric Association, 2000). However, mixed episodes do not simply consist of the simultaneous or sequential occurrence of polar opposite affective symptoms but rather of complex, fluctuating, and unstable clinical features (Kruger et al., 2005). Thus, the DSM-IV-TR criteria for mixed states in bipolar disorder are too narrow and have a too high threshold; as a result, many patients who are actually suffering from these features may be excluded from this diagnosis. The DSM, Fifth Edition (DSM-5) definition of mixed states in bipolar disorder uses a more dimensional perspective that defines mixed features during an episode as a particular subtype of mood disorder (Micoulaud Franchi et al., 2013). The new specifier “with mixed features” that has been included in the DSM-5 may be applied to episodes of mania/hypomania in which depressive features are present and to episodes of depression in the context of major depressive disorder or bipolar disorder when features of mania/hypomania are present (American Psychiatric Association, 2013). These changes reflect a more liberal application of the “with mixed features” specifier to both polarities of bipolar disorder and will likely have an impact on the rate of diagnosis of bipolar disorder with mixed features, the strategies used to treat this
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subtype, and clinical research regarding mood disorders. However, the effects and clinical implications associated with use of the DSM specifier “with mixed features”, including the presence of specific clinical characteristics have yet to be fully assessed. Therefore, the present study investigated the increase in prevalence rates of the diagnosis of bipolar disorder with mixed features based on DSM-5 criteria. Additionally, patients diagnosed with bipolar I, bipolar II, or bipolar disorder not otherwise specified (NOS) according to DSMIV-TR criteria were re-categorized into four groups based on the new DSM-5 criteria in order to examine the clinical implications of the “with mixed features” specifier on the demographic and clinical characteristics of patients with bipolar disorder.
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The index episode for each patient was defined as any mood episode that led to a hospitalization between 2003 and 2013. If a patient experienced more than one hospitalization during the study period, only the data from the most recent admission were analyzed. To identify a state with mixed features, the patients were monitored for symptoms of the opposite polarity of the primary mood episode. Additionally, patients with symptoms that met the full episode criteria for both polarities simultaneously, such as a mixed episode according to the DSM-IV-TR, were diagnosed as manic/hypomanic with mixed features. Two independent physicians (W.Y.S. and B.W.M.) who were blind to the purpose of the study separately evaluated the medical records of the patients for symptoms of the opposite polarity. 2.3. Statistical analysis
2. Patients and methods 2.1. Patients The medical charts of all participants included in the present study were retrospectively reviewed at Yeouido St. Mary's Hospital, College of Medicine at The Catholic University of Korea in Seoul, Korea. All patients hospitalized in this institution were diagnosed by a boardcertified psychiatrist using the clinical interview for Axis I disorders in accordance with DSM-IV-TR criteria for mood disorders. All subjects met the DSM-IV-TR criteria for bipolar I, bipolar II, or bipolar disorder, NOS, during the period from 2003 to 2013 as well as the following inclusion criteria: (1) a current diagnosis of bipolar disorder with any type of mood episode based on DSM-IV-TR criteria and (2) aged between 15 and 75 years. The exclusion criteria consisted of insufficient data, a severe comorbid medical or neurological condition that could contribute to mood symptoms, an organic brain lesion that could influence mood symptoms, a thought disorder (such as schizophrenia or schizoaffective disorder), a personality disorder as a principle diagnosis, or a cognitive disorder (such as dementia) that could confound the phenomenology of a mood episode. The charts of 371 inpatients diagnosed with bipolar I, bipolar II, or bipolar disorder, NOS, were initially assessed, and 40 cases were excluded based on the above criteria. Thus, a total of 331 patients were enrolled in the present study and categorized into four groups: manic/hypomanic with mixed features, manic/hypomanic without mixed features, depressed with mixed features, and depressed without mixed features. These classifications were performed in accordance with the DSM-5 definition of bipolar disorder and the “with mixed features” specifier, which is as follows: the full criteria are met for a manic/hypomanic or depressed episode and at least three symptoms of the opposite polarity are present. 2.2. Assessments All observed changes in terms of the prevalence and clinical implications of a diagnosis of bipolar disorder with mixed features based on the DSM-IV-TR definition vs. the DSM-5 definition were assessed. The charts of all patients were reviewed to estimate the prevalence rate of mixed features and demographic and clinical characteristics including age of onset, age at admission, sex, family history of mood disorder (especially family history of bipolar and depressive disorders), number of mood episodes (total number of mood episodes, number of depressed episodes, number of manic/ hypomanic episodes, and number of mixed episodes), number of hospitalizations for mood episodes (total number of hospitalizations for mood episodes, number of hospitalizations for depressed episodes, number of hospitalizations for manic episodes, and number of hospitalizations for mixed episodes), suicidality (defined as any suicide attempts during the patient's lifetime), rapid cycling, and psychotic features.
All statistical analyses were performed using SAS for Windows, version 9.3 (SAS Institute, Cary, NC, USA). Chi-square tests or Fisher's exact tests were used for categorical variables, and independent ttests or Mann–Whitney U-tests were used for continuous variables. Additionally, logistic regression analyses were used for categorical variables, and either analysis of covariance (ANCOVA) or the Wilcoxon rank–sum test (rank ANCOVA) was used for continuous variables, with clinical characteristics such as age at hospitalization included as covariates for adjustment. A p-value o0.05 was considered statistically significant, and a p-value between 0.05 and 0.10 was considered to indicate a trend toward statistical significance. 2.4. Ethics The present study was conducted according to the Declaration of Helsinki, and approval to conduct the chart review was obtained from the Institutional Review Board. Because this was a retrospective study and the data were obtained during routine psychiatric examinations and treatment, the board determined that informed consent was unnecessary.
3. Results 3.1. Demographic characteristics at the index episode The distribution of patients meeting the criteria for bipolar I, bipolar II, and bipolar disorder, NOS, with any mood episode according to the DSM-IV-TR is provided in Table 1. Of the 331 patients included in the final analysis, 266 (80.4%) were diagnosed with any mood episode without mixed features, 165 (49.8%) did not exhibit depressive symptoms during manic/hypomanic episodes (manic/hypomanic without mixed features), 101 (30.5%) did not exhibit manic/hypomanic symptoms during depressed episodes (depressed without mixed features), 65 (19.6%) were diagnosed with any mood episode with mixed features, 52 (15.7%) exhibited three or more depressive symptoms during manic/ hypomanic episodes (manic/hypomanic with mixed features), and 13 (3.9%) exhibited three or more manic symptoms during depressed episodes (depressed with mixed features). 3.2. The prevalence of mixed features The prevalence rate for mood episodes based on the DSM-IV-TR definition of mixed features and that for the DSM-5 “with mixed features” specifier is presented in Fig. 1. Based on DSM-IV-TR criteria, 59.5% of the mood episodes were manic/hypomanic, 34.4% were depressed, and 6.0% were mixed episodes. However, when using the DSM-5 definition and the “with mixed features” specifier, there was a threefold greater risk for mixed features in patients with bipolar disorder. In this case, 49.8% of mood episodes
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Table 1 Demographic and clinical characteristics at the index episode. Without mixed features N ¼266
Manic/ hypomanic without mixed features N ¼ 165 Age (years) Onset At hospitalization Sex (male), n (%) Family history, n (%) Mood disorder Bipolar Disorder Depressive disorder Number of mood episodes Depressed Manic/hypomanic Mixed Number of hospitalization Depressed Manic Mixed Suicidality, n (%) Rapid cycling, n (%) Psychosis, n (%) n
†
With mixed features N ¼ 65
Manic/ hypomanic with mixed features N ¼ 52
Depressed without mixed features N ¼ 101
Significance (without mixed features vs. with mixed features)
Significance (without mixed features vs. with mixed features in mania/hypomania)
Significance (without mixed features vs. with mixed features in depression)
Depressed with mixed features N ¼13
34.2 7 13.6 32.5 7 12.7 43.8 7 13.4 42.6 7 12.3 114 (42.9) 74 (44.8)
37.17 14.6 21.6 7 7.0 22.17 7.6 45.8 7 14.9 25.2 79.1 26.3 79.7 40 (39.6) 24 (36.9) 19 (36.5)
19.6 72.8 20.5 7 2.9 8 (61.5)
o 0.001n o 0.001n 0.384
o 0.001n o 0.001n 0.291
o0.001n o0.001n 0.937
66 (24.8) 29 (10.9) 42 (15.8) 5.3 7 4.5 1.9 7 2.5 3.3 7 3.8 0.17 0.4 3.3 7 2.8 1.1 71.7 2.2 7 2.7 07 0.2 19 (7.1) 6 (2.3) 95 (35.7)
30 (29.7) 15 (14.9) 19 (18.8) 5.5 7 4.2 3.4 7 2.8 2.0 7 2.1 0.1 70.6 2.7 7 2.6 2.0 7 2.0 0.6 7 1.5 07 0.2 14 (13.9) 4 (4.0) 15 (14.9)
3 (23.1) 1 (7.7) 2 (15.4) 3.9 7 2.2 2.5 7 1.4 1.5 7 1.2 0 1.1 70.3 1.0 7 0 0.17 0.3 0 7 (53.8) 1 (7.7) 1 (7.7)
0.747 0.220 0.751 0.871 0.656 0.592 0.120 0.362 0.972 0.154 o 0.001n 0.076† 0.977 0.152
0.764 0.567 0.410 0.894 0.364 0.655 o 0.001n 0.237 0.672 0.052† o 0.001n 0.053† 0.485 0.491
0.559 0.705 0.606 0.094† 0.294 0.633 0.217 o0.001n o0.001n 0.084† 0.195 0.836 0.786 0.273
36 (21.8) 14 (8.5) 23 (13.9) 5.2 7 4.7 1.17 1.8 4.1 74.4 07 0.1 3.6 7 3.0 0.5 7 1.0 3.1 72.8 07 0.1 5 (3.0) 2 (1.2) 80 (48.5)
15 (23.1) 3 (4.6) 13 (20.0) 4.17 3.4 1.3 7 1.7 2.6 72.3 0.2 70.6 2.4 72.3 0.5 70.7 1.7 7 2.1 0.2 70.5 13 (20.0) 3 (4.6) 32 (49.2)
12 (23.1) 2 (3.8) 11 (21.2) 4.2 73.6 1.17 1.7 2.9 72.4 0.2 70.6 2.7 72.5 0.4 70.7 2.17 2.1 0.2 70.5 6 (11.5) 2 (3.8) 31 (59.6)
Po 0.05. 0.05 r †P o 0.10.
were manic/hypomanic, 30.5% were depressed, 15.7% were manic/ hypomanic episodes with mixed features, and 3.9% were depressed episodes with mixed features. Thus, the prevalence rates of mixed features were significantly different when using the DSM-5 criteria vs. the DSM-IV-TR criteria (19.6% vs. 6.0%, respectively; po0.001). 3.3. Clinical characteristics at the index episode 3.3.1. The group without mixed features vs. the group with mixed features The comparison of the group without and the group with mixed features revealed several significant differences in demographic and clinical characteristics including age of onset, age at hospitalization, number of hospitalizations for a mixed episode, and suicidality. Patients with mixed features had a significantly younger age of onset (21.677.0 vs. 34.2 713.6 years; p o0.001), younger age at hospitalization (25.2 79.1 vs. 43.87 13.4 years; p o0.001), and more hospitalizations for a mixed episode (0.27 0.5 vs. 0 70.2; p o0.001) compared with patients without mixed features. Although there was a trend toward significance for patients with mixed features to have a higher rate of suicidality than patients without, this difference was not significant (20.0% vs. 7.1%, p¼ 0.076). 3.3.2. The group without mixed features vs. the group with mixed features among patients with primary mania/hypomania The comparison of the group without and the group with mixed features group among patients with manic/hypomanic episodes revealed that those with mixed features had a significantly younger age of onset (22.1 77.6 vs. 32.5 712.7; p o0.001), younger age at hospitalization (26.3 79.7 vs. 42.6 712.3; p o0.001), more mixed episodes (0.2 7 0.6 vs. 0 70.1; p o0.001), and more hospitalizations for mixed episodes (0.2 70.5 vs. 07 0.1;
po 0.001) compared with the manic/hypomanic group without mixed features. Although there was a tendency for manic/hypomanic patients with mixed features to have fewer hospitalizations for manic episodes compared with patients without mixed features, this difference was not significant (2.17 2.1 vs. 3.17 2.8; p¼ 0.052). Similarly, there was a tendency for the manic/hypomanic patients with mixed features to have a higher rate of suicidality compared with those without mixed features, but this difference was not significant (11.5% vs. 3.0%, p ¼0.053). 3.3.3. The group without vs. the group with mixed features among patients with primary depressive episodes The comparison of the group without and the group with mixed features among patients with depressive episodes revealed that the depressed patients with mixed features had a significantly younger age of onset (19.6 72.8 vs. 37.17 14.6 years; po 0.001), younger age at hospitalization (20.5 72.9 vs. 45.8 714.9 years; po 0.001), fewer hospitalizations (1.1 70.3 vs. 2.7 7 2.6; po 0.001), and fewer hospitalizations for depressive episodes (1.0 70 vs. 2.0 72.0; p o0.001) than did depressed patients without mixed features. Although there was tendency for depressed patients with mixed features group to experience fewer mood episodes than those without, this difference was not significant (3.972.2 vs. 5.5 74.2; p ¼0.094). Similarly, there was a tendency for depressed patients with mixed features to be hospitalized more often for manic episodes compared with depressed patients without mixed features, but this difference was not significant (0.17 0.3 vs. 0.6 71.5; p ¼0.084). 4. Discussion In the present study, the prevalence rates of mixed features in patients with bipolar disorder were compared using the DSM-IV-
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DSM -IV TR *Mixed
episode 6.0 %
Depressive episode 34.4 % Manic/hypomanic episode 59.5 %
DSM -5
Depressive episode 30.5 %
*With
Manic/hypomanic episode 49.8 %
mixed features 19.6 %
Manic/hypomanic, with mixed features15.7 %
Depressed, with mixed features 3.9 %
Fig. 1. The prevalence of mixed features during any mood episode in bipolar disorder using the DSM-IV-TR criteria vs. the DSM-5 criteria. *Po 0.05.
TR definition of a mixed episode and the DSM-5 definition of an episode associated with the “with mixed features” specifier. Additionally, the clinical characteristics associated with the new specifier “with mixed features” were compared, with a special focus on clinical implications. There was an approximately threefold greater risk for the presence of mixed features in patients with bipolar disorder when using the DSM-5 criteria than when using the DSM-IV-TR criteria. Patients with mixed features showed a younger age of onset, younger age at hospitalization, more frequent hospitalizations for mixed episodes, and greater risk of suicide compared with patients without mixed features. Additionally, manic/hypomanic patients with mixed features had a younger age of onset, younger age at hospitalization, more frequent mixed episodes, more frequent hospitalizations for mixed episodes, and a higher risk of suicide compared with manic/hypomanic patients without mixed features. Patients who were depressed with mixed features had a younger age of onset, younger age at hospitalization, less frequent mood episodes, and fewer hospitalizations for depressive or manic episodes than did depressed patients without mixed features. The prevalence rates of the subtypes with mixed features and without mixed features were dependent on the definition used. When the more restrictive DSM-IV-TR criteria (the simultaneous presence of full manic and full depressive syndromes for at least 1 week of bipolar I disorder) were used, 6.0% of patients in the present study were considered to have mixed episodes. However, when the DSM-5 criteria were applied together with the specifier “with mixed features”, there was a greater than threefold increase in the number of bipolar patients (19.6%) diagnosed with mixed features instead of pure manic/hypomanic or depressed episodes. Of all the patients included in the present study, approximately 20% were diagnosed with mixed features; 24% of patients in the manic/ hypomanic group exhibited mixed features, and 11% of patients in the depressed group exhibited mixed features. These results are consistent with those of prospective studies that reported that the
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prevalence of mixed manic states was 6.7–66% according to which definition was used (Cassidy et al., 2008) and with a cross-sectional study that relied on more restrictive criteria and clinicians' judgments that reported the prevalence was 9–23% (Vieta and Morralla, 2010). However, predominantly depressive mixed states have been less studied, but the reported rates vary between 20% and 70% depending on the use of a narrow or broad definition (Vieta and Valenti, 2013). It has been reported that increased use of a diagnoses, or diagnostic inflation, can occur with the introduction of new disorders and when diagnostic criteria are broadened (Malhi, 2013). The use of the new diagnostic criteria for a mixed episode and the subsequent increase in prevalence rates of mixed features among bipolar disorder patients have a number of clinical implications. First, the additional patients with mixed features that have been identified since the introduction of the new DSM-5 “with mixed features” specifier may reflect patients with sub-syndromal presentation of mixed features based on previous criteria. The literature related to the nosology of mixed features in bipolar disorder generally advocates dimensional approaches that require satisfaction of at least one to three criteria of the opposite polarity. Patients with the sub-syndromal presentation of mixed features demonstrated differences in clinical and treatment responses compared with patients without mixed features. Thus, the identification of additional patients with mixed features according to the updated DSM-5 definition affirms that the separation of these more severe subtypes of mood episodes from manic or depressive states alone is necessary in clinical settings. Second, under the new diagnostic criteria, patients with mixed features may be recommended for treatment of a distinct affective state rather than for a pure manic/ hypomanic or depressed episode. Patients with mixed features typically have a poor response to pharmacological treatment compared with patients with pure mood episodes, and combination therapy is often required to treat the former group of patients. However, second-generation antipsychotic monotherapy options for treating mixed features may become more common (Fountoulakis et al., 2012; González-Pinto et al., 2011). Moreover, there is no clear pharmacological treatment recommendation for depressed patients with mixed features, and evidence supporting the use of antidepressants as an adjunctive therapy for bipolar patients with mixed features is lacking (Rosa et al., 2010). Third, these new dimensional assessments and criteria will likely have a positive influence on clinical research that focuses on the unsolved issues associated with the mixed features of bipolar disorder such as biomarkers, pathophysiology, pharmacology, and the more accurate conceptualization of this disease. Henceforth, clinical research may favor more dimensionally oriented and less restrictive criteria and may investigate many of the sub-syndromal mixed features of bipolar disorder that were excluded by the narrower DSM-IV-TR definition. Thus, the increased number of patients with mixed features will be helpful for the identification of more obvious clinical research outcomes in this population. Additionally, the unification of diverse criteria by further clinical research will be beneficial when interpreting future research outcomes and comparing the various clinical characteristics and treatment responses found in previous research data. The novel classifications of bipolar disorder with mixed features and bipolar disorder without mixed features using the new quantitative measures (manic/hypomanic with three to six mixed features or depressed with three to seven mixed features) will also be helpful for statistical measurements, the quantification of severity, and stratified analyses investigating changes between mood disorder categories or severity levels (Vieta and Valenti, 2013). However, use of the DSM-5 “with mixed features” specifier may also have negative consequences. For example, the inclusion of milder or subsyndromal cases of mixed features may lead to an increase in the inclusion of false-positive patients in clinical trials and an increase in the placebo effect. Therefore, it may become more difficult to find a
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statistically significant difference when patient populations are defined using the lower thresholds in terms of diagnostic criteria (Butlen-Ducuing et al., 2012). The present findings correspond well those of an earlier study that found that Kraepelin's mixed states had greater underlying severity or affective instability, which drives the emergence of combined symptoms (Kraepelin, 1921). In other words, regardless of whether a mixed mood state is primarily depressed or primarily manic based on the individual characteristics of the patient, the course of illness and treatment outcome will be similar. In the present study, patients in the group with mixed features had a significantly younger age of onset and younger age at hospitalization compared with those in the group without mixed features. Moreover, the earlier age of onset for patients with mixed features was seen in both the manic/hypomanic group and the depressed group. These findings are similar to those reported by González-Pinto et al. (2011) who reported that mixed-episode patients were more likely to have a younger age at onset than were non-mixed patients. The early age of onset, as well as the poor outcomes, such as more frequent suicidal ideation or attempts and increased severity, in mixed-episode patients may be associated with a genetic liability in susceptible individuals with mixed features (Carter et al., 2003; Schurhoff et al., 2000). In the present study, suicidality during one's lifetime was more common in the group with mixed features than in the group without, and it was more common in patients who were manic/hypomanic with mixed features than in patients who were manic/hypomanic without mixed features. Patients with mixed mania and mixed depression were at an increased risk for suicidal behavior (Balazs et al., 2006; Dilsaver et al., 1994). When the number of mixed episodes and the number of hospitalizations for mixed episodes in the groups in the present study were compared, patients with mixed features experienced more frequent mixed episodes than did patients without mixed features. These differences may be due to the instability of mixed episodes, the more severe course of this subtype of bipolar disorder, and/or the psychopathological complexity that characterizes these episodes. Similarly, a history of mixed episodes was evident in patients who currently exhibited mixed symptoms (Cassidy et al., 2008), and it has been suggested that mixed states do not typically appear randomly but tend to recur consistently in susceptible individuals following inter-episode stability (Cassidy et al., 2002; Sato et al., 2004). The recurrent pattern of mixed symptoms is supported by the stability of mixed and non-mixed episodes throughout the course of the illness, which suggests that there may be various subtypes of bipolar disorder including manicprone, depression-prone, and mixed states. Additionally, although these data suggest that this relationship persists regardless of the dominant polarity of the mixed state, they contrast with the findings from the depressed group with mixed features in the present study. Thus, the number of episodes and the risk for subsequent recurrent episodes need to be clarified. Several limitations of the present study need to be considered when interpreting the findings. First, retrospective nature of the diagnoses based on chart review. This may have resulted in under diagnosis of mixed states and may have affected mixed depression more than mixed mania, given its later emergence as a topic of clinical attention. Second, substance- and/or medication-induced mood disorders, such as with antidepressant treatment, were not included in the present study. Based on the DSM-5 criteria for bipolar disorder, mood episodes induced by medication or electroconvulsive therapy may be diagnosed as bipolar disorder depending on the persistence of symptoms at a fully syndromal level beyond the normal physiological effects. Third, the limitation of the group to inpatients may have an over representation of mixed mania and also mixed depression given increase risk for suicide and possible increased past history of attempts. Taken together, the present findings demonstrate that the number of patients experiencing mixed features during any mood-related episode of bipolar disorder increased by more than threefold when
the DSM-5 criteria including the specifier “with mixed features” were used compared with when the DSM-IV-TR definition of a mixed episode was used. The additional patients identified using the DSM-5 criteria may represent patients with sub-syndromal and nonoverlapping mixed features and could indicate that patients with mixed features are underdiagnosed. These DSM-5-related changes will help to identify bipolar disorder patients with mixed features in clinical practice and further the understanding of the clinical course, clinical characteristics, and pharmacological treatment of this bipolar disorder subtype. Additionally, these changes will help to focus future research on various topics, including the development of an accurate definition of mixed features in patients with bipolar disorder.
Role of funding source Nothing declared.
Conflict of interest No conflict of interest declared.
Contributors Author In Hee Shim designed the study and wrote the protocol. Author In Hee Shim, Young Sup Woo, and Won-Myong Bahk managed the literature searches, summaries of previous related work. Author In Hee Shim undertook the statistical analysis and wrote the first draft of the manuscript. All authors contributed to and have approved the final manuscript. Acknowledgment The authors had no conflicts of interest in conducting this study or preparing the manuscript.
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