Research report
Mania and depression. Mixed, not stirred

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Abstract

Objective

Current criteria for mixed bipolar episode do not allow an adequate understanding of a vast majority of bipolar patients with mixed (hypo) manic-depressive features, keeping the qualification of “mixed episodes” for bipolar type I only. This study was aimed to test the existence of a bipolar-mixed continuum by comparing the characteristics of three groups classified according to patterns of past and current manic or mixed episodes.

Method

134 bipolar I inpatients were divided according to their pattern of excitatory “mixed-like” episodes in three groups: 1) lifetime history of purely manic episodes without mixed features (PMA); 2) lifetime history of both manic and mixed episodes (MIX) and 3) lifetime history exclusively of mixed, but not manic, episodes (PMIX). Differences in clinical and demographic characteristics were analyzed by using chi-square head-to-head for categorical data, one-way ANOVA for continuous variables and Tukey's post-hoc comparison. Logistic regression was used to control for data validity.

Results

PMIX had higher rates of depressive predominant polarity and less lifetime history of psychotic symptoms, and had received more antidepressants both lifetime and during 6 months prior to index episode. PMIX had more suicide attempts and Axis I comorbidity than PMA.

Discussion

PMIX is likely to have a higher risk for suicide and higher rates of comorbidities; current DSM-IV-TR criteria are not fit for correctly classifying these patients and this may affect treatment appropriateness. The concept of “mixicity” should be extended beyond bipolar I disorder to other bipolar disorder subtypes.

Introduction

Mixed states are broadly defined as the coexistence of both manic and depressive features within the same mood episode. Mixed states were first described by Emil Kraepelin (1899) and Wilhelm Weygandt (1899). These authors pointed at these episodes as the cornerstone of manic-depressive insanity. Since then, the definition of mixed states by the nosology has suffered from several changes: in the first edition of the DSM (American Psychiatric Association, 2000), for instance, the term “manic depressive reaction, mixed type” was used rather loosely, while the second edition (1968) required that “manic and depressive symptoms appeared almost simultaneously” in order to diagnose “mixed” manic-depressive. In the DSM-III (1980) and DSM-III-R (1987), the diagnosis of bipolar disorder, mixed, required the “full symptomatic picture of both manic and major depressive episodes, intermixed or rapidly alternating every few days”, whereas in the DSM-IV (1994) and the DSM-IV-TR (2000), the term “mixed episode” was introduced and required that criteria were met for both manic and depressive episodes each day for at least 1 week, that either socio-professional and/or everyday life impairment or psychosis be present, and that medical conditions and drugs do not account for symptoms.

However, these narrow criteria fail to include many presentations seen in everyday practice (Perugi et al., 1997, Perugi et al., 2001, Suppes et al., 2005, Benazzi, 2007, Vieta and Suppes, 2008). Thankfully, the Task Force for the DSM-5 (First, 2011) is oriented towards abolishing the mixed episode and shifting it to “mixed features specifier”. This would allow clinicians to consider mixed states in a less restrictive way, and extend them beyond the bipolar I subtype.

Limiting mixed states to bipolar I disorder disregards the clinical relevance of subthreshold mixed symptoms occurring in the context of a broader bipolar spectrum, with relevant clinical and treatment implications (Vieta, 2005, Swann et al., 2009, Goldberg et al., 2009, Dodd et al., 2010).

Recent efforts focused on establishing operational definitions of mixed states, especially according to prevalent polarity (depressive or manic); this enhances sensitivity in their detection (McElroy et al., 1992, Koukopoulos and Koukopoulos, 1999, Akiskal and Benazzi, 2004, Vieta, 2005, Henry et al., 2007, Swann et al., 2009). Despite this, the definition and operationalization of mixed states remain still unsolved, leading to important limitations in the management of bipolar patients (Vieta, 2005).

The prevalence of mixed states ranges from 9% to 23%, depending on the diagnostic criteria applied to a cohort; more restrictive criteria, like those of DSM-IV (American Psychiatric Association, 2000) and ICD-10 (WHO, 1992), yield lower figures, while the broader Cincinnati criteria (McElroy et al., 1992), based on clinical judgment, yield higher figures. However, higher concordance was found between the Cincinnati and ICD-10 criteria, which had moderate concordance with DSM-IV-TR criteria (Vieta and Morralla, 2010).

Mixed states are associated with earlier age at first hospitalization and longer duration of illness (Cassidy and Carroll, 2001, Valentí et al., 2011), with an increased relapse risk (Kessing, 2008, Baldessarini et al., 2010), a higher prevalence of substance use (González-Pinto et al., 2007) and other comorbidities (Goldberg and McElroy, 2007), a higher risk of suicide (Henry et al., 2007, Goldberg et al., 2009, Swann et al., 2009, González-Pinto et al., 2007, González-Pinto et al., 2010, Valentí et al., 2011), lower recovery rates in the long-term (Azorin et al., 2009), and lower response to antidepressant drugs (ADs) (Goldberg et al., 2007, Frye et al., 2009, Valentí et al., 2011).

Baldessarini et al., (2010) found that bipolar I patients followed-up for 24 months after hospitalization for their first manic episode differed from those hospitalized for their first mixed episode in morbidity. Overall morbidity was 1.6-times higher in bipolar patients with an initial mixed state than in bipolar patients with a first purely manic episode; the former subsequently developed mixed states 12 times more than the latter, they were affected from major depression 6.5 times more often than the latter and had 69% more dysthymia during follow-up than patients presenting with an initial manic episode. These investigators concluded that their results do not support the equivalence of mania and mixed states, pointing to the existence of distinct clinical subtypes (Baldessarini et al., 2010).

The hypothesis of the present study is that bipolar I patients, regardless of the occurrence of purely depressive and hypomanic episodes, may differ on the grounds of whether their history includes past or current manic episodes only (purely manic, PMA), past or current manic and mixed episodes (MIX), or past or current mixed episodes only (purely mixed, PMIX). We expect these three groups to differ regarding their clinical course and characteristics.

Section snippets

Methods

One hundred and thirty four (N = 134) consecutive bipolar type I inpatients were included in the present study. All patients were admitted between January and June 2009 at the psychiatric Unit of Sant'Andrea Hospital (Rome, Italy) for a major affective acute episode (depressive, manic or mixed index episode). Diagnoses were made according to the DSM-IV criteria and confirmed through the Structured Clinical Interview (SCID-I and SCID-II) for DSM-IV-TR (First et al., 1996, First et al., 1997).

All

Results

Of the 134 Bipolar I inpatients included in the final sample, 46 (34.3%), had a history of pure manic episodes (PMA), 53 (39.5%) had a history of both manic and mixed episodes (MIX), and 35 (26.1%) had a history of pure mixed episodes (PMIX). All patients had a lifetime history of past depressive episodes and 47 (35%) had also a lifetime history of hypomanic episodes. Although there were no differences between groups regarding demographic variables, the PMIX patients had a lower professional

Discussion

In our study we found some significant differences between patients with bipolar disorder according to their pattern of past and current episodes. Patients with past and current purely mixed, hypomanic or depressive (PMIX) episodes differed from those with a history of depressive, (hypo) manic and mixed episodes (MIX) as well as from those without mixed episodes (PMA), while PMA and MIX groups showed more similarities than differences in most variables. As expected, the PMIX group was

Role of the funding source

The funding sources played no role in the design or conduct of the study; in the collection, management, analysis or interpretation of the data; or in the preparation, review, or approval for the manuscript.

Conflicts of interest

Dr. Isabella Pacchiarotti declares no conflicts of interest.

Dr. Lorenzo Mazzarini declares no conflicts of interest.

Dr Giorgio D. Kotzalidis declares no conflicts of interest.

Dr. Marc Valentí declares no conflicts of interest.

Dr. Alessandra MA Nivoli has received support from Bristol-Myers-Squibb.

Dr. Gabriele Sani declares no conflicts of interest.

Dr. Carla Torrent declares no conflicts of interest.

Dr. Andrea Murru has received support from Bristol-Myers-Squibb.

Dr. Jose Sánchez-Moreno declares

Acknowledgments

The authors of this study would like to thank the support and funding of the Spanish Ministry of Health, Instituto de Salud Carlos III, CIBERSAM and an unrestricted grant from the Generalitat of Catalunya to the Bipolar Disorders Group (2009 SGR 1022).

Dr. Colom is funded by the Spanish Ministry of Science and Innovation, Instituto Carlos III, through a “Miguel Servet” postdoctoral contract (CP08/00140) and a FIS grant (PS09⁄01044).

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