Research reportMania and depression. Mixed, not stirred
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).
References (52)
- et al.
The DSM-IV and ICD-10 categories of recurrent [major] depressive and bipolar II disorders: evidence that they lie on a dimensional spectrum
J. Affect. Disord.
(2006) - et al.
The close link between suicide attempts and mixed (bipolar) depression: implications for suicide prevention
J. Affect. Disord.
(2006) - et al.
Dissimilar morbidity following initial mania versus mixed-states in type-I bipolar disorder
J. Affect. Disord.
(2010) Bipolar disorder—focus on bipolar II disorder and mixed depression
Lancet
(2007)- et al.
Mood state at study entry as predictor of the polarity of relapse in bipolar disorder
Biol. Psychiatry
(2004) - et al.
Clinical and therapeutic implications of predominant polarity in bipolar disorder
J. Affect. Disord.
(2006) - et al.
A prospective study of the impact of subthreshold mixed states on the 24-month clinical outcomes of bipolar I disorder or schizoaffective disorder
J. Affect. Disord.
(2010) - et al.
STEP-BD investigators. Antidepressant-associated chronic irritable dysphoria (ACID) in STEP-BD patients
J. Affect. Disord.
(2008) - et al.
Towards a reconceptualization of mixed states, based on an emotional-reactivity dimensional model
J. Affect. Disord.
(2007) - et al.
Agitated depression as a mixed state and the problem of melancholia
Psychiatr. Clin. North Am.
(1999)
Predominant polarity and temperament in bipolar and unipolar affective disorders
J. Affect. Disord.
Differential outcome of bipolar patients receiving antidepressant monotherapy versus combination with an antimanic drug
J. Affect. Disord.
Clinical subtypes of bipolar mixed states: validating a broader European definition in 143 cases
J. Affect. Disord.
Clinical characterization of depressive mixed state in bipolar-I patients: Pisa–San Diego collaboration
J. Affect. Disord.
Prevalence of mixed mania using 3 definitions
J. Affect. Disord.
Validating Kraepelin's two types of depressive mixed states: "depression with flight of ideas" and "excited depression"
World J. Biol. Psychiatry
Agitated “unipolar” depression re-conceptualized as a depressive mixed state: implications for the antidepressant–suicide controversy
J. Affect. Disord.
Mixed states vs. pure mania in the French sample of the EMBLEM study: results at baseline and 24 months—European mania in bipolar longitudinal evaluation of medication
BMC Psychiatry
The clinical epidemiology of pure and mixed manic episodes
Bipolar Disord.
DSM-5 proposals for mood disorders: a cost–benefit analysis
Curr. Opin. Psychiatry
Structured Clinical Interview for the DSM-IV Axis I Disorders (SCID-I)
Structured Clinical Interview for DSM-IV AXIS II Personality Disorders (SCID-II)
Correlates of treatment-emergent mania associated with antidepressant treatment in bipolar depression
Am. J. Psychiatry
Treatment of rapid-cycling bipolar disorder: are antidepressants mood destabilizers?
Am. J. Psychiatry
Bipolar mixed episodes: characteristics and comorbidities
J. Clin. Psychiatry
Cited by (78)
Affective temperaments mediate aggressive dimensions in bipolar disorders: A cluster analysis from a large, cross-sectional, international study
2023, Journal of Affective DisordersUse of cariprazine in bipolar disorder: A systematic review and practical considerations
2022, Psiquiatria BiologicaPrevalence and psychiatric correlates of suicidal ideation in UK university students
2020, Journal of Affective DisordersMixed episodes and suicide risk: A community sample of young adults
2020, Journal of Affective DisordersThe Ring of Fire: Childhood Trauma, Emotional Reactivity, and Mixed States in Mood Disorders
2020, Psychiatric Clinics of North AmericaMixed States: Historical Impact and Evolution of the Concept
2020, Psychiatric Clinics of North AmericaCitation Excerpt :This work produced renewed attention to mixed states in the past 2 decades. Classic clinical-descriptive studies,67–71 and studies based on careful psychopathological observations,72–76 specific characteristics, such as suicidality77,78 and treatment strategies,79–86 led to alternative diagnostic criteria,8,87,88 new conceptual models,89 and specific diagnostic tools,90,91 including the observation that the extent to which symptoms are mixed may be more important than whether the episode itself was depressive or manic.8 Nevertheless, response to treatment and long-term outcome in mixed states still remain dramatically unsatisfactory.