0
Get Alert
Please Wait... Processing your request... Please Wait.
You must sign in to sign-up for alerts.

Please confirm that your email address is correct, so you can successfully receive this alert.

1
Reviews and Overviews   |    
Bipolar Mixed States: An International Society for Bipolar Disorders Task Force Report of Symptom Structure, Course of Illness, and Diagnosis
Alan C. Swann, M.D.; Beny Lafer, M.D.; Giulio Perugi, M.D.; Mark A. Frye, M.D.; Michael Bauer, M.D.; Won-Myong Bahk, M.D.; Jan Scott, M.D.; Kyooseob Ha, M.D.; Trisha Suppes, M.D., Ph.D.
Am J Psychiatry 2013;170:31-42. doi:10.1176/appi.ajp.2012.12030301
View Author and Article Information

Dr. Swann is a consultant for Merck; is a speaker for Abbott Laboratories, AstraZeneca, Merck, and Sanofi-Aventis; and is on data safety and monitoring boards for Cephalon and Pfizer. Prof. Perugi has received consulting fees from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, and Sanofi-Aventis; has received research support from AstraZeneca, Boehringer Ingheleim, Eli Lilly, GlaxoSmith Kline; is on the speakers/advisory boards of AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Jannsen-Cilag, Lundbeck, Pfizer, Sanofi Aventis, and Wyeth. Dr. Frye receives grant support from the Mayo Foundation, Myriad, NARSAD, NIMH, National Institute of Alcohol Abuse and Alcoholism, and Pfizer. Dr. Bauer receives advisory board fees from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Jannssen-Cilag, Lundbeck, Otsuka, and Servier and receives honoraria from AstraZeneca, Eli Lilly, Servier, Lundbeck, Bristol-Myers Squibb, Otsuka, Pfizer, and GlaxoSmithKline. Dr. Scott is supported by Fondation FondaMental and has received funding from the Medical Research Council UK BP II Cohort Study, NHS UK Research for Patient Benefit, NHS UK Service Delivery and Organization Program, NTW FSF Research Fund, and the Jansen-Cilag Unrestricted Educational Grant; she has received conference travel funding, speaking fees, or advisory board fees from AstraZeneca, Bristol-Myers Squibb-Otsuka, Eli Lilly, GlaxoSmithKline, Jansen-Cilag, Lundbeck, Sanofi-Aventis, and Servier. Dr. Ha has received research support from AstraZeneca, Eli Lilly, Otsuka, and Pfizer and has received honoraria from AstraZeneca, GlaxoSmithKline, Otsuka, and Pfizer. Dr. Suppes has received funding or medications for clinical grants from AstraZeneca, NIMH, Pfizer, and Sunovion Pharmaceuticals and has received royalties from Jones and Bartlett (formerly Compact Clinicals). Dr. Lafer and Dr. Bahk report no financial relationships with commercial interests.

From the Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston; the Department of Psychiatry, Bipolar Disorder Research Program, Institute of Psychiatry, University of São Paulo Medical School, São Paulo, Brazil; Department of Psychiatry, University of Pisa, Pisa, Italy; the G. De Lisio Institute of Behavioral Sciences, Pisa; the Mayo Clinic, Rochester, Minn.; the Department of Psychiatry and Psychotherapy, University Hospital, Carl Gustav Carus Technical University, Dresden, Germany; the Department of Psychiatry, College of Medicine, The Catholic University of Korea, Seoul; the Institute of Neuroscience, Newcastle University, U.K.; University of Paris East, Creteil, France; the Translational Research Center and Department of Neuropsychiatry, Seoul National University Bundang Hospital, Seongnam, Gyeonggi, Korea; the Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, Calif.; and VA Palo Alto Health Care System, Palo Alto, Calif.

Address correspondence to Dr. Swann (Alan.C.Swann@uth.tmc.edu).

Copyright © 2013 by the American Psychiatric Association

Received March 04, 2012; Revised April 29, 2012; Accepted May 10, 2012.

Objective  Episodes of bipolar disorder are defined as depressive or manic, but depressive and manic symptoms can combine in the same episode. Coexistence or rapid alternation of depressive and manic symptoms in the same episode may indicate a more severe form of bipolar disorder and may pose diagnostic and treatment challenges. However, definitions of mixed states, especially those with prominent depression, are not well established.

Method  The authors performed literature searches for bipolar disorder, multivariate analyses, and the appearance of the terms “mixed” in any field; references selected from the articles found after the search were combined after a series of conferences among the authors.

Results  The authors reviewed the evolution of the concept of mixed states and examined the symptom structure of mixed states studied as predominantly manic, predominantly depressive, and across both manic and depressive episodes, showing essentially parallel structures of mixed states based on manic or depressive episodes. The authors analyzed the relationships between mixed states and a severely recurrent course of illness in bipolar disorder, with early onset and increased co-occurring anxiety-, stress-, and substance-related disorders, and they used this information to derive proposed diagnostic criteria for research or clinical use.

Conclusions  The definitions and properties of mixed states have generated controversy, but the stability of their characteristics over a range of clinical definitions and diagnostic methods shows that the concept of mixed states is robust. Distinct characteristics related to the course of illness emerge at relatively modest opposite polarity symptom levels in depressive or manic episodes.

Abstract Teaser
Figures in this Article

Bipolar disorder suggests two discrete states, depression and mania. Yet episodes combining depressive and manic elements are not uncommon. Understanding these mixed states will improve our ability to define what constitutes an episode of bipolar disorder and the relationship between episode and illness course characteristics.

The first challenge in the investigation of mixed states is to define them. It is easy to regard depressive and manic states as opposites. Yet it has long been known that manic and depressive symptoms are not mutually exclusive (1). Manic and depressive symptoms are not generally negatively correlated—whether subjects in a study are mainly depressed (2), manic (3, 4), or either (5, 6).

Combinatorial models for mixed states posit essentially linear combinations of depressive and manic features. Emil Kraepelin (1) proposed combinations of elements that can each be considered depressed or manic. A second noncombinatorial model, based on proposals by the Vienna school (7), emphasized the underlying mechanisms of mixed states.

Mixed states significantly affect clinical course and treatment. Understanding them will enhance our grasp of bipolar and related disorders. Here, we concentrate on operationalizable definitions of mixed states, addressing the development of the concept, the symptomatic structure, the relationships between susceptibility to mixed states and course of illness, and the practical criteria for mixed states based on these factors.

+

Origins

The idea of manic-depressive illness, including mixed states, originated with classical physicians, especially Hippocrates (ca. 460–370 BCE) and Aretaeus of Cappadocia (ca. 30–130 CE) (8). Perhaps the first modern psychiatrist to describe mixed states systematically was Johann Christian August Heinroth (1773–1843), who categorized mental disorders as exaltations (“hyperthymias”), depressions (“asthenias”), and mixed states of exaltation and weakness (“hypo-asthenias”), further divided into mixed mood, mental, and volition disorders (9).

+

Combinatorial Models

Emil Kraepelin (1856–1926) systematized previous observations, positing three elements of behavior that could be increased (manic) or decreased (depressed) independent of the others: mood, thought, and volition. Mixed states (“Mischzustande”) or mixed forms (“Mischformen”) were the six combinations of depressed and manic elements: depression with flight of ideas (“ideenfluchtige Depression”), excited depression (“erregte Depression”), depressive-anxious mania (“depressive oder angstliche Manie”), unproductive mania with poverty of thought (“ideenarme Manie”), inhibited mania (“gehemmte Manie”), and manic stupor (“manischer Stupor”). He proposed that mixed states were driven by a mechanism resembling hyperarousal and represented a more severe form of bipolar disorder. Wilhelm Weygandt (1870–1939), a pupil and colleague of Kraepelin, published the first book on mixed states, On the Mixed States of Manic-Depressive Insanity (10), in which Weygandt introduced the term “agitated depression” (“agitierte Depression”).

Kraepelin further classified mixed states temporally: either transitional between depression and mania or autonomic. Autonomic forms were the most unfavorable manifestations of manic-depressive insanity, with longer course, more chronicity, and longer episodes (1, 10)—confirmed 100 years later, as discussed below.

Kraepelin’s basic elements were derived from observation alone without access to the neurobiological or clinical information now available. Also, he proposed no method for measuring whether an element was “depressed” or “manic.” Therefore, we may accept Kraepelin’s basic approach, but we must look critically at how to apply it.

+

Noncombinatorial Models

In Clinical Psychopathology (11), Schneider wrote, “we no longer believe in mixed states.…[W]hat might give the appearance of this is really an actual change or reversal, insofar as we can call the situation cyclothymic at all.” Berner et al. (7), however, developed the Vienna research criteria based on the “dynamic” concept proposed by Janzarik (12), which involved biological mechanisms governing drive and emotions. The Vienna criteria delineate a mixed affective subtype with sustained instability, the “persistent presence of a drive state contradictory to the mood state and/or the emotional resonance” (13, p. 164).

DSM-III, DSM-IV, and ICD-10 adopted a pragmatic, descriptive approach that emphasized manic episodes with prominent depressive features. In the past 30 years, a rebirth of interest in mixed states has led to the investigation of mixed mania (mania plus less than syndromal depression) and, more recently, mixed depression (major depression plus less than syndromal mania). This approach addressed depressive and manic episodes separately, regarding mixed states as subtypes of these episodes rather than in terms of episode components (like Kraepelin) or underlying mechanisms (like Berner). One current challenge is to develop models in which reliably observable clinical characteristics can drive research on the mechanisms and treatments of these states.

+

Summary

Centuries ago, clinicians realized that manic and depressive characteristics could combine in the same episode, potentially representing unusually severe illness, and that these combinations appeared to result from some driving force. More recently, mixed states were conceptualized as forms of depression or of mania. In the next section, we explore carefully observed clinical properties of mixed states, reviewing characteristics that differentiate mixed from nonmixed episodes and comparing mixed states derived from manic or depressive episodes.

Kraepelin formulated mixed states as freestanding or transitional episodes rather than as depressive or manic subtypes (1). However, mixed states have generally been studied as subtypes of manic or depressive episodes. Below, we review the properties of predominantly manic or depressive mixed states and their potential convergence.

+

Predominant Polarity

+

Manic.

While current definitions require full syndromal mania and depression, episodes with subsyndromal depression differ in treatment response (14, 15), and mixed hypomanic episodes appear common (16). Definitions of mixed mania range from narrow definitions in DSM-IV or ICD-9 to definitions based on subsyndromal depressive symptoms (including the Cincinnati criteria of at least three depressive symptoms in mania [17]); treatment response differs with two depressive symptoms (14).

+

Depressive.

Although they were not addressed in DSM-IV or ICD-9, depressive episodes with concurrent hypomania or mania appear common (1820). The range of definitions for depressive mixed states resembles that for mania. Clinical studies suggest that features distinguishing mixed depressive episodes emerge at low levels of manic symptoms (2) and are often missed (21).

Some patients may experience hypomanic or manic symptoms only during depressive episodes (19, 22), especially early in the course of illness (20). These patients had early onset, frequent episodes, and family history of bipolar disorder, resembling patients with freestanding hypomania (18). Manic symptoms in depressive episodes have been shown to be related to severe illness course; receiver operating characteristic analysis revealed a threshold at modest manic symptom levels (Mania Rating Scale score, 6) (2). Large prospective studies have demonstrated that subsyndromal manic symptoms during depressive episodes in patients diagnosed with major depressive disorder are associated with family history and illness course characteristics resembling bipolar disorder (20) and with eventual diagnostic change to bipolar disorder (23).

+

Independent of predominant polarity.

Kraepelin’s classification of mixed states was not specific to depressive or manic episodes (1). Yet, mixed states in the context of affective episodes in general have rarely been addressed. The data we review below suggest that regardless of dominant polarity, characteristics of mixed states emerge with two or three symptoms of opposite polarity, although this has rarely been studied directly.

+

Threshold Symptom Levels

Manic episodes with two or more nonoverlapping depressive symptoms were found to have a poorer response to lithium than those with fewer depressive symptoms (14). Greater anxiety emerged with two symptoms; suicidal behavior and early onset of illness emerged with three or more (6).

The presence of two or three manic symptoms (defined to not overlap with potential depressive symptoms) in a major depressive episode confers properties generally associated with bipolar disorder (history of freestanding manic or hypomanic episodes and family history of bipolar disorder) and mixed states (severe course and co-occurring disorders) (19, 20). Two symptoms may be too sensitive, and three symptoms may be too specific (19).

+

Clinical Characteristics

+

Affective symptoms in mixed states.

Manic symptoms that characterize mixed manic episodes include greater mood lability and irritability and decreased grandiosity, euphoria, pressured speech, and need for sleep compared with nonmixed episodes (24). Manic symptoms have been reported as less severe (25), more severe (15, 26), or comparable in severity (27) in mixed compared with nonmixed manic episodes.

Depressive symptoms shown to be associated with mixed manic episodes included dysphoric mood, anxiety, excessive guilt, and suicidality (24). Mixed manic episodes have been found to be similar to agitated depressive episodes without other manic symptoms in severity of depression and anxiety, with more severe agitation, irritability, and cognitive impairment (28).

Manic symptoms that have been identified in mixed depressive episodes include irritable mood, distractibility, racing thoughts, and increased talking (19). In the Systematic Treatment Enhancement Program–Bipolar Disorder study (N=1,380), distractibility, racing thoughts/flight of ideas, and agitation were the most common manic symptoms during depressive episodes (29). In patients originally diagnosed with major depressive disorder, decreased need for sleep, increased energy, and increased goal-directed activity were found to predict a diagnostic change to bipolar disorder (23).

+

Depressive symptoms in mixed depressive episodes.

Unlike the case for manic episodes, we know of no reports on depressive symptoms distinguishing mixed from nonmixed depressive episodes. The severity of depressive symptoms appears similar in depressive episodes with or without concurrent manic symptoms (2, 20).

+

Symptoms regardless of polarity.

Greater anxiety was found to be predicted by at least two depressive symptoms in mania or at least one manic symptom in depression. Discriminant function analysis identified worry, negative self-evaluation, increased energy, visible hyperactivity, and racing thoughts as associated with mixed states, regardless of polarity (6).

+

Nonmood Symptoms in Mixed Episodes

Mood is only part of depressive and manic states. Nonmood symptoms, including anxiety, agitation, or psychosis, could be basic to mixed states. Specificity of relationships to mixed states may differ between predominantly manic or depressive mixed states because their roles in depressive and manic syndromes differ.

+

Anxiety.

Kraepelin used “depressive” and “anxious” mania interchangeably, describing the patients as “frantically anxious,” reflecting general hyperarousal (1). Subsequent evidence confirmed this. In mania, high anxiety scores are associated with depression (30) and lithium resistance (15). Anxiety scores were found to be correlated with depression scores in mania (6) and were minimal in nonmixed mania (6, 15, 28). Anxiety appears to be a core symptom of mixed manic episodes (31).

Severity of anxiety in manic mixed states resembles nonmanic agitated depression (28), associated with increased tension and intensity of affect (32).

Unlike mania, in which anxiety is basically limited to mixed episodes, anxiety is pervasive in depression, mixed or not (28). Sato et al. (33) wrote that anxiety is “unlikely to play a major role in the core phenomenological features of mixed depression.” Yet, in bipolar depressive episodes, the severity of anxiety correlates with mania (6) as well as depression scores (2). Therefore, anxiety is strongly related to depressive mixed states, although its diagnostic utility is limited because anxiety is also prominent in nonmixed depressive states.

Anxiety has been shown to correlate with depressive symptoms in manic episodes, with manic symptoms in depressive episodes, and with the degree to which symptoms were mixed regardless of polarity (6). This pervasive role of anxiety is consistent with mixed states being driven by hyperarousal (1, 34).

+

Agitation.

Agitation, prominent in depressive, manic, and mixed states, includes two basic disturbances (35). The first is painful inner tension, which produces increased non-goal-directed motor activity (pacing and wringing of hands) and is often prominent in depressive episodes, regardless of whether manic symptoms are present (28, 35). The second is increased, poorly regulated goal-directed activity, often with irritability and impatience, which is prominent in manic episodes, regardless of whether depressive symptoms are present (28, 35). Mixed episodes, whether predominantly depressive or manic, generally include both aspects of agitation (1, 28).

It has been proposed that agitated depressed states are, of necessity, mixed (36), but this may not be the case. The Zurich Study, following 591 individuals over 20 years, found both agitated and retarded depressions associated with bipolar disorder and anxiety. Combined agitated and retarded depressions occurred in bipolar disorder, while purely agitated depressions characterized unipolar disorder (37). These findings, along with other research (28, 35), show that some but not all agitated depressive states are bipolar (37).

+

Psychosis.

Manic episodes have a high prevalence of psychotic symptoms, so severity of psychosis is not generally greater in mixed than in nonmixed mania (15, 38). Multivariate statistics identify a psychotic manic subtype that is distinct from depressive mania (3, 27, 38, 39).

As with mania, factor analysis of bipolar depressive episodes yields a psychosis/delusions factor (33). The prevalence of psychotic symptoms is lower in depression than in mania, so psychotic symptoms correlate with manic symptom severity in bipolar depressive episodes (2) as well as with the degree to which affective symptoms are mixed (6). Data show that psychotic features are more likely to be mood incongruent in mixed than in nonmixed bipolar depressions (40).

+

Structure of Episodes: Multivariate Analyses

We reviewed studies that used multivariate analyses of symptoms in manic episodes, depressive episodes, and across both manic and depressive episodes, focusing on prospective studies with validated symptom or behavioral measures.

+

Manic and mixed manic episodes.

Based on factor analysis of manic episodes, cluster analysis characterizes subgroups, including mixed states, as summarized in Table 1. The results are basically consistent across analyses. The factors included depressive appearance and behavior, manic appearance and behavior, irritability, and psychosis. The depression factor scores were sometimes biphasic (3, 27); other factors were normally distributed. Cluster analyses consistently revealed “classic” euphoric, delusional/psychotic, hostile/irritable/dysphoric, and Kraepelinian depressive/anxious mania subtypes.

 
Anchor for Jump
TABLE 1.Symptomatic Structure of Manic and Mixed-Manic Episodesa
Table Footer Note

aGOM=grade of membership analysis; HAM-D=Hamilton Depression Rating Scale; MRS=Mania Rating Scale; ROC=receiver operating characteristic; SADS=Schedule for Affective Disorders and Schizophrenia; SCID=Structured Clinical Interview for DSM-IV.

Table Footer Note

bBiphasic distribution.

+

Depressive and mixed depressive episodes.

Table 2 summarizes factor analyses of depressive episodes. Here, we found fewer cluster analyses of the type in Table 1. These studies focused on the relationships between severity or number of manic symptoms and clinical characteristics. Activated (41) or emotionally hyperreactive (32) depressed patients potentially represent mixed depressive states. Measuring these characteristics may improve detection and monitoring of mixed states.

 
Anchor for Jump
TABLE 2.Symptomatic Structure of Depressive and Mixed-Depressive Episodesa
Table Footer Note

aMMPI-2=Minnesota Multiphasic Personality Inventory; SCID=Structured Clinical Interview for DSM-IV.

+

Episodes across polarities.

Multivariate analyses across polarities are summarized in Table 3. Depressive or manic symptom factors can exist independently or in combination (42, 43). Contrary to Kraepelin’s negative relationship between manic and depressive symptoms (1), these analyses, like those reported in Tables 1 and 2, imply that manic and depressive symptoms are orthogonal (5, 6). The results support Kraepelin’s dimensional model but suggest different dimensions. They also identify constructs, including dysphoria, that may be useful in identifying mixed states regardless of polarity (34). One study (6) developed a measure of the extent to which symptoms were mixed independent of dominant affect—the Mixed State Index, essentially the product of normalized depression and mania scores. A high score on the Mixed State Index was related to severe course of illness and suicidal behavior. Factor analyses of personality scales across states identified subjects at risk for mixed states, personality disorders, and co-occurring disorders (44).

 
Anchor for Jump
TABLE 3.Studies Across Depressive and Manic Statesa
Table Footer Note

aCES-D=Clinical Evaluation Scale for Depression; MINI=Mini-International Neuropsychiatric Interview; TEMPS-A=Temperament Evaluation of Memphis, Pisa, Paris, and San Diego; SCID=Structured Clinical Interview for DSM-IV; MSI=Mixed State Index; SADS=Schedule for Affective Disorders and Schizophrenia.

+

Phenomenology.

During mixed states, depressive and manic symptoms cover the full range of severity, each potentially varying negatively, positively, or independently over time (26). The characteristics of depressive and manic mixed states are similar, and they emerge as the severity of the opposite polarity increases. This raises the question of whether a group of patients with bipolar disorder is susceptible to mixed states. This susceptibility may be reflected in the course of illness.

The relationships between mixed features and course of illness have been studied through recurrence-related characteristics, such as age at onset, stability of mixed states, and number of episodes, and complications, such as co-occurring disorders, suicide risk, and treatment resistance.

+

Recurrence

In mixed mania, the results from studies of age at onset are inconsistent (17, 45). In general, subjects were those in whom any manic episode was mixed, but one negative study focused on mixed first episodes (46). Onset was earlier in individuals with at least one mixed episode over a 10-year period (47). Interpretation is limited by variable definitions of age at onset and of mixed states. Specificity of early age at onset for mixed states compared with stronger genetic liability to bipolarity is unclear. In a small study of age- and gender-matched bipolar patients, after controlling for age at onset, mixed states occurred only in those with a family history of bipolar disorder (48).

Studies of mixed depressive patients found consistently earlier age at onset than in nonmixed depressions (2, 29, 49). Mixed features across polarities were also related to early onset, independent of episode type (6). This may reflect increased severity of early-onset bipolar disorder in general (50).

+

Lifetime Number and Frequency of Episodes

Patients with mixed manic or depressive states have more lifetime episodes of illness than those without mixed states (27, 47, 5154). Mixed states can also present as fewer episodes of longer duration (52). In either case, individuals with mixed states experience longer periods of mood instability.

Time to syndrome resolution is longer for mixed episodes than for depressive or manic episodes (49, 52, 55, 56). One study of 143 mixed and 118 manic episodes found that mixed episodes were longer, with lower rates of interepisode remission (52). After remission, mixed states relapsed sooner (57). Accordingly, course and prognosis of mixed mania are worse than for nonmixed mania (17, 45).

+

Stability of Mixed States

The possibility of a subtype of bipolar disorder characterized by susceptibility to mixed states can be addressed by prospectively investigating outcome after an index mixed episode or by retrospectively examining whether a current mixed state is associated with a higher than expected frequency of past mixed episodes. This susceptibility could be present from the outset or could emerge over the course of illness.

In 247 manic patients (97 mixed and 150 nonmixed) followed for 24 months after hospitalization, index mixed states were followed by 12 times more subsequent mixed states, 6.5 times more depressive episodes, and 69% more dysthymia than nonmixed manic index episodes. In contrast, nonmixed manic index episodes were followed by 10 times more manic episodes, six times more hypomanic episodes, and 35% more psychotic illness than were mixed index episodes (58). In 68 prospectively evaluated subjects with two discrete manic or mixed episodes, recurrence was true to type whether using a more (DSM-III-R) or less (Duke receiver operating characteristic criteria) inclusive definition for mixed mania (59). In bipolar depression, mixed depressive states were found to be relatively, but not absolutely, stable over 2 years (60). These studies support stability of mixed and nonmixed bipolar disorder, at least over 12–24 months.

Retrospective studies using DSM-III, DSM-III-R, the Pisa criteria, and the Cincinnati criteria for mixed states consistently found more histories of mixed episodes in patients with a current mixed presentation (52, 61, 62). Patients whose manic episodes were exclusively mixed had more previous mixed episodes than those with both mixed and nonmixed manic episodes (54).

Prospective studies, with the advantage of directly observed episodes, and retrospective studies, with the advantage of longer periods of observation, concur that susceptibility to mixed states is stable within individuals, for mania or depression.

+

Suicidality

+

Predominantly manic.

Mixed mania combines depression with the impulsivity and hyperactivity of mania. Greater suicidal ideation, comparable to depressive episodes, was found in mixed relative to nonmixed mania (24, 39, 51, 6265). A chart review of 184 inpatients with bipolar I disorder found higher past suicidality in patients with mixed manic episodes, defined by at least three depressive symptoms (65). Prospectively studied patients in mixed episodes had a higher rate of suicide attempts than those without mixed states, but not after adjusting for age at onset (47). Patients with exclusively mixed manic states had higher risk for suicide than patients whose history included nonmixed manic episodes (54). Suicidal ideation was found to be greater with at least three depressive symptoms in manic episodes not meeting DSM mixed-state criteria (66), and it correlated with depressive symptoms during manic episodes (64).

+

Predominantly depressive.

Mixed depressive episodes combine the hopelessness of depression with the impulsivity and hyperactivity of mania (67). Depressed bipolar patients with subsyndromal or presumptive DSM-IV-defined mixed episodes were found to be more likely to have attempted suicide than those without concomitant manic features (29). Greater anxiety in mixed states may increase suicide risk further (68). In one study, suicidal behavior was increased with “subsyndromal hypomania” during depression compared with purely depressive episodes; age at onset did not differ (20).

Unlike manic episodes, risk of suicide is already increased in nonmixed depression. Presence of manic symptoms adds to risk. Noneuphoric hypomanic symptoms have been shown to be associated with increased suicidality in depressed patients who had never experienced freestanding hypomania or mania (22). In bipolar depression, receiver operating characteristic analysis has shown increased suicide attempt history with a Mania Rating Scale score of 8, parallel to increased impulsivity (2).

Mixed states—depressive or manic—combine hopelessness with impulsivity and activation, leading to high risk for suicidal behavior. It is useful to know whether an individual is susceptible to mixed states, as emergence of mixed features in an initially nonmixed episode may increase the risk for suicide. This could occur pharmacologically (69).

+

Co-Occurring Conditions

Individuals with mixed manic or depressive episodes are more likely to have experienced early-life stressors and to have stress-related disorders (70).

Co-occurring anxiety disorders are more common in patients with mixed than nonmixed manic (63) or depressive episodes (71). This was confirmed by two large longitudinal studies: the National Epidemiologic Survey on Alcohol and Related Conditions (N=43,093) (72) and the Zurich Study (37). Co-occurring anxiety disorders are associated with a poor course of illness and increased service utilization (73).

Alcohol and substance abuse may be more prevalent in mixed than nonmixed manic episodes (2, 55, 74) and are associated with poor outcome and less favorable response to lithium (55). Differences in lifetime alcohol abuse, however, were not always confirmed (62). History of substance use disorder predicted greater mood instability in bipolar depressive episodes (75), possibly contributing to increased risk for mixed features and suicidal behavior.

Manic or depressive syndromes can be related to many medical and substance-related disorders. Diagnostic criteria for mixed states (discussed below) define them as primary affective syndromes, as do the articles cited in this review. As with other mood states, clinicians should be alert to the possibility that even with clear previous primary episodes, any episode may be related to another medical condition requiring treatment. This is especially true in mixed states, which may be more likely than other episodes to be associated with substance-related, nonpsychiatric medical, or neurological disorders (55).

+

Response to Treatment

Naturalistic studies, prospective and retrospective, have demonstrated that mixed states are difficult to treat, suggesting that mixed episodes respond poorly to lithium and other monotherapies (14, 55, 76). Placebo-controlled data generally derive from subanalyses of randomized clinical trials, whose enrollment criteria may have excluded patients with co-occurring conditions and suicidality (typical of mixed states); these studies have supported divalproex, carbamazepine, and second-generation antipsychotic agents (77). One study found a reduction in lithium effects with two or more depressive symptoms, without effect on response to divalproex; lithium was highly effective in episodes without depressive symptoms (14).

Mixed depressive episodes pose their own challenges. Akiskal et al. (22) proposed that mixed depressive episodes should not be treated with antidepressants because of increased activation and risk for suicidality. Compared with nonmixed depression, mixed depression had longer duration, worse outcome, and poorer response to treatments (49). In a large chart review study, Koukopoulos et al. (69) reported poor response to antidepressants in agitated, largely mixed, depressed patients. A large prospective study confirmed the poor response to antidepressants (78). In summary, antidepressants without mood-stabilizing treatments have limited efficacy and the potential for harm in bipolar disorder, and properly defined mixed depressive episodes are part of bipolar disorder.

Patients with mixed states have a poorer long-term prophylactic response to treatment in general (47). One question, given the high risk for suicidal behavior in mixed states, is the role of prophylactic lithium in patients susceptible to mixed states. Notably, data show that lithium appears to reduce suicidal behavior even when it is not effective in preventing affective episodes (79).

+

Course of Illness

Patients who are susceptible to mixed states differ from those who are not—they have more episodes, increased suicidality, higher rates of co-occurring conditions, and poorer response to treatments. Similarly, patients with a more unstable form of bipolar disorder, including susceptibility to mixed states, are likely to be resistant to lithium (76). Patients with mixed states are more likely than other patients to have future mixed states. These illness-course characteristics, like the symptomatic characteristics described earlier in this review, appear consistent across mixed depression and mania. They raise questions of common mechanisms underlying mixed episodes and severe course of illness and of how, since they have important potential clinical and treatment consequences, mixed states can be identified efficiently.

+

Potential Mechanisms of Mixed States

Both Kraepelin (1) and the Vienna school (7) proposed that mixed episodes resulted from a pathological drive state, possibly related to emotional lability (32) and activation (41). Of the six Kraepelinian mixed states, the most prevalent are the activated states: depressive/anxious mania, depression with flight of ideas, and activated depression. Consistent with clinical studies, catecholaminergic function in mixed states has been shown to be greater than in nonmixed manic episodes (53, 80). These results, over nearly 100 years, converge to suggest that hyperarousal underlies mixed episodes.

Mixed states occur in the context of early onset, frequent episodes or prolonged affective instability, and increased stress-related (70) and substance use (74, 75) disorders. Mechanisms of this relationship between susceptibility to episode-related behavioral instability and a long-term unfavorable illness course represent an important target in understanding mechanisms and treatment targets in bipolar disorder.

Combined depressive and manic features could result from any of the following:

1. Superimposed physiological states: Mixed manic states combine the hypothalamic-pituitary-adrenocortical (HPA) activation of depression with increased catecholamine function exceeding nonmixed mania (80). Mixed mania is associated with increased HPA axis function, correlating with depressive symptoms. Low thyroid function has been associated with affective instability, but relationships between mixed states and thyroid function are inconsistent (81, 82). This implies a combinatorial structure, possibly driven by poorly regulated arousal and mood lability (32, 41).

2. Rapid alternation between mood states, such as ultradian cycling or extreme mood instability (83): Affective instability, including ultradian and other extremely rapid cycles, should be distinguished from episodes in which they occur, which can be prolonged (84). Similarly, mixed states should be differentiated from rapid cycling, which consists of frequent episodes of illness that could be manic, depressive, or mixed. Evidence for validators of rapid cycling other than frequent episodes has been inconsistent; most characteristics of rapid cycling appear as functions of episode frequency (85).

3. Transitions to and from mixed states: Such transitions do occur, although mixed states may also be stable and prolonged (52). Kraepelin suggested that some mixed states were transitions between depressive and manic episodes (1), but this may not generally be the case (86). Transitions between manic or depressive states and mixed states may be more common, as demonstrated in a longitudinal study (26). Polyphasic episodes, in which state changes occur without a stable period, have unfavorable illness course characteristics resembling mixed states (87).

In summary, mixed episodes are characterized by combined or rapidly alternating behavioral states, possibly driven by hyperarousal and increased catecholaminergic function. They are associated with early onset, recurrent course (or prolonged mood instability), early stressors, and substance use disorders. These characteristics suggest that mixed states are an expression of behavioral sensitization in bipolar disorder. Exaggerated behavioral sensitization could result from interacting genetic susceptibilities and environmental or pharmacological sensitizing stimuli.

+

Assessment of Mixed States

+

Need for comprehensive assessment.

Mixed states require clinical vigilance. Mixed features can be present in, or emerge during, any episode. Therefore, it is vital to monitor both depressive and manic features in any bipolar disorder episode, as well as in patient self-monitoring by mood charting. Distinct clinical features emerge with mild symptoms of the nondominant polarity, easily missed if not sought specifically. Identification of opposite polarity symptoms must account for symptoms that could overlap between depression and mania, such as irritability, agitation, anxiety, or insomnia. This is addressed in the Cincinnati criteria (17) and the Schedule for Affective Disorders and Schizophrenia–Change Version (SADS–C) (88). Comprehensive scales include the SADS-C, the Internal State Scale (89), and the Multidimensional Assessment of Thymic States (32). In addition to conventional psychiatric symptoms, emotional intensity and affective instability may contribute to the assessment and understanding of mixed states (90).

Depressive and manic symptoms may have different diurnal rhythms that could cause mixed features to be missed with once-daily monitoring (91). Monitoring should reflect maximum symptoms over a 24-hour period.

+

Potential ascertainment bias.

Detection and description of mixed states may be distorted by ascertainment biases, such as Berkson’s bias (92), where relationships between clinical characteristics may appear exaggerated if derived from a population with independently increased susceptibilities to them. Associations between manic and depressive symptoms would be exaggerated if individuals with both were artificially more likely to be included in a study. However, bipolar disorder, by definition, includes both depressive and manic states, and mixed affective symptoms have been demonstrated in nonclinical populations (Table 3) (42).

For example, manic and depressive symptoms have been shown to contribute independently to service use, implying that these symptoms are more independent than clinical studies suggest (93). Symptoms were measured at times remote to service use, and depressive and manic symptoms were not necessarily concomitant. Contributions of depression and mania may appear independent because they increase service use through different mechanisms. Interestingly, combined symptoms had larger effects than either alone.

Berkson’s bias would not affect the existence or structure of mixed states. It may contribute to apparent prevalence, which is not our focus. If mixed states occur with early onset and frequent episodes, Berkson’s bias could affect apparent rates of co-occurring substance use or anxiety disorders, which have similar illness course relationships. Berkson’s bias can be minimized with proper controls (94), but the potential should be taken into account.

+

Practical Identification of Mixed States

Tables 1, 2, and 3 suggest that symptomatic and illness course characteristics of mixed states emerge, in depressive or manic episodes, with two or three independent opposite polarity symptoms. The properties of predominantly depressive and manic mixed states converge. These characteristics can yield parsimonious criteria for mixed episodes, summarized in Table 4. The research criteria may be more detailed, including symptom scales, than optimal for general clinical use. Table 4 also includes practical clinical criteria. As with the specifier proposed by the DSM-5 Mood Disorders Work Group, the focus is on symptoms of the opposite pole that are unlikely to overlap.

 
Anchor for Jump
TABLE 4.Proposed Research and Clinical Criteria for Mixed Statesa
Table Footer Note

aSADS=Schedule for Affective Disorders and Schizophrenia; YMRS=Young Mania Rating Scale; HAM-D=Hamilton Depression Rating Scale.

Components of what are considered manic and depressive states can combine in bipolar disorder. Mixed features may be associated with illness course and treatment response characteristics distinct from more exclusively depressive or manic states. Clinical characteristics, including co-occurring conditions, suicidal behavior, anxiety, poor treatment outcome, and severely recurrent and complicated course, appear stable across definitions and criteria for mixed states. The importance of recognizing and monitoring mixed features during a hypomanic, manic, or depressed episode is highlighted by their relationship to recurrent course, treatment resistance, co-occurring substance use, and potential for suicidality.

The authors thank the International Society for Bipolar Disorders, and especially Chad Daversa, its executive director, for organizational support. The International Society on Bipolar Disorders did not participate in the preparation or writing of this paper.

Kraepelin  E:  Manic-Depressive Illness and Paranoia . Edited by Robertson  GM;  Barclay  RBT.  Edinburgh, Scotland,  E & S Livingstone, 1921
 
Swann  AC;  Moeller  FG;  Steinberg  JL;  Schneider  L;  Barratt  ES;  Dougherty  DM:  Manic symptoms and impulsivity during bipolar depressive episodes.  Bipolar Disord 2007; 9:206–212
[CrossRef] | [PubMed]
 
Cassidy  F;  Forest  K;  Murry  E;  Carroll  BJ:  A factor analysis of the signs and symptoms of mania.  Arch Gen Psychiatry 1998; 55:27–32
[CrossRef] | [PubMed]
 
Dilsaver  SC;  Chen  YR;  Shoaib  AM;  Swann  AC:  Phenomenology of mania: evidence for distinct depressed, dysphoric, and euphoric presentations.  Am J Psychiatry 1999; 156:426–430
[PubMed]
 
Johnson  SL;  Morriss  R;  Scott  J;  Paykel  E;  Kinderman  P;  Kolamunnage-Dona  R;  Bentall  RP:  Depressive and manic symptoms are not opposite poles in bipolar disorder.  Acta Psychiatr Scand 2011; 123:206–210
[CrossRef] | [PubMed]
 
Swann  AC;  Steinberg  JL;  Lijffijt  M;  Moeller  GF:  Continuum of depressive and manic mixed states in patients with bipolar disorder: quantitative measurement and clinical features.  World Psychiatry 2009; 8:166–172
[PubMed]
 
Berner  P;  Gabriel  E;  Katschnig  H;  Keiffer  W;  Koehler  K;  Lenz  G;  Simhandl  C:  Diagnostic Criteria for Schizophrenia and Affective Psychoses (World Psychiatric Association) .  Washington, DC,  American Psychiatric Association, 1983
 
Angst  J;  Marneros  A:  Bipolarity from ancient to modern times: conception, birth and rebirth.  J Affect Disord 2001; 67:3–19
[CrossRef] | [PubMed]
 
Heinroth  JCA:  Lehrbuch der Storungen des Seelenlebens oder der Seelenstorungen und ihrer Behandlung - aus rationaler Sicht .  Leipzig,  Vogel, 1818
 
Weygandt  W:  Uber die Mischzustande des manisch-depressiven Irreseins .  Munich,  JF Lehmann, 1899
 
Schneider  K:  Klinische Psychopathologie, 5 .  Stuttgart,  Thieme, 1959
 
Janzarik  W:  Dynamische Grundkonstellationen in endogenen Psychosen .  Berlin, Gottingen, Heidelberg,  Springer, 1959
 
Berner  P;  Gabriel  E;  Katschnig  H;  Kieffer  W;  Koehlert  K;  Lenz  G;  Nutzinger  D;  Schanda  H;  Simhandl  C:  Diagnostic Criteria for the Functional Psychoses, 2nd ed .  New York,  Cambridge University Press, 1993, p 164
 
Swann  AC;  Bowden  CL;  Morris  D;  Calabrese  JR;  Petty  F;  Small  JG;  Dilsaver  SC;  Davis  JM:  Depression during mania: treatment response to lithium or divalproex.  Arch Gen Psychiatry 1997; 54:37–42
[CrossRef] | [PubMed]
 
Swann  AC;  Secunda  SK;  Katz  MM;  Koslow  SH;  Maas  JW;  Chang  S;  Robins  E:  Lithium treatment of mania: clinical characteristics, specificity of symptom change, and outcome.  Psychiatry Res 1986; 18:127–141
[CrossRef] | [PubMed]
 
Suppes  T;  Mintz  J;  McElroy  SL;  Altshuler  LL;  Kupka  RW;  Frye  MA;  Keck  PE  Jr;  Nolen  WA;  Leverich  GS;  Grunze  H;  Rush  AJ;  Post  RM:  Mixed hypomania in 908 patients with bipolar disorder evaluated prospectively in the Stanley Foundation Bipolar Treatment Network: a sex-specific phenomenon.  Arch Gen Psychiatry 2005; 62:1089–1096
[CrossRef] | [PubMed]
 
McElroy  SL;  Keck  PE  Jr;  Pope  HG  Jr;  Hudson  JI;  Faedda  GL;  Swann  AC:  Clinical and research implications of the diagnosis of dysphoric or mixed mania or hypomania.  Am J Psychiatry 1992; 149:1633–1644
[PubMed]
 
Akiskal  HS;  Benazzi  F:  Family history validation of the bipolar nature of depressive mixed states.  J Affect Disord 2003; 73:113–122
[CrossRef] | [PubMed]
 
Benazzi  F;  Akiskal  HS:  Delineating bipolar II mixed states in the Ravenna-San Diego collaborative study: the relative prevalence and diagnostic significance of hypomanic features during major depressive episodes.  J Affect Disord 2001; 67:115–122
[CrossRef] | [PubMed]
 
Zimmermann  P;  Brückl  T;  Nocon  A;  Pfister  H;  Lieb  R;  Wittchen  HU;  Holsboer  F;  Angst  J:  Heterogeneity of DSM-IV major depressive disorder as a consequence of subthreshold bipolarity.  Arch Gen Psychiatry 2009; 66:1341–1352
[CrossRef] | [PubMed]
 
Mazza  M;  Mandelli  L;  Zaninotto  L;  Nicola  MD;  Martinotti  G;  Harnic  D;  Bruschi  A;  Catalano  V;  Tedeschi  D;  Colombo  R;  Bria  P;  Serretti  A;  Janiri  L:  Factors associated with the course of symptoms in bipolar disorder during a 1-year follow-up: depression vs. sub-threshold mixed state.  Nord J Psychiatry 2011; 65:419–426
[CrossRef] | [PubMed]
 
Akiskal  HS;  Benazzi  F;  Perugi  G;  Rihmer  Z:  Agitated “unipolar” depression re-conceptualized as a depressive mixed state: implications for the antidepressant-suicide controversy.  J Affect Disord 2005; 85:245–258
[CrossRef] | [PubMed]
 
Fiedorowicz  JG;  Endicott  J;  Leon  AC;  Solomon  DA;  Keller  MB;  Coryell  WH:  Subthreshold hypomanic symptoms in progression from unipolar major depression to bipolar disorder.  Am J Psychiatry 2011; 168:40–48
[CrossRef] | [PubMed]
 
Cassidy  F;  Murry  E;  Forest  K;  Carroll  BJ:  Signs and symptoms of mania in pure and mixed episodes.  J Affect Disord 1998; 50:187–201
[CrossRef] | [PubMed]
 
Goldberg  JF;  Garno  JL;  Portera  L;  Leon  AC;  Kocsis  JH:  Qualitative differences in manic symptoms during mixed versus pure mania.  Compr Psychiatry 2000; 41:237–241
[CrossRef] | [PubMed]
 
Kotin  J;  Goodwin  FK:  Depression during mania: clinical observations and theoretical implications.  Am J Psychiatry 1972; 129:679–686
[PubMed]
 
Swann  AC;  Janicak  PL;  Calabrese  JR;  Bowden  CL;  Dilsaver  SC;  Morris  DD;  Petty  F;  Davis  JM:  Structure of mania: depressive, irritable, and psychotic clusters with different retrospectively-assessed course patterns of illness in randomized clinical trial participants.  J Affect Disord 2001; 67:123–132
[CrossRef] | [PubMed]
 
Swann  AC;  Secunda  SK;  Katz  MM;  Croughan  J;  Bowden  CL;  Koslow  SH;  Berman  N;  Stokes  PE:  Specificity of mixed affective states: clinical comparison of dysphoric mania and agitated depression.  J Affect Disord 1993; 28:81–89
[CrossRef] | [PubMed]
 
Goldberg  JF;  Perlis  RH;  Bowden  CL;  Thase  ME;  Miklowitz  DJ;  Marangell  LB;  Calabrese  JR;  Nierenberg  AA;  Sachs  GS:  Manic symptoms during depressive episodes in 1,380 patients with bipolar disorder: findings from the STEP-BD.  Am J Psychiatry 2009; 166:173–181
[CrossRef] | [PubMed]
 
González-Pinto  A;  Aldama  A;  Mosquera  F;  González Gómez  C:  Epidemiology, diagnosis and management of mixed mania.  CNS Drugs 2007; 21:611–626
[CrossRef] | [PubMed]
 
Cassidy  F:  Anxiety as a symptom of mixed mania: implications for DSM-5.  Bipolar Disord 2010; 12:437–439
[CrossRef] | [PubMed]
 
Henry  C;  M’Baïlara  K;  Poinsot  R;  Casteret  AA;  Sorbara  F;  Leboyer  M;  Vieta  E:  Evidence for two types of bipolar depression using a dimensional approach.  Psychother Psychosom 2007; 76:325–331
[CrossRef] | [PubMed]
 
Sato  T;  Bottlender  R;  Kleindienst  N;  Möller  HJ:  Irritable psychomotor elation in depressed inpatients: a factor validation of mixed depression.  J Affect Disord 2005; 84:187–196
[CrossRef] | [PubMed]
 
Bertschy  G;  Gervasoni  N;  Favre  S;  Liberek  C;  Ragama-Pardos  E;  Aubry  JM;  Gex-Fabry  M;  Dayer  A:  Frequency of dysphoria and mixed states.  Psychopathology 2008; 41:187–193
[CrossRef] | [PubMed]
 
Katz  MM;  Koslow  SH;  Berman  N;  Secunda  S;  Maas  JW;  Casper  R;  Kocsis  JH;  Stokes  PE:  A multi-vantaged approach to measurement of behavioral and affect states for clinical and psychobiological research.  Psychol Rep 1984; 55:619–671
[CrossRef] | [PubMed]
 
Koukopoulos  A;  Koukopoulos  A:  Agitated depression as a mixed state and the problem of melancholia.  Psychiatr Clin North Am 1999; 22:547–564
[CrossRef] | [PubMed]
 
Angst  J;  Gamma  A;  Benazzi  F;  Ajdacic  V;  Rössler  W:  Does psychomotor agitation in major depressive episodes indicate bipolarity? Evidence from the Zurich Study.  Eur Arch Psychiatry Clin Neurosci 2009; 259:55–63
[CrossRef] | [PubMed]
 
González-Pinto  A;  Aldama  A;  Pinto  AG;  Mosquera  F;  Pérez de Heredia  JL;  Ballesteros  J;  Gutiérrez  M:  Dimensions of mania: differences between mixed and pure episodes.  Eur Psychiatry 2004; 19:307–310
[CrossRef] | [PubMed]
 
Sato  T;  Bottlender  R;  Kleindienst  N;  Möller  HJ:  Syndromes and phenomenological subtypes underlying acute mania: a factor analytic study of 576 manic patients.  Am J Psychiatry 2002; 159:968–974
[CrossRef] | [PubMed]
 
Perugi  G;  Akiskal  HS;  Micheli  C;  Toni  C;  Madaro  D:  Clinical characterization of depressive mixed state in bipolar I patients: Pisa-San Diego collaboration.  J Affect Disord 2001; 67:105–114
[CrossRef] | [PubMed]
 
Biondi  M;  Picardi  A;  Pasquini  M;  Gaetano  P;  Pancheri  P:  Dimensional psychopathology of depression: detection of an “activation” dimension in unipolar depressed outpatients.  J Affect Disord 2005; 84:133–139
[CrossRef] | [PubMed]
 
Meyer  TD;  Hautzinger  M:  The structure of affective symptoms in a sample of young adults.  Compr Psychiatry 2003; 44:110–116
[CrossRef] | [PubMed]
 
Adler  M;  Liberg  B;  Andersson  S;  Isacsson  G;  Hetta  J:  Development and validation of the Affective Self Rating Scale for manic, depressive, and mixed affective states.  Nord J Psychiatry 2008; 62:130–135
[CrossRef] | [PubMed]
 
Perugi  G;  Toni  C;  Maremmani  I;  Tusini  G;  Ramacciotti  S;  Madia  A;  Fornaro  M;  Akiskal  HS:  The influence of affective temperaments and psychopathological traits on the definition of bipolar disorder subtypes: a study on bipolar I Italian national sample.  J Affect Disord 2012; 136:e41–e49
[CrossRef] | [PubMed]
 
Cassidy  F;  Yatham  LN;  Berk  M;  Grof  P:  Pure and mixed manic subtypes: a review of diagnostic classification and validation.  Bipolar Disord 2008; 10:131–143
[CrossRef] | [PubMed]
 
Baldessarini  RJ;  Bolzani  L;  Cruz  N;  Jones  PB;  Lai  M;  Lepri  B;  Perez  J;  Salvatore  P;  Tohen  M;  Tondo  L;  Vieta  E:  Onset-age of bipolar disorders at six international sites.  J Affect Disord 2010; 121:143–146
[CrossRef] | [PubMed]
 
González-Pinto  A;  Barbeito  S;  Alonso  M;  Alberich  S;  Haidar  MK;  Vieta  E;  Tabarés-Seisdedos  R;  Zorrilla  I;  González-Pinto  MA;  López  P:  Poor long-term prognosis in mixed bipolar patients: 10-year outcomes in the Vitoria prospective naturalistic study in Spain.  J Clin Psychiatry 2011; 72:671–676
[CrossRef] | [PubMed]
 
Moorhead  S;  Scott  J:  Clinical characteristics of familial and non-familial bipolar disorder.  Bipolar Disord 2000; 2:136–139
[CrossRef] | [PubMed]
 
Benazzi  F:  Bipolar disorder—focus on bipolar II disorder and mixed depression.  Lancet 2007; 369:935–945
[CrossRef] | [PubMed]
 
Suppes  T;  Leverich  GS;  Keck  PE;  Nolen  WA;  Denicoff  KD;  Altshuler  LL;  McElroy  SL;  Rush  AJ;  Kupka  R;  Frye  MA;  Bickel  M;  Post  RM:  The Stanley Foundation Bipolar Treatment Outcome Network. II. Demographics and illness characteristics of the first 261 patients.  J Affect Disord 2001; 67:45–59
[CrossRef] | [PubMed]
 
Hantouche  EG;  Akiskal  HS;  Azorin  JM;  Châtenet-Duchêne  L;  Lancrenon  S:  Clinical and psychometric characterization of depression in mixed mania: a report from the French National Cohort of 1090 manic patients.  J Affect Disord 2006; 96:225–232
[CrossRef] | [PubMed]
 
Perugi  G;  Akiskal  HS;  Micheli  C;  Musetti  L;  Paiano  A;  Quilici  C;  Rossi  L;  Cassano  GB:  Clinical subtypes of bipolar mixed states: validating a broader European definition in 143 cases.  J Affect Disord 1997; 43:169–180
[CrossRef] | [PubMed]
 
Post  RM;  Rubinow  DR;  Uhde  TW;  Roy-Byrne  PP;  Linnoila  M;  Rosoff  A;  Cowdry  R:  Dysphoric mania: clinical and biological correlates.  Arch Gen Psychiatry 1989; 46:353–358
[CrossRef] | [PubMed]
 
Pacchiarotti  I;  Mazzarini  L;  Kotzalidis  GD;  Valentí  M;  Nivoli  AM;  Sani  G;  Torrent  C;  Murru  A;  Sanchez-Moreno  J;  Patrizi  B;  Girardi  P;  Vieta  E;  Colom  F:  Mania and depression: mixed, not stirred.  J Affect Disord 2011; 133:105–113
[CrossRef] | [PubMed]
 
Himmelhoch  JM;  Garfinkel  ME:  Sources of lithium resistance in mixed mania.  Psychopharmacol Bull 1986; 22:613–620
[PubMed]
 
Berk  M;  Dodd  S;  Malhi  GS:  “Bipolar missed states”: the diagnosis and clinical salience of bipolar mixed states.  Aust N Z J Psychiatry 2005; 39:215–221
[PubMed]
 
Tohen  M;  Waternaux  CM;  Tsuang  MT:  Outcome in mania: a 4-year prospective follow-up of 75 patients utilizing survival analysis.  Arch Gen Psychiatry 1990; 47:1106–1111
[CrossRef] | [PubMed]
 
Baldessarini  RJ;  Salvatore  P;  Khalsa  HM;  Tohen  M:  Dissimilar morbidity following initial mania versus mixed-states in type-I bipolar disorder.  J Affect Disord 2010; 126:299–302
[CrossRef] | [PubMed]
 
Cassidy  F;  Ahearn  E;  Carroll  BJ:  A prospective study of inter-episode consistency of manic and mixed subtypes of bipolar disorder.  J Affect Disord 2001; 67:181–185
[CrossRef] | [PubMed]
 
Sato  T;  Bottlender  R;  Sievers  M;  Schröter  A;  Kleindienst  N;  Möller  HJ:  Evaluating the inter-episode stability of depressive mixed states.  J Affect Disord 2004; 81:103–113
[CrossRef] | [PubMed]
 
Marneros  A;  Röttig  S;  Wenzel  A;  Blöink  R;  Brieger  P:  Affective and schizoaffective mixed states.  Eur Arch Psychiatry Clin Neurosci 2004; 254:76–81
[CrossRef] | [PubMed]
 
Akiskal  HS;  Hantouche  EG;  Bourgeois  ML;  Azorin  JM;  Sechter  D;  Allilaire  JF;  Lancrenon  S;  Fraud  JP;  Châtenet-Duchêne  L:  Gender, temperament, and the clinical picture in dysphoric mixed mania: findings from a French national study (EPIMAN).  J Affect Disord 1998; 50:175–186
[CrossRef] | [PubMed]
 
Dilsaver  SC;  Chen  YW;  Swann  AC;  Shoaib  AM;  Tsai-Dilsaver  Y;  Krajewski  KJ:  Suicidality, panic disorder and psychosis in bipolar depression, depressive-mania and pure-mania.  Psychiatry Res 1997; 73:47–56
[CrossRef] | [PubMed]
 
Strakowski  SM;  McElroy  SL;  Keck  PE  Jr;  West  SA:  Suicidality among patients with mixed and manic bipolar disorder.  Am J Psychiatry 1996; 153:674–676
[PubMed]
 
Goldberg  JF;  Garno  JL;  Leon  AC;  Kocsis  JH;  Portera  L:  Association of recurrent suicidal ideation with nonremission from acute mixed mania.  Am J Psychiatry 1998; 155:1753–1755
[PubMed]
 
Goldberg  JF;  Garno  JL;  Portera  L;  Leon  AC;  Kocsis  JH;  Whiteside  JE:  Correlates of suicidal ideation in dysphoric mania.  J Affect Disord 1999; 56:75–81
[CrossRef] | [PubMed]
 
Balázs  J;  Benazzi  F;  Rihmer  Z;  Rihmer  A;  Akiskal  KK;  Akiskal  HS:  The close link between suicide attempts and mixed (bipolar) depression: implications for suicide prevention.  J Affect Disord 2006; 91:133–138
[CrossRef] | [PubMed]
 
Diefenbach  GJ;  Woolley  SB;  Goethe  JW:  The association between self-reported anxiety symptoms and suicidality.  J Nerv Ment Dis 2009; 197:92–97
[CrossRef] | [PubMed]
 
Koukopoulos  A;  Sani  G;  Koukopoulos  AE;  Manfredi  G;  Pacchiarotti  I;  Girardi  P:  Melancholia agitata and mixed depression.  Acta Psychiatr Scand Suppl 2007; (433):50–57
 
Garno  JL;  Goldberg  JF;  Ramirez  PM;  Ritzler  BA:  Impact of childhood abuse on the clinical course of bipolar disorder.  Br J Psychiatry 2005; 186:121–125
[CrossRef] | [PubMed]
 
Akiskal  HS:  The dark side of bipolarity: detecting bipolar depression in its pleomorphic expressions.  J Affect Disord 2005; 84:107–115
[CrossRef] | [PubMed]
 
Agosti  V;  Stewart  JW:  Hypomania with and without dysphoria: comparison of comorbidity and clinical characteristics of respondents from a national community sample.  J Affect Disord 2008; 108:177–182
[CrossRef] | [PubMed]
 
Goldstein  BI;  Levitt  AJ:  The specific burden of comorbid anxiety disorders and of substance use disorders in bipolar I disorder.  Bipolar Disord 2008; 10:67–78
[CrossRef] | [PubMed]
 
Strakowski  SM;  Tohen  M;  Stoll  AL;  Faedda  GL;  Goodwin  DC:  Comorbidity in mania at first hospitalization.  Am J Psychiatry 1992; 149:554–556
[PubMed]
 
Ostacher  MJ;  Perlis  RH;  Nierenberg  AA;  Calabrese  J;  Stange  JP;  Salloum  I;  Weiss  RD;  Sachs  GS;  STEP-BD Investigators:  Impact of substance use disorders on recovery from episodes of depression in bipolar disorder patients: prospective data from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD).  Am J Psychiatry 2010; 167:289–297
[CrossRef] | [PubMed]
 
Duffy  A;  Alda  M;  Kutcher  S;  Cavazzoni  P;  Robertson  C;  Grof  E;  Grof  P:  A prospective study of the offspring of bipolar parents responsive and nonresponsive to lithium treatment.  J Clin Psychiatry 2002; 63:1171–1178
[CrossRef] | [PubMed]
 
Krüger  S;  Trevor Young  L;  Bräunig  P:  Pharmacotherapy of bipolar mixed states.  Bipolar Disord 2005; 7:205–215
[CrossRef] | [PubMed]
 
Goldberg  JF;  Perlis  RH;  Ghaemi  SN;  Calabrese  JR;  Bowden  CL;  Wisniewski  S;  Miklowitz  DJ;  Sachs  GS;  Thase  ME:  Adjunctive antidepressant use and symptomatic recovery among bipolar depressed patients with concomitant manic symptoms: findings from the STEP-BD.  Am J Psychiatry 2007; 164:1348–1355
[CrossRef] | [PubMed]
 
Müller-Oerlinghausen  B:  Arguments for the specificity of the antisuicidal effect of lithium.  Eur Arch Psychiatry Clin Neurosci 2001; 251(Suppl 2):II72–II75
[CrossRef] | [PubMed]
 
Swann  AC;  Stokes  PE;  Secunda  SK;  Maas  JW;  Bowden  CL;  Berman  N;  Koslow  SH:  Depressive mania versus agitated depression: biogenic amine and hypothalamic-pituitary-adrenocortical function.  Biol Psychiatry 1994; 35:803–813
[CrossRef] | [PubMed]
 
Chang  KD;  Keck  PE  Jr;  Stanton  SP;  McElroy  SL;  Strakowski  SM;  Geracioti  TD  Jr:  Differences in thyroid function between bipolar manic and mixed states.  Biol Psychiatry 1998; 43:730–733
[CrossRef] | [PubMed]
 
Cassidy  F;  Ahearn  EP;  Carroll  BJ:  Thyroid function in mixed and pure manic episodes.  Bipolar Disord 2002; 4:393–397
[CrossRef] | [PubMed]
 
Kramlinger  KG;  Post  RM:  Ultra-rapid and ultradian cycling in bipolar affective illness (see comments). Br J Psychiatry 1996; 168:314–323
[CrossRef] | [PubMed]
 
Tillman  R;  Geller  B:  Definitions of rapid, ultrarapid, and ultradian cycling and of episode duration in pediatric and adult bipolar disorders: a proposal to distinguish episodes from cycles.  J Child Adolesc Psychopharmacol 2003; 13:267–271
[CrossRef] | [PubMed]
 
Bauer  M;  Beaulieu  S;  Dunner  DL;  Lafer  B;  Kupka  R:  Rapid cycling bipolar disorder—diagnostic concepts.  Bipolar Disord 2008; 10:153–162
[CrossRef] | [PubMed]
 
Benazzi  F:  Is depressive mixed state a transition between depression and hypomania? Eur Arch Psychiatry Clin Neurosci 2004; 254:69–75
[CrossRef] | [PubMed]
 
Turvey  CL;  Coryell  WH;  Solomon  DA;  Leon  AC;  Endicott  J;  Keller  MB;  Akiskal  H:  Long-term prognosis of bipolar I disorder.  Acta Psychiatr Scand 1999; 99:110–119
[CrossRef] | [PubMed]
 
Spitzer  RL;  Endicott  J:  Schedule for Affective Disorders and Schizophrenia—Change Version, 3rd edition .  New York,  New York State Psychiatric Institute, Biometrics Research, 1978.
 
Bauer  MS;  Vojta  C;  Kinosian  B;  Altshuler  L;  Glick  H:  The Internal State Scale: replication of its discriminating abilities in a multisite, public sector sample.  Bipolar Disord 2000; 2:340–346
[CrossRef] | [PubMed]
 
Henry  C;  M’Bailara  K;  Lépine  JP;  Lajnef  M;  Leboyer  M:  Defining bipolar mood states with quantitative measurement of inhibition/activation and emotional reactivity.  J Affect Disord 2010; 127:300–304
[CrossRef] | [PubMed]
 
Dilsaver  SC;  Akiskal  HS:  “Mixed hypomania” in children and adolescents: is it a pediatric bipolar phenotype with extreme diurnal variation between depression and hypomania? J Affect Disord 2009; 116:12–17
[CrossRef] | [PubMed]
 
Berkson  J:  Limitations of the application of fourfold table analysis to hospital data.  Biometrics 1946; 2:47–53
[CrossRef] | [PubMed]
 
Regeer  EJ;  Krabbendam  L;  De Graaf  R;  Have  MT;  Nolen  WA;  Van Os  J:  Berkson’s bias and the mood dimensions of bipolar disorder.  Int J Methods Psychiatr Res 2009; 18:279–286
[PubMed]
 
Feinstein  AR;  Walter  SD;  Horwitz  RI:  An analysis of Berkson’s bias in case-control studies.  J Chronic Dis 1986; 39:495–504
[CrossRef] | [PubMed]
 
Harvey  PD;  Endicott  JM;  Loebel  AD:  The factor structure of clinical symptoms in mixed and manic episodes prior to and after antipsychotic treatment.  Bipolar Disord 2008; 10:900–906
[CrossRef] | [PubMed]
 
Benazzi  F:  A tetrachoric factor analysis validation of mixed depression.  Prog Neuropsychopharmacol Biol Psychiatry 2008; 32:186–192
[CrossRef] | [PubMed]
 
References Container
Anchor for Jump
TABLE 1.Symptomatic Structure of Manic and Mixed-Manic Episodesa
Table Footer Note

aGOM=grade of membership analysis; HAM-D=Hamilton Depression Rating Scale; MRS=Mania Rating Scale; ROC=receiver operating characteristic; SADS=Schedule for Affective Disorders and Schizophrenia; SCID=Structured Clinical Interview for DSM-IV.

Table Footer Note

bBiphasic distribution.

Anchor for Jump
TABLE 2.Symptomatic Structure of Depressive and Mixed-Depressive Episodesa
Table Footer Note

aMMPI-2=Minnesota Multiphasic Personality Inventory; SCID=Structured Clinical Interview for DSM-IV.

Anchor for Jump
TABLE 3.Studies Across Depressive and Manic Statesa
Table Footer Note

aCES-D=Clinical Evaluation Scale for Depression; MINI=Mini-International Neuropsychiatric Interview; TEMPS-A=Temperament Evaluation of Memphis, Pisa, Paris, and San Diego; SCID=Structured Clinical Interview for DSM-IV; MSI=Mixed State Index; SADS=Schedule for Affective Disorders and Schizophrenia.

Anchor for Jump
TABLE 4.Proposed Research and Clinical Criteria for Mixed Statesa
Table Footer Note

aSADS=Schedule for Affective Disorders and Schizophrenia; YMRS=Young Mania Rating Scale; HAM-D=Hamilton Depression Rating Scale.

+

References

Kraepelin  E:  Manic-Depressive Illness and Paranoia . Edited by Robertson  GM;  Barclay  RBT.  Edinburgh, Scotland,  E & S Livingstone, 1921
 
Swann  AC;  Moeller  FG;  Steinberg  JL;  Schneider  L;  Barratt  ES;  Dougherty  DM:  Manic symptoms and impulsivity during bipolar depressive episodes.  Bipolar Disord 2007; 9:206–212
[CrossRef] | [PubMed]
 
Cassidy  F;  Forest  K;  Murry  E;  Carroll  BJ:  A factor analysis of the signs and symptoms of mania.  Arch Gen Psychiatry 1998; 55:27–32
[CrossRef] | [PubMed]
 
Dilsaver  SC;  Chen  YR;  Shoaib  AM;  Swann  AC:  Phenomenology of mania: evidence for distinct depressed, dysphoric, and euphoric presentations.  Am J Psychiatry 1999; 156:426–430
[PubMed]
 
Johnson  SL;  Morriss  R;  Scott  J;  Paykel  E;  Kinderman  P;  Kolamunnage-Dona  R;  Bentall  RP:  Depressive and manic symptoms are not opposite poles in bipolar disorder.  Acta Psychiatr Scand 2011; 123:206–210
[CrossRef] | [PubMed]
 
Swann  AC;  Steinberg  JL;  Lijffijt  M;  Moeller  GF:  Continuum of depressive and manic mixed states in patients with bipolar disorder: quantitative measurement and clinical features.  World Psychiatry 2009; 8:166–172
[PubMed]
 
Berner  P;  Gabriel  E;  Katschnig  H;  Keiffer  W;  Koehler  K;  Lenz  G;  Simhandl  C:  Diagnostic Criteria for Schizophrenia and Affective Psychoses (World Psychiatric Association) .  Washington, DC,  American Psychiatric Association, 1983
 
Angst  J;  Marneros  A:  Bipolarity from ancient to modern times: conception, birth and rebirth.  J Affect Disord 2001; 67:3–19
[CrossRef] | [PubMed]
 
Heinroth  JCA:  Lehrbuch der Storungen des Seelenlebens oder der Seelenstorungen und ihrer Behandlung - aus rationaler Sicht .  Leipzig,  Vogel, 1818
 
Weygandt  W:  Uber die Mischzustande des manisch-depressiven Irreseins .  Munich,  JF Lehmann, 1899
 
Schneider  K:  Klinische Psychopathologie, 5 .  Stuttgart,  Thieme, 1959
 
Janzarik  W:  Dynamische Grundkonstellationen in endogenen Psychosen .  Berlin, Gottingen, Heidelberg,  Springer, 1959
 
Berner  P;  Gabriel  E;  Katschnig  H;  Kieffer  W;  Koehlert  K;  Lenz  G;  Nutzinger  D;  Schanda  H;  Simhandl  C:  Diagnostic Criteria for the Functional Psychoses, 2nd ed .  New York,  Cambridge University Press, 1993, p 164
 
Swann  AC;  Bowden  CL;  Morris  D;  Calabrese  JR;  Petty  F;  Small  JG;  Dilsaver  SC;  Davis  JM:  Depression during mania: treatment response to lithium or divalproex.  Arch Gen Psychiatry 1997; 54:37–42
[CrossRef] | [PubMed]
 
Swann  AC;  Secunda  SK;  Katz  MM;  Koslow  SH;  Maas  JW;  Chang  S;  Robins  E:  Lithium treatment of mania: clinical characteristics, specificity of symptom change, and outcome.  Psychiatry Res 1986; 18:127–141
[CrossRef] | [PubMed]
 
Suppes  T;  Mintz  J;  McElroy  SL;  Altshuler  LL;  Kupka  RW;  Frye  MA;  Keck  PE  Jr;  Nolen  WA;  Leverich  GS;  Grunze  H;  Rush  AJ;  Post  RM:  Mixed hypomania in 908 patients with bipolar disorder evaluated prospectively in the Stanley Foundation Bipolar Treatment Network: a sex-specific phenomenon.  Arch Gen Psychiatry 2005; 62:1089–1096
[CrossRef] | [PubMed]
 
McElroy  SL;  Keck  PE  Jr;  Pope  HG  Jr;  Hudson  JI;  Faedda  GL;  Swann  AC:  Clinical and research implications of the diagnosis of dysphoric or mixed mania or hypomania.  Am J Psychiatry 1992; 149:1633–1644
[PubMed]
 
Akiskal  HS;  Benazzi  F:  Family history validation of the bipolar nature of depressive mixed states.  J Affect Disord 2003; 73:113–122
[CrossRef] | [PubMed]
 
Benazzi  F;  Akiskal  HS:  Delineating bipolar II mixed states in the Ravenna-San Diego collaborative study: the relative prevalence and diagnostic significance of hypomanic features during major depressive episodes.  J Affect Disord 2001; 67:115–122
[CrossRef] | [PubMed]
 
Zimmermann  P;  Brückl  T;  Nocon  A;  Pfister  H;  Lieb  R;  Wittchen  HU;  Holsboer  F;  Angst  J:  Heterogeneity of DSM-IV major depressive disorder as a consequence of subthreshold bipolarity.  Arch Gen Psychiatry 2009; 66:1341–1352
[CrossRef] | [PubMed]
 
Mazza  M;  Mandelli  L;  Zaninotto  L;  Nicola  MD;  Martinotti  G;  Harnic  D;  Bruschi  A;  Catalano  V;  Tedeschi  D;  Colombo  R;  Bria  P;  Serretti  A;  Janiri  L:  Factors associated with the course of symptoms in bipolar disorder during a 1-year follow-up: depression vs. sub-threshold mixed state.  Nord J Psychiatry 2011; 65:419–426
[CrossRef] | [PubMed]
 
Akiskal  HS;  Benazzi  F;  Perugi  G;  Rihmer  Z:  Agitated “unipolar” depression re-conceptualized as a depressive mixed state: implications for the antidepressant-suicide controversy.  J Affect Disord 2005; 85:245–258
[CrossRef] | [PubMed]
 
Fiedorowicz  JG;  Endicott  J;  Leon  AC;  Solomon  DA;  Keller  MB;  Coryell  WH:  Subthreshold hypomanic symptoms in progression from unipolar major depression to bipolar disorder.  Am J Psychiatry 2011; 168:40–48
[CrossRef] | [PubMed]
 
Cassidy  F;  Murry  E;  Forest  K;  Carroll  BJ:  Signs and symptoms of mania in pure and mixed episodes.  J Affect Disord 1998; 50:187–201
[CrossRef] | [PubMed]
 
Goldberg  JF;  Garno  JL;  Portera  L;  Leon  AC;  Kocsis  JH:  Qualitative differences in manic symptoms during mixed versus pure mania.  Compr Psychiatry 2000; 41:237–241
[CrossRef] | [PubMed]
 
Kotin  J;  Goodwin  FK:  Depression during mania: clinical observations and theoretical implications.  Am J Psychiatry 1972; 129:679–686
[PubMed]
 
Swann  AC;  Janicak  PL;  Calabrese  JR;  Bowden  CL;  Dilsaver  SC;  Morris  DD;  Petty  F;  Davis  JM:  Structure of mania: depressive, irritable, and psychotic clusters with different retrospectively-assessed course patterns of illness in randomized clinical trial participants.  J Affect Disord 2001; 67:123–132
[CrossRef] | [PubMed]
 
Swann  AC;  Secunda  SK;  Katz  MM;  Croughan  J;  Bowden  CL;  Koslow  SH;  Berman  N;  Stokes  PE:  Specificity of mixed affective states: clinical comparison of dysphoric mania and agitated depression.  J Affect Disord 1993; 28:81–89
[CrossRef] | [PubMed]
 
Goldberg  JF;  Perlis  RH;  Bowden  CL;  Thase  ME;  Miklowitz  DJ;  Marangell  LB;  Calabrese  JR;  Nierenberg  AA;  Sachs  GS:  Manic symptoms during depressive episodes in 1,380 patients with bipolar disorder: findings from the STEP-BD.  Am J Psychiatry 2009; 166:173–181
[CrossRef] | [PubMed]
 
González-Pinto  A;  Aldama  A;  Mosquera  F;  González Gómez  C:  Epidemiology, diagnosis and management of mixed mania.  CNS Drugs 2007; 21:611–626
[CrossRef] | [PubMed]
 
Cassidy  F:  Anxiety as a symptom of mixed mania: implications for DSM-5.  Bipolar Disord 2010; 12:437–439
[CrossRef] | [PubMed]
 
Henry  C;  M’Baïlara  K;  Poinsot  R;  Casteret  AA;  Sorbara  F;  Leboyer  M;  Vieta  E:  Evidence for two types of bipolar depression using a dimensional approach.  Psychother Psychosom 2007; 76:325–331
[CrossRef] | [PubMed]
 
Sato  T;  Bottlender  R;  Kleindienst  N;  Möller  HJ:  Irritable psychomotor elation in depressed inpatients: a factor validation of mixed depression.  J Affect Disord 2005; 84:187–196
[CrossRef] | [PubMed]
 
Bertschy  G;  Gervasoni  N;  Favre  S;  Liberek  C;  Ragama-Pardos  E;  Aubry  JM;  Gex-Fabry  M;  Dayer  A:  Frequency of dysphoria and mixed states.  Psychopathology 2008; 41:187–193
[CrossRef] | [PubMed]
 
Katz  MM;  Koslow  SH;  Berman  N;  Secunda  S;  Maas  JW;  Casper  R;  Kocsis  JH;  Stokes  PE:  A multi-vantaged approach to measurement of behavioral and affect states for clinical and psychobiological research.  Psychol Rep 1984; 55:619–671
[CrossRef] | [PubMed]
 
Koukopoulos  A;  Koukopoulos  A:  Agitated depression as a mixed state and the problem of melancholia.  Psychiatr Clin North Am 1999; 22:547–564
[CrossRef] | [PubMed]
 
Angst  J;  Gamma  A;  Benazzi  F;  Ajdacic  V;  Rössler  W:  Does psychomotor agitation in major depressive episodes indicate bipolarity? Evidence from the Zurich Study.  Eur Arch Psychiatry Clin Neurosci 2009; 259:55–63
[CrossRef] | [PubMed]
 
González-Pinto  A;  Aldama  A;  Pinto  AG;  Mosquera  F;  Pérez de Heredia  JL;  Ballesteros  J;  Gutiérrez  M:  Dimensions of mania: differences between mixed and pure episodes.  Eur Psychiatry 2004; 19:307–310
[CrossRef] | [PubMed]
 
Sato  T;  Bottlender  R;  Kleindienst  N;  Möller  HJ:  Syndromes and phenomenological subtypes underlying acute mania: a factor analytic study of 576 manic patients.  Am J Psychiatry 2002; 159:968–974
[CrossRef] | [PubMed]
 
Perugi  G;  Akiskal  HS;  Micheli  C;  Toni  C;  Madaro  D:  Clinical characterization of depressive mixed state in bipolar I patients: Pisa-San Diego collaboration.  J Affect Disord 2001; 67:105–114
[CrossRef] | [PubMed]
 
Biondi  M;  Picardi  A;  Pasquini  M;  Gaetano  P;  Pancheri  P:  Dimensional psychopathology of depression: detection of an “activation” dimension in unipolar depressed outpatients.  J Affect Disord 2005; 84:133–139
[CrossRef] | [PubMed]
 
Meyer  TD;  Hautzinger  M:  The structure of affective symptoms in a sample of young adults.  Compr Psychiatry 2003; 44:110–116
[CrossRef] | [PubMed]
 
Adler  M;  Liberg  B;  Andersson  S;  Isacsson  G;  Hetta  J:  Development and validation of the Affective Self Rating Scale for manic, depressive, and mixed affective states.  Nord J Psychiatry 2008; 62:130–135
[CrossRef] | [PubMed]
 
Perugi  G;  Toni  C;  Maremmani  I;  Tusini  G;  Ramacciotti  S;  Madia  A;  Fornaro  M;  Akiskal  HS:  The influence of affective temperaments and psychopathological traits on the definition of bipolar disorder subtypes: a study on bipolar I Italian national sample.  J Affect Disord 2012; 136:e41–e49
[CrossRef] | [PubMed]
 
Cassidy  F;  Yatham  LN;  Berk  M;  Grof  P:  Pure and mixed manic subtypes: a review of diagnostic classification and validation.  Bipolar Disord 2008; 10:131–143
[CrossRef] | [PubMed]
 
Baldessarini  RJ;  Bolzani  L;  Cruz  N;  Jones  PB;  Lai  M;  Lepri  B;  Perez  J;  Salvatore  P;  Tohen  M;  Tondo  L;  Vieta  E:  Onset-age of bipolar disorders at six international sites.  J Affect Disord 2010; 121:143–146
[CrossRef] | [PubMed]
 
González-Pinto  A;  Barbeito  S;  Alonso  M;  Alberich  S;  Haidar  MK;  Vieta  E;  Tabarés-Seisdedos  R;  Zorrilla  I;  González-Pinto  MA;  López  P:  Poor long-term prognosis in mixed bipolar patients: 10-year outcomes in the Vitoria prospective naturalistic study in Spain.  J Clin Psychiatry 2011; 72:671–676
[CrossRef] | [PubMed]
 
Moorhead  S;  Scott  J:  Clinical characteristics of familial and non-familial bipolar disorder.  Bipolar Disord 2000; 2:136–139
[CrossRef] | [PubMed]
 
Benazzi  F:  Bipolar disorder—focus on bipolar II disorder and mixed depression.  Lancet 2007; 369:935–945
[CrossRef] | [PubMed]
 
Suppes  T;  Leverich  GS;  Keck  PE;  Nolen  WA;  Denicoff  KD;  Altshuler  LL;  McElroy  SL;  Rush  AJ;  Kupka  R;  Frye  MA;  Bickel  M;  Post  RM:  The Stanley Foundation Bipolar Treatment Outcome Network. II. Demographics and illness characteristics of the first 261 patients.  J Affect Disord 2001; 67:45–59
[CrossRef] | [PubMed]
 
Hantouche  EG;  Akiskal  HS;  Azorin  JM;  Châtenet-Duchêne  L;  Lancrenon  S:  Clinical and psychometric characterization of depression in mixed mania: a report from the French National Cohort of 1090 manic patients.  J Affect Disord 2006; 96:225–232
[CrossRef] | [PubMed]
 
Perugi  G;  Akiskal  HS;  Micheli  C;  Musetti  L;  Paiano  A;  Quilici  C;  Rossi  L;  Cassano  GB:  Clinical subtypes of bipolar mixed states: validating a broader European definition in 143 cases.  J Affect Disord 1997; 43:169–180
[CrossRef] | [PubMed]
 
Post  RM;  Rubinow  DR;  Uhde  TW;  Roy-Byrne  PP;  Linnoila  M;  Rosoff  A;  Cowdry  R:  Dysphoric mania: clinical and biological correlates.  Arch Gen Psychiatry 1989; 46:353–358
[CrossRef] | [PubMed]
 
Pacchiarotti  I;  Mazzarini  L;  Kotzalidis  GD;  Valentí  M;  Nivoli  AM;  Sani  G;  Torrent  C;  Murru  A;  Sanchez-Moreno  J;  Patrizi  B;  Girardi  P;  Vieta  E;  Colom  F:  Mania and depression: mixed, not stirred.  J Affect Disord 2011; 133:105–113
[CrossRef] | [PubMed]
 
Himmelhoch  JM;  Garfinkel  ME:  Sources of lithium resistance in mixed mania.  Psychopharmacol Bull 1986; 22:613–620
[PubMed]
 
Berk  M;  Dodd  S;  Malhi  GS:  “Bipolar missed states”: the diagnosis and clinical salience of bipolar mixed states.  Aust N Z J Psychiatry 2005; 39:215–221
[PubMed]
 
Tohen  M;  Waternaux  CM;  Tsuang  MT:  Outcome in mania: a 4-year prospective follow-up of 75 patients utilizing survival analysis.  Arch Gen Psychiatry 1990; 47:1106–1111
[CrossRef] | [PubMed]
 
Baldessarini  RJ;  Salvatore  P;  Khalsa  HM;  Tohen  M:  Dissimilar morbidity following initial mania versus mixed-states in type-I bipolar disorder.  J Affect Disord 2010; 126:299–302
[CrossRef] | [PubMed]
 
Cassidy  F;  Ahearn  E;  Carroll  BJ:  A prospective study of inter-episode consistency of manic and mixed subtypes of bipolar disorder.  J Affect Disord 2001; 67:181–185
[CrossRef] | [PubMed]
 
Sato  T;  Bottlender  R;  Sievers  M;  Schröter  A;  Kleindienst  N;  Möller  HJ:  Evaluating the inter-episode stability of depressive mixed states.  J Affect Disord 2004; 81:103–113
[CrossRef] | [PubMed]
 
Marneros  A;  Röttig  S;  Wenzel  A;  Blöink  R;  Brieger  P:  Affective and schizoaffective mixed states.  Eur Arch Psychiatry Clin Neurosci 2004; 254:76–81
[CrossRef] | [PubMed]
 
Akiskal  HS;  Hantouche  EG;  Bourgeois  ML;  Azorin  JM;  Sechter  D;  Allilaire  JF;  Lancrenon  S;  Fraud  JP;  Châtenet-Duchêne  L:  Gender, temperament, and the clinical picture in dysphoric mixed mania: findings from a French national study (EPIMAN).  J Affect Disord 1998; 50:175–186
[CrossRef] | [PubMed]
 
Dilsaver  SC;  Chen  YW;  Swann  AC;  Shoaib  AM;  Tsai-Dilsaver  Y;  Krajewski  KJ:  Suicidality, panic disorder and psychosis in bipolar depression, depressive-mania and pure-mania.  Psychiatry Res 1997; 73:47–56
[CrossRef] | [PubMed]
 
Strakowski  SM;  McElroy  SL;  Keck  PE  Jr;  West  SA:  Suicidality among patients with mixed and manic bipolar disorder.  Am J Psychiatry 1996; 153:674–676
[PubMed]
 
Goldberg  JF;  Garno  JL;  Leon  AC;  Kocsis  JH;  Portera  L:  Association of recurrent suicidal ideation with nonremission from acute mixed mania.  Am J Psychiatry 1998; 155:1753–1755
[PubMed]
 
Goldberg  JF;  Garno  JL;  Portera  L;  Leon  AC;  Kocsis  JH;  Whiteside  JE:  Correlates of suicidal ideation in dysphoric mania.  J Affect Disord 1999; 56:75–81
[CrossRef] | [PubMed]
 
Balázs  J;  Benazzi  F;  Rihmer  Z;  Rihmer  A;  Akiskal  KK;  Akiskal  HS:  The close link between suicide attempts and mixed (bipolar) depression: implications for suicide prevention.  J Affect Disord 2006; 91:133–138
[CrossRef] | [PubMed]
 
Diefenbach  GJ;  Woolley  SB;  Goethe  JW:  The association between self-reported anxiety symptoms and suicidality.  J Nerv Ment Dis 2009; 197:92–97
[CrossRef] | [PubMed]
 
Koukopoulos  A;  Sani  G;  Koukopoulos  AE;  Manfredi  G;  Pacchiarotti  I;  Girardi  P:  Melancholia agitata and mixed depression.  Acta Psychiatr Scand Suppl 2007; (433):50–57
 
Garno  JL;  Goldberg  JF;  Ramirez  PM;  Ritzler  BA:  Impact of childhood abuse on the clinical course of bipolar disorder.  Br J Psychiatry 2005; 186:121–125
[CrossRef] | [PubMed]
 
Akiskal  HS:  The dark side of bipolarity: detecting bipolar depression in its pleomorphic expressions.  J Affect Disord 2005; 84:107–115
[CrossRef] | [PubMed]
 
Agosti  V;  Stewart  JW:  Hypomania with and without dysphoria: comparison of comorbidity and clinical characteristics of respondents from a national community sample.  J Affect Disord 2008; 108:177–182
[CrossRef] | [PubMed]
 
Goldstein  BI;  Levitt  AJ:  The specific burden of comorbid anxiety disorders and of substance use disorders in bipolar I disorder.  Bipolar Disord 2008; 10:67–78
[CrossRef] | [PubMed]
 
Strakowski  SM;  Tohen  M;  Stoll  AL;  Faedda  GL;  Goodwin  DC:  Comorbidity in mania at first hospitalization.  Am J Psychiatry 1992; 149:554–556
[PubMed]
 
Ostacher  MJ;  Perlis  RH;  Nierenberg  AA;  Calabrese  J;  Stange  JP;  Salloum  I;  Weiss  RD;  Sachs  GS;  STEP-BD Investigators:  Impact of substance use disorders on recovery from episodes of depression in bipolar disorder patients: prospective data from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD).  Am J Psychiatry 2010; 167:289–297
[CrossRef] | [PubMed]
 
Duffy  A;  Alda  M;  Kutcher  S;  Cavazzoni  P;  Robertson  C;  Grof  E;  Grof  P:  A prospective study of the offspring of bipolar parents responsive and nonresponsive to lithium treatment.  J Clin Psychiatry 2002; 63:1171–1178
[CrossRef] | [PubMed]
 
Krüger  S;  Trevor Young  L;  Bräunig  P:  Pharmacotherapy of bipolar mixed states.  Bipolar Disord 2005; 7:205–215
[CrossRef] | [PubMed]
 
Goldberg  JF;  Perlis  RH;  Ghaemi  SN;  Calabrese  JR;  Bowden  CL;  Wisniewski  S;  Miklowitz  DJ;  Sachs  GS;  Thase  ME:  Adjunctive antidepressant use and symptomatic recovery among bipolar depressed patients with concomitant manic symptoms: findings from the STEP-BD.  Am J Psychiatry 2007; 164:1348–1355
[CrossRef] | [PubMed]
 
Müller-Oerlinghausen  B:  Arguments for the specificity of the antisuicidal effect of lithium.  Eur Arch Psychiatry Clin Neurosci 2001; 251(Suppl 2):II72–II75
[CrossRef] | [PubMed]
 
Swann  AC;  Stokes  PE;  Secunda  SK;  Maas  JW;  Bowden  CL;  Berman  N;  Koslow  SH:  Depressive mania versus agitated depression: biogenic amine and hypothalamic-pituitary-adrenocortical function.  Biol Psychiatry 1994; 35:803–813
[CrossRef] | [PubMed]
 
Chang  KD;  Keck  PE  Jr;  Stanton  SP;  McElroy  SL;  Strakowski  SM;  Geracioti  TD  Jr:  Differences in thyroid function between bipolar manic and mixed states.  Biol Psychiatry 1998; 43:730–733
[CrossRef] | [PubMed]
 
Cassidy  F;  Ahearn  EP;  Carroll  BJ:  Thyroid function in mixed and pure manic episodes.  Bipolar Disord 2002; 4:393–397
[CrossRef] | [PubMed]
 
Kramlinger  KG;  Post  RM:  Ultra-rapid and ultradian cycling in bipolar affective illness (see comments). Br J Psychiatry 1996; 168:314–323
[CrossRef] | [PubMed]
 
Tillman  R;  Geller  B:  Definitions of rapid, ultrarapid, and ultradian cycling and of episode duration in pediatric and adult bipolar disorders: a proposal to distinguish episodes from cycles.  J Child Adolesc Psychopharmacol 2003; 13:267–271
[CrossRef] | [PubMed]
 
Bauer  M;  Beaulieu  S;  Dunner  DL;  Lafer  B;  Kupka  R:  Rapid cycling bipolar disorder—diagnostic concepts.  Bipolar Disord 2008; 10:153–162
[CrossRef] | [PubMed]
 
Benazzi  F:  Is depressive mixed state a transition between depression and hypomania? Eur Arch Psychiatry Clin Neurosci 2004; 254:69–75
[CrossRef] | [PubMed]
 
Turvey  CL;  Coryell  WH;  Solomon  DA;  Leon  AC;  Endicott  J;  Keller  MB;  Akiskal  H:  Long-term prognosis of bipolar I disorder.  Acta Psychiatr Scand 1999; 99:110–119
[CrossRef] | [PubMed]
 
Spitzer  RL;  Endicott  J:  Schedule for Affective Disorders and Schizophrenia—Change Version, 3rd edition .  New York,  New York State Psychiatric Institute, Biometrics Research, 1978.
 
Bauer  MS;  Vojta  C;  Kinosian  B;  Altshuler  L;  Glick  H:  The Internal State Scale: replication of its discriminating abilities in a multisite, public sector sample.  Bipolar Disord 2000; 2:340–346
[CrossRef] | [PubMed]
 
Henry  C;  M’Bailara  K;  Lépine  JP;  Lajnef  M;  Leboyer  M:  Defining bipolar mood states with quantitative measurement of inhibition/activation and emotional reactivity.  J Affect Disord 2010; 127:300–304
[CrossRef] | [PubMed]
 
Dilsaver  SC;  Akiskal  HS:  “Mixed hypomania” in children and adolescents: is it a pediatric bipolar phenotype with extreme diurnal variation between depression and hypomania? J Affect Disord 2009; 116:12–17
[CrossRef] | [PubMed]
 
Berkson  J:  Limitations of the application of fourfold table analysis to hospital data.  Biometrics 1946; 2:47–53
[CrossRef] | [PubMed]
 
Regeer  EJ;  Krabbendam  L;  De Graaf  R;  Have  MT;  Nolen  WA;  Van Os  J:  Berkson’s bias and the mood dimensions of bipolar disorder.  Int J Methods Psychiatr Res 2009; 18:279–286
[PubMed]
 
Feinstein  AR;  Walter  SD;  Horwitz  RI:  An analysis of Berkson’s bias in case-control studies.  J Chronic Dis 1986; 39:495–504
[CrossRef] | [PubMed]
 
Harvey  PD;  Endicott  JM;  Loebel  AD:  The factor structure of clinical symptoms in mixed and manic episodes prior to and after antipsychotic treatment.  Bipolar Disord 2008; 10:900–906
[CrossRef] | [PubMed]
 
Benazzi  F:  A tetrachoric factor analysis validation of mixed depression.  Prog Neuropsychopharmacol Biol Psychiatry 2008; 32:186–192
[CrossRef] | [PubMed]
 
References Container
+
+

CME Activity

There is currently no quiz available for this resource. Please click here to go to the CME page to find another.
Submit a Comments
Please read the other comments before you post yours. Contributors must reveal any conflict of interest.
Comments are moderated and will appear on the site at the discertion of APA editorial staff.

* = Required Field
(if multiple authors, separate names by comma)
Example: John Doe



Related Content
Articles
Books
DSM-5™ Clinical Cases > Chapter 4.  >
The American Psychiatric Publishing Textbook of Psychiatry, 5th Edition > Chapter 11.  >
Textbook of Traumatic Brain Injury, 2nd Edition > Chapter 35.  >
Textbook of Psychotherapeutic Treatments > Chapter 6.  >
Gabbard's Treatments of Psychiatric Disorders, 4th Edition > Chapter 1.  >
Topic Collections
Psychiatric News
APA Guidelines
PubMed Articles