Mixed states constitute a wondrously variegated universe of psychopathology. These states are characterized by the intrusion of features characteristic of depression into states of hypomania or mania and the converse. Mixed states assume a myriad of forms that as a family may be among the most commonly encountered states of affective illness.
In 1854, the French psychiatrist Falret described “transitional states” that emerged during the switch from mania to depression and depression to mania.1 He observed that during transitions from depression into mania, vestiges of depression mingled with components of mania; during transitions of mania into depression, vestiges of mania mingle with components of depression. These transitional states were veritable “mixed states,” although this terminology was not used in reference to them.
Kraepelin2 described a variety of mixed states based on the meticulous observation of patients with “manic-depressive insanity.” This great student of psychopathology subsumed any and all recurring disorders of mood under this rubric. He did not conceive a unipolar-bipolar dichotomy. A fundamental basis for viewing the universe of recurrent disorders of mood as belonging to a single family was the perception that mixed states in their manifold forms provided a unifying, inseparable link between depression and mania.
Leonhard3 introduced the unipolar-bipolar dichotomy in 1957. He observed that patients who had episodes of both depression and mania fell within the domain of manic-depressive insanity; he used the term “bipolar” to refer to these patients. He also observed patients who had recurrent episodes of depression but who did not have episodes of mania. He used the term “monopolar” to refer to these individuals.
Although DSM does not acknowledge the existence of mixed hypomania, Kraepelin viewed the pervasiveness of mixed states in their marvelously colorful forms to be incompatible with the bipolar-unipolar dichotomy. I agree and present evidence in support of this position. The literature on differing forms of mixed hypomania, techniques useful in the diagnosis of these states, and methods of treatment are reviewed in this first of a 3-part series of articles. Identifying states of mixed hypomania requires skill and can be time-consuming. However, failure to detect these states may result in the implementation of inappropriate and even harmful treatment strategies.
Origin of the contemporary focus on mixed states
Mixed states are ubiquitous, and they may well be the most common presentation of states of “manic-depressive insanity” in the sense that Kraepelin used these words—an illness that encompasses any and all recurring disorders of mood. This perspective entails the view that the term “bipolar” is misleading, given the pervasiveness of mixed states among those who are confirmed to be in the midst of a major depressive episode (MDE).
Post and colleagues4 described dysphoric mania in 1989. This, to the best of my knowledge, revived interest in the importance of mixed states. In 1992, McElroy and colleagues5 proposed operational criteria for “mixed state.” These criteria were later reflected in the recognition of “mixed episode” (mixed mania) set forth in DSM-IV.
Epidemiology and social impact of bipolar spectrum disorder
Bipolar disorders are early-onset phenomena that greatly impair function. Bipolar disorder ranked as the sixth leading cause of disability worldwide among persons aged 15 through 44 years in a 1996 World Health Organization report.6 The total direct and indirect costs of bipolar I and II disorders was estimated to be a minimum of $151 billion in the United States in 2009.7 This figure is based on the assumption that the lifetime prevalences of bipolar I and II disorders come to 2.1%.6
Merikangas and colleagues8 used the National Comorbidity Survey Replication database to estimate that 4.4% of the population have a bipolar spectrum disorder. Judd and Akiskal9 used slightly different criteria to define the scope of the bipolar spectrum. They estimated that bipolar spectrum disorders affect up to 6.4% of the population. An epidemiological study of 10 European countries determined that the prevalence of bipolar spectrum disorders is essentially identical to that reported by Judd and Akiskal.9,10 Obviously, bipolar spectrum disorders constitute a serious public health problem and create ineffable suffering and disability. The primary focus of this 3-part series of articles is on mixed phenomena.
Bipolar spectrum disorders are frequently complex, have polymorphous manifestations, and challenge the skills of even the most experienced and knowledgeable clinicians. However, successfully coping with this multifaceted disorder and the ability to recognize the many symptoms of bipolar spectrum disorders is essential for both clinical and research purposes.
Bipolar II disorder is a much more common variant of bipolarity than bipolar I disorder in epidemiological and clinical databases. In one of the first articles to call attention to this issue, Akiskal and Mallya11 reported that 50% of 200 patients with depression could be classified as having a “soft” bipolar spectrum disorder. In these patients, bipolar spectrum included bipolar I and II disorders and cyclothymia. Benazzi12 reported that in a private practice setting, 45% of 203 consecutively presenting outpatients who met the criteria for MDE had bipolar II disorder. In a subsequent analysis, 58% of consecutively presenting patients were found to have bipolar II disorder.13 The French National Epidemiology of Depression Study found that 65% of the subjects with an affective disorder had a bipolar spectrum disorder.14
Despite the scope of the bipolar spectrum, the conventional literature has predominantly focused on bipolar I disorder.
The criteria for MDE and hypomania are presented in Tables 1 and 2, respectively. Mixed or dysphoric hypomania has been described in adult samples quite recently.
TABLE 1: Criteria for major depressive episodes
Five (or more) of the following symptoms have been present during the same 2-week period and represent a change from previous functioning; at least 1 of the symptoms is either depressed mood or loss of interest or pleasure.
1. Depressed mood most of the day, nearly every day, as indicated by either subjective report (eg, feels sad or empty) or observation made by others (eg, appears tearful); in children and adolescents, can be irritable mood
2. Markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day (as indicated by either subjective account or observation made by others)
3. Significant weight loss without dieting or weight gain (eg, a change of more than 5% of body weight in a month), or a decrease or increase in appetite nearly every day; in children, consider failure to make expected weight gains
4. Insomnia or hypersomnia nearly every day
5. Psychomotor agitation or retardation nearly every day (observable by others, not merely subjective feelings of restlessness
or being slowed down)
6. Fatigue or loss of energy nearly every day
7. Feelings of worthlessness or excessive or inappropriate guilt (may be delusional) nearly every day (not merely self-reproach or guilt about being sick)
8. Diminished ability to think or concentrate, or indecisiveness, nearly every day (either by subjective account or as observed by others)
9. Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan, or a suicide attempt or a specific plan for committing suicide
Note: Do note include symptoms that are clearly due to a general medical condition, or mood-incongruent delusions or hallucinations. Adapted from American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Revised 4th ed. 2000.25
Bauer and colleagues15 tested 5 definitions of mixed hypomania and mania. Their definitions of mixed hypomania required that a patient have persistently elevated or irritable mood concurrent with the presence of depressed mood or 1 or more other depressive symptoms. As one would expect, the prevalence of dysphoric hypomania varied as a function of the definition used. It ranged from 5% to 73%.
Bauer and colleageus15 discovered that dysphoric symptoms existing in the context of hypomania-mania were continuously rather than bimodally distributed. This suggests that those features entailed in the popular concepts of hypomania and depression fall along a continuum. It also implies that hypomania as stereotypically conceived (a state characterized by elevated mood) does not differ categorically from dysphoric or mixed hypomania.
TABLE 2: Criteria for hypomania
A. A distinct period of persistently elevated, expansive or irritable mood, lasting throughout at least 4 days, that is clearly different from the usual nondepressed mood
B. During the period of mood disturbance, 3 (or more) of the following symptoms have persisted (4 if the mood is only irritable) and have been present to a significant degree
1. Inflated self-esteem or grandiosity
2. Decreased need for sleep (eg, feels rested after only 3 hours of sleep)
3. More talkative than usual or pressure to keep talking
4. Flight of ideas or subjective experience that thoughts are racing
5. Distractibility (ie, attention too easily drawn to unimportant or irrelevant external stimuli)
6. Increase in goal-directed activity (at work, at school, or sexually) or psychomotor agitation
7. Excessive involvement in pleasurable activities that have a high potential for painful consequences (eg, engaging in unrestrained buying sprees, sexual indiscretions, or foolish business investments)
C. The episode is associated with an unequivocal change in functioning that is uncharacteristic of the person when not symptomatic
D. The disturbance in mood and the change in functioning are observable by others
E. The mood disturbance is not severe enough to cause marked impairment in social or occupational functioning, or to necessitate hospitalization, and there are no psychotic features
F. The symptoms are not due to the direct physiological effects of a substance (eg, a drug of abuse, a medication or other treatment) or a general medical condition (eg, hyperthyroidism)
Note: Hypomanic-like episodes that are clearly caused by somatic antidepressant treatment (eg, medication, electroconvulsive therapy, light therapy) should not count toward a diagnosis of bipolar II disorder. Adapted from American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Revised 4th ed. 2000.25
In 2005, Akiskal and Benazzi16 published an article describing dysphoric hypomania. The definition of dysphoric hypomania they used unequivocally indicated that the topic of the contribution was mixed hypomania. The database included 320 patients with bipolar II disorder. The diagnosis of hypomania required the presence of irritable mood plus 4 Category B criteria. Thus, for all intents and purposes, the criteria paralleled the DSM-IV definition of mixed episode. Forty-five patients (14%) met the operational criteria for mixed hypomania.
Suppes and colleagues17 published a similar article using the Stanley Foundation Bipolar Treatment Network database. The 908 study participants were seen an average of 15.8 times over a span of 7 years in 4 academic centers in the United States and 3 in Europe. Patients presented in a state of hypomania during 1044 (7.3%) of 14,328 visits. Of these, 57% met the criteria for mixed hypomania.
Diagnosing mixed hypomania
The recognition and diagnosis of mixed hypomania states require patience, practice, and most importantly, genuine interest in the welfare of patients, because detecting the presence of these states often requires the dedication of more time to patient care than is generally expected to be necessary by third-party carriers and institutions for the completion of initial evaluations and the length of subsequent visits.
A useful aid in diagnosing mixed hypomania involves not only questioning and observing patients but also using simple hand gestures. A rapid up-and-down motion of the hands is used while asking questions about oscillating mood, such as “Do you experience rapid mood shift between periods of elevation or euphoria, depression, irritability and anxiousness, or some combination of these?” The rapid movement of the hands nicely conveys the idea of inexplicably, perplexingly fast changes in the mood state. Patients relate excellently to this visual mode of communication when it is used in conjunction with the question.
Patients may not understand what elevated, or euphoric, mood means, so it may be necessary to define these terms. Similarly, the meaning of “irritable” may be unclear to patients. Many patients do not regard themselves as irritable if they can refrain from expressing their easy propensity to anger. Therefore, it is critical to emphasize that although the anger may not be expressed outwardly, the emotion of simply feeling irritable is significant.
Mixed hypomania with marked ultradian cycling
Dilsaver and Akiskal18 described a form of mixed hypomania in children and adolescents between the ages of 7 and 17 years that markedly differed from a form of mixed hypomania that had been recognized previously. While large-scale studies are required to confirm this, findings suggest that it is the most common form of mixed hypomania not only in the pediatric population but in adults as well.19
The diagnosis of mixed hypomania with marked ultradian cycling can be labor-intensive. A history of the patient’s clinical status over 24-hour cycles across days—including the subjective experience—needs to be taken into account. Information from a third party can prove extremely helpful.
This variant of mixed hypomania is characterized by marked ultradian cycling between morning depression and a combination of nocturnal rising of elevated mood or euphoric mood, irritability, pressured speech, heightened level of energy, psychomotor agitation (excessive, purposeless movement), and increased goal-directed activity. The goal-directed activity may be productive or unproductive and may involve rapid shifting from one activity to another without completing anything meaningful. In addition, a marked phase delay in the onset of nocturnal sleep is normative in patients who have mixed hypomania with marked ultradian cycling.
When seen in the morning, patients with mixed hypomania with marked ultradian cycling usually appear depressed and do not manifest an admixture of concurrent depressive and hypomanic symptoms. When seen in midafternoon to late afternoon, the patients may be in the process of emerging from what is superficially a classic state of depression. When seen in the clinic in the afternoon, patients may be either inwardly or outwardly irritable. Distractibility and the emergence of restlessness (eg, constant movement of the lower extremities) and talkativeness (relative to earlier in the day) may occur. These features may be viewed as indicative of transitional states marking the passage from depression to hypomania.1
Mixed hypomania may be treated with the same regimens used to treat mixed episodes as defined in DSM-IV. Patients in states of mixed hypomania frequently experience a high global level of both psychic (eg, worry, fear) and somatic anxiety. The anxiety may be unbearable and may be a greater source of distress than depressed mood. Despite this, some patients do not spontaneously report feeling anxious. Consequently, it is prudent to ask the patient whether he or she is anxious; if the answer is yes, try to gauge the degree to which anxiety interferes with function due to impairment of attention, concentration, and memory.
Panic attacks are frequently comorbid with high levels of anxiety. Determining whether a patient meets the criteria for panic disorder is not necessary for making treatment decisions. Comorbid anxiety can minimize responsiveness to mood-stabilizing agents.20-22 Comorbid anxiety disorders and anxiety are frequently not treated aggressively, and ineffective treatment of symptoms is associated with poor long-term outcomes as indicated by measures of quality of life, suicide attempts, and completed suicide.22-24
Although there is no clear evidence that antipanic effects are limited to specific benzodiazepines, these agents are generally highly effective when used to reduce a patient’s acute anxiety. In my experience, clonazepam, alprazolam, or extended-release alprazolam can be beneficial during panic attacks. The benzodiazepine should be administered on a scheduled basis, especially if a patient has panic attacks, because once a panic attack starts, a dose of a benzodiazepine, even one with antipanic properties, will not abort the attack.
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