Mixed Episodes and Rapid Cycling

Mixed Episodes and Rapid Cycling

The identification of mixed affective states is one of the most critical items related to hypomania that has only recently begun receiving attention. Mixed affective states (sometimes referred to as mixed episodes, mixed states or mixed mood episodes) are those in which depressive and/or manic/hypomanic symptoms simultaneously occur. Although described by Kraeplin in the 19th century, the presence and importance of mixed affective states had been lost over the past 40 years as our diagnostic categories have focused on polarity—the presence of pure depression and pure mania isolated from one another.

Although included in the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) text revision (TR), the understanding of mixed episodes has evolved such that many real-world symptomatic episodes that contain simultaneous elements of both depression and hypomania are excluded by the current definition. According to DSM-IV TR, mixed episodes require that full criteria for a manic episode as well as a major depressive episode be fulfilled for most days during a one-week period (see Table 8.1). Although, some patient’s symptoms may fit this criterion, such categorization is one of the least likely presentations of mixed states.

A mixed episode must also be sufficiently severe to cause marked impairment in social or occupational functioning, or necessitate a hospitalization to prevent self-harm. This definition excludes those patients regularly seen in an
outpatient practice who may have less than full manic criteria interspersed with depressive symptoms. Also, patients whose symptoms may cause some measure of impairment, but not to the required level of “marked impairment” are frequently seen. Lastly, the criteria require that the symptoms are not the direct effect of a substance, including drugs of abuse, alcohol, or other medications. Because mixed affective states frequently overlap with substance abuse, significant problems exist in distinguishing dysphoria coexisting with substance abuse from underlying mixed affective states unrelated to substance abuse. DSM-IV TR criteria appear, therefore, to be exclusionary rather than inclusionary, omitting patients with symptoms shown in Table 8.2.

TABLE 8.1 Diagnostic and Statistical Manual of Mental Disorders-IV text revision criteria for mixed episode


These criteria are met both for a manic episode and for a depressive episode (except for duration) nearly every day during at least a 1-week period


The mood disturbance is sufficiently severe to cause marked impairment in occupational functioning or in usual social activities or relationships with others, or to necessitate hospitalization to prevent harm to self or others, or there are psychotic features


The symptoms are not due to the direct physiologic effects of a substance (e.g., a drug of abuse, a medication, or other treatment) or a general medical condition (e.g., hyperthyroidism)

Note: Mixed-like episodes that are clearly caused by somatic antidepressant treatment (e.g., medication, electroconvulsive therapy, light therapy) should not count toward a diagnosis of bipolar I disorder.

Recent evidence suggests that mixed episodes occur frequently and may be far more common than formerly believed. Bauer et al. (1) in a survey of bipolar outpatients in the hypomanic state showed that 94.1% of these patients also had significant depressive symptoms, although only 17.6% met DSM-IV
TR criteria for a mixed affective state. Also, in this study, 70.1% of those in a depressive episode had clinically significant coexisting manic symptoms (108 out of 154).

TABLE 8.2 Mixtures of elevated and depressed mood states not identified by current Diagnostic and Statistical Manual of Mental Disorders criteria of a mixed episode

Episodes with subsyndromal mood symptoms that do not meet full manic or major depression criteria

Episodes lasting less than 1 week

Episodes causing limited impairment

Episodes clouded by the presence of substance abuse

Newer perspectives on mixed affective states

The exact number of symptoms necessary to qualify as a mixed affective episode in a purely phenotypic nosology system remains hotly debated (2,3,4,5). For purposes of this text, mixed affective states are more broadly defined as any episode lasting 2 or more days that includes a mixture of three or more depressed symptoms and three or more hypomanic/manic symptoms, as suggested by Benazzi (2,3). Although this debate persists, it is clear that many patients identified by this definition fall short of the current DSM-IV TR criteria for a mixed affective episode. Nonetheless, such patients present with significant distress and are seen frequently in a variety of clinical settings. This mixed affective state definition subsumes several other diagnostic labels, including dysphoric mania, agitated depression, energized depression, mixed hypomania, and dysphoric hypomania that may or may not be discrete entities.

Two particularly common clinical presentations of mixed affective states are defined as follows:

  • A person with primarily depressive complaints, who has two or more hypomanic symptoms occurring simultaneously (such as goal-directed hyperactivity, grandiosity, racing thoughts, hypersexuality, pressured speech, reduced need for sleep, or severe aggressiveness)

  • An individual with primarily elevated mood symptoms who also has interspersed two or more depressed symptoms (depressed mood, suicidal ideation, lack of interest in activities, or hypersomnia).

The definition of a mixed affective state and its clinical recognition is more than simply a theoretical interest. Patients experiencing mixed episodes tend to be chronic and difficult to treat (6). Of specific concern to clinicians is the level of suicidality in these patients with mixed affective episodes. Suicidality has been noted to be significantly higher in elevated mood patients with mixed mania when compared with nonmanic patients (54.5% vs. 2%) (7,8,9).

Characteristics of mixed affective states

Demographic elements of mixed affective states have been further elucidated, as shown in Table 8.3.

A number of sources have suggested that mixed states are more common in women than in men, particularly during the postpartum period (10,11,12,13,14). For women, also, the incidence of depressive symptoms generally increases with the severity of hypomania; there is a similar, but weaker relationship, shown in men. In women, however, it is a nonlinear response, showing that at the highest levels of hypomania the rate of mixed symptoms declines, whereas the relationship for men is linear throughout.

TABLE 8.3 Demographic elements of mixed affective states


Incidence significantly greater in women than in men


Common comorbidities of substance abuse and other psychiatric conditions


More incidence of earlier depressive episodes than manic episodes


A family history with predominantly depressive, rather than manic episodes.


Men with high incidence of irritability and agitation


High suicide risk

Adapted from Freeman MP, McElroy SL. Clinical picture and etiologic models fmixed states. Psychiatr Clin North Am. 1999;22[3]:535-546, vii; Akiskal HS, Hantouche EG, Bourgeois ML, et al. Gender, temperament, and clinical picture in dysphoric mixed mania: Findings from a French national study [EPIMAN]. J Affect Disord. 1998;50:175-186; Perugi G, Akiskal HS, Micheli C, et al. Clinical characterization of depressive mixed state in bipolar I patients. J Affect Disord. 2001;57:105-114, (10,11,12).

An important clue

A diagnostic clue to the presence of a mixed affective state may occur when a mood stabilizer is used to treat a misdiagnosed bipolar disorder without recognition of the mixed state. Patients quickly report feeling “much worse” on mood stabilizer monotherapy. In this case, the mood stabilizer (e.g., lithium, valproic acid, or carbamazepine—all of which are more effective on elevated mood symptoms than on depressed symptoms) may decrease or eliminate hypomanic elements seen clinically, leaving only the depressed elements. This can lead to the patient feeling significantly more depressed (see Figures 8.1 and 8.2). Patients with mixed states have a mixture of hypomanic and depressed symptomatology. In Figure 8.1, the hypomanic symptoms are in white and the depressive symptoms in crosshatch. Although they are of varying intensities, the symptoms coexist. Figure 8.2 represents the clinical picture after treatment with a mood stabilizer. Here the hypomanic symptoms are lessened considerably, leaving the depressive symptoms more prominent although their absolute severity may be roughly equivalent to that before mood stabilization. The patient perceives this as “increased depression” when, in fact, it is a dampening of the hypomanic symptoms, leaving a picture of predominant depression.

Subsequently, these patients often have a significant aversion to a specific medication, which in their opinion, made them feel worse. It takes some skill on the part of the clinician to convince the patient that although uncomfortable, this reaction carries useful diagnostic information, confirming a mixed affective state. In some cases, the clinician may recommend continued mood stabilizer treatment in combination with an antidepressant. In other cases, it may be more useful to utilize a medication listed in Chapter 7 (e.g.,
lamotrigine, fluoxetine/olanzapine combination or an atypical antipsychotic), which may treat both elements of the mixed state more effectively.

Figure 8.1 Mixed affective state before treatment.

Figure 8.2 Mixed affective state after mood stabilizer.

Treatment of mixed affective states

Although there is no reference literature on the nonmedication treatment of mixed affective states, education and psychotherapeutic strategies, as outlined in Chapter 6, are likely to be useful techniques.

Despite a more chronic and poorer prognosis, there are a variety of medications that have been shown to be beneficial when treating mixed affective states. The principles guiding the use of medication to treat mixed affective states are listed in Table 8.4.

Although patients with mixed affective states may present with primarily elevated mood and few depressive symptoms, they present more typically with a chief complaint of depressed mood but also have a mixture of accelerated or hypomanic traits. It has been common practice for clinicians to treat this latter group of patients with antidepressants, often because mixed affective state has been undiagnosed. Although there is limited evidence for some beneficial use of antidepressants in treating bipolar depression (15,16), there is virtually no evidence that the use of antidepressants in mixed states is beneficial. A randomized study of the use of imipramine in patients with mixed episodes found no benefit (17). The Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) Project likewise found no benefit in the use of newer antidepressants in the depressive aspect of mixed affective state (18). Additionally, there is some suggestion that antidepressants frequently appear to cause mixed episodes in bipolar patients (19). Depressive symptoms did not improve in these patients and manic symptoms worsened (18). Despite this cited evidence, antidepressants are more frequently prescribed for mixed episodes than for pure mood episodes in the hospital (20).

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Jul 29, 2016 | Posted by in GENERAL | Comments Off on Mixed Episodes and Rapid Cycling
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