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Activity Chair
Michael H. Allen, MD
Director of Inpatient Psychiatry
Colorado Psychiatric Health
Professor of Psychiatry
University of Colorado School of
  Medicine

Estimated time to complete activity: 0.5 hours

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Supported by an educational grant from
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Release Date: May 18, 2011
Expiration Date: May 17, 2012

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Target Audience
This activity has been designed to meet the educational needs of psychiatrists and other mental health care providers involved in the management of patients with bipolar disorder.

Program Overview
Patients with bipolar disorder often present with concomitant depressive and manic symptoms. These mixed states represent some of the most complex clinical challenges in terms of both diagnosis and treatment. It is important that clinicians recognize when a symptomatic episode includes more than pure mania, hypomania, or depression and whether the episode is predominantly depressive or manic. Bipolar mixed states are associated with greater severity of illness as well as treatment resistance. Effective management depends on identification and assessment of symptoms associated with both poles and may require specific adjustments in pharmacotherapy.

Learning Objectives
After participating in this activity, participants should be better able to:
  • Recognize mixed symptoms in patients with bipolar disorder
  • Describe the impact of mixed symptoms on the course of bipolar illness
  • Develop effective treatment strategies for patients with bipolar mixed states

Accreditation Statement
SciMed is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

Credit Designation
SciMed designates this educational activity for a maximum of 0.5 AMA PRA Category 1 CreditsTM. Physicians should only claim credit commensurate with the extent of their participation in the activity.

Disclosure and Resolution of Conflicts of Interest
SciMed requires all individuals who are involved in the development or delivery of content in any of its activities to disclose financial relationships they may have with commercial interests. Should SciMed determine that any of the disclosed relationships constitutes a conflict of interest, as defined by the ACCME, SciMed will act to resolve such a conflict. When asked to report relevant financial relationships with commercial interests, the faculty reported the following:

Michael H. Allen, MD Grants/research support: Ortho-McNeil-Janssen Rater training: United BioSource Corporation, i3 Research

Shari Fallet, DO, an employee of SciMed and a member of the planning committee for this activity, reports owning stock in Pfizer Inc.

All other SciMed personnel involved in the development of content for this activity have no relevant financial relationships to report. The materials for this activity were peer reviewed by Robert M. Post, MD, and Joseph McEvoy, MD. Drs. Post and McEvoy disclosed the following financial relationships with commercial interests:

Robert M. Post, MD
Consultant: AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, PureTech Ventures Speakers bureau:  AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline. Honorarium: Janssen-Cilag

Joseph McEvoy, MD
Consultant: Roche, Sunovion Speakers bureau: Eli Lilly and Company, Sunovion, Merck & Co, Inc

Off-Label Product Discussion
The faculty have indicated that this activity includes no off-label discussions.

Credit Requirements

There are no fees for participating in and receiving CME credit for this activity. To obtain CME credit for participating in this activity between the period May 18, 2011, through May 17, 2012, participants must:

  • Read the learning objectives and disclosure statements
  • Study the entire educational activity
  • Complete the posttest by recording the best answer to each question
  • Complete the activity evaluation, which includes a request-for-credit section
  • Mail or fax the evaluation form with answer key to SciMed per the instructions on the form

Participants will be mailed a certificate or statement of credit within 4 to 6 weeks.


Disclaimer

The opinions or views expressed in this CME activity are those of the presenters and do not necessarily reflect the opinions or recommendations of SciMed, LLC or Bristol-Myers Squibb and Otsuka America Pharmaceuticals Inc. Participants should critically appraise the information presented and are encouraged to consult appropriate resources for information surrounding any product, device, or procedure mentioned.

Introduction

In the book Manic-Depressive Insanity, published in English in 1921, Dr. Emil Kraepelin described 6 variants of mixed states in patients with bipolar disorder: depression with flight of ideas, excited depression, depressive-anxious mania, inhibited mania, unproductive mania, and manic stupor. Dr. Kraepelin’s description of manic depression is more inclusive than the modern definition of bipolar disorder found in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV).1

The DSM-IV defines a mixed episode as a period of at least 1 week in which the criteria for both a major depressive episode (MDE) and a manic episode are met nearly every day. During a mixed episode, an individual experiences rapidly alternating periods of sadness and irritability and of euphoria accompanied by symptoms of a manic episode. The symptom presentation frequently includes agitation, insomnia, appetite dysregulation, psychotic features, and suicidal thinking. The mood disturbance causes severe impairment in occupational functioning, usual social activities, or relationships with others; requires hospitalization; and is accompanied by psychotic features. In addition, the symptoms are not caused by drug use or a medical condition.1 According to these strict diagnostic criteria, relatively few people with bipolar disorder ever experience a mixed episode.


Classification Dilemmas

Ongoing debate exists about what constitutes a mixed state and whether the restrictive criteria set forth in the DSM-IV should be expanded. Some argue that the use of rigid and narrow criteria may lead to under-recognition or misdiagnosis of patients with mixed affective states.2

The definition of mixed states according to the DSM-IV restricts the concept to patients with mania and full syndromal depression. However, research has shown that mania with few depressive symptoms comprises the most prevalent clinical presentation of mixed or dysphoric mania. The converse situation—patients with major depression and a few concomitant manic symptoms—was described by the Pisa-San Diego collaborative study. The most common features of the depressive mixed state were agitation, psychotic depression with irritable mood, pressured speech, and/or flight of ideas.3

It is not clear how many symptoms of depression and mania should represent the minimum threshold for mixed states; various criteria have been used in research studies. According to one of the most validated definitions, the diagnosis of depressive mixed state requires the presence of ≥3 hypomanic symptoms during an MDE.4 In a study of 377 outpatients with a psychoactive drug-free MDE, 58% of patients previously diagnosed with bipolar II disorder and 23% of patients previously diagnosed with unipolar depression met criteria for depressive mixed state, which was defined as an MDE plus ≥3 intra-episodic hypomanic symptoms (DMX3). Patients with unipolar DMX3 had significantly more family history of bipolar II disorder compared with patients with unipolar nondepressive mixed state, a clinical characteristic that distinguishes bipolar disorder from strictly defined unipolar disorders. The authors suggest that DMX3 should be included in the bipolar spectrum.5

Other studies have demonstrated that a threshold of 2 depressive symptoms is enough to confirm "mixity." Data from the French national multisite collaborative study on the clinical epidemiology of mania, EPIMAN-II Thousand (EPIMAN-II MILLE), showed that out of 3 patients who present with mania, 1 has mixed symptoms as defined by at least 2 depressive symptoms.6 Furthermore, the existence of "excited depression" and "depression with flight of ideas" subtypes has been documented. The clinical features of "excited depression" include psychomotor agitation, talkativeness, irritable mood, and distractibility, whereas "depression with flight of ideas" manifests as racing/crowded thoughts and risky pleasurable impulses, including intense sexual arousal.7

There is controversy about how patients with agitated depression should be classified—as unipolar or bipolar—and whether agitated depression represents a mixed state. In a study of 254 outpatients diagnosed with unipolar major depressive disorder (MDD), 20% had agitated depression, which was defined as an MDE with a Hypomania Interview Guide (HIGH-C) psychomotor agitation score ≥2. Patients with agitated depression had fewer recurrences, less chronicity, and a higher rate of family history of bipolar disorder compared with nonagitated patients. There was a strong association between agitated depression and depressive mixed state, which was defined as ≥3 intra-MDE hypomanic symptoms, identified using the Structured Clinical Interview for DSM-IV (SCID-CV) and the HIGH-C. The hypomanic symptoms were, in decreasing order of frequency, distractibility, racing/crowded thoughts, irritable mood, talkativeness, and risky behavior.8 Note that elevated mood, or euphoria, is not prominent in these descriptions of mixed states.


Prevalence of Mixed States

Mixed states, in which manic and depressive symptoms occur simultaneously, are common in patients with bipolar disorder.2 Studies have shown that approximately 40% of patients with bipolar disorder experience a mixed state at some point during their lifetime.9 The spectrum of clinical presentations comprising "mixity" ranges from the occurrence of depressive features within mania to the occurrence of manic features within depression.

The presence of depressive symptoms during an acute manic episode has been termed mixed mania, dysphoric mania, depressive mania, or mixed bipolar disorder.10 Studies have reported various prevalence rates of dysphoric mania among acutely manic patients with bipolar disorder ranging from 5% to 70%, depending on the criteria used to define the condition. The overall mean prevalence of dysphoric mania has been reported as 31%.11 Data from the French national multisite collaborative study on the clinical epidemiology of mania (EPIMAN) indicate that dysphoric mania exists along a spectrum of mixity. Only 7% of 104 manic inpatients met DSM-IV criteria for mania with full syndromal depression (≥5 depressive symptoms), whereas 37% of the patients fulfilled a broader definition of dysphoric mania (presence of ≥2 depressive symptoms).12

Depressive symptoms are also common in patients with symptoms of hypomania. A naturalistic prospective study performed at several research sites in the United States and Europe found that 57% of patients with hypomanic symptoms met criteria for mixed hypomania, defined as a Young Mania Rating Scale score ≥12 and an Inventory of Depressive Symptomatology–Clinician Rated Version score ≥15. The likelihood of depression during hypomania was significantly greater for women.13

Data from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEPBD) indicate that two-thirds of participants with bipolar depressed episodes had concomitant manic symptoms, most often distractibility, flight of ideas or racing thoughts, and psychomotor agitation.14

Figure1

Depressive mixed states, which manifest as MDEs with a few co-occurring hypomanic symptoms, are frequently seen in clinical practice, but these subthreshold mixed states are not included in the DSM-IV system. Only 15% of patients in the STEP-BD study who presented with syndromal depression met DSM-IV criteria for mixed episodes. However, slightly more than half of patients with syndromal depression had concomitant subsyndromal features of mania.

Figure2


Manic symptoms were present in 30% of patients with bipolar I disorder and in 71% of patients with bipolar II disorder who were experiencing a depressive episode. In addition, the data indicate that full depressive episodes are more likely to involve concomitant manic symptoms among men than women.14


Clinical Consequences of Mixity

The course and prognosis of mixed mania are worse than that of pure mania, with higher recurrence rates, higher frequency of comorbid substance abuse, greater risk of suicidal ideation and attempts, increased depression during follow-up, greater risk of rapid cycling course, and higher prevalence of physical comorbidities, particularly thyroid dysfunction.10 Compared with patients presenting with pure bipolar major depression, patients with depressive mixed states have fewer episodes, but their episodes are of a longer duration, they have less interepisodic remission, and they tend to begin with a mixed episode more often.3 Patients with bipolar disorder who present with a first-episode mixed state are more likely to experience mixed, depressive, and dysthymic morbidity during follow-up, and they have a worse overall prognosis than patients with first-episode pure mania.15

A prospective observational study demonstrated that measures of quality of life, mental health, and physical health are significantly worse for individuals with bipolar I disorder who present with mixed states. The presence of subthreshold symptoms of opposite polarity was associated with poorer clinical outcomes over a 2-year period. Patients with depressive mixed states were at higher risk of manic symptomatology during the follow-up period compared with patients with pure depression.16

Mixed states have also been implicated in the variability of treatment responses seen in patients with bipolar disorder. In 1 study of 179 patients hospitalized for acute mania, depressive symptoms were associated with poor antimanic response to lithium and with better response to divalproex, independent of differences in overall severity of illness, substance abuse, gender, age, or history.17

Clinical Features

Patients with mixed symptoms are more likely to have an earlier age at illness onset, rapid cycling, bipolar I subtype, history of suicide attempts, and more days with irritability or mood elevation.14 Patients with depressive mixed states—dysphoric mania or depression during hypomania—are more often female.12,13 Depressive episodes with concomitant manic symptoms are more likely to occur in men with bipolar disorder than in women with bipolar disorder.14 Patients with mixed states have family histories of bipolar disorder more often than patients with bipolar disorder who do not experience mixed states.7

Data from the EPIMAN study indicate that subthreshold depressive admixtures with mania represent the more common presentation of dysphoric mania. In addition, a female preponderance was noted in the dysphoric mania group, as were fewer typical manic symptoms such as elation, grandiosity, and excessive involvement. Irritability was common and there was a higher prevalence of psychotic features in the patients with dysphoric mania.12

Patients with agitated depression have a significantly higher rate of suicidal ideation compared with nonagitated patients. The increased rate of suicidality raises concern about an unrecognized bipolar mixed state in patients identified as "unipolar" and about the possible role of antidepressants used in the treatment of those patients. In light of the activated symptoms, namely the risk-taking behaviors noted in these patients, researchers have suggested that a preferred term would be "excited (mixed) depression" rather than "agitated depression" and that those patients may be regarded as "pseudo-unipolar."18

Recent concern about suicidality in patients receiving antidepressants prompted a study in which 644 outpatients with major depressive symptoms (58% had bipolar II disorder) were interviewed using the SCID-CV. Suicidal ideation, which was present in almost half of the patients, favored patients with bipolar II disorder compared with MDD and was significantly associated with depressive mixed states.18 The high prevalence of depressive mixed states in patients with bipolar II disorder,7 which is characterized by mental and motor activation, may have contributed to the high prevalence of transition from suicidal ideation to suicidal action observed in these patients.19,20

Patients experiencing mixed states have high rates of comorbidity with anxiety, personality disorders, and substance abuse.21 Manic symptoms during depression are also associated with greater impulsivity.22

Figure3

Dysphoria is strongly associated with mixed states in patients with mood disorders. In 1 study, which defined dysphoria as the presence of 3 of the following: inner tension, irritability, aggressive behavior, or hostility, the frequency of dysphoria was 17.5% in patients with pure depression, 22.7% in patients with pure mania, and 73.3% in patients experiencing a full mixed state as defined by the DSM-IV. Additionally, the frequency of dysphoria increased from 17.5% to 61.1% when the number of manic symptoms in patients with depression increased from 0 to 1, and the frequency of dysphoria increased from 14.3% to 69.2% when the number of depressive symptoms in patients with mania increased from 2 to 3.23

Treatment of Mixed States

Mixed episodes are more difficult to treat than episodes of depression or mania alone.2 Indeed, mixed states represent some of the most challenging situations encountered in the management of patients with bipolar illness. Effective treatment of mixed states depends on identifying both states, starting treatment for both states early, and considering maintenance treatment and long-term outcome in addition to acute management.10

Mixed symptoms may delay diagnosis of bipolar disorder, because the predominant complaint is often depression or dysphoric mood, and key manic features (eg, increased motor drive, reduced sleep, and crowded or racing thoughts) may be overlooked.21 An important issue to consider is whether a patient presenting with apparent mixed symptoms suffers from an agitated depression or a mixed manic episode, as these 2 conditions can have similar clinical presentations.2 It is important to assess all of a patient’s symptoms at every visit rather than the more common practice of only gathering information concerning the dominant state initially presented by the patient.14 A semistructured interview is useful to identify depressive symptoms that might support a diagnosis of dysphoric mania. These symptoms include depressed mood, irritability, mood lability, anhedonia, hopelessness or helplessness, suicidal ideation and/or attempt, guilt, fatigue, agitation, insomnia, and weight changes.9

The goals of treatment in patients with bipolar illness include resolution of acute symptoms and the establishment of mood stability. In contrast to the extensive literature on the frequent occurrence of depressive symptoms in manic patients, there is little information about manic symptoms in bipolar depression. Only dysphoric (mixed) mania has been reasonably addressed in clinical trials; little is known about the treatment of other mixed states due to their pleomorphism and nosologic confusion. Although there are no controlled studies designed to exclusively evaluate the treatment of mixed mania, subanalyses of randomized clinical trials in mania treatment provide some data regarding treatment efficacy.10

The presence of depressive symptoms during manic episodes is associated with poor response to psychopharmacologic treatments. This is an important consideration, because although overall efficacy in acute mania has been shown to be similar for lithium and divalproex,24 these agents may be most effective in clinically and biologically distinct groups of patients. Evidence indicates that mixed mania may be more responsive to anticonvulsants than to lithium.25,26 Mixed states predict a relatively poor response to lithium; divalproex has been found to be more effective,17 and carbamazepine has also shown efficacy in the treatment of mixed mania.27 Divalproex, and to a lesser extent carbamazepine, may be used either as monotherapy or as an adjunct to lithium.26 However, none of the classic "mood stabilizers" have shown significant efficacy for bipolar depression in adequate and well-controlled trials (ie, they are more effective for mania than depression).

The role of antidepressants is controversial even in patients with pure bipolar depression. Evidence of their value in bipolar depression is limited, while there is evidence that at least some antidepressants are associated with higher rates of switching to mania.28 Evidence from STEP-BD29 also suggests that antidepressants are associated with more cycling over time even after controlling for other contributors to cycling. In a retrospective study of depressed patients treated with antidepressants alone, those who were only later diagnosed with bipolar disorder experienced more treatment-emergent mixed symptoms than a comparison group with stable diagnoses of unipolar depression.30 This difference in the response of bipolar depression to antidepressants is one of the key reasons to identify mixed states. Opinions may differ as to the value of antidepressants in pure bipolar depression, but initiation of antidepressant treatment is certainly not recommended in patients with mixed states because it may worsen some symptoms. Consensus favors discontinuing antidepressants if mixed mania emerges during treatment with antidepressants.10,28

At one time, this left few alternatives. However, a number of atypical antipsychotics may be effective and safe either as monotherapy or in combination with lithium or valproate, both in the acute phase and for relapse prevention.31 Aripiprazole, asenapine, olanzapine, quetiapine XR, and risperidone have received approval from the US Food and Drug Administration for the treatment of acute mixed episodes in patients with bipolar disorder, both as monotherapy and as an adjunct to lithium or valproate32-36; ziprasidone is indicated only as monotherapy for the acute treatment of bipolar mixed episodes.37

Combination therapy may be required in patients with mixed states,25 particularly those with severe symptoms in whom valproate or lithium plus an atypical antipsychotic may be effective. High doses of medications are frequently necessary, and time to remission is longer than in pure affective episodes. In addition, patients with mixed manic episodes have more adverse events associated with pharmacologic treatment.10

Taken together, the literature suggests the value of identifying patients with mixed states, both because the burden associated with mixed symptoms is worse and because the treatment is more complex. Regular assessment of symptoms associated with both poles is recommended in routine practice, and any mixture of depressive and manic symptoms should be considered in understanding a patient’s course and response to treatment.

CME test

References:

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