Indications for Mood Stabilizers
Bipolar Disorder
Bipolar disorder (BPD) (formerly manic/depressive illness) represents one of the most dramatic presentations in all of medicine and simultaneously poses one of the more difficult therapeutic challenges. Its core characteristic is mood instability characterized by mania or hypomania, alternating irregularly or intermingling with episodes of depression.Severity of either mania or depression can also fluctuate. A small group may only experience recurrent manic episodes (i.e., unipolar mania) (1). Although there are few known risk factors, a family history of psychotic disorders and advancing paternal age (especially for early-onset BPD) appear to increase susceptibility (2,3).
The estimated risk of developing BPD is 0.5% to 1%, and the incidence of new cases per year is in the range of 0.01% for men and 0.01% to 0.03% for women (4). The lifetime prevalence is estimated at 1.2% to 1.6% in the United States. Bipolar spectrum is conceived of as a continuum from more to less severe clinical presentations, including
Bipolar I
Bipolar II
Cyclothymic disorder
BPDs not otherwise specified (e.g., subsyndromal or subclinical mood disorders)
Data from the National Comorbidity Survey indicate that the prevalence of bipolar spectrum disorder is 2.4% for lifetime and 1.4% over 12 months (5).
Onset usually occurs by the third decade of life, but can develop later (6). Data indicate that BPD is more prevalent in adolescents and children than previously believed (7,8). In this age group, episode duration is often longer; symptoms may be more chronic; and the illness may be difficult to distinguish from schizophrenia because psychosis often complicates early-onset BPD (7,8,9 and 10). This is supported by reports from the National Institute of Mental Health (NIMH)-sponsored Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) Study indicating that very early or early-onset BPD predicts a more chronic course and greater rates of comorbidity (e.g., anxiety disorders and substance abuse). In addition, very early or early-onset BPD may be associated with (11,12)
More recurrences
Shorter periods of euthymia
Greater likelihood of suicide attempts and violence
Further, the STEP-BD study found that onset of mood symptoms before the age of 13 predicted an earlier recurrence of mood episodes after initial remission, fewer days euthymic and more impairment in functioning and quality of life compared with onset of symptoms after the age of 18. (13) Those with onset between the ages of 13 and 18 followed an intermediate course (see Chapter 10 for more details of the STEP-BD Study).
Because BPD consists of manic and depressive episodes, as well as an intermingling of these mood states, it presents an organizational problem for any text. This problem occurs partly because the depressive phase is clinically similar to major depressive disorder (MDD) and partly because discussion of its treatment is more complicated. Further, bipolar patients often first present with one or more depressive episodes
before experiencing a manic or mixed episode. Thus, initial depressive episodes in a young adult do not necessarily dictate the diagnosis of MDD, especially in those with a family history of mood disorders. We emphasize that the management of BPD requires a different approach than that of MDD. Its successful treatment, including the prevention of either phase, is best accomplished with mood stabilizers.
before experiencing a manic or mixed episode. Thus, initial depressive episodes in a young adult do not necessarily dictate the diagnosis of MDD, especially in those with a family history of mood disorders. We emphasize that the management of BPD requires a different approach than that of MDD. Its successful treatment, including the prevention of either phase, is best accomplished with mood stabilizers.
Understanding the interplay between the manic and depressive phases is integral to understanding BPD. Thus, depression may
Precede an episode of hypomania or mania
Intermingle with hypomanic or manic symptoms during an acute exacerbation (e.g., mixed episodes)
Succeed a hypomanic or manic phase
Occur as distinct episodes, which can vary in severity, in an intermittent and irregularly alternating pattern with hypomanic or manic episodes
Exist in a more chronic subsyndromal form
Bipolar patients will experience the majority of their illness as depressive symptoms. Thus, while mania or hypomania are the defining characteristics of this condition, depression and its associated higher risk of suicide must be recognized and adequately addressed (14). In addition, subsyndromal manic symptoms frequently occur in the context of bipolar depression. For example, the STEP-BD Study reported that two thirds of 1,380 bipolar I or II patients in a depressed phase also demonstrated manic symptoms (most often distractability flight of ideas, racing thoughts, and psychomotor agitation) and these episodes were more severe compared to pure depressive syndromes (15). These issues are further complicated by the longstanding focus on treating the manic phase, with less information available regarding treatment of depressive symptoms in the context of BPD.
These circumstances have important implications for management because drug treatment of the depressive phase may precipitate mood elevation, accelerate the frequency of cycles, induce rapid cycling (i.e., ≥4 cycles in 12 months), or produce a more virulent course of the illness. In terms of antidepressant-induced mood elevations, this most often occurs in bipolar I disorder (hypomania and mania occurring at similar rates) (16). The incidence is intermediate with bipolar II disorder and least often with MDD. In the latter two, mood elevations are almost exclusively hypomania. The STEP-BD study also considered selfreported history of switching from depression to mania or hypomania in 338 bipolar patients on antidepressants (17). In this cohort, 44% reported at least one occurrence. Short illness duration, multiple past antidepressant trials, and a past history of switching with at least one antidepressant appeared to increase the risk.
Therefore, if BPD is known or suspected, patients are best managed acutely, as well as for maintenance/prophylaxis, with a mood stabilizer. Although antidepressants are often added to the primary mood stabilizer, the evidence for their benefit is unclear (18,19).
Another important consideration is the high comorbidity associated with BPD, including
Anxiety disorders
Substance abuse or dependence
Attention-deficit hyperactivity disorder (ADHD)
Conduct or oppositional defiant disorders
Further, symptoms associated with substance use disorders (e.g., cocaine abuse) often overlap with manic, hypomanic, or depressive features; mimic these features; exacerbate them; and/or attenuate response to therapeutic interventions. This may lead to overdiagnosis of BPD in patients with drug-induced mood instability (20). As another example, Wilens et al. found that the majority of adults with ADHD also suffer from BPD (usually type II) (21). Further, they manifest the typical symptoms of each condition, which suggests a higher comorbidity and increased difficulty in distinguishing each condition clinically. Lifetime comorbid anxiety disorders were present in over 50% of the first 500 bipolar patients enrolled in the STEP-BD study (22). Further, there was an independent association of comorbid anxiety with severity of illness and level of impairment. Such comorbidities, coupled with the common misdiagnosis of BPD (usually as MDD), explain why accurate assessment and appropriate treatment intervention is often delayed for several years (23).
Because bipolar patients are often misdiagnosed with MDD, they should be carefully evaluated for symptoms of mania, hypomania, or a positive family history. The Mood Disorder Questionnaire (MDQ) is a screening tool that aids appropriate diagnosis (24). The MDQ consists of 13 questions that require a yes/no
response, 1 question regarding co-occurrence of symptoms, and 1 regarding severity of functional impairment. A positive MDQ requires
response, 1 question regarding co-occurrence of symptoms, and 1 regarding severity of functional impairment. A positive MDQ requires
The presence of at least seven symptoms
The co-occurrence of two or more symptoms during the same period
Moderate or severe impairment in work, family, monetary, or legal areas
Although a positive screen does not confirm the diagnosis, it should prompt a full evaluation for possible BPD.
BIPOLAR MANIA
The essential feature of mania is a distinct period of an elevated, expansive, or irritable mood accompanied by several other symptoms (25). Mania is not synonymous with euphoria or elation but is a syndrome that can occur in a wide variety of disorders and involves disruption in mood, behavior, and thinking. Other clinical manifestations include
Hyperactivity
Pressure of speech
Flight of ideas
Inflated self-esteem
Decreased need for sleep
Distractibility
Excessive involvement in activities that have a high potential for painful consequences
The estimated average length of an untreated acute episode is 4 to 13 months, with a range from as brief as 1 day to as long as several years (26).
Hypomania is a less severe form of its manic counterpart, typically without many of the consequences experienced during an acute, full episode. Subtle indicators of hypomania may include
Increased productivity
Heightened perceptions
Altered view of spouse, friends, others
Some have postulated a continuum from mild cognitive, perceptual and behavioral disorganization to more severe presentations, ranging from hypomania to acute mania to manic delirium, rarely culminating in a chronic manic state. Carlson and Goodwin (27) described the various stages of mania using this model and presented important differential diagnostic considerations at each stage (Table 9-1). This model helps to characterize the severity of an episode as well as to guide the level of treatment intervention.
TABLE 9-1 STAGES OF MANIA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Primary Symptoms of Mania
The elevated mood may be initially experienced as feeling unusually good, happy, or cheerful and later as euphoric or elated. It often has an expansive quality, characterized by indiscriminate involvement with people and the environment. In this early period, manic patients can be playful and unaware of their changing mood, but these symptoms are often recognized as excessive by those who know them well. In more severe episodes, thinking may develop into delusional notions about one’s own power and selfimportance.
Although an elevated mood is the prototypical symptom, the predominant disturbance may be irritability, which is most evident when the individual’s goal-directed behavior is thwarted.Indeed, the clinical picture can change suddenly, with the euphoric mood quickly replaced by irritability and anger. Because these patients are acutely sensitive to criticism, they often become contentious and easily upset, even by seemingly harmless remarks. Verbal abuse is common, with physical violence occurring less commonly.
Goodwin and Jamison (26) summarized the incidence of typical mood symptoms during a manic phase from 14 studies (n = 751 patients) as follows:
Irritability (80%)
Depression (72%)
Euphoria (71%)
Lability (69%)
Expansiveness (60%)
We note that depressive symptoms occurred in about 70% of these patients, again underscoring the common presence of depression and the interplay between the two mood states in BPD.
Psychomotor acceleration often accompanies the mood disturbance and is manifested by increased sociability, including efforts to renew old acquaintances, quick changes from one activity to another, and/or inappropriate increase in sexual activity. Because of inflated self-esteem, unwarranted optimism, and poor judgment patients may engage in buying sprees, reckless driving, or foolish business investments. Such behavior may have a disorganized, flamboyant, or even bizarre quality (e.g., wearing brightly colored or strange garments or excessive, distasteful makeup). Many patients, however, demonstrate a marked tendency to neglect themselves.
Speech can be loud, rapid, and often difficult to interrupt. It is often punctuated by jokes, puns, word play, rhymes, and witty, risqué, or droll irrelevancies. Euphoria often leads to speaking with a theatrical or dramatic flair.As the activity level increases, associations may loosen and speech can become totally incoherent, virtually indistinguishable from an acute schizophrenic exacerbation. When mood is predominantly irritable, verbalizations may present as complaints, hostile comments, and angry tirades.
Goodwin and Jamison (26) calculated the incidence of behavioral symptoms per episode and found the following:
Rapid speech (98%)
Overtalkativeness (89%)
Hyperactivity (87%)
Reduced sleep (81%)
Hypersexuality (57%)
Overspending (55%)
Patients are usually brought for evaluation and treatment when their behaviors create the potential for more severe consequences (e.g., selfinjurious behavior, atypical sexual behavior, and significant financial indiscretions).
Associated Symptoms of Mania
Flight of ideas is an almost continuous flow of accelerated speech with abrupt changes from one topic to another, at times so pronounced that they become incomprehensible. These ideas are usually based on understandable associations, distracting stimuli, or plays on words.
Distractibility is common and characterized by rapid changes in speech or activity resulting from a tendency to respond to irrelevant external stimuli, such as background noises or objects.
Inflated self-esteem may range from uncritical self-confidence to marked grandiosity, often reaching delusional proportions. Patients may give advice on matters for which they are untrained or about which they have no special knowledge. Despite having average talents, they may unrealistically boast of extraordinary abilities (e.g., that they can compose music, write poetry, publish books, or design new inventions).
Lability of affect is characterized by rapid shifts from euphoria to anger or depression. Depressive symptoms (e.g., tearfulness, suicidal threats, and insomnia) may last moments, hours, or, more rarely, days, occasionally intermingled with or rapidly alternating with mania (e.g., mixed episode or dysphoric mania).
Disrupted sleep is often an early prodromal symptom and may have a bidirectional relationship with daytime affective regulation (28,29). It is often characterized by early awakening (sometimes by several hours), a significant reduction in total sleep time, and, when severe, consecutive sleepless days with no apparent fatigue. Hypersomnia may also occur. Results from the STEP-BD study indicate that compared with a normal sleep duration, short sleep duration was associated with a more severe symptom presentation, while both short and long sleep duration were associated with poorer functioning and quality of life (30).
Psychotic symptoms, such as delusions and hallucinations, may be present in more severe episodes in both manic and depressed phases and are often (but not always) mood congruent. The delusions seen in mania often have a religious, sexual, or persecutory theme. Grandiose delusions can lead to convictions about a special relationship with God or some well-known figure from the political, religious, or entertainment world. Persecutory delusions may incorporate the idea that the individual is singled out because of some special relationship or attribute (31). Hallucinations may be auditory or visual (e.g., seeing or hearing God)
and are usually consistent with the patient’s mood (27).
and are usually consistent with the patient’s mood (27).
Secondary effects of BPD can include
Frequent job changes, moves, marriages, and divorces
Bankruptcy
Hypersexuality
Altered self-concept (e.g., grandiosity and low self-esteem)
Criteria for an Acute Manic Episode
In the United States, the Research Diagnostic Criteria (RDC; 32) and the Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision (DSM-IV-TR; 33) both provide clear inclusion and exclusion criteria for a current episode (Table 9-2). Evaluation of past episodes is accomplished with the Schedule for Affective Disorders and Schizophrenia— Lifetime Version (SADS-L; 34) or the Structured Clinical Interview for DSM (35). In other countries, use of the Present State Exam (PSE; 36) also reliably distinguishes mania from other disorders. Table 9-3 reviews the various types of primary BPD as categorized by Klerman (37) and their related DSM-IV-TR diagnoses.
TABLE 9-2 COMPARISON OF DSM-IV-TR AND RDC CRITERIA FOR MANIA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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TABLE 9-3 PRIMARY BIPOLAR DISORDERS | |||||||||||||||||||||||||||
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BIPOLAR DEPRESSION
Results from the NIMH Collaborative Depression Study indicate that depression is the most common mood problem in bipolar I disorder. Further, bipolar II patients spend about half of their time depressed (vs. only 1.3% of their time hypomanic) (14,38). In this context, episodes characterized by mood lability, changes in energy and activity levels, and daydreaming are often predictive of eventually meeting the criteria for bipolar II disorder (39). In summary, depression is the most frequently experienced mood symptom in bipolar patients, produces greater functional impairment (even with subsyndromal depressive symptoms), and is associated with a higher risk of suicidality (40). Further, data from the STEP-BD study indicate that this phase of the illness is associated with greater objective and subjective caregiver burden (41).
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