CHAPTER 10

Bipolar and Related Disorders

Terence A. Ketter, M.D.

Kiki D. Chang, M.D.

Bipolar disorders are common, recurrent, frequently debilitating, and in many instances tragically fatal illnesses, characterized by oscillations in mood, energy, and ability to function (Ketter 2010). In this chapter, we describe the clinical features of bipolar and related disorders, summarize knowledge of their epidemiology and pathogenesis, and outline current approaches to treatment.

Phenomenology of Bipolar and Related Disorders

The clinical manifestations of bipolar disorders have been recognized since antiquity (Goodwin and Jamison 2007). However, approaches to bipolar disorder phenomenology continue to evolve.

Trends in Nosology of Bipolar and Related Disorders

Over the last century, conceptualization of bipolar disorders evolved from Kraepelin's unitary model of manic-depressive psychosis that included both unipolar and bipolar mood disorders, with recurrence as the central feature (Kraepe-lin 1921), to Leonhard's dichotomous model that was based on a bipolar versus unipolar polarity distinction (Leonhard 1957) to hybrid unitary-dichotomous models that attempt to include features of both approaches (American Psychiatric Association 2000, 2013). Although some authors continue to emphasize the utility of the unitary model (Goodwin and Jamison 2007), the Diagnostic and Statistical Manual of Mental Disorders (DSM) has evolved using a hybrid unitary-dichotomous model (American Psychiatric Association 2000, 2013).

DSM-IV-TR Bipolar Disorder Nosology

The chapter structure of DSM-IV-TR (American Psychiatric Association 2000) was consistent with a unitary model, grouping bipolar disorders and depressive disorders in a single mood disorders chapter that emphasized their overlapping features. DSM-IV-TR built its mood disorder nosology by first specifying different types of mood episodes: manic, hypomanic, depressive, and mixed. The criteria for major depressive episodes, which reflect the predominant pole for both bipolar and depressive illnesses (Judd et al. 2002, 2003), were identical for patients with bipolar and depressive disorders. However, the DSM-IV-TR mood disorders included distinct disorder clusters based on polarity (bipolar and depressive disorders), consistent with a dichotomous model, with the presence or absence of manic, hypomanic, or mixed episodes or features thereof distinguishing bipolar from depressive disorders.

DSM-5 Bipolar and Related Disorders Nosology

The DSM-5 (American Psychiatric Association 2013) chapter structure reflects a dichotomous model, with bipolar and related disorders having their own chapter located between the schizophrenia and depressive disorders chapters. This structure emphasizes not only the differences between bipolar and depressive disorders but also that the biological and clinical features associated with bipolar disorders may be considered intermediate between those seen in schizophrenia and those seen in unipolar depressive disorders. Nevertheless, a unitary mood disorders model is also suggested by major depressive episodes having identical criteria (even including the new "with mixed features" specifier) for patients with bipolar and depressive disorders.

Mood Episodes

DSM-5, like DSM-IV-TR, builds its mood disorder nosology by first specifying different types of mood episodes—manic, hypomanic, and depressive (but no longer mixed) episodes—and includes the dichotomous model approach of using the presence or absence of manic or hypomanic episodes to distinguish bipolar from depressive disorders.

Major depressive episode. In DSM-5, as in DSM-IV-TR, a major depressive episode is characterized by the presence of sadness or anhedonia (absence of positive emotion) accompanied by additional symptoms to yield a total of at least five pervasive (most of the day, nearly every day) symptoms for at least 2 weeks (Box 10-1). Curiously, in children and adolescents, the mood may be irritable, creating overlap with the criteria for mood elevation episodes. The specific additional symptoms include poor concentration (inability to focus), poor energy, poor selfesteem/guilt, suicidality, sleep disturbance, weight change, and psychomotor disturbance. The latter three symptoms are heterogeneous, including increased or decreased weight, sleep, and psychomotor activity.

For major depressive episodes (like manic and hypomanic episodes), it is required that symptoms are primary (due to a mood disorder) rather than secondary (due to effects of substances or general medical conditions). It is also noted that major depressive episodes need to be distinguished from normal and expected responses to events involving significant loss, such as bereavement, financial ruin, or natural disaster, and that the presence of feelings of worthlessness, suicidal ideation, psychomotor retardation, and severe functional impairment suggest the presence of a major depressive episode rather than a mere normal response to significant loss. For major depressive episodes there is a relatively low severity threshold, stipulating merely that symptoms must cause clinically significant distress or impairment in psychosocial or occupational function, and there are no requirements with respect to psychosis or hospitalization. Thus, the degree of impairment and symptom severity for major depressive episodes can vary considerably (ranging from mild to moderate to marked), and major depressive episodes may be associated with psychosis, hospitalization, or marked impairment. In comparison, the criteria for manic episodes require psychosis, hospitalization, or marked impairment, whereas the criteria for hypomanic episodes specifically exclude psychosis, hospitalization, and marked impairment.

Although the criteria for major depressive episodes are identical for patients with bipolar disorders and depressive disorders, as noted below (see section "Strengths and Limitations of DSM-5 Mood Disorders Nosology" later in chapter), some data not integrated into DSM suggest tendencies toward differential profiles of depressive symptoms in bipolar disorders as compared with depressive disorders.

"With mixed features" specifier for major depressive episode. DSM-5, unlike DSM-IV-TR, includes a "with mixed features" specifier for major depressive episodes (Box 10-2). This specifier is applied if at least three mood-elevation symptoms (including elevated/expansive mood, inflated self-esteem/grandiosity, over-talkativeness, racing thoughts, increased energy/goal-directed activity, impulsivity, and decreased need for sleep; but excluding distractibility, irritability, and psychomotor agitation, which may occur in either pole) occur concurrently with at least five depressive symptoms. DSM-5 indicates that episodes that meet full criteria for both mania and depression simultaneously should be labeled as manic episodes "due to the marked impairment and clinical severity of full mania," yielding a diagnosis of bipolar I disorder. In contrast, DSM-5 is silent regarding episodes that meet full criteria for both hypomania and depression simultaneously, neither prohibiting nor endorsing simultaneously diagnosing hypomanic and depressive episodes (as opposed to selecting one pole for the episode and adding a "with mixed features" specifier), although such patients would have a diagnosis of bipolar II disorder. It is important to note that major depressive episodes with mixed features can occur in both bipolar and depressive disorders, consistent with a unitary mood disorders model.

Note. The mixed features specifier can apply to the current manic, hypomanic, or depressive episode in bipolar I or bipolar II disorder.

Manic episode and hypomanic episode. DSM-5 mood elevation (manic or hypomanic) episode criteria, like those in DSM-IV-TR, require the presence of at least 4-7 days (or any duration if hospitalized) of abnormally euphoric, expansive, or irritable mood as well as increased activity/energy (increased activity/energy has been newly added as a core symptom) plus at least three (or at least four if mood is merely irritable rather than euphoric or expansive) out of a possible seven mood elevation symptoms, which include inflated self-esteem, decreased need for sleep, over-talkativeness, flight of ideas, distractibility (overly rapid shifting of focus), excessive goal-directed activity/psychomotor agitation, and impulsivity (Boxes 10-3 and 10-4). Manic episodes are by definition severe, entailing psychosis, hospitalization, or severe impairment of occupational or psychosocial function. Hypomanic episodes are defined similarly to manic episodes with one important difference being that they are not severe—that is, they do not entail psychosis, hospitalization, or severe impairment. Indeed, function may be enhanced. In addition, the minimum duration for hypomanic compared with manic episodes is briefer, being 4 rather 7 days. For both manic and hypomanic episodes, there are requirements that symptoms are primary (due to a mood disorder) rather than secondary (due to effects of substances or general medical conditions). However, in DSM-5 (but not DSM-TV-TR) a full manic or hypomanic episode that arises during antidepressant treatment (e.g., medication or electroconvulsive therapy) and persists beyond the physiological effect of the treatment is sufficient evidence for a manic or hypomanic episode diagnosis.

"With mixed features" specifier for manic or hypomanic episode. Another change from DSM-IV-TR is that DSM-5 has replaced mixed episodes with manic episode with mixed features and includes the new hypomanic episode with mixed features. In these instances, the "with mixed features" specifier for mood elevation episodes (Box 10-5) is applied if at least three depressive symptoms (including depressed mood, anhedonia, psychomotor retardation, fatigue, feelings of worthlessness/guilt, and suicidal ideation; but excluding indecisiveness, in-somnia/hypersomnia per se, and psychomotor agitation, which may occur in either pole) occur concurrently with at least three (or four) mood elevation symptoms.

Note. The mixed features specifier can apply to the current manic, hypomanic, or depressive episode in bipolar I or bipolar II disorder.

The "with mixed features" specifier is consistent with the presence of such features representing a different (perhaps combined elevated/depressed) syndrome compared with "pure" mood elevation episodes. However, mixed features could also be thought to represent other constructs, including 1) ultradian (within a day) mood cycling, 2) transitional states (between mood elevation and depression), and 3) particularly severe mood elevation or depression (McElroy et al. 1992). In some patients, mixed features may be characterized by simultaneous (concurrent) depressive and manic symptoms. However, consistent with the first construct listed above, in other patients mixed features may be characterized by cyclic mood changes within a day. In occasional patients, consistent with the second construct, mixed features may predominantly arise during transitions between mood states (e.g., when switching from a manic or hypo-manic episode to a major depressive episode or vice versa). Finally, consistent with the third construct, in some patients "pure" mood episodes may escalate in severity to include mixed features.

Adding the "with mixed features" specifier to DSM-5 was in part based on clinical observations that patients with manic episodes more commonly experienced concurrent depressive symptoms that did not meet full criteria for a major depressive episode (meeting the full criteria for a major depressive episode was required for the DSM-IV-TR mixed episode). Such episodes were referred to by the non-DSM-IV-TR term dysphoric mania, which required a full manic episode accompanied by at least three "nonoverlapping" depressive symptoms (McElroy et al. 1992). The new DSM-5 manic episode with mixed features includes not only episodes with sufficient concurrent depressive symptoms to meet criteria for a major depressive episode (i.e., DSM-IV-TR mixed episodes) but also episodes with only three or four (as opposed to five or more) depressive symptoms that were formerly described as dysphoric mania. Similarly, the new DSM-5 hypo-manic episode with mixed features includes episodes with three or four depressive symptoms that were formerly described as dysphoric hypomania.

Bipolar and Related Disorders

Bipolar I disorder. Patients with bipolar I disorder (Box 10-6) have experienced at least one manic episode. Mood episodes in bipolar I disorder (and in bipolar II disorder) are not permitted to be better accounted for by schizoaffective disorder or superimposed on schizophrenia, schizophreniform disorder, delusional disorder, or other specified or unspecified schizophrenia spectrum and other psychotic disorder. It is noteworthy that although the vast majority of patients with bipolar I disorder also experience major depressive episodes, such episodes are not required for the diagnosis of bipolar I disorder. Less than 10% of patients with bipolar I disorder only experience a single manic episode (with no other manic episodes or major depressive episodes); the vast majority of patients with bipolar I disorder experience recurrent episodes. DSM-5 differs from DSM-IV-TR in that it no longer has the diagnosis of bipolar I disorder, single manic episode. Diagnostic codes for bipolar I disorder are based on type of current or most recent episode and its status with respect to current severity, presence of psychotic features, and remission status. These are followed by as many of the following specifiers without codes as apply to the current or most recent episode: with anxious distress (presence of at least two of the following symptoms: 1) feeling keyed up/tense, 2) feeling unusually restless, 3) difficulty concentrating due to worry, 4) fear of something awful happening, 5) fear of loss of control); with mixed features (as in Boxes 10-2 and 10-5); with rapid cycling (if there have been at least four syndromal major depressive, manic, or hypomanic episodes in the prior 12 months); with melancholic features (for depression); with atypical features (for depression); with mood-congruent or mood-incongruent psychotic features; with catatonia; with peripartum onset; and with seasonal pattern.

NOTICE. Criteria set above contains only the diagnostic criteria and specifiers; refer to DSM-5 for the full criteria set, including specifier descriptions and coding and reporting procedures.

Bipolar II disorder. Patients with bipolar II disorder (Box 10-7) have experienced at least one hypomanic episode as well as at least one major depressive episode, but no manic episode. Bipolar II disorder has only one diagnostic code. Its status with respect to current severity, presence of psychotic features, course, and other specifiers cannot be coded but should be indicated in writing. Thus, current or most recent episode is specified as hypomanic or depressed. This is followed by as many of the following specifiers as apply to the current or most recent episode: with anxious distress, rapid cycling, mood-congruent or mood-incongruent psychotic features, catatonia, peripartum onset, and seasonal pattern (for depressive episodes). These are followed by either a course specifier (in partial remission, or in full remission) if full criteria for a mood episode are not met, or by a severity specifier (mild, moderate, or severe) if full criteria for a mood episode are met.

NOTICE. Criteria set above contains only the diagnostic criteria and specifiers; refer to DSM-5 for the full criteria set, including specifier descriptions and coding and reporting procedures.

Cyclothymic disorder. Patients with cyclothymic disorder (Box 10-8) have a chronic (at least 2 years' duration in adults and at least 1 year in children and adolescents, without a 2-month interruption) pattern of subsyndromal mood elevation and depression symptoms. Cyclothymic disorder may not be diagnosed if there has been any major depressive, manic, or hypomanic episode during the first 2 years of the disturbance (1 year in children and adolescents); if such an episode occurs during this time period, the chronic subsyndromal mood swings may be considered to be residual symptoms of bipolar I disorder or bipolar II disorder. However, after the initial 2-year period (1 year in children and adolescents) of cyclothymic disorder, there may be superimposed manic episodes (in which case both bipolar I disorder and cyclothymic disorder may be diagnosed), hypo-manic episodes (in which case both other specified bipolar and related disorder and cyclothymic disorder may be diagnosed), or major depressive episodes (in which case both major depressive disorder and cyclothymic disorder may be diagnosed). Such instances might be considered as cyclothymic disorders that have progressed to situations in which syndromal mood episodes occur in addition to baseline chronic subsyndromal mood instability. Cyclothymic disorder may be considered to be a bipolar analog of unipolar dysthymic disorder, with each of these representing affective temperaments that may or may not ultimately lead to disorders that include syndromal mood episodes.

NOTICE. Criteria set above contains only the diagnostic criteria and specifiers; refer to DSM-5 for the full criteria set, including specifier descriptions and coding and reporting procedures.

Substance/medication-induced bipolar and related disorder. Substance/medication-induced bipolar and related disorder (Box 10-9) is associated with the ingestion of a substance (e.g., a drug of abuse, a medication, or another treatment; Table 10-1) or the withdrawal of that substance. In DSM-5 (but not DSM-IV-TR) a full manic or hypomanic episode emerging during antidepressant treatment (medication, electroconvulsive therapy, etc.) and persisting beyond the physiological effect of that treatment is sufficient evidence for a manic or hypomanic episode diagnosis. However, caution is indicated to ensure that one or two symptoms (particularly increased irritability, edginess, or agitation following antidepressant use) are not taken as sufficient for diagnosis of a manic or hypomanic episode. Secondary mood disorders (such as substance-induced bipolar disorder and bipolar disorder due to another medical condition) are more common in individuals with mixed features, in individuals with frequent episodes, and in the elderly (Krauthammer and Klerman 1978).

NOTICE. Criteria set above contains only the diagnostic criteria and specifiers; refer to DSM-5 for the full criteria set, including specifier descriptions and coding and reporting procedures.

Bipolar and related disorder due to another medical condition. Bipolar and related disorder due to another medical condition (Box 10-10) in DSM-5 is a function of the direct physiological effects of another medical condition (Table 10-2). Bipolar disorder secondary to medical conditions (particularly neurological and endocrine disorders) is especially common in older adults because of the high prevalence of medical disorders in that age group (Ketter 2010; Sajatovic and Blow 2007).

NOTICE. Criteria set above contains only the diagnostic criteria and specifiers; refer to DSM-5 for the full criteria set, including specifier descriptions and coding and reporting procedures.

Other specified or unspecified bipolar and related disorder. Other specified bipolar and related disorder (Box 10-11) and unspecified bipolar and related disorder (Box 10-12) in DSM-5 replace the DSM-IV-TR category bipolar disorder not otherwise specified. These new diagnoses apply to individuals experiencing significant manic or hypomanic and depressive symptoms that do not meet diagnostic criteria for any other disorder from the "Bipolar and Related Disorders" chapter or the "Depressive Disorders" chapter of DSM-5 and are not attributable to the direct physiological effects of a substance or a general medical condition.

A noteworthy change in DSM-5 is the addition of the category other specified bipolar and related disorder. Examples of presentations for which this designation would be appropriate include the following: 1) short-duration hypomanic episodes (2-3 days) and major depressive episodes; 2) hypomanic episodes with insufficient symptoms and major depressive episodes; 3) hypomanic episode without prior major depressive episodes; and 4) short-duration cyclothymia (less than 24 months). Presentation 1 above was of sufficient interest to be included in Section III (Conditions for Further Study) of DSM-5; see proposed criteria for depressive episodes with short-duration hypomania (Box 10-13).

Strengths and Limitations of DSM-5 Mood Disorders Nosology

The DSM-5 mood disorders nosology has the strength of being a systematic evolution of an established approach (i.e., DSM-IV-TR) that was familiar to major stakeholders such as advocacy groups, clinicians, regulatory agencies, and third-party payers and is expected to be broadly adopted by such stakeholders. The categorical nature of DSM-5 is amenable to its use in genetic, neurobiological, epidemiological, phenomenological, and therapeutic studies. In particular, this categorical approach can yield reliable diagnosis, which facilitates not only randomized controlled trials of interventions but also similar characterization of patients by their providers interested in applying the findings of such studies in clinical settings.

On the other hand, the DSM-5 mood disorder nosology is substantially limited by being a complex yet not comprehensive system that 1) relies on only a limited subset of mood symptom phenomenology (e.g., a subset of symptoms of mood episodes, and limited course of illness information), 2) fails to include other important aspects of mood symptom phenomenology and course of illness information (e.g., onset age, patterns of episode onset and offset, comorbidity), 3) fails to include treatment effects, 4) fails to include family history and genetics, and 5) attempts to distinguish bipolar from unipolar episodes and disorders in a hybrid categorical/dimensional rather than fully dimensional fashion. For example, the categorical DSM-5 mood episode nosology only begins to reflect the rich diversity of combinations of symptoms of mood elevation and depression that are encountered clinically. Other limitations are described below and can be found in the International Society for Bipolar Disorders Diagnostic Guidelines Task Force Report (Ghaemi et al. 2008).

A crucial limitation of the DSM-5 mood disorders nosology is its use of a hybrid categorical/dimensional rather than a fully dimensional approach. Bipolar disorder and major depressive disorder have characteristics such as genetics, phenomenology, biology, therapeutic response, and brain imaging findings that suggest both commonalities with and dissociations from one another. Taken together, these characteristics are in some instances more consistent with a dimensional view, with bipolar and related disorders being on a continuum with depressive disorders, especially for patients with highly recurrent treatment-resistant forms of the latter (Akiskal and Pinto 1999; Ghaemi et al. 2004). Similarly, bipolar and related disorders may be considered to be on a continuum with psychotic disorders such as schizoaffective disorder and schizophrenia (Ketter et al. 2004) and with personality disorders such as borderline personality disorder (Akiskal et al. 1985). Nevertheless, in some instances a categorical approach still appears useful. Although more research is clearly necessary to address the dimensional versus categorical controversy, it is feasible that, at least in the interim, a hybrid categorical/dimensional approach could provide additional insights into pathophysiology and management options, which would not be available using only one of these models.

Some patients are particularly focused on obtaining a definitive categorical diagnosis of either a bipolar disorder or a depressive disorder, and they are distressed by any ambiguity. In instances where the patient's diagnosis appears to be at the boundary of a category, a dimensional approach emphasizing commonalities across categories may prove useful. For example, in patients with frequently recurring major depressive disorder who have subthreshold mood elevation symptoms and antidepressant resistance, intervention with mood stabilizers may yield benefit.

For clinicians, a key challenge is determining when to think categorically versus dimensionally. It is hoped that addressing this challenge will be facilitated in future schemas. In the meantime, clinicians are faced with integrating a lively debate regarding this issue. One topical approach emphasizes the importance of temperament and bipolar features when assessing patients with mood disorders and advocates the concept of a broad bipolar spectrum (Akiskal et al. 1989). This approach emphasizes the importance of not only cyclothymic (chronic alternating subsyndromal mood elevation and depressive symptoms) and dysthymic (chronic sub-syndromal depressive symptoms) temperaments that are accounted for by cyclothymic disorder and dysthymia, respectively, in DSM-5, but also hyperthymic (chronic subsyndromal mood elevation symptoms) and irritable temperaments as important non-DSM-5 components of the mood disorder nosology.

The late twentieth and early twenty-first centuries have already seen a substantial broadening of the concept of bipolar disorders to include not only classical forms of the disorder, characterized by euphoric mania, infrequent episodes, and excellent lithium responses, but also forms with mixed mania, rapid cycling, and poor response to lithium. To date, this degree of broadening has appeared useful, as mood-stabilizing anticonvulsants (such as divalproex, carbamazepine, and lamotrigine) and atypical antipsychotics (such as olanzapine, risperidone, quetiapine, ziprasidone, aripiprazole, and asen-apine) may have utility in such lithium-resistant, nonclassical forms of bipolar and related disorders.

However, there is spirited controversy regarding the advisability of further expansion of bipolar disorders to include the broad bipolar spectrum concept. Critics of the bipolar spectrum approach may argue that it entails potential overdiagnosis of bipolar disorder (at the expense of other disorders such as major depressive disorder and borderline personality disorder), leading to overutilization of mood stabilizers and underutilization of other potentially effective medical and psychotherapeutic interventions.

Differential Diagnosis of Bipolar and Related Disorders

The average patient with a bipolar disorder may endure as long as a decade of affective symptoms before appropriate diagnosis and treatment. The most common incorrect initial diagnosis is major depressive disorder (Ghaemi et al. 2000). This unfortunate situation is most likely related to multiple causes:

• The complex, variable phenomenology of bipolar disorder, which includes different subtypes, mood states, illness courses, and age-dependent presentations (e.g., disruptive behavior disorders in juveniles)
• The pervasiveness of depressive symptoms, which makes major depressive disorder crucial in the differential diagnosis
• The complex and confounding comorbidities encountered, including disruptive behavior disorders (attention-deficit/hyperactivity disorder [ADHD], oppositional defiant disorder, conduct disorder), substance use disorders, anxiety disorders, and Cluster B personality disorders

A variety of diagnostic challenges commonly occur in patients with bipolar disorders. One such challenge occurs because patients (who frequently present during major depressive episodes) may not recall prior manic episodes or be able to distinguish them from major depressive episodes, thus raising the risk that they may be incorrectly diagnosed with major depressive disorder. Also, approximately half of patients with bipolar disorders have an index major depressive episode rather than an index mood elevation episode, initially suggesting a major depressive disorder, only to later have a mood elevation episode revealing a bipolar disorder. In addition, the severity of mood elevation episodes may be inconclusive, making it unclear whether the patient has bipolar I disorder or bipolar II disorder. Another challenge is the phenomenon of treatment-emergent affective switch (TEAS) with antidepressant medications, which can cause manic- or hypomanic-like episodes or mixed-like episodes. DSM-5 (but not DSM-IV-TR) permits persistent TEAS to count toward a diagnosis of bipolar disorder. Indeed, patients with TEAS are at high risk for future spontaneous mood elevation and need to be treated with considerable caution, often in a fashion similar to patients with bipolar disorders.

Prominent psychotic symptoms in patients with bipolar I disorder may suggest a diagnosis of schizoaffective disorder or even schizophrenia, particularly early in the illness, when the longitudinal course characteristics (e.g., recurrent vs. chronic) remain to be established. Also, slower resolution of psychotic compared with mood symptoms after intervention with mood stabilizers could lead clinicians to consider a diagnosis of schizoaffective disorder. Despite Kraepelin's (1921) formulation categorically differentiating bipolar disorder (then manic-depressive psychosis) and schizophrenia (then dementia praecox), emerging evidence supports the existence of a continuum between these disorders, with schizoaffective disorder being an intermediate condition (Ketter et al. 2004), but more research is needed in this area.

Comorbidity in Bipolar and Related Disorders

Comorbid conditions may confound the diagnosis of a bipolar disorder. Mood elevation symptoms may be caused or exacerbated by alcohol and substance (particularly stimulants and cocaine) use disorders, especially in younger patients; by medical disorders (particularly certain neurological and endocrine disorders); or by the treatment (e.g., steroids) of medical disorders, particularly in older patients. These situations make the diagnosis of a bipolar disorder more challenging. Symptoms of other concurrent psychiatric disorders (e.g., anxiety disorders, disruptive behavior disorders such as ADHD, eating disorders, and Cluster B personality disorders) may contribute prominently to complaints of patients and their families at the time of initial presentation to clinicians and thus delay the diagnosis of a bipolar disorder.

Phenomenology of Bipolar and Related Disorders in Women and Special Age Groups

Women

Bipolar II disorder is more common in women than in men, although bipolar I disorder affects men and women equally (Freeman et al. 2002; Ketter 2010). Although substance abuse is more common in men compared with women in the general population and among people with bipolar and related disorders, women with these disorders have a higher rate of alcohol abuse than women in the general population. Women with bipolar and related disorders are more likely than men with these disorders to experience rapid cycling and mixed states and comorbid eating disorders. Women with bipolar and related disorders are more likely to experience depressive symptoms than men with these disorders, which may be accounted for in part by women's higher rates of rapid cycling, mixed states, and anxiety disorders. The female reproductive cycle appears to influence the course of bipolar and related disorders, with the postpartum period, the late luteal phase, and (to a lesser extent) possibly the menopausal transition entailing increased risk of exacerbation of these disorders. In contrast, pregnancy itself generally does not affect the course of bipolar disorders, although the teratogenic effects of multiple treatments for a bipolar disorder can make management decisions challenging.

Children and Adolescents

Patients with early-onset mood disorders can present considerable diagnostic challenges. Approximately 30% of prepubertal patients with major depressive episodes may ultimately receive a bipolar disorder diagnosis (Geller et al. 2001). Moreover, approximately 40% of patients with severe major depressive episodes in late adolescence to early adulthood (ages 18-25 years) ultimately receive a bipolar disorder diagnosis (Goldberg et al. 2001).

Pediatric patients may present with disruptive behavior disorders that may have considerable symptom overlap with bipolar disorders. In such instances, the presence of a family history of a bipolar disorder (particularly in a parent) may provide an important indicator of risk of a bipolar outcome (Chang et al. 2000). In juveniles with symptoms of ADHD, missing a diagnosis of a bipolar disorder could lead to administration of stimulant medication in the absence of antimanic agents, potentially causing mood destabilization. Similarly, antidepressant exposure in youth with depression and unrecognized mania or hypomania could also lead to increased symptoms of mania and depression (Goldsmith et al. 2011). These considerations may have contributed to a recent rapid increase in the diagnosis of pediatric bipolar and related disorders, which has indicated the need for clinical epidemiological reliability studies to determine the accuracy of clinical diagnoses of child and adolescent bipolar disorders in community practice (Moreno et al. 2007).

Older Adults

At the other end of the age spectrum, elderly patients may present diagnostic challenges related to general medical conditions or treatments thereof that raise the possibility of a secondary bipolar disorder (Ketter 2010; Sajatovic and Blow 2007).

Epidemiology of Bipolar and Related Disorders

Bipolar and related disorders, although less common than depressive disorders, when considered in their broadest sense may have a lifetime prevalence as high as 4% (1% bipolar I disorder, 1% bipolar II disorder, and 2% subthreshold bipolar disorder) (Merikangas et al. 2007). The peak age at onset for bipolar and related disorders is in the late teens to early 20s, with the mean onset age being earliest in bipolar I disorder, intermediate in bipolar II disorder, and latest in major depressive disorder. The prevalence of bipolar I or II disorder in adolescents in the United States is approximately 2.5% (Merikangas et al. 2012). Although there are similar numbers of women and men with bipolar I disorder, there is a female predominance in bipolar II disorder, and an even greater female predominance in major depressive disorder. Thus, women compared with men with bipolar disorder experience more depression, rapid cycling, mixed states, and bipolar II disorder. Clinical samples suggest that patients with bipolar and related disorders are commonly not able to maintain full-time employment, even if they have at least some college education (Kogan et al. 2004).

Having a family member with a bipolar disorder is a clear risk factor for developing the illness, and having a parent with a bipolar disorder increases the risk of developing earlier-onset (in childhood rather than adolescence or young adulthood) and more severe illness. Childhood trauma also appears to increase the risk of developing a bipolar disorder in vulnerable individuals.

Bipolar and related disorders are inversely related to age and education level. They are more common in previously married individuals compared with the currently married (only for subthreshold bipolar disorder) and in the unemployed-disabled compared with the employed. Bipolar disorder is unrelated to race/ethnicity and family income.

The recurrent mood disorder episodes and interepisode residual symptoms associated with bipolar and related disorders inflict large human and financial costs (Guo et al. 2007, 2008) and contribute to these disorders ranking second among mental illnesses causing disability in working-age adults (Murray and Lopez 1997).

Pathogenesis of Bipolar and Related Disorders

Studies of the pathogenesis of bipolar and related disorders have included diverse important themes (Goodwin and Jamison 2007; Yatham and Maj 2010). Although there appears to be a very robust familial risk (not uncommonly accounting for over half the risk of a bipolar outcome), this appears to be mediated by multiple small-effect genes rather than single large-effect genes. In addition, genetic vulnerability may interact with preventive or precipitating environmental factors to yield resiliency or illness, respectively. Regardless of the specific pathophysiology underlying bipolar disorders, clinical and basic evidence suggests that recurrent mood episodes may cause gradually accumulating damage (broadly analogous to the kindling model of epileptogenesis), resulting in episodes progressing from reactive (to stress) to spontaneous and becoming more frequent, more severe, and ultimately resistant to treatment (Post 1992).

Important neurochemical themes in bipolar and related disorders overlap those for depressive disorders and substantively implicate diverse mechanisms in the pathogenesis of bipolar disorders. The relevant mechanisms are hormonal (hypothalamic-pituitary-adrenal, hypo-thalamic-pituitary-thyroid, and hypothalamic-pituitary-gonadal axes), monoaminergic (dopamine, norepinephrine, and serotonin), ion channel (calcium, sodium), excitatory/inhibitory neurotransmitter (glutamate and γ-aminobutyric acid [GABA]), intracellular signaling (inositol monophosphatase, protein kinase C, and glycogen synthase kinase-3 beta), and mitochondrial (impaired energy production, altered phospholipid metabolism) (Li et al. 2012).

Neuroimaging studies consistently indicate that dysfunction in anterior paralimbic and overlying prefrontal regions that contribute importantly to normal human emotions, mood, and cognition may contribute to the pathogenesis and clinical phenomenology of bipolar and related disorders. Findings of neuroimaging studies assessing specific biochemical disruptions in these structures have been somewhat less consistent than those focusing on the structures implicated.

Deficits in neuroplasticity and neurotrophic factors (e.g., brain-derived neurotrophic factor) have also been implicated in the pathophysiology of bipolar and related disorders. Indeed, postmortem neuropathological studies suggest regional neuronal and glial deficits in patients with bipolar disorders.

In contrast to depressive disorders, the impact of psychological theories of the pathogenesis of bipolar and related disorders has been more limited.

Treatment of Bipolar and Related Disorders

Somatic Treatment of Bipolar and Related Disorders

The mood stabilizers lithium, valproate, lamotrigine, and carbamazepine may be argued to be the foundational pharmacotherapies for bipolar disorders, but second-generation antipsychotics (SGAs) have been increasingly used (Ketter 2010). In addition, antidepressants, anxiolytics/hypnotics, other anticonvulsants, and other medications are commonly combined with mood stabilizers and SGAs in clinical settings (Ketter 2010).

Evidence-based treatment of bipolar and related disorders begins with considering agents approved by the U.S. Food and Drug Administration (FDA). Such interventions are considered the most well-established management options, having demonstrated efficacy and safety in adequately sized, multicenter, randomized, double-blind, placebo-controlled trials (Table 10-3).

Mood Stabilizers

Lithium. Lithium is an established treatment for acute mania and bipolar maintenance therapy that with chronic treatment appears to decrease suicidal behavior and suicide (Baldessarini et al. 2006; Bauer et al. 2006; Jefferson et al. 1987). Lithium has impressive efficacy in classic bipolar disorder (euphoric manias, not rapid cycling) but appears less effective in patients with manic episodes with mixed features; patients with rapid cycling (at least four episodes per year); patients with comorbid substance abuse; patients with severe, psychotic, or secondary manias; adolescents; and patients who have had three or more prior episodes. In addition, its utility is limited by adverse effects, which can undermine compliance.

The U.S. prescribing information for lithium includes a boxed warning regarding the risk of lithium toxicity that can occur at doses close to therapeutic levels (Physicians' Desk Reference 2012). Lithium intoxication can present with central nervous system (CNS), cardiovascular, renal, and gastrointestinal symptoms. In severe cases, lithium intoxication can result in irreversible CNS, cardiac, or renal problems, and even death. The risk of lithium toxicity is high in patients with significant renal or cardiovascular disease, those with severe debilitation, those with dehydration, those with sodium depletion, or those taking diuretics or angiotensin-converting enzyme (ACE) inhibitors. However, in medically healthy individuals, at dosages of 900 mg/day or less, lithium is usually well tolerated, and even with low serum levels it may yield benefit in milder forms of bipolar disorders or when used as an adjunct to other mood stabilizers, antipsychotics, or antidepressants.

Other warnings for lithium include the risks of renal problems (e.g., nephrogenic diabetes insipidus and morphological changes, including glomerular and interstitial fibrosis and nephron atrophy with chronic therapy) and drug interactions. Patients need to maintain adequate fluid and sodium intake, and caution is indicated in the setting of protracted sweating, diarrhea, infection, and fever.

Lithium can cause common benign as well as rare serious renal adverse effects. Nephrogenic diabetes insipidus may occur in as many as 10% of patients with chronic lithium therapy. Chronic lithium less commonly causes more long-standing and serious renal complications that are apparently more prevalent in cases with repeated lithium toxicity, advanced age, and concurrent nonsteroidal antiinflammatory drug (NSAID) therapy or chronic medical illness.

Weight gain can occur with lithium therapy and can be a significant contributor to compliance problems. Weight gain appears to be more of an issue with lithium than with lamotrigine, particularly in patients who are already obese, but less of a problem than with valproate or olanzapine. The lithium extended-release compared with the immediate-release formulation may cause fewer gastrointestinal side effects. Dermatological side effects with lithium therapy include acneiform and maculopapular eruptions, psoriasis, and folliculitis. Lithium can also cause thyroid problems. Lithium can have adverse cardiac effects, ranging from benign electrocardiographic T wave morphological changes to clinically significant sinus node dysfunction or sinoatrial block, and onset or aggravation of ventricular irritability. Like the other mood stabilizers, lithium is a teratogen (FDA Pregnancy Category D).

Note. ER=extended release; ERC=extended-release capsule; LAI=long-acting injectable formulation;

XR=extended release.

^aPediatric and adult.

^bAdjunctive and monotherapy.

Source. Adapted from Ketter 2010.

It should be noted that lithium has the most evidence for neurotrophic effect on brain structures, most commonly leading to findings of preserved or increased brain volume in, for example, the amygdala and hippocampus (Hafeman et al. 2012). However, the exact mechanism and beneficial effect of this finding are unknown.

In acute settings, such as the inpatient treatment of mania, lithium therapy is commonly initiated at 600-1,200 mg/day in two or three divided doses and increased as necessary and tolerated every 2-4 days by 300 mg/day, with final dosages not usually exceeding 1,800 mg/day. Some patients may better tolerate weighting the dose toward bedtime or even taking the entire daily dose at bedtime. Euthymic or depressed patients tend to tolerate aggressive initiation less well than manic patients. In less acute situations, such as the initiation of prophylaxis or adjunctive use, lithium can be started at 300-600 mg/day and increased as necessary and tolerated by 300 mg/day every 4-7 days. Thus, lithium target dosages are commonly between 900 and 1,800 mg/day, yielding serum levels from 0.6 to 1.2 mEq/L (0.6 to 1.2 mM/L), with the higher portion of the range used acutely and lower doses used in adjunctive therapy or prophylaxis.

Lithium has primarily renally mediated pharmacokinetic drug-drug interactions, so that thiazide diuretics, certain NSAIDs, ACE I inhibitors, and angiotensin H receptor type 1 antagonists can increase serum lithium concentrations and cause lithium toxicity. Case reports suggest that some individuals may develop serious adverse effects such as neuroleptic malignant syndrome when lithium is combined with SGAs. However, observational and controlled clinical trials suggest that combining lithium with such agents does not generally cause more than merely additive adverse effects. Indeed, several SGAs have received FDA approval for combination with lithium (or valproate) for the treatment of acute mania and for bipolar maintenance treatment.

Patients need to be advised of lithium adverse effects, drug interactions, and the importance of adequate hydration. Clinical assessments with lithium therapy includes a baseline physical examination and routinely querying patients at baseline and during treatment regarding CNS (sedation, tremor, ataxia), gastrointestinal (nausea, vomiting, diarrhea), metabolic (weight gain), and renal (polyuria, polydipsia) disorders and adverse effects. Laboratory monitoring includes a baseline pregnancy test, electrocardiogram (in patients over 40 years of age), and renal (blood urea nitrogen, serum creatinine, and electrolytes) and thyroid (thyroid-stimulating hormone [TSH]) indices, with reevaluation of renal and thyroid indices at 3 and 6 months and then every 6-12 months thereafter, and as clinically indicated (American Psychiatric Association 2002). Serum lithium concentrations are commonly assessed at steady state, which occurs at about 5 days after a dosage change, and then as indicated by inefficacy or adverse effects. More frequent laboratory monitoring is prudent in the medically ill and in patients with abnormal indices.

Valproate. Valproate has demonstrated efficacy for acute manic and mixed episodes in adults, but not in patients under 18 years of age. Although a controlled trial of valproate maintenance therapy in adults failed, perhaps due to methodological limitations, valproate is commonly recommended for longer-term therapy in patients with bipolar disorder (American Psychiatric Association 2002; Suppes et al. 2005), and several SGAs have been FDA approved for bipolar maintenance treatment combined with valproate (or lithium).

The U.S. prescribing information for valproate includes boxed warnings regarding the risks of hepatotoxicity, teratogenicity, and pancreatitis (Physicians' Desk Reference 2012). Valproate, like the other mood stabilizers, is a teratogen (FDA Pregnancy Category D), and rates of major congenital malformations with valproate exposure could be higher compared with lamotrigine, carbamazepine, or no anticonvulsant exposure. Other warnings include the risks of hyperammonemic encephalopathy in patients with urea cycle disorders, somnolence in older adults, thrombocytopenia, hypothermia, multiorgan hypersensitivity reactions, and suicidality (an anticonvulsant class warning). Valproate therapy has also been associated with polycystic ovarian syndrome.

Common dose-related adverse effects with valproate include gastrointestinal (nausea, vomiting, dyspepsia, diarrhea), hepatic (transaminase elevations), CNS (tremor, sedation, dizziness), and metabolic (weight gain, osteoporosis) problems and hair loss. CNS adverse effects may be attenuated by weighting the dose toward bedtime or reducing the dose. The divalproex extended-release compared with the delayed-release formulation may cause fewer gastrointestinal side effects, and the delayed-release formulation in turn may be better tolerated than valproic acid. Valproate can cause weight gain, which appears to be more problematic than with lithium, but less problematic than with olanzapine.

In older dosing strategies used in acute settings (such as inpatient treatment of mania), valproate therapy was commonly initiated at 750-2,000 mg/day and increased as necessary and tolerated by 250 mg/day every 1-2 days. Newer strategies feature more aggressive valproate initiation in acute mania using divalproex formulations. Thus, with divalproex, initiating at 10 mg/lb (20 mg/kg) or even loading with 30 mg/kg/day for 1 or 2 days, followed by 20 mg/kg/day, appears to be adequately tolerated in acute mania. However, euthymic or depressed patients tend to tolerate aggressive initiation less well than manic patients. In less acute situations, such as the initiation of prophylaxis or adjunctive use, valproate is often started at 250-500 mg/day and increased as necessary and tolerated by 250 mg/day every 4-7 days. In the past, target dosages were commonly between 750 and 2,500 mg/day, yielding serum levels from 50 to 125 μg/mL (350-850 mM/L), with the higher portion of this range used acutely and lower dosages used in adjunctive therapy or prophylaxis. However, in a more recent acute mania study with divalproex extended-release formulation (Bowden et al. 2006), target serum levels ranged from 85 to 125 μg/mL (600-850 mM/L).

Valproate inhibits hepatic metabolism, and thus can increase serum concentrations of other medications such as lamotrigine, carbamazepine epoxide, and the anticonvulsants ethosuximide, felbamate, phenobarbital, and phenytoin. Also, hepatic enzyme inducers such as the anticonvulsants carbamazepine, phenobarbital, and phenytoin can decrease valproate serum concentrations.

Patients need to be advised of valproate adverse effects and drug interactions. Clinical assessments with valproate therapy include a baseline physical examination and routinely querying patients at baseline and during treatment regarding hepatic and hematological disorders and adverse effects. Laboratory monitoring during valproate therapy commonly includes baseline complete blood count, differential, platelets, and hepatic indices, and reevaluation every 6-12 months and as clinically indicated (American Psychiatric Association 2002). Serum valproate concentrations are typically assessed at steady state and then as clinically indicated by inefficacy or adverse effects.

Lamotrigine. Lamotrigine is approved for bipolar maintenance treatment in adults and is generally well tolerated, particularly in comparison with other treatment options. The most common adverse events in patients with bipolar disorders in clinical trials were headache, benign rash, dizziness, diarrhea, dream abnormality, and pruritus.

The U.S. prescribing information for lamotrigine includes a boxed warning regarding the risk of serious rashes requiring hospitalization, which have included Stevens-Johnson syndrome (Physicians' Desk Reference 2012). The risk of rash is higher in patients under age 16 years, and may be higher when lamotrigine is coadministered with valproate, when exceeding the recommended initial lamotrigine dose, and when exceeding the recommended lamotrigine dose escalation. Benign rash may be seen in 10% of patients, but because any rash is potentially serious, discontinuation of lamotrigine is required unless the rash is clearly not drug related. Other warnings in the prescribing information include the following risks:

• Suicidality (an anticonvulsant class warning)
• Hypersensitivity reactions (with fever and lymphadenopathy, but not necessarily rash)
• Acute multiorgan failure
• Blood dyscrasia
• Aseptic meningitis
• Medication errors (confusion with other medications)
• Lower and higher lamotrigine serum concentrations when given with hormonal contraceptives and valproate, respectively
• Binding in the eye and other melanin-containing tissues
• Withdrawal seizures in bipolar disorder patients; for this reason, lamotrigine should be tapered over 2 weeks unless safety concerns demand abrupt discontinuation

Lamotrigine can cause CNS (headache, somnolence, insomnia, dizziness, tremor) and gastrointestinal (nausea, diarrhea) adverse effects. In most instances these problems attenuate or resolve with time or lamotrigine dosage adjustment, but in some patients may require lamotrigine discontinuation. Unlike other mood stabilizers, lamotrigine has not been associated with weight gain.

Lamotrigine dosage is initially titrated very slowly to decrease the risk of rash. When given without valproate, the prescribing information recommends starting lamotrigine at 25 mg/day for 2 weeks, increasing to 50 mg/day for the next 2 weeks, then increasing to 100 mg/day for 1 week, and finally increasing to 200 mg/day in a single daily dose. Dosages exceeding 200 mg/day are not recommended unless concurrent hormonal contraceptives (which decrease serum lamotrigine concentrations) are administered. Even in the absence of hormonal contraceptives, selected patients may benefit from further gradual lamotrigine titration to final dosages as high as 400-500 mg/day.

When lamotrigine is added to valproate, recommended doses are halved, so lamotrigine is started at 25 mg every other day (although 12.5 mg/day maybe worth considering) for 2 weeks, increasing to 25 mg/day for the next 2 weeks, then increasing to 50 mg/day for 1 week, and finally increasing to 100 mg/day in a single daily dose. Dosages exceeding 100 mg/day are not recommended unless concurrent hormonal contraceptives are administered. Even in the absence of hormonal contraceptives, selected patients concurrently taking valproate may benefit from further gradual lamotrigine titration to final dosages as high as 250 mg/day.

When given with carbamazepine, dosages maybe doubled, so that lamotrigine may be started at 50 mg/day for 2 weeks, increased to 100 mg/day for the next 2 weeks, then increased to 300 mg/day for 1 week, and finally increased to 400 mg/day in divided doses. Dosages exceeding 400 mg/day are not recommended unless concurrent hormonal contraceptives are administered. Even in the absence of hormonal contraceptives, selected patients concurrently taking carbamazepine may benefit from further gradual lamotrigine titration to final dosages as high as 800 mg/day.

Patients should be advised that if they fail to take lamotrigine for 5 half-lives (e.g., approximately 5 days in the absence of carbamazepine or 3 days in the presence of carbamazepine), gradual reintroduction as described above is necessary. Rashes have been reported with rapid reintroduction.

Lamotrigine tends to be a target rather than an instigator of drug interactions. Thus, valproate increases and carbamazepine, hormonal contraceptives, and rifampin decrease serum lamotrigine concentrations.

Patients need to be advised of lamotrigine adverse effects and drug interactions. Clinical assessments with lamotrigine therapy include a baseline physical examination and routinely querying patients regarding rash at baseline and during treatment. Lamotrigine is generally well tolerated and serum concentrations have not been related to therapeutic effects in patients with bipolar disorders, so therapeutic drug monitoring with lamotrigine is not generally performed.

Carbamazepine. Carbamazepine has demonstrated efficacy for acute manic and mixed episodes in adults, but complexity of use (related to drug interactions and side effects) and lack of a maintenance indication make it less commonly used than other mood stabilizers.

Carbamazepine therapy is associated with common, benign adverse events as well as rare, serious adverse events. The most common dose-related adverse effects with carbamazepine involve CNS (diplopia, blurred vision, fatigue, sedation, dizziness, and ataxia) or gastrointestinal system (nausea, vomiting) problems. Gradual initial dosing and careful attention to potential drug-drug interactions can help attenuate such problems.

The U.S. prescribing information for carbamazepine includes boxed warnings regarding the risks of serious dermatological reactions in patients with the HLA-B*1502 allele (Asians should be genetically tested and, if HLA-B*1502 positive, should not be treated with carbamazepine unless benefit clearly outweighs risk), aplastic anemia (16/million patient-years), and agranulocytosis (48/million patient-years) (Physicians' Desk Reference 2012). Other warnings in the prescribing information include the risks of teratogenicity, increased intraocular pressure due to mild anticholinergic activity, and suicidality (an anticonvulsant class warning). Carbamazepine can cause hematological (benign leukopenia, benign thrombocytopenia), dermatological (benign rash), electrolyte (asymptomatic hyponatremia), and hepatic (benign transaminase elevations) problems. Much less commonly, carbamazepine can cause analogous serious problems. Rash presenting with systemic illness or involving the eyes, mouth, or bladder (dysuria) constitutes a medical emergency; in this situation, carbamazepine should be immediately discontinued and the patient assessed emergently.

Although carbamazepine can cause modest TSH increases, frank hypothyroidism is very uncommon. Carbamazepine may affect cardiac conduction and should be used with caution in patients with cardiac disorders. Carbamazepine appears less likely than lithium or valproate to cause weight gain. Carbamazepine-induced hyponatremia is often tolerated in young physically well individuals, but can cause obtundation and other serious sequelae in medically frail older adult patients. Carbamazepine, like the other mood stabilizers, is a teratogen (FDA Pregnancy Category D).

In acute settings, such as the inpatient treatment of mania, carbamazepine therapy is commonly initiated at 200-400 mg/day and increased as necessary and tolerated by 200 mg/day every 2-4 days. Euthymic or depressed patients tend to tolerate aggressive initiation less well than manic patients. In less acute situations, such as the initiation of prophylaxis or adjunctive use, carbamazepine is often started at 100-200 mg/day and increased as necessary and tolerated by 200 mg/day every 4-7 days. Even this gradual initiation may cause adverse effects. Starting with 50 mg (half of a chewable 100-mg tablet) at bedtime and increasing by 50 mg every 4 days can yield a better-tolerated initiation. Because of autoinduction, doses after 2-4 weeks of therapy may need to be twice as high as in the first week to yield comparable serum levels. Target dosages are commonly between 600 and 1,200 mg/day, yielding serum levels from 6 to 12 μg/mL (20-60 mM/L), with the higher portion of the range used acutely and lower dosages used in prophylaxis or adjunctive therapy.

Carbamazepine has multiple problematic drug-drug interactions (in excess of those seen with lithium or valproate). These interactions are predominantly related to it being a potent hepatic inducer that can decrease serum concentrations and efficacy of psychotropic (including valproate, lamotrigine, most SGAs, and multiple antidepressants and anxiolytics) and nonpsychotropic medications, and to the ability of certain enzyme inhibitors to increase carbamazepine serum concentrations and cause toxicity. Detailed reviews of carbamazepine drug-drug interactions may be found in articles by Ketter et al. (1991a, 1991b).

Patients need to be advised of carbamazepine adverse effects and drug interactions. Clinical assessments with carbamazepine therapy include a baseline physical examination and routinely querying patients at baseline and during treatment regarding hepatic and hematological disorders and adverse effects. In the past, recommended laboratory monitoring during carbamazepine therapy has included baseline complete blood count, differential, platelets, hepatic indices, and serum sodium, with reevaluation at 2, 4, 6, and 8 weeks, and then every 3 months and as clinically indicated (American Psychiatric Association 2002). In contemporary clinical practice, somewhat less focus is placed on scheduled monitoring, and clinically indicated (e.g., when a patient becomes ill with a fever) monitoring is emphasized. Patients who have abnormal or marginal indices at any point merit careful scheduled and clinically indicated monitoring. Serum carbamazepine concentrations are typically assessed at steady state, and then as indicated by inefficacy or adverse effects.

Second-Generation Antipsychotics

Based on their efficacy profiles and lower risks of extrapyramidal symptoms and tardive dyskinesia, SGAs have displaced first-generation antipsychotics in the management of bipolar and related disorders. Multiple SGAs have FDA indications for monotherapy and adjunctive (combined with lithium or valproate) therapy for acute mania and bipolar maintenance in adults. In addition, risperidone, aripiprazole, olanzapine, and quetiapine have pediatric mania monotherapy indications. Aripiprazole also has a pediatric mania adjunctive (to lithium or valproate) indication and a pediatric bipolar maintenance monotherapy indication. Olanzapine (combined with fluoxetine) and quetiapine monotherapy have acute bipolar depression indications in adults. Although (as of early 2013) cariprazine and lurasidone lack FDA indications for bipolar disorders, controlled trials suggest their efficacy in acute mania^ and bipolar depression, respectively, and clozapine may be effective in treatment-refractory patients. Short-acting injectable formulations of SGAs such as olanzapine, ziprasidone, and aripiprazole appear useful in the treatment of agitation, and a long-acting injectable (LAI, depot) formulation of risperidone may prove useful in patients with bipolar disorders who have poor medication compliance. Olanzapine LAI, although approved for the treatment of schizophrenia, is not approved for the treatment of bipolar and related disorders.

Second-generation antipsychotics compared with mood stabilizers entail more safety and tolerability challenges that can attenuate their efficacy benefits (e.g., weight gain with olanzapine, extra-pyramidal symptoms with risperidone, sedation with quetiapine, and akathisia with ziprasidone and aripiprazole). The U.S. prescribing information includes multiple warnings and precautions for these agents (Physicians' Desk Reference 2012). Indeed, the six SGAs (olanzapine, risperidone, quetiapine, ziprasidone, aripiprazole, and asenapine) with FDA indications for bipolar disorders (as well as lurasidone, which as of early 2013 was approved for schizophrenia but not yet for bipolar depression) have in common 12 such warnings and precautions:

1. Increased mortality in elderly patients with dementia-related psychosis; this is a boxed warning, with a reminder that SGAs are not approved for dementia-related psychosis
2. Neuroleptic malignant syndrome; the drug should be discontinued and the patient should be monitored closely
3. Tardive dyskinesia; the drug should be discontinued if clinically appropriate
4. Hyperglycemia and diabetes mellitus; the patient should be monitored for hyperglycemia symptoms such as polydipsia, polyuria, polyphagia, and weakness, and glucose should be monitored if there is a diabetes risk
5. Orthostatic hypotension with or without syncope; the drug should be used with caution if the patient has cardiovascular or cerebrovascular disease
6. Leukopenia, neutropenia, and agranulocytosis; the patient should be monitored if there is prior or baseline leukopenia, and the drug should be discontinued if there is a decrease in white blood cells in the absence of other causative factors
7. Seizures; the drug should be used with caution if the patient has a seizure disorder or seizure risk
8. Potential for cognitive and motor impairment; the patient should use caution when operating machinery
9. Body temperature regulation (pyrexia, feeling hot); caution should be used when prescribing the drug to a patient who may be doing strenuous exercise, may be exposed to extreme heat, may become dehydrated, or is taking an anticholinergic medication)
10. Suicide (risk related to bipolar disorders and schizophrenia); high-risk individuals should be closely supervised
11. Dysphagia; the drug should be used with caution if there is a risk of aspiration pneumonia
12. Use in patients with concomitant illness; the drug should be used with caution if the patient has cardiovascular or another systemic disease

The presence or absence of additional warnings and precautions indicates within-class safety and tolerability differences between individual SGAs. For example, to date, the U.S. prescribing information includes four additional warnings and precautions for all of the above SGAs, with exceptions as noted:

1. Weight gain (ziprasidone excepted); the patient's weight should be monitored
2. Hyperprolactinemia (aripiprazole excepted); includes risk of galactorrhea, amenorrhea, gynecomastia, and impotence
3. Hyperlipidemia/dyslipidemia (ziprasidone and asenapine excepted); the patient's lipids should be monitored
4. Cerebrovascular accidents, including stroke, in elderly patients with dementia-related psychosis (quetiapine and ziprasidone excepted); SGAs are not approved for dementia-related psychosis

Other, less widespread warnings and precautions distinguishing individual SGAs from one another are noted in the following subsections on specific drugs.

Olanzapine. The most common adverse reactions in adult acute mania trials with oral olanzapine monotherapy included somnolence (35% vs. 13% with placebo, number needed to harm [NNH]= 5), dry mouth (22% vs. 7% with placebo, NNH=7), and dizziness (18% vs. 6% with placebo, NNH=9). Somnolence is the most common adverse effect with intramuscular olanzapine. Maximal dosing of intramuscular olanzapine may cause substantial orthostatic hypotension, so administration of additional doses to patients with clinically significant postural changes in systolic blood pressure is not recommended.

In 13 placebo-controlled adult olanzapine monotherapy studies with 8-week median exposure, at least 7% weight gain was seen in 22.2% of patients versus 3% with placebo (NNH=6). In long-term adult olanzapine monotherapy studies, at least 7% weight gain was seen in 64% of patients. Weight gain appears even more problematic in adolescents than in adults. In placebo-controlled adolescent olanzapine acute monotherapy studies, at least 7% weight gain was seen in 40.6% of patients versus 9.8% (NNH=4). In long-term adolescent olanzapine monotherapy studies, at least 7% weight gain was seen in 89% of patients. Thus, olanzapine can cause weight gain, diabetes, and hyperlipidemia, with the risk (as with clozapine) being greater than with other SGAs (American Diabetes Association et al. 2004).

The warnings and precautions in U.S. prescribing information for olanzapine, in addition to those mentioned earlier for multiple SGAs, include caution using olanzapine in combination with lithium or valproate (refer to the lithium/valproate warnings and precautions). To date, olanzapine has not been associated with congenital malformations in humans (FDA Pregnancy Category C).

Acute mania dosing recommendations for olanzapine in adult monotherapy include initiating at 10-15 mg once daily and titrating by 5-mg increments as necessary and tolerated to final dosages as high as 20 mg once daily. Recommendations for adult adjunctive (added to lithium or valproate) therapy include initiating at 10 mg once daily and titrating as necessary and tolerated to final dosages as high as 20 mg once daily. Acute mania dosing recommendations for olanzapine in adolescent monotherapy include initiating at 2.5-5 mg once daily and titrating by 2.5-5 mg increments as necessary and tolerated, with a target dosage of 10 mg once daily. Acute bipolar depression dosing recommendations for olanzapine plus fluoxetine in adults include initiating olanzapine at 5 mg and fluoxetine at 20 mg once daily and titrating as necessary and tolerated to within the ranges of olanzapine 5-12.5 mg/day and fluoxetine 20-50 mg/day. It is generally recommended that patients responding to olanzapine be continued beyond the acute response, but at the lowest dose needed to maintain remission.

Risperidone. Common adverse reactions in adult acute mania trials with risperidone monotherapy at dosages ≤6 mg/day included parkinsonism (25% vs. 9% with placebo, NNH=7), akathisia (9% vs. 3% with placebo, NNH=17), and sedation (6% vs. 2% with placebo, NNH= 25). In adult acute mania/schizophrenia trials, at least 7% weight gain was seen with risperidone dosages ≤8 mg/day in 8.7% of patients versus 2.9% with placebo (NNH= 18) and with risperidone dosages >8 mg/day in 20.9% of patients versus 2.9% with placebo (NNH=6). In pediatric acute mania, schizophrenia, and autism trials, at least 7% weight gain was seen with risperidone dosages ≤6 mg/day in 32.6% of patients versus 6.9% with placebo (NNH= 4). Common adverse reactions in risperidone LAI bipolar maintenance trials included weight gain (5% in monotherapy trial), tremor, and parkinsonism (≥10% in adjunctive therapy trial). Thus, risperidone, like other SGAs, can cause weight gain, diabetes, and hyperlipidemia, with the risk considered intermediate—less than with clozapine and olanzapine but more than with ziprasidone and aripiprazole (American Diabetes Association et al. 2004).

The warnings and precautions in U.S. prescribing information for risperidone, in addition to those mentioned earlier for multiple SGAs, include the following:

• Priapism (in common with quetiapine and ziprasidone); if severe the condition may require surgery
• Thrombotic thrombocytopenic purpura; one postmarketing case has been reported
• Intravenous administration; the LAI formulation should be carefully injected into the deltoid or gluteal muscle
• Antiemetic effect; this effect may mask drug overdose, intestinal obstruction, Reye syndrome, or brain tumor
• Osteodystrophy and tumors in animals; osteodystrophy and renal tubular/adrenomedullary tumors have been seen in rats

To date, risperidone has not been associated with congenital malformations in humans (FDA Pregnancy Category C).

Acute mania dosing recommendations for risperidone in adults include initiating at 2-3 mg/day and increasing by 1 mg/day to final dosages as high as 6 mg/day; for children and adolescents, recommendations include initiating at 0.5 mg/day and increasing by 0.5-1 mg/day to final dosages as high as 2.5 mg/day. To limit adverse effects, risperidone in bipolar disorder patients who are not manic may be started at 0.25-0.5 mg/day and increased as necessary and tolerated every 4r-7 days by 0.25-0.5 mg/day, with an initial target dosage of 1-2 mg/day. In bipolar disorder patients, risperidone is often administered all or mostly at bedtime, and commonly in combination with other medications. Once the tolerability of oral risperidone has been established, risperidone LAI is initiated at 25 mg im every 2 weeks, with dosages eventually as high as 50 mg im every 2 weeks yielding benefit in some patients.

Quetiapine. The most common adverse reactions in adult acute mania and schizophrenia trials with quetiapine monotherapy included somnolence (18% vs. 8% with placebo, NNH=10) and at least 7% weight gain (21.1% vs. 6.6% with placebo, NNH=7). In a pediatric acute mania trial, quetiapine monotherapy was associated with at least 7% weight gain in 11.5% of patients versus 0.0% with placebo (NNH= 9). In a 26-week pediatric open follow-up study, quetiapine monotherapy was associated with at least 7% weight gain in 45% of patients. Thus, quetiapine can cause weight gain, diabetes, and hyperlipidemia, with the risk considered intermediate—less than with clozapine and olanzapine but more than with ziprasidone and aripiprazole (American Diabetes Association et al. 2004). To date, quetiapine has not been associated with congenital malformations in humans (FDA Pregnancy Category C).

The warnings and precautions in U.S. prescribing information for quetiapine, in addition to those mentioned earlier for multiple SGAs, include the following:

• Clinical worsening and suicide risk in patients age <25 years (this is a boxed warning, in common with aripiprazole, olanzapine plus fluoxetine combination, and all antidepressants); the patient should be closely monitored clinically
• QT prolongation (in common with ziprasidone and asenapine); see below for risk management recommendations
• Priapism (in common with risperidone and ziprasidone); if severe the condition may require surgery
• Increased blood pressure in children and adolescents; the patient's blood pressure should be monitored
• Cataracts; the patient's ocular lens should be monitored
• Hypothyroidism; this is generally asymptomatic
• Transaminase elevations; these are asymptomatic and reversible
• Withdrawal (insomnia, nausea, and vomiting); gradual discontinuation of the drug is recommended

Quetiapine (in common with ziprasidone), unlike several other SGAs, lacks a warning or precaution regarding cerebrovascular accidents, including stroke, in elderly patients with dementia-related psychosis.

Recommended management of the QT prolongation risk includes avoiding quetiapine in any of the following situations:

• Cardiac arrhythmia
• Hypokalemia/hypomagnesemia
• Concomitant use of Class IA or IH anti-arrhythmics, certain antipsychotics (e.g., ziprasidone, asenapine, chlorpromazine, thioridazine), certain antibiotics (e.g., gatifloxacin, moxifloxacin), or medication classes that prolong QT (e.g., pentamidine, levomethadyl acetate, methadone)
• Congenital QT prolongation

Caution using quetiapine is recommended if the patient is elderly or has cardiovascular disease, a family history of QT prolongation, congestive heart failure, or heart hypertrophy.

Acute mania dosing recommendations for quetiapine in adults include initiating at 100 mg/day on day 1; increasing to 200 mg/day on day 2, to 300 mg/day on day 3, and to 400 mg/day on day 4; and further increasing by no more than 200 mg/day to final dosages as high as 800 mg/day by day 6. Acute mania dosing recommendations for quetiapine in children and adolescents include initiating at 50 mg/day on day 1; increasing to 100 mg/day on day 2, to 200 mg/day on day 3, to 300 mg/day on day 4, and to 400 mg/day on day 5; and further increasing by no more than 100 mg/day to final dosages as high as 600 mg/day. Quetiapine acute bipolar depression dosing recommendations for adults include initiating at 50 mg at bedtime on day 1 and increasing to 100 mg at bedtime on day 2, to 200 mg at bedtime on day 3, and to 300 mg at bedtime on day 4. Adjunctive (added to lithium or valproate) quetiapine bipolar maintenance dosing recommendations for adults include taking 400-800 mg/day, generally continuing the same dosage that yielded acute mood stabilization. Although the U.S. prescribing information recommends two divided doses in acute mania and bipolar maintenance, quetiapine in these instances is commonly administered as it is in acute bipolar depression, in a single bedtime dose to attenuate daytime somnolence.

Ziprasidone. The most common adverse reactions in adult acute mania trials with oral ziprasidone monotherapy included somnolence and extrapyramidal symptoms (both 31% vs. 12% with placebo, NNH=6). The most common adverse reaction in an adjunctive (added to lithium or valproate) maintenance trial was tremor. The most common adverse events with intramuscular ziprasidone for agitation in schizophrenia patients were headache, nausea, and somnolence. Ziprasidone, unlike other SGAs, lacks warnings/precautions regarding weight gain and (in common with asenapine) hyperlipidemia/dyslipidemia. Indeed, the report of a consensus development conference suggested the risks of obesity, diabetes, and hyperlipidemia with ziprasidone were similar to those with aripiprazole and less than with other SGAs (American Diabetes Association et al. 2004).

Thus, ziprasidone and aripiprazole, compared with risperidone, olanzapine, and quetiapine, cause less sedation and weight gain but more akathisia. In patients with acute mania, akathisia is commonly accompanied by and at times difficult to distinguish from agitation and anxiety. These overlapping symptoms may be attenuated with adjunctive benzodiazepine therapy. To date, ziprasidone has not been associated with congenital malformations in humans (FDA Pregnancy Category C).

The warnings and precautions in U.S. prescribing information for ziprasidone, in addition to those mentioned earlier for multiple SGAs, include the following:

• QT prolongation (in common with quetiapine and asenapine); the drug should be discontinued if QTc≥500 msec. A Holter monitor should be used if the patient experiences dizziness, palpitations, or syncope. See the earlier "Quetiapine" section for additional risk management recommendations.
• Priapism (in common with risperidone and quetiapine); if the condition is severe, surgery may be required.
• Rash; the drug should be discontinued if the patient develops a rash without alternative etiology.

Although premarketing studies suggested that ziprasidone was associated with cardiac conduction delays, postmarketing experience failed to indicate clinically significant problems with cardiac conduction. Ziprasidone (in common with quetiapine), unlike several other SGAs, lacks a warning or precaution regarding cerebrovascular accidents, including stroke, in elderly patients with dementia-related psychosis.

Acute mania dosing recommendations for ziprasidone in adult monotherapy include initiating at 40 mg twice daily with food, increasing to 60 or 80 mg twice daily with food on day 2, and titrating as necessary and tolerated to final dosages of 40-80 mg twice daily with food. Ziprasidone adjunctive (added to lithium or valproate) bipolar maintenance recommendations for adults include continuing the same dosage that yielded mood stabilization, within the range of 40-80 mg twice daily. In clinical practice, lower (e.g., <80 mg/day) compared with higher (e.g., ≥80 mg/day) ziprasidone dosages may increase the risk of akathisia, so optimal titration of this agent may involve avoiding lower dosages to prevent akathisia or abruptly increasing to higher dosages if akathisia develops at lower dosages. For convenience, and in view of the risk of sedation, dosing may be weighted toward dinnertime or bedtime with a snack. Ziprasidone for agitation in schizophrenia is administered as 10 mg im, repeating 10 mg im as often as every 2 hours as necessary and tolerated, with a maximum dosage of 40 mg/day im for 3 days.

Aripiprazole. The most common adverse reactions in adult acute mania trials with oral aripiprazole monotherapy included akathisia (13% vs. 4% with placebo, NNH=12) and sedation (8% vs. 3% with placebo, NNH=20). Aripiprazole-related akathisia (like ziprasidone-related akathisia) may respond to benzodiazepines. In adult acute mania trials, oral aripiprazole monotherapy was associated with at least 7% weight gain in 2.2% of patients versus 2.7% with placebo (NNH= -200). The most common adverse reactions in pediatric acute mania trials with oral aripiprazole monotherapy included somnolence (23% vs. 3% with placebo, NNH=5) and extrapyramidal symptoms (20% vs. 3% with placebo, NNH=6). In pediatric acute mania and schizophrenia trials, oral aripiprazole monotherapy was associated with at least 7% weight gain in 5.2% of patients versus 1.6% with placebo (NNH= 28). In open-label extensions of adolescent schizophrenia and pediatric bipolar disorder, 32.8% of patients gained ≥7% of their weight. The report of a consensus development conference suggested the risks of obesity, diabetes, and hyperlipidemia with aripiprazole were similar to those with ziprasidone, and less than with other SGAs (American Diabetes Association et al. 2004).

Gastrointestinal adverse effects such as nausea, dyspepsia, vomiting, constipation, and diarrhea may be related to dopamine partial agonist effects and tend to diminish with ongoing exposure. Although in view of its long half-life aripiprazole can be dosed once daily, during the first few days of treatment the lower maximum concentrations associated with divided doses may offer enhanced tolerability. Thus, tolerability may be enhanced in patients with gastrointestinal or other adverse effects if aripiprazole is initiated at 15 mg twice daily (or lower if necessary) for a few days before increasing to 30 mg once daily. To date, aripiprazole has not been associated with congenital malformations in humans (FDA Pregnancy Category C).

The warnings and precautions in U.S. prescribing information for aripiprazole, in addition to those mentioned earlier for multiple SGAs, include clinical worsening and suicide risk in patients younger than 25 years (this is a boxed warning, in common with quetiapine, olanzapine plus fluoxetine combination, and all antidepressants); the patient should be closely monitored clinically. Aripiprazole, unlike other SGAs, lacks a warning/precaution regarding hyperprolactinemia.

Acute mania dosing recommendations for aripiprazole in adult monotherapy include initiating at 15 mg/day, with a recommended dosage of 15 mg/day and a maximum dosage of 30 mg/day. For adult adjunctive (added to lithium or valproate) therapy, recommendations include initiating at 10-15 mg/day, with a recommended dosage of 15 mg/day and a maximum dosage of 30 mg/day. For pediatric monotherapy or adjunctive therapy, recommendations include initiating at 2 mg/day, with a recommended dosage of 10 mg/day and a maximum dosage of 30 mg/day. In early adult acute mania trials, mean final aripiprazole dosages were approximately 28 mg/day. Aripiprazole monotherapy and adjunctive (added to lithium or valproate) maintenance dosing recommendations include taking the same dosage that yielded acute mood stabilization. In monotherapy maintenance treatment for bipolar I disorder, oral aripiprazole final dosages average approximately 24 mg/day.

In two negative acute bipolar I non-psychotic depression studies, aripiprazole monotherapy was initiated at 10 mg/day and flexibly dosed within a range of 5-30 mg/day, with a pooled mean dosage of 16.5 mg/day (Thase et al. 2006). Citing high discontinuation rates, the authors speculated that this dosing may have been too aggressive for acute bipolar depression. Indeed, dosing recommendations for adjunctive (added to antidepressants) aripiprazole treatment of unipolar major depressive disorder include initiating at 2-5 mg/day and titrating to a recommended dosage of 5-10 mg/day, with a maximum dosage of 15 mg/day. It may be that this more conservative dosing would be better tolerated in depressed or euthymic bipolar disorder patients.

Intramuscular aripiprazole is recommended to be administered as a 9.75-mg injection, or a 5.25-mg injection if clinically indicated; these injections should be repeated as often as every 2 hours as necessary and tolerated, with a maximum dosage of 30 mg/day. The prescribing information does not recommend 15-mg injections, because of concerns regarding adverse effects and the lack of additional benefit with doses higher than 9.75 mg per injection in clinical trials.

Asenapine. The most common adverse reactions in adult acute mania trials with oral asenapine monotherapy included somnolence (24% vs. 6% with placebo, NNH=6) and dizziness (11% vs. 3% with placebo, NNH=13). In adult acute mania trials, asenapine was associated with at least 7% weight gain in 5.8% of patients versus 0.5% with placebo (NNH= 9). Due to the sublingual route of administration, patients may complain of oral hypoesthesia and/or a bitter taste. Use of the black cherry flavor asenapine formulation may mitigate the latter problem. To date, asenapine has not been associated with congenital malformations in humans (FDA Pregnancy Category C).

The warnings and precautions in U.S. prescribing information for asenapine, in addition to those mentioned earlier for multiple SGAs, include QT prolongation (in common with quetiapine and ziprasidone; see earlier "Quetiapine" section for risk management recommendations) and hypersensitivity reactions (anaphylaxis, angioedema, hypotension, tachycardia, swollen tongue, dyspnea, wheezing, and rash). Asenapine (in common with ziprasidone), unlike other SGAs, lacks a warning or precaution regarding hyperlipidemia/dyslipidemia.

Acute mania dosing recommendations for asenapine in adult monotherapy include initiating at 10 mg sublingually twice daily, which is also the maximum dosage, with the recommended dosage being 5-10 mg twice daily For acute mania adjunctive (added to lithium or valproate) therapy, recommendations include initiating at 5 mg sublingually twice daily, with a maximum dosage of 10 mg twice daily and a recommended dosage of 5-10 mg twice daily. Asenapine sublingual tablets should be placed under the tongue and left to dissolve completely (which occurs within seconds), and eating and drinking should be avoided for 10 minutes after administration.

Lurasidone. The most common adverse reactions in adult acute schizophrenia trials with lurasidone monotherapy included somnolence (17% vs. 7% with placebo, NNH=10) and akathisia (13% vs. 3% with placebo, NNH=10). In these trials, lurasidone monotherapy was associated with at least 7% weight gain in 4.8% of patients versus 3.3% with placebo (NNH=67). To date, lurasidone has not been associated with congenital malformations in humans or animals (FDA Pregnancy Category B).

Lurasidone is a cytochrome P450 3A4 (CYP3A4) substrate, so coadministration with strong CYP3A4 inhibitors and inducers is contraindicated.

Lurasidone acute schizophrenia dosing recommendations for adult monotherapy include initiating at 40 mg once daily with food, with a maximum dosage of 160 mg once daily with food.

Adjunctive Antidepressants, Anxiolytics/Hypnotics, Other Anticonvulsants, Other Medications, and Other Somatic Therapies

Diverse adjunctive somatic interventions are commonly administered off-label in combination with mood stabilizers and/or SGAs in the clinical management of bipolar and related disorders. Arguably, adjunctive antidepressants are the most common and controversial of such agents. In the absence of definitive data from large controlled trials, some clinicians opine that adjunctive antidepressants are effective and well tolerated, while others contend such agents are ineffective and/or cause mood elevation or cycle acceleration. Indeed, there appears to be considerable interindividual variation in efficacy and tolerability of adjunctive antidepressants, making them potentially useful for some patients and problematic for others.

Adjunctive anxiolytics/hypnotics are commonly used in patients with bipolar disorders to manage anxiety and insomnia. For some patients these agents carry a favorable risk-benefit ratio, but for other patients the risks of tolerance, withdrawal, and/or abuse may limit their utility.

Adjunctive use of other anticonvulsants (i.e., other than valproate, lamotrigine, and carbamazepine) is generally not effective for bipolar and related disorders, although some agents may be effective for comorbid conditions. Examples include gabapentin/pregabalin for pain or anxiety; topiramate for migraines, obesity, and alcohol abuse; and zonisamide for obesity.

As with adjunctive antidepressants, adjunctive stimulants and stimulant-like agents (e.g., modafinil or armodafinil) may offer a favorable risk-benefit ratio in some patients but may have efficacy and tolerability challenges in other patients.

Adjunctive neuromodulation interventions such as electroconvulsive therapy, transcranial magnetic stimulation, and vagus nerve stimulation may offer benefits for some patients with bipolar disorders (Rosa and Lisanby 2012).

Psychotherapeutic Treatment of Bipolar and Related Disorders

Adjunctive (added to pharmacotherapy) psychotherapy interventions such as psychoeducation, cognitive-behavioral therapy, family-focused therapy, and interpersonal and social rhythm therapy have demonstrated efficacy in acute bipolar depression and bipolar maintenance treatment, with effect sizes comparable to pharmacotherapy. Such interventions may be particularly attractive for psychologically minded patients and patients who have inadequate efficacy and/or tolerability with somatic therapies.

Integrative Management of Bipolar and Related Disorders

Given the complexity of bipolar disorders and the efficacy and tolerability limitations of somatic therapies, it is crucial to integrate such interventions with other therapeutic modalities such as psychotherapy and lifestyle interventions.

Treatment of Bipolar and Related Disorders in Women and Special Age Groups

Women

Management of bipolar and related disorders in women entails accounting for the effects of the female reproductive cycle (menarche, menstrual cycle, pregnancy, postpartum period, and menopause), gender-related clinical presentations, concurrent nonpsychiatric medications (e.g., hormonal contraceptives), and gender-related differences in the efficacy and tolerability of psychiatric medications (Freeman et al. 2002; Ketter 2010). The complexity of pharmacotherapy in women with bipolar disorders is increased by the risks of teratogenicity and breastfeeding and drug interactions with hormonal contraceptives.

Children and Adolescents

Management of bipolar and related disorders in children and adolescents entails accounting for the effects of normal development, age-related clinical presentations, concurrent psychiatric disorders (e.g., ADHD, anxiety disorders, and substance use disorders), and age-related differences in the efficacy and tolerability of psychiatric medications (Ketter 2010). For example, as detailed earlier in this chapter, youth with bipolar disorders commonly experience significantly more weight gain with SGAs than do adults. Furthermore, children and adolescents require additional attention to family environments, parental practices, and educational settings in order to maximize positive outcomes for this population.

Patients with earlier-onset bipolar disorders (i.e., in childhood and adolescence) typically have more morbidity and poorer outcomes than those with later-onset bipolar disorders (Carter et al. 2003).

Older Adults

Management of bipolar and related disorders in older adults entails accounting for the effects of normal aging, age-related clinical presentations, concurrent medical disorders and related nonpsychiatric medications, and age-related differences in the efficacy and tolerability of psychiatric medications (Ketter 2010; Sajatovic and Blow 2007). Because of tolerability challenges and pharmacokinetic differences, medication doses in older compared with younger adults are not uncommonly 50% lower. Tolerability limitations of somatic therapies with more side effects (e.g., SGAs) may be particularly important in older adults.

Key Clinical Points

• Bipolar and related disorders are common, in their broadest definition affecting approximately 4% of the population. As a group, these disorders are also one of the leading causes of psychiatric disability.
• The causes of bipolar and related disorders are multifactorial and commonly include both genetic and environmental contributions.
• Diagnosis of bipolar disorder can be challenging because presentations vary with age and gender and there is limited ability to detect past mood-elevation episodes.
• Bipolar and related disorders are chronic and recurring illnesses that require not only acute but also preventive treatment.
• Treatment of bipolar and related disorders begins with selecting pharmacotherapy that is appropriate to illness subtype and phase.
• Although mood stabilizers are an established treatment for bipolar and related disorders, the addition of other agents (e.g., SGAs, antidepressants, and novel adjuncts) is commonly required. Adjunctive psychotherapy is also commonly used.

¹ In distinguishing grief from a major depressive episode (MDE), it is useful to consider that in grief the predominant affect is feelings of emptiness and loss, while in MDE it is persistent depressed mood and the inability to anticipate happiness or pleasure. The dysphoria in grief is likely to decrease in intensity over days to weeks and occurs in waves, the so-called pangs of grief. These waves tend to be associated with thoughts or reminders of the deceased. The depressed mood of MDE is more persistent and not tied to specific thoughts or preoccupations. The pain of grief may be accompanied by positive emotions and humor that are uncharacteristic of the pervasive unhappiness and misery characteristic of MDE. The thought content associated with grief generally features a preoccupation with thoughts and memories of the deceased, rather than the self-critical or pessimistic ruminations seen in MDE. In grief, selfesteem is generally preserved, whereas in MDE feelings of worthlessness and self-loathing are common. If self-derogatory ideation is present in grief, it typically involves perceived failings vis-a-vis the deceased (e.g., not visiting frequently enough, not telling the deceased how much he or she was loved). If a bereaved individual thinks about death and dying, such thoughts are generally focused on the deceased and possibly about "joining" the deceased, whereas in MDE such thoughts are focused on ending one's own life because of feeling worthless, undeserving of life, or unable to cope with the pain of depression.

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Suggested Readings

Colom F, Vieta E, Scott J: Psychoeducation Manual for Bipolar Disorder. New York, Cambridge University Press, 2006

Frank E: Treating Bipolar Disorder: A Clinician's Guide to Interpersonal and Social Rhythm Therapy. New York, Guilford, 2005

Goodwin FR, Jamison K: Manic-Depressive Illness: Bipolar Disorders and Recurrent Depression, 2nd Edition. New York, Oxford University Press, 2007

Ketter TA (ed): Handbook of Diagnosis and Treatment of Bipolar Disorder. Washington, DC, American Psychiatric Publishing, 2010

Ketter TA, Citrome L, Wang PW, et al: Treatments for bipolar disorder: can number needed to treat/harm help inform clinical decisions? Acta Psychiatr Scand 123:175-189, 2011

Ramirez Basco M, Rush A: Cognitive-Behavioral Therapy for Bipolar Disorders, 2nd Edition. New York, Guilford, 2005

Schatzberg AF, Nemeroff CB (eds): Essentials of Psychopharmacology, 5th Edition. Washington, DC, American Psychiatric Publishing, 2012

Online Resources

American Psychiatric Association: http://www.psychiatry.org/mental-health/key-topics/bipolar-disorder ("Bipolar Disorder" Web page; includes link to "Let's Talk Facts About Bipolar Disorder (Manic Depression)" brochure)

Balanced Mind Foundation: http://www.thebalancedmind.org

Bipolar Network News: http://bipolarnews.org

Collaborative Psychiatric Epidemiology Surveys: http://www.icpsr.umich.edu/icpsrweb/CPES/diagnoses.jsp?ti-tle=DSM-IV+Bipolar

Depression and Bipolar Support Alliance: http://www.dbsalliance.org

National Institute of Mental Health: http://www.nimh.nih.gov/health/publica-tions/bipolar-disorder-listing.shtml