Bipolar Disorder

Discuss this article

Borderline personality disorder (BPD) and bipolar disorder are frequently confused with each other, in part because of their considerable symptomatic overlap. This redundancy occurs despite the different ways these disorders are conceptualized: BPD as a personality disorder and bipolar disorder as a brain disease among Axis I clinical disorders.

BPD and bipolar disorder—especially bipolar II—often co-occur ( Box ) and are frequently misidentified, as shown by clinical and epidemiologic studies. Misdiagnosis creates problems for clinicians and patients. When diagnosed with BPD, patients with bipolar disorder may be deprived of potentially effective pharmacologic treatments.¹ Conversely, the stigma that BPD carries—particularly in the mental health community—may lead clinicians to:

• not even disclose the BPD diagnosis to patients²
• lean in the direction of diagnosing BPD as bipolar disorder, potentially resulting in treatments that have little relevance or failure to refer for more appropriate psychosocial treatments.

To help you avoid confusion and the pitfalls of misdiagnosis, this article clarifies the distinctions between bipolar disorder and BPD. We discuss symptom overlap, highlight key differences between the constructs, outline diagnostic differences, and provide useful suggestions to discern the differential diagnosis.

Box

Nonchance explanations for the diagnostic overlap
between BPD and bipolar disorder*

1. Inability of current nosology to separate 2 distinct conditions

Relatively indistinct diagnostic boundaries confuse the differentiation of borderline personality disorder (BPD) and bipolar disorder (5 of 9 BPD criteria may occur with mania or hypomania). In this model, the person has 1 disorder but because of symptom overlap receives a diagnosis of both. Because structured interviews do not allow for subjective judgment or expert opinion, the result is the generation of 2 diagnoses when 1 may provide a more parsimonious and valid explanation.

2. BPD exists on a spectrum with bipolar disorder

The mood lability of BPD may be viewed as not unlike that seen with bipolar disorder.¹ Behaviors displayed by patients with BPD are subsequently conceptualized as arising from their unstable mood. Supporting arguments cite family study data and evidence from pharmacotherapy trials of anticonvulsants, including divalproex, for rapid cycling bipolar disorder and BPD.² Family studies have been notable for their failure to directly characterize family members, however, and clinical trials have been quite small. Further, treatment response may have very limited nosologic implications.

3. Bipolar disorder is a risk factor for BPD

4. BPD is a risk factor for bipolar disorder

Early emergence of a bipolar disorder (in preadolescent or adolescent patients) has been proposed to disrupt psychological development, leading to BPD. This adverse impact on personality development—the “scar hypothesis”³ —is supported by data showing greater risk of co-occurring BPD with earlier onset bipolar disorder.⁴ More important, prospective studies of patients with bipolar disorder show a greater risk for developing BPD.⁵

BPD also may be a risk factor for the development of bipolar disorder—the “vulnerability hypothesis.”³ Patients with BPD are more likely to develop bipolar disorder, even compared to patients with other personality disorders.⁵

5. Shared risk factors

BPD and bipolar disorder may be linked by shared risk factors, such as shared genes or trait neuroticism.³

*Some evidence supports each potential explanation, and they are not necessarily mutually exclusive

References

a. Akiskal HS. Demystifying borderline personality: critique of the concept and unorthodox reflections on its natural kinship with the bipolar spectrum. Acta Psychiatr Scand. 2004;110(6):401-407.

b. Mackinnon DF, Pies R. Affective instability as rapid cycling: theoretical and clinical implications for borderline personality and bipolar spectrum disorders. Bipolar Disord. 2006;8(1):1-14.

c. Christensen MV, Kessing LV. Do personality traits predict first onset in depressive and bipolar disorder? Nord J Psychiatry. 2006;60(2):79-88.

d. Goldberg JF, Garno JL. Age at onset of bipolar disorder and risk for comorbid borderline personality disorder. Bipolar Disord. 2009;11(2):205-208.

e. Gunderson JG, Weinberg I, Daversa MT, et al. Descriptive and longitudinal observations on the relationship of borderline personality disorder and bipolar disorder. Am J Psychiatry. 2006;163(7):1173-1178.

Overlapping symptoms

Bipolar disorder is generally considered a clinical disorder or brain disease that can be understood as a broken mood “thermostat.” The lifetime prevalence of bipolar types I and II is approximately 2%.³ Approximately one-half of patients have a family history of illness, and multiple genes are believed to influence inheritance. Mania is the disorder’s hallmark,⁴ although overactivity has alternatively been proposed as a core feature.⁵ Most patients with mania ultimately experience depression⁶ ( Table 1 ).

No dimensional personality correlates have been consistently demonstrated in bipolar disorder, although co-occurring personality disorders—often the “dramatic” Cluster B type—are common^4,7 and may adversely affect treatment response and suicide risk.^8,9

Both bipolar disorder and BPD are associated with considerable risk of suicide or suicide attempts.^10,11 Self-mutilation or self-injurious behavior without suicidal intent are particularly common in BPD.¹² Threats of suicide—which may be manipulative or help-seeking—also are common in BPD and tend to be acute rather than chronic.¹³

Borderline personality disorder is characterized by an enduring and inflexible pattern of thoughts, feelings, and behaviors that impairs an individual’s psychosocial or vocational function. Its estimated prevalence is approximately 1%,¹⁴ although recent community estimates approach 6%.¹⁵ Genetic influences play a lesser etiologic role in BPD than in bipolar disorder.

Several of BPD’s common features ( Table 2 )—impulsivity, mood instability, inappropriate anger, suicidal behavior, and unstable relationships—are shared with bipolar disorder, but patients with BPD tend to show higher levels of impulsiveness and hostility than patients with bipolar disorder.¹⁶ Dimensional assessments of personality traits suggest that BPD is characterized by high neuroticism and low agreeableness.¹⁷ BPD also has been more strongly associated with a childhood history of abuse, even when compared with control groups having other personality disorders or major depression.¹⁸ The male-to-female ratio for bipolar disorder approximates 1:1;³ in BPD this ratio has been estimated at 1:4 in clinical samples¹⁹ and near 1:1 in community samples.¹⁵

BPD and bipolar disorder often co-occur. Evidence indicates ≤20% of patients with BPD have comorbid bipolar disorder²⁰ and 15% of patients with bipolar disorder have comorbid BPD.²¹ Co-occurrence happens much more often than would be expected by chance. These similar bidirectional comorbidity estimates (15% to 20%) would not be expected for conditions of such differing prevalence (<1% vs 2% or more). This suggests:

• the estimated prevalence of bipolar disorder in BPD is too low
• the estimated prevalence of BPD in bipolar disorder samples is too high
• borderline personality disorder is present in >1% of the population
• bipolar disorder is less common
• some combination of the above.

Among these possibilities, the prevalence estimates of bipolar disorder are the most consistent. Several studies suggest that BPD may be much more common, with some estimates exceeding 5%.¹⁵

Table 1

Common signs and symptoms
associated with mania and depression in bipolar disorder

Table 2

Borderline personality disorder: Commonly reported features

Roots of misdiagnosis

The presence of bipolar disorder or BPD may increase the risk that the other will be misdiagnosed. When symptoms of both are present, those suggesting 1 diagnosis may reflect the consequences of the other. A diagnosis of BPD could represent a partially treated or treatment-resistant bipolar disorder, or a BPD diagnosis could be the result of several years of disruption by a mood disorder.

Characteristics of bipolar disorder have contributed to clinician bias in favor of that diagnosis rather than BPD ( Table 3 ).^22,23 Bipolar disorder also may be misdiagnosed as BPD. This error may most likely occur when the history focuses excessively on cross-sectional symptoms, such as when a patient with bipolar disorder shows prominent mood lability or interpersonal sensitivity during a mood episode but not when euthymic.

Bipolar II disorder. The confusion between bipolar disorder and BPD may be particularly problematic for patients with bipolar II disorder or subthreshold bipolar disorders. The manias of bipolar I disorder are much more readily distinguishable from the mood instability or reactivity of BPD. The manic symptoms of bipolar I are more florid, more pronounced, and lead to more obvious impairment.

The milder highs of bipolar II may resemble the mood fluctuations seen in BPD. Further, bipolar II is characterized by a greater chronicity and affective morbidity than bipolar I, and episodes of illness may be characterized by irritability, anger, and racing thoughts.²⁴ Whereas impulsivity or aggression are more characteristic of BPD, bipolar II is similar to BPD on dimensions of affective instability.^24,25

When present in BPD, affective instability or lability is conceptualized as ultra-rapid or ultradian, with a frequency of hours to days. BPD is less likely than bipolar II to show affective lability between depression and euthymia or elation and more likely to show fluctuations into anger and anxiety.²⁶

Nonetheless, because of the increased prominence of shared features and reduced distinguishing features, bipolar II and BPD are prone to misdiagnosis and commonly co-occur.

Table 3

Clinician biases that may favor a bipolar disorder diagnosis, rather than BPD

History, the diagnostic key

A thorough and rigorous psychiatric history is essential to distinguish BPD from bipolar disorder. Supplementing the patient’s history with an informant interview is often helpful.

Because personality disorders are considered a chronic and enduring pattern of maladaptive behavior, focus the history on longitudinal course and not simply cross-sectional symptoms. Thus, symptoms suggestive of BPD that are confined only to clearly defined episodes of mood disturbance and are absent during euthymia would not warrant a BPD diagnosis.

Temporal relationship. A detailed chronologic history can help determine the temporal relationship between any borderline features and mood episodes. When the patient’s life story is used as a scaffold for the phenomenologic portions of the psychiatric history, one can determine whether any such functional impairment is confined to episodes of mood disorder or appears as an enduring pattern of thinking, acting, and relating. Exploring what happened at notable life transitions—leaving school, loss of job, divorce/separation—may be similarly helpful.

Family history of psychiatric illness may provide a clue to an individual’s genetic predisposition but, of course, does not determine diagnosis. A detailed family and social history that provides evidence of an individual’s function in school, work, and interpersonal relationships is more relevant.

Abandonment and identity issues. Essential to BPD is fear of abandonment, often an undue fear that those important to patients will leave them. Patients may go to extremes to avoid being “abandoned,” even when this threat is not genuine.^27,28 Their insecure attachments often lead them to fear being alone. The patient with BPD may:

• make frantic phone calls or send text messages to a friend or lover seeking reassurance
• take extreme measures such as refusing to leave the person’s home or pleading with them not to leave.

Patients with BPD often struggle with identity disturbance, leading them to wonder who they are and what their beliefs and core values are.²⁹ Although occasionally patients with bipolar disorder may have these symptoms, they are not characteristic of bipolar disorder.

Mood lability. The time course of changes in affect or mood swings also may help distinguish BPD from bipolar disorder.

• With bipolar disorder the shift typically is from depression to elation or the reverse, and moods are sustained. Manias or hypomanias are often immediately followed by a “crash” into depression.
• With BPD, “roller-coaster moods” are typical, mood shifts are nonsustained, and the poles often are anxiety, anger, or desperation.

Patients with BPD often report moods shifting rapidly over minutes or hours, but they rarely describe moods sustained for days or weeks on end—other than perhaps depression. Mood lability of BPD often is produced by interpersonal sensitivity, whereas mood lability in bipolar disorder tends to be autonomous and persistent.

Young patients. Assessment can be particularly challenging in young adults and adolescents because symptoms of an emerging bipolar disorder can be more difficult to distinguish from BPD.³⁰ Patients this young also may have less longitudinal history to distinguish an enduring pattern of thinking and relating from a mood disorder. For these cases, it may be particularly important to classify the frequency and pattern of mood symptoms.

Affective dysregulation is a core feature of BPD and is variably defined as a mood reactivity, typically of short duration (often hours). Cycling in bipolar disorder classically involves a periodicity of weeks to months. Even the broadest definitions include a minimum duration of 2 days for hypomania.⁵

Mood reactivity can occur within episodes of bipolar disorder, although episodes may occur spontaneously and without an obvious precipitant or stressor. Impulsivity may represent more of an essential feature of BPD than affective instability or mood reactivity and may be of particular diagnostic relevance.

Treatment implications

When you are unable to make a clear diagnosis, describe your clinical reasoning and differential diagnosis in the assessment or formulation. With close follow-up, the longitudinal history and course of illness may eventually lead you to an accurate diagnosis.

There are good reasons to acknowledge both conditions when bipolar disorder and BPD are present. Proper recognition of bipolar disorder is a prerequisite to taking full advantage of proven pharmacologic treatments. The evidence base for pharmacologic management of BPD remains limited,³¹ but recognizing this disorder may help the patient understand his or her psychiatric history and encourage the use of effective psychosocial treatments.

Psychosocial treatments for bipolar disorder may target demoralization and circadian rhythms with sleep hygiene or social rhythms therapy. Acknowledging BPD:

• helps both clinician and patient to better understand the condition
• facilitates setting realistic treatment goals because BPD tends to respond to medication less robustly than bipolar disorder.

Recognizing BPD also allows for referral to targeted psychosocial treatments, including dialectical behavior therapy, mentalization-based treatment, or Systems Training for Emotional Predictability and Problem Solving (STEPPS).^32-34

Related resources

• National Institute of Mental Health. Overview on borderline personality disorder. www.nimh.nih.gov/health/publications/borderline-personality-disorder-fact-sheet/index.shtml.
• National Institute of Mental Health. Bipolar disorder. www.nimh.nih.gov/health/publications/bipolar-disorder/index.shtml.
• Systems Training for Emotional Predictability and Problem Solving (STEPPS). www.uihealthcare.com/topics/medicaldepartments/psychiatry/stepps/index.html.

Drug brand name

• Divalproex • Depakote, Depakene, others

Disclosures

Dr. Fiedorowicz reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Black receives research/grant support from AstraZeneca and Forest Laboratories and is a consultant to Jazz Pharmaceuticals.

Acknowledgment

The authors would like to thank Nancee Blum, MSW, and Nancy Hale, RN, for their assistance and expertise in the preparation of this article.

Discuss this article

Borderline personality disorder (BPD) and bipolar disorder are frequently confused with each other, in part because of their considerable symptomatic overlap. This redundancy occurs despite the different ways these disorders are conceptualized: BPD as a personality disorder and bipolar disorder as a brain disease among Axis I clinical disorders.

BPD and bipolar disorder—especially bipolar II—often co-occur ( Box ) and are frequently misidentified, as shown by clinical and epidemiologic studies. Misdiagnosis creates problems for clinicians and patients. When diagnosed with BPD, patients with bipolar disorder may be deprived of potentially effective pharmacologic treatments.¹ Conversely, the stigma that BPD carries—particularly in the mental health community—may lead clinicians to:

• not even disclose the BPD diagnosis to patients²
• lean in the direction of diagnosing BPD as bipolar disorder, potentially resulting in treatments that have little relevance or failure to refer for more appropriate psychosocial treatments.

To help you avoid confusion and the pitfalls of misdiagnosis, this article clarifies the distinctions between bipolar disorder and BPD. We discuss symptom overlap, highlight key differences between the constructs, outline diagnostic differences, and provide useful suggestions to discern the differential diagnosis.

Box

Nonchance explanations for the diagnostic overlap
between BPD and bipolar disorder*

1. Inability of current nosology to separate 2 distinct conditions

Relatively indistinct diagnostic boundaries confuse the differentiation of borderline personality disorder (BPD) and bipolar disorder (5 of 9 BPD criteria may occur with mania or hypomania). In this model, the person has 1 disorder but because of symptom overlap receives a diagnosis of both. Because structured interviews do not allow for subjective judgment or expert opinion, the result is the generation of 2 diagnoses when 1 may provide a more parsimonious and valid explanation.

2. BPD exists on a spectrum with bipolar disorder

The mood lability of BPD may be viewed as not unlike that seen with bipolar disorder.¹ Behaviors displayed by patients with BPD are subsequently conceptualized as arising from their unstable mood. Supporting arguments cite family study data and evidence from pharmacotherapy trials of anticonvulsants, including divalproex, for rapid cycling bipolar disorder and BPD.² Family studies have been notable for their failure to directly characterize family members, however, and clinical trials have been quite small. Further, treatment response may have very limited nosologic implications.

3. Bipolar disorder is a risk factor for BPD

4. BPD is a risk factor for bipolar disorder

Early emergence of a bipolar disorder (in preadolescent or adolescent patients) has been proposed to disrupt psychological development, leading to BPD. This adverse impact on personality development—the “scar hypothesis”³ —is supported by data showing greater risk of co-occurring BPD with earlier onset bipolar disorder.⁴ More important, prospective studies of patients with bipolar disorder show a greater risk for developing BPD.⁵

BPD also may be a risk factor for the development of bipolar disorder—the “vulnerability hypothesis.”³ Patients with BPD are more likely to develop bipolar disorder, even compared to patients with other personality disorders.⁵

5. Shared risk factors

BPD and bipolar disorder may be linked by shared risk factors, such as shared genes or trait neuroticism.³

*Some evidence supports each potential explanation, and they are not necessarily mutually exclusive

References

a. Akiskal HS. Demystifying borderline personality: critique of the concept and unorthodox reflections on its natural kinship with the bipolar spectrum. Acta Psychiatr Scand. 2004;110(6):401-407.

b. Mackinnon DF, Pies R. Affective instability as rapid cycling: theoretical and clinical implications for borderline personality and bipolar spectrum disorders. Bipolar Disord. 2006;8(1):1-14.

c. Christensen MV, Kessing LV. Do personality traits predict first onset in depressive and bipolar disorder? Nord J Psychiatry. 2006;60(2):79-88.

d. Goldberg JF, Garno JL. Age at onset of bipolar disorder and risk for comorbid borderline personality disorder. Bipolar Disord. 2009;11(2):205-208.

e. Gunderson JG, Weinberg I, Daversa MT, et al. Descriptive and longitudinal observations on the relationship of borderline personality disorder and bipolar disorder. Am J Psychiatry. 2006;163(7):1173-1178.

Overlapping symptoms

Bipolar disorder is generally considered a clinical disorder or brain disease that can be understood as a broken mood “thermostat.” The lifetime prevalence of bipolar types I and II is approximately 2%.³ Approximately one-half of patients have a family history of illness, and multiple genes are believed to influence inheritance. Mania is the disorder’s hallmark,⁴ although overactivity has alternatively been proposed as a core feature.⁵ Most patients with mania ultimately experience depression⁶ ( Table 1 ).

No dimensional personality correlates have been consistently demonstrated in bipolar disorder, although co-occurring personality disorders—often the “dramatic” Cluster B type—are common^4,7 and may adversely affect treatment response and suicide risk.^8,9

Both bipolar disorder and BPD are associated with considerable risk of suicide or suicide attempts.^10,11 Self-mutilation or self-injurious behavior without suicidal intent are particularly common in BPD.¹² Threats of suicide—which may be manipulative or help-seeking—also are common in BPD and tend to be acute rather than chronic.¹³

Borderline personality disorder is characterized by an enduring and inflexible pattern of thoughts, feelings, and behaviors that impairs an individual’s psychosocial or vocational function. Its estimated prevalence is approximately 1%,¹⁴ although recent community estimates approach 6%.¹⁵ Genetic influences play a lesser etiologic role in BPD than in bipolar disorder.

Several of BPD’s common features ( Table 2 )—impulsivity, mood instability, inappropriate anger, suicidal behavior, and unstable relationships—are shared with bipolar disorder, but patients with BPD tend to show higher levels of impulsiveness and hostility than patients with bipolar disorder.¹⁶ Dimensional assessments of personality traits suggest that BPD is characterized by high neuroticism and low agreeableness.¹⁷ BPD also has been more strongly associated with a childhood history of abuse, even when compared with control groups having other personality disorders or major depression.¹⁸ The male-to-female ratio for bipolar disorder approximates 1:1;³ in BPD this ratio has been estimated at 1:4 in clinical samples¹⁹ and near 1:1 in community samples.¹⁵

BPD and bipolar disorder often co-occur. Evidence indicates ≤20% of patients with BPD have comorbid bipolar disorder²⁰ and 15% of patients with bipolar disorder have comorbid BPD.²¹ Co-occurrence happens much more often than would be expected by chance. These similar bidirectional comorbidity estimates (15% to 20%) would not be expected for conditions of such differing prevalence (<1% vs 2% or more). This suggests:

• the estimated prevalence of bipolar disorder in BPD is too low
• the estimated prevalence of BPD in bipolar disorder samples is too high
• borderline personality disorder is present in >1% of the population
• bipolar disorder is less common
• some combination of the above.

Among these possibilities, the prevalence estimates of bipolar disorder are the most consistent. Several studies suggest that BPD may be much more common, with some estimates exceeding 5%.¹⁵

Table 1

Common signs and symptoms
associated with mania and depression in bipolar disorder

Table 2

Borderline personality disorder: Commonly reported features

Roots of misdiagnosis

The presence of bipolar disorder or BPD may increase the risk that the other will be misdiagnosed. When symptoms of both are present, those suggesting 1 diagnosis may reflect the consequences of the other. A diagnosis of BPD could represent a partially treated or treatment-resistant bipolar disorder, or a BPD diagnosis could be the result of several years of disruption by a mood disorder.

Characteristics of bipolar disorder have contributed to clinician bias in favor of that diagnosis rather than BPD ( Table 3 ).^22,23 Bipolar disorder also may be misdiagnosed as BPD. This error may most likely occur when the history focuses excessively on cross-sectional symptoms, such as when a patient with bipolar disorder shows prominent mood lability or interpersonal sensitivity during a mood episode but not when euthymic.

Bipolar II disorder. The confusion between bipolar disorder and BPD may be particularly problematic for patients with bipolar II disorder or subthreshold bipolar disorders. The manias of bipolar I disorder are much more readily distinguishable from the mood instability or reactivity of BPD. The manic symptoms of bipolar I are more florid, more pronounced, and lead to more obvious impairment.

The milder highs of bipolar II may resemble the mood fluctuations seen in BPD. Further, bipolar II is characterized by a greater chronicity and affective morbidity than bipolar I, and episodes of illness may be characterized by irritability, anger, and racing thoughts.²⁴ Whereas impulsivity or aggression are more characteristic of BPD, bipolar II is similar to BPD on dimensions of affective instability.^24,25

When present in BPD, affective instability or lability is conceptualized as ultra-rapid or ultradian, with a frequency of hours to days. BPD is less likely than bipolar II to show affective lability between depression and euthymia or elation and more likely to show fluctuations into anger and anxiety.²⁶

Nonetheless, because of the increased prominence of shared features and reduced distinguishing features, bipolar II and BPD are prone to misdiagnosis and commonly co-occur.

Table 3

Clinician biases that may favor a bipolar disorder diagnosis, rather than BPD

History, the diagnostic key

A thorough and rigorous psychiatric history is essential to distinguish BPD from bipolar disorder. Supplementing the patient’s history with an informant interview is often helpful.

Because personality disorders are considered a chronic and enduring pattern of maladaptive behavior, focus the history on longitudinal course and not simply cross-sectional symptoms. Thus, symptoms suggestive of BPD that are confined only to clearly defined episodes of mood disturbance and are absent during euthymia would not warrant a BPD diagnosis.

Temporal relationship. A detailed chronologic history can help determine the temporal relationship between any borderline features and mood episodes. When the patient’s life story is used as a scaffold for the phenomenologic portions of the psychiatric history, one can determine whether any such functional impairment is confined to episodes of mood disorder or appears as an enduring pattern of thinking, acting, and relating. Exploring what happened at notable life transitions—leaving school, loss of job, divorce/separation—may be similarly helpful.

Family history of psychiatric illness may provide a clue to an individual’s genetic predisposition but, of course, does not determine diagnosis. A detailed family and social history that provides evidence of an individual’s function in school, work, and interpersonal relationships is more relevant.

Abandonment and identity issues. Essential to BPD is fear of abandonment, often an undue fear that those important to patients will leave them. Patients may go to extremes to avoid being “abandoned,” even when this threat is not genuine.^27,28 Their insecure attachments often lead them to fear being alone. The patient with BPD may:

• make frantic phone calls or send text messages to a friend or lover seeking reassurance
• take extreme measures such as refusing to leave the person’s home or pleading with them not to leave.

Patients with BPD often struggle with identity disturbance, leading them to wonder who they are and what their beliefs and core values are.²⁹ Although occasionally patients with bipolar disorder may have these symptoms, they are not characteristic of bipolar disorder.

Mood lability. The time course of changes in affect or mood swings also may help distinguish BPD from bipolar disorder.

• With bipolar disorder the shift typically is from depression to elation or the reverse, and moods are sustained. Manias or hypomanias are often immediately followed by a “crash” into depression.
• With BPD, “roller-coaster moods” are typical, mood shifts are nonsustained, and the poles often are anxiety, anger, or desperation.

Patients with BPD often report moods shifting rapidly over minutes or hours, but they rarely describe moods sustained for days or weeks on end—other than perhaps depression. Mood lability of BPD often is produced by interpersonal sensitivity, whereas mood lability in bipolar disorder tends to be autonomous and persistent.

Young patients. Assessment can be particularly challenging in young adults and adolescents because symptoms of an emerging bipolar disorder can be more difficult to distinguish from BPD.³⁰ Patients this young also may have less longitudinal history to distinguish an enduring pattern of thinking and relating from a mood disorder. For these cases, it may be particularly important to classify the frequency and pattern of mood symptoms.

Affective dysregulation is a core feature of BPD and is variably defined as a mood reactivity, typically of short duration (often hours). Cycling in bipolar disorder classically involves a periodicity of weeks to months. Even the broadest definitions include a minimum duration of 2 days for hypomania.⁵

Mood reactivity can occur within episodes of bipolar disorder, although episodes may occur spontaneously and without an obvious precipitant or stressor. Impulsivity may represent more of an essential feature of BPD than affective instability or mood reactivity and may be of particular diagnostic relevance.

Treatment implications

When you are unable to make a clear diagnosis, describe your clinical reasoning and differential diagnosis in the assessment or formulation. With close follow-up, the longitudinal history and course of illness may eventually lead you to an accurate diagnosis.

There are good reasons to acknowledge both conditions when bipolar disorder and BPD are present. Proper recognition of bipolar disorder is a prerequisite to taking full advantage of proven pharmacologic treatments. The evidence base for pharmacologic management of BPD remains limited,³¹ but recognizing this disorder may help the patient understand his or her psychiatric history and encourage the use of effective psychosocial treatments.

Psychosocial treatments for bipolar disorder may target demoralization and circadian rhythms with sleep hygiene or social rhythms therapy. Acknowledging BPD:

• helps both clinician and patient to better understand the condition
• facilitates setting realistic treatment goals because BPD tends to respond to medication less robustly than bipolar disorder.

Recognizing BPD also allows for referral to targeted psychosocial treatments, including dialectical behavior therapy, mentalization-based treatment, or Systems Training for Emotional Predictability and Problem Solving (STEPPS).^32-34

Related resources

• National Institute of Mental Health. Overview on borderline personality disorder. www.nimh.nih.gov/health/publications/borderline-personality-disorder-fact-sheet/index.shtml.
• National Institute of Mental Health. Bipolar disorder. www.nimh.nih.gov/health/publications/bipolar-disorder/index.shtml.
• Systems Training for Emotional Predictability and Problem Solving (STEPPS). www.uihealthcare.com/topics/medicaldepartments/psychiatry/stepps/index.html.

Drug brand name

• Divalproex • Depakote, Depakene, others

Disclosures

Dr. Fiedorowicz reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Black receives research/grant support from AstraZeneca and Forest Laboratories and is a consultant to Jazz Pharmaceuticals.

Acknowledgment

The authors would like to thank Nancee Blum, MSW, and Nancy Hale, RN, for their assistance and expertise in the preparation of this article.

Discuss this article

Borderline personality disorder (BPD) and bipolar disorder are frequently confused with each other, in part because of their considerable symptomatic overlap. This redundancy occurs despite the different ways these disorders are conceptualized: BPD as a personality disorder and bipolar disorder as a brain disease among Axis I clinical disorders.

BPD and bipolar disorder—especially bipolar II—often co-occur ( Box ) and are frequently misidentified, as shown by clinical and epidemiologic studies. Misdiagnosis creates problems for clinicians and patients. When diagnosed with BPD, patients with bipolar disorder may be deprived of potentially effective pharmacologic treatments.¹ Conversely, the stigma that BPD carries—particularly in the mental health community—may lead clinicians to:

• not even disclose the BPD diagnosis to patients²
• lean in the direction of diagnosing BPD as bipolar disorder, potentially resulting in treatments that have little relevance or failure to refer for more appropriate psychosocial treatments.

To help you avoid confusion and the pitfalls of misdiagnosis, this article clarifies the distinctions between bipolar disorder and BPD. We discuss symptom overlap, highlight key differences between the constructs, outline diagnostic differences, and provide useful suggestions to discern the differential diagnosis.

Box

Nonchance explanations for the diagnostic overlap
between BPD and bipolar disorder*

1. Inability of current nosology to separate 2 distinct conditions

Relatively indistinct diagnostic boundaries confuse the differentiation of borderline personality disorder (BPD) and bipolar disorder (5 of 9 BPD criteria may occur with mania or hypomania). In this model, the person has 1 disorder but because of symptom overlap receives a diagnosis of both. Because structured interviews do not allow for subjective judgment or expert opinion, the result is the generation of 2 diagnoses when 1 may provide a more parsimonious and valid explanation.

2. BPD exists on a spectrum with bipolar disorder

The mood lability of BPD may be viewed as not unlike that seen with bipolar disorder.¹ Behaviors displayed by patients with BPD are subsequently conceptualized as arising from their unstable mood. Supporting arguments cite family study data and evidence from pharmacotherapy trials of anticonvulsants, including divalproex, for rapid cycling bipolar disorder and BPD.² Family studies have been notable for their failure to directly characterize family members, however, and clinical trials have been quite small. Further, treatment response may have very limited nosologic implications.

3. Bipolar disorder is a risk factor for BPD

4. BPD is a risk factor for bipolar disorder

Early emergence of a bipolar disorder (in preadolescent or adolescent patients) has been proposed to disrupt psychological development, leading to BPD. This adverse impact on personality development—the “scar hypothesis”³ —is supported by data showing greater risk of co-occurring BPD with earlier onset bipolar disorder.⁴ More important, prospective studies of patients with bipolar disorder show a greater risk for developing BPD.⁵

BPD also may be a risk factor for the development of bipolar disorder—the “vulnerability hypothesis.”³ Patients with BPD are more likely to develop bipolar disorder, even compared to patients with other personality disorders.⁵

5. Shared risk factors

BPD and bipolar disorder may be linked by shared risk factors, such as shared genes or trait neuroticism.³

*Some evidence supports each potential explanation, and they are not necessarily mutually exclusive

References

a. Akiskal HS. Demystifying borderline personality: critique of the concept and unorthodox reflections on its natural kinship with the bipolar spectrum. Acta Psychiatr Scand. 2004;110(6):401-407.

b. Mackinnon DF, Pies R. Affective instability as rapid cycling: theoretical and clinical implications for borderline personality and bipolar spectrum disorders. Bipolar Disord. 2006;8(1):1-14.

c. Christensen MV, Kessing LV. Do personality traits predict first onset in depressive and bipolar disorder? Nord J Psychiatry. 2006;60(2):79-88.

d. Goldberg JF, Garno JL. Age at onset of bipolar disorder and risk for comorbid borderline personality disorder. Bipolar Disord. 2009;11(2):205-208.

e. Gunderson JG, Weinberg I, Daversa MT, et al. Descriptive and longitudinal observations on the relationship of borderline personality disorder and bipolar disorder. Am J Psychiatry. 2006;163(7):1173-1178.

Overlapping symptoms

Bipolar disorder is generally considered a clinical disorder or brain disease that can be understood as a broken mood “thermostat.” The lifetime prevalence of bipolar types I and II is approximately 2%.³ Approximately one-half of patients have a family history of illness, and multiple genes are believed to influence inheritance. Mania is the disorder’s hallmark,⁴ although overactivity has alternatively been proposed as a core feature.⁵ Most patients with mania ultimately experience depression⁶ ( Table 1 ).

No dimensional personality correlates have been consistently demonstrated in bipolar disorder, although co-occurring personality disorders—often the “dramatic” Cluster B type—are common^4,7 and may adversely affect treatment response and suicide risk.^8,9

Both bipolar disorder and BPD are associated with considerable risk of suicide or suicide attempts.^10,11 Self-mutilation or self-injurious behavior without suicidal intent are particularly common in BPD.¹² Threats of suicide—which may be manipulative or help-seeking—also are common in BPD and tend to be acute rather than chronic.¹³

Borderline personality disorder is characterized by an enduring and inflexible pattern of thoughts, feelings, and behaviors that impairs an individual’s psychosocial or vocational function. Its estimated prevalence is approximately 1%,¹⁴ although recent community estimates approach 6%.¹⁵ Genetic influences play a lesser etiologic role in BPD than in bipolar disorder.

Several of BPD’s common features ( Table 2 )—impulsivity, mood instability, inappropriate anger, suicidal behavior, and unstable relationships—are shared with bipolar disorder, but patients with BPD tend to show higher levels of impulsiveness and hostility than patients with bipolar disorder.¹⁶ Dimensional assessments of personality traits suggest that BPD is characterized by high neuroticism and low agreeableness.¹⁷ BPD also has been more strongly associated with a childhood history of abuse, even when compared with control groups having other personality disorders or major depression.¹⁸ The male-to-female ratio for bipolar disorder approximates 1:1;³ in BPD this ratio has been estimated at 1:4 in clinical samples¹⁹ and near 1:1 in community samples.¹⁵

BPD and bipolar disorder often co-occur. Evidence indicates ≤20% of patients with BPD have comorbid bipolar disorder²⁰ and 15% of patients with bipolar disorder have comorbid BPD.²¹ Co-occurrence happens much more often than would be expected by chance. These similar bidirectional comorbidity estimates (15% to 20%) would not be expected for conditions of such differing prevalence (<1% vs 2% or more). This suggests:

• the estimated prevalence of bipolar disorder in BPD is too low
• the estimated prevalence of BPD in bipolar disorder samples is too high
• borderline personality disorder is present in >1% of the population
• bipolar disorder is less common
• some combination of the above.

Among these possibilities, the prevalence estimates of bipolar disorder are the most consistent. Several studies suggest that BPD may be much more common, with some estimates exceeding 5%.¹⁵

Table 1

Common signs and symptoms
associated with mania and depression in bipolar disorder

Table 2

Borderline personality disorder: Commonly reported features

Roots of misdiagnosis

The presence of bipolar disorder or BPD may increase the risk that the other will be misdiagnosed. When symptoms of both are present, those suggesting 1 diagnosis may reflect the consequences of the other. A diagnosis of BPD could represent a partially treated or treatment-resistant bipolar disorder, or a BPD diagnosis could be the result of several years of disruption by a mood disorder.

Characteristics of bipolar disorder have contributed to clinician bias in favor of that diagnosis rather than BPD ( Table 3 ).^22,23 Bipolar disorder also may be misdiagnosed as BPD. This error may most likely occur when the history focuses excessively on cross-sectional symptoms, such as when a patient with bipolar disorder shows prominent mood lability or interpersonal sensitivity during a mood episode but not when euthymic.

Bipolar II disorder. The confusion between bipolar disorder and BPD may be particularly problematic for patients with bipolar II disorder or subthreshold bipolar disorders. The manias of bipolar I disorder are much more readily distinguishable from the mood instability or reactivity of BPD. The manic symptoms of bipolar I are more florid, more pronounced, and lead to more obvious impairment.

The milder highs of bipolar II may resemble the mood fluctuations seen in BPD. Further, bipolar II is characterized by a greater chronicity and affective morbidity than bipolar I, and episodes of illness may be characterized by irritability, anger, and racing thoughts.²⁴ Whereas impulsivity or aggression are more characteristic of BPD, bipolar II is similar to BPD on dimensions of affective instability.^24,25

When present in BPD, affective instability or lability is conceptualized as ultra-rapid or ultradian, with a frequency of hours to days. BPD is less likely than bipolar II to show affective lability between depression and euthymia or elation and more likely to show fluctuations into anger and anxiety.²⁶

Nonetheless, because of the increased prominence of shared features and reduced distinguishing features, bipolar II and BPD are prone to misdiagnosis and commonly co-occur.

Table 3

Clinician biases that may favor a bipolar disorder diagnosis, rather than BPD

History, the diagnostic key

A thorough and rigorous psychiatric history is essential to distinguish BPD from bipolar disorder. Supplementing the patient’s history with an informant interview is often helpful.

Because personality disorders are considered a chronic and enduring pattern of maladaptive behavior, focus the history on longitudinal course and not simply cross-sectional symptoms. Thus, symptoms suggestive of BPD that are confined only to clearly defined episodes of mood disturbance and are absent during euthymia would not warrant a BPD diagnosis.

Temporal relationship. A detailed chronologic history can help determine the temporal relationship between any borderline features and mood episodes. When the patient’s life story is used as a scaffold for the phenomenologic portions of the psychiatric history, one can determine whether any such functional impairment is confined to episodes of mood disorder or appears as an enduring pattern of thinking, acting, and relating. Exploring what happened at notable life transitions—leaving school, loss of job, divorce/separation—may be similarly helpful.

Family history of psychiatric illness may provide a clue to an individual’s genetic predisposition but, of course, does not determine diagnosis. A detailed family and social history that provides evidence of an individual’s function in school, work, and interpersonal relationships is more relevant.

Abandonment and identity issues. Essential to BPD is fear of abandonment, often an undue fear that those important to patients will leave them. Patients may go to extremes to avoid being “abandoned,” even when this threat is not genuine.^27,28 Their insecure attachments often lead them to fear being alone. The patient with BPD may:

• make frantic phone calls or send text messages to a friend or lover seeking reassurance
• take extreme measures such as refusing to leave the person’s home or pleading with them not to leave.

Patients with BPD often struggle with identity disturbance, leading them to wonder who they are and what their beliefs and core values are.²⁹ Although occasionally patients with bipolar disorder may have these symptoms, they are not characteristic of bipolar disorder.

Mood lability. The time course of changes in affect or mood swings also may help distinguish BPD from bipolar disorder.

• With bipolar disorder the shift typically is from depression to elation or the reverse, and moods are sustained. Manias or hypomanias are often immediately followed by a “crash” into depression.
• With BPD, “roller-coaster moods” are typical, mood shifts are nonsustained, and the poles often are anxiety, anger, or desperation.

Patients with BPD often report moods shifting rapidly over minutes or hours, but they rarely describe moods sustained for days or weeks on end—other than perhaps depression. Mood lability of BPD often is produced by interpersonal sensitivity, whereas mood lability in bipolar disorder tends to be autonomous and persistent.

Young patients. Assessment can be particularly challenging in young adults and adolescents because symptoms of an emerging bipolar disorder can be more difficult to distinguish from BPD.³⁰ Patients this young also may have less longitudinal history to distinguish an enduring pattern of thinking and relating from a mood disorder. For these cases, it may be particularly important to classify the frequency and pattern of mood symptoms.

Affective dysregulation is a core feature of BPD and is variably defined as a mood reactivity, typically of short duration (often hours). Cycling in bipolar disorder classically involves a periodicity of weeks to months. Even the broadest definitions include a minimum duration of 2 days for hypomania.⁵

Mood reactivity can occur within episodes of bipolar disorder, although episodes may occur spontaneously and without an obvious precipitant or stressor. Impulsivity may represent more of an essential feature of BPD than affective instability or mood reactivity and may be of particular diagnostic relevance.

Treatment implications

When you are unable to make a clear diagnosis, describe your clinical reasoning and differential diagnosis in the assessment or formulation. With close follow-up, the longitudinal history and course of illness may eventually lead you to an accurate diagnosis.

There are good reasons to acknowledge both conditions when bipolar disorder and BPD are present. Proper recognition of bipolar disorder is a prerequisite to taking full advantage of proven pharmacologic treatments. The evidence base for pharmacologic management of BPD remains limited,³¹ but recognizing this disorder may help the patient understand his or her psychiatric history and encourage the use of effective psychosocial treatments.

Psychosocial treatments for bipolar disorder may target demoralization and circadian rhythms with sleep hygiene or social rhythms therapy. Acknowledging BPD:

• helps both clinician and patient to better understand the condition
• facilitates setting realistic treatment goals because BPD tends to respond to medication less robustly than bipolar disorder.

Recognizing BPD also allows for referral to targeted psychosocial treatments, including dialectical behavior therapy, mentalization-based treatment, or Systems Training for Emotional Predictability and Problem Solving (STEPPS).^32-34

Related resources

• National Institute of Mental Health. Overview on borderline personality disorder. www.nimh.nih.gov/health/publications/borderline-personality-disorder-fact-sheet/index.shtml.
• National Institute of Mental Health. Bipolar disorder. www.nimh.nih.gov/health/publications/bipolar-disorder/index.shtml.
• Systems Training for Emotional Predictability and Problem Solving (STEPPS). www.uihealthcare.com/topics/medicaldepartments/psychiatry/stepps/index.html.

Drug brand name

• Divalproex • Depakote, Depakene, others

Disclosures

Dr. Fiedorowicz reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Black receives research/grant support from AstraZeneca and Forest Laboratories and is a consultant to Jazz Pharmaceuticals.

Acknowledgment

The authors would like to thank Nancee Blum, MSW, and Nancy Hale, RN, for their assistance and expertise in the preparation of this article.

Even the experts say it's a tough call to diagnose a child–particularly a young child–with bipolar disorder, making for enigmatic medication decisions in the pediatric population.

“It's always difficult, and the diagnosis is the most important thing before beginning treatment,” said Dr. Kiki Chang, founder and director of the Pediatric Bipolar Disorders Program at Stanford (Calif.) University.

“It's a diagnosis I've been looking at for the better part of 35 years, and I still find it very hard,” agreed Dr. Gabrielle Carlson, professor of psychiatry and behavioral science at the State University of New York at Stony Brook. When it comes to very young children–under the age of 10–“you get into really dicey territory.”

The problem is that diagnostic criteria for bipolar I, bipolar II, and bipolar disorder not otherwise specified in the DSM-IV were developed based on research in adults and may be exceedingly difficult to apply to children.

It's been said that all normal 4-year-olds look a bit bipolar, with wild mood swings, euphoria, racing thoughts, grandiosity, periods of extreme creative and physical energy, reports of monsters under their beds, and a seemingly reduced need for sleep (by parental report).

Clinical experience and many longitudinal studies do point to profoundly troubled behavior in some children that does have a flavor of bipolar disorder, and many of these children do go on to have unequivocal bipolar disorder in adulthood.

In the most recently published report from Dr. Barbara Geller's group at Washington University, St. Louis, 44% of young adults identified in childhood with bipolar I disorder symptoms had a manic episode after the age of 18, a rate 13–44 times higher than in the general population (Arch. Gen. Psychiatry 2008;65:1125–33).

However, community diagnoses are notoriously fallible, illustrated by the fact that half of the children referred to the Pediatric Bipolar Disorders Program at Stanford do not have the disease. Often, they prove to have unipolar depression marked by irritability. Or pervasive developmental disorder. Or autism, Dr. Chang said.

Significant language impairment and developmental delays complicated the diagnosis of one of Dr. Carlson's patients who, at age 5, nearly got killed running alongside cars because he thought he could run faster than anyone else. He jumped out of a tree, and displayed other examples of “clearly grandiose” behavior. When he was 7, she asked him about chasing traffic and he said, “I was little at the time.” The tree? “I never did that again,” he said. Later, he boasted he could swim across Long Island Sound–a claim he later traced to his grandfather's musing that he could “swim like a fish.”

By age 10, it was clear that child's diagnosis was autism. “He always had interesting ways of putting the world together. But he wasn't delusional when pressed,” said Dr. Carlson.

Being precise about a diagnosis in children with unusual, shocking, and/or harmful behaviors would make little difference if medication management was the same whether a child has bipolar disorder or one of the many differential diagnoses masquerading as bipolar disorder, such as depression, attention-deficit/hyperactivity disorder (ADHD), pervasive developmental disorder, anxiety disorders, Tourette syndrome, or the autism spectrum disorders. But it's not.

“The question of diagnosis makes a big difference,” Dr. Carlson said. In the case of “diagnostic ambiguity” between severe ADHD and bipolar disorder, she chooses to treat the ADHD first, unless there are clear signs of mania.

One advantage of treating ADHD with stimulants is their quick action, sometimes providing rapid evidence of improvement. Plus, their use over many years in multiple clinical trials in children provides reassurance of their safety and guidance about dosing.

It can be difficult to start on a conservative course of action in the face of extreme behavior and symptoms, but Dr. Carlson remembers the lesson she learned from an adolescent who had been unsuccessfully treated with anticonvulsants and atypical antipsychotics for 5 years.

So frightening were the child's early meltdowns that the mother and a community psychiatrist feared that stimulant medication would be contraindicated, with the potential of making a “nightmare” situation worse. But after years of treatment, the youth's symptoms worsened and he was hospitalized. She decided to taper his medications and try traditional stimulants for ADHD, along with time-outs and consistent behavior-modification strategies. “He responded very nicely,” she said. “What was heartwarming was how proud he was that he had control of himself. The mother told me, 'I was able to be a regular mom.'”

Dr. Chang also favors treating ADHD when the diagnosis tends to lean that way (and doesn't include frank mania). He starts with standard doses of short-acting methylphenidate, even when one or more parents has a history of bipolar disorder.

Whereas experts once believed that stimulants would “tip” most children with undiagnosed bipolar disorder into manic episodes, the consensus now is that this is a rare occurrence and fairly easily managed, he said. “Just stop the stimulants.”

An alternative therapy for ADHD symptoms might be atomoxetine (Strattera), a hydrochloride salt, which Dr. Chang considers if stimulants aggravate hyperactive behavior.

If a traditional therapy for ADHD reduces symptoms, both specialists said they feel comfortable in closely monitoring a child through adolescence, when more typical symptoms of bipolar disorder may emerge.

In looking at studies of patients under the age of 10, Dr. Carlson today sees few data to support the use of “powerful, fat-making antipsychotics” for the rest of the child's life (assuming the child proves to have bipolar disorder). She believes there is support in the literature for the short-term use of atypical antipsychotics for management of aggression associated with many diagnoses, however.

Of note, an international review of five longitudinal studies of the children of parents with bipolar disorder found little evidence of classically defined mania in prepubertal children (J. Can. Acad. Child Adoles. Psychiatry 2009;18:200–5).

In the study by Dr. Anne Duffy of Dalhousie University in Halifax, Nova Scotia, children who went on to develop mood disorders seemed to follow a fairly predictable course leading to a first activated episode in adolescence or early adulthood–nonspecific anxiety and sleep problems in childhood, then mood swings in adolescence, with depressive episodes predating mania by several years.

Dr. Chang said while prepubertal mania has been described, it is likely less common than postpubertal mania, “and harder to diagnose given the natural neurodevelopmental propensity of young children to rapidly cycle with their moods.”

Many experts have called for an evaluation of what symptoms constitute a diagnosis of bipolar disorder in children, rather than trying to shade adult-oriented symptoms to fit children. A precise definition would tailor subjects enrolled in clinical trials so that findings would be meaningful and applicable to the children seen in clinical practice, hopefully pointing the way to an evidence-based approach to pharmacotherapy.

In the meantime, treatment guidelines developed by an expert consensus panel that included Dr. Carlson and Dr. Chang offer diagnostic support and provide algorithms for treatment of bipolar I disorder with or without psychosis in children and adolescents (J. Amer. Acad. Child Adolesc. Psychiatry 2005;44:213–35).

A practice parameter with 11 specific recommendations also offers comprehensive guidance to clinicians (J. Am. Acad. Child Adolesc. Psychiatry 2007; 46:107–25).

Dr. Carlson and Dr. Chang describe personal prescribing patterns that conform to these guidelines, most often selecting lithium or another mood stabilizer or an atypical antipsychotic as first line monotherapy, but sometimes recommending combination therapy.

Lithium, valproate, aripiprazole, and quetiapine all figure prominently in his initial treatment strategies, with quetiapine edging out the others if sleep regulation is a particular problem.

A child presenting with rather classic euphoric mania might make Dr. Chang prescribe lithium first, whereas a more chronic picture of predominantly irritable mania or a mixed state would make him lean toward an atypical antipsychotic.

Depression remains a challenge in youthful populations as well as in adults, and Dr. Chang is generally reluctant to prescribe selective serotonin reuptake inhibitors if there is a reasonable suspicion that the child has bipolar disorder.

“We stay away from them if at all possible,” concerned that they may precipitate a manic episode.

He might consider lamotrigine for a child who is already overweight, dosing it very cautiously at first, especially in smaller children, and being cognizant of the risk of a severe rash. He also now considers adding metformin to the regimen of any child or adolescent who gains considerable weight on the atypicals.

Dr. Carlson cited the same sorts of considerations. Atypical antipsychotics, for example, might be her treatment of choice for a child whose most concerning symptoms are aggression and emotional lability, because these drugs tend to ameliorate these symptoms regardless of whether the ultimate diagnosis is bipolar disorder.

Most children with bipolar disorder end up requiring combination therapy for their symptoms, plus occasional agents to manage side effects.

As the regimens grow more complex, the already limited evidence base shrinks to nearly nil, Dr. Chang said. Side effect patterns in children are also poorly understood. “Cognitive side effects have not really been studied at all. We don't have much evidence to guide us, and compared with adults, the cognitive piece is really important,” he said.

When the adult literature suggests a problematic cognitive picture, as in the case of topiramate, Dr. Chang tends to avoid prescribing that drug.

Both clinicians emphasized the need to address the child's environment within the context of his or her symptoms, incorporating psychotherapeutic and educational interventions in any treatment strategy. “Medication in the absence of the others [interventions] is rarely successful,” Dr. Chang said.

Dr. Carlson reported that she is a consultant for many of the pharmaceutical companies conducting research into bipolar disorder and ADHD and is currently participating in a study of lamotrigine (GlaxoSmithKline). Dr. Chang said he has received research or grant support from, or served on the speakers bureau for, AstraZeneca Pharmaceuticals, Bristol-Myers Squibb, Eli Lilly & Co., Otsuka America Pharmaceutical Inc., and GlaxoSmithKline.

By Betsy Bates. Share your thoughts and suggestions at [email protected]

Few data support the use of 'powerful, fat-making antipsychotics' for the rest of the child's life.

Source DR. CARLSON

Even the experts say it's a tough call to diagnose a child–particularly a young child–with bipolar disorder, making for enigmatic medication decisions in the pediatric population.

“It's always difficult, and the diagnosis is the most important thing before beginning treatment,” said Dr. Kiki Chang, founder and director of the Pediatric Bipolar Disorders Program at Stanford (Calif.) University.

“It's a diagnosis I've been looking at for the better part of 35 years, and I still find it very hard,” agreed Dr. Gabrielle Carlson, professor of psychiatry and behavioral science at the State University of New York at Stony Brook. When it comes to very young children–under the age of 10–“you get into really dicey territory.”

The problem is that diagnostic criteria for bipolar I, bipolar II, and bipolar disorder not otherwise specified in the DSM-IV were developed based on research in adults and may be exceedingly difficult to apply to children.

It's been said that all normal 4-year-olds look a bit bipolar, with wild mood swings, euphoria, racing thoughts, grandiosity, periods of extreme creative and physical energy, reports of monsters under their beds, and a seemingly reduced need for sleep (by parental report).

Clinical experience and many longitudinal studies do point to profoundly troubled behavior in some children that does have a flavor of bipolar disorder, and many of these children do go on to have unequivocal bipolar disorder in adulthood.

In the most recently published report from Dr. Barbara Geller's group at Washington University, St. Louis, 44% of young adults identified in childhood with bipolar I disorder symptoms had a manic episode after the age of 18, a rate 13–44 times higher than in the general population (Arch. Gen. Psychiatry 2008;65:1125–33).

However, community diagnoses are notoriously fallible, illustrated by the fact that half of the children referred to the Pediatric Bipolar Disorders Program at Stanford do not have the disease. Often, they prove to have unipolar depression marked by irritability. Or pervasive developmental disorder. Or autism, Dr. Chang said.

Significant language impairment and developmental delays complicated the diagnosis of one of Dr. Carlson's patients who, at age 5, nearly got killed running alongside cars because he thought he could run faster than anyone else. He jumped out of a tree, and displayed other examples of “clearly grandiose” behavior. When he was 7, she asked him about chasing traffic and he said, “I was little at the time.” The tree? “I never did that again,” he said. Later, he boasted he could swim across Long Island Sound–a claim he later traced to his grandfather's musing that he could “swim like a fish.”

By age 10, it was clear that child's diagnosis was autism. “He always had interesting ways of putting the world together. But he wasn't delusional when pressed,” said Dr. Carlson.

Being precise about a diagnosis in children with unusual, shocking, and/or harmful behaviors would make little difference if medication management was the same whether a child has bipolar disorder or one of the many differential diagnoses masquerading as bipolar disorder, such as depression, attention-deficit/hyperactivity disorder (ADHD), pervasive developmental disorder, anxiety disorders, Tourette syndrome, or the autism spectrum disorders. But it's not.

“The question of diagnosis makes a big difference,” Dr. Carlson said. In the case of “diagnostic ambiguity” between severe ADHD and bipolar disorder, she chooses to treat the ADHD first, unless there are clear signs of mania.

One advantage of treating ADHD with stimulants is their quick action, sometimes providing rapid evidence of improvement. Plus, their use over many years in multiple clinical trials in children provides reassurance of their safety and guidance about dosing.

It can be difficult to start on a conservative course of action in the face of extreme behavior and symptoms, but Dr. Carlson remembers the lesson she learned from an adolescent who had been unsuccessfully treated with anticonvulsants and atypical antipsychotics for 5 years.

So frightening were the child's early meltdowns that the mother and a community psychiatrist feared that stimulant medication would be contraindicated, with the potential of making a “nightmare” situation worse. But after years of treatment, the youth's symptoms worsened and he was hospitalized. She decided to taper his medications and try traditional stimulants for ADHD, along with time-outs and consistent behavior-modification strategies. “He responded very nicely,” she said. “What was heartwarming was how proud he was that he had control of himself. The mother told me, 'I was able to be a regular mom.'”

Dr. Chang also favors treating ADHD when the diagnosis tends to lean that way (and doesn't include frank mania). He starts with standard doses of short-acting methylphenidate, even when one or more parents has a history of bipolar disorder.

Whereas experts once believed that stimulants would “tip” most children with undiagnosed bipolar disorder into manic episodes, the consensus now is that this is a rare occurrence and fairly easily managed, he said. “Just stop the stimulants.”

An alternative therapy for ADHD symptoms might be atomoxetine (Strattera), a hydrochloride salt, which Dr. Chang considers if stimulants aggravate hyperactive behavior.

If a traditional therapy for ADHD reduces symptoms, both specialists said they feel comfortable in closely monitoring a child through adolescence, when more typical symptoms of bipolar disorder may emerge.

In looking at studies of patients under the age of 10, Dr. Carlson today sees few data to support the use of “powerful, fat-making antipsychotics” for the rest of the child's life (assuming the child proves to have bipolar disorder). She believes there is support in the literature for the short-term use of atypical antipsychotics for management of aggression associated with many diagnoses, however.

Of note, an international review of five longitudinal studies of the children of parents with bipolar disorder found little evidence of classically defined mania in prepubertal children (J. Can. Acad. Child Adoles. Psychiatry 2009;18:200–5).

In the study by Dr. Anne Duffy of Dalhousie University in Halifax, Nova Scotia, children who went on to develop mood disorders seemed to follow a fairly predictable course leading to a first activated episode in adolescence or early adulthood–nonspecific anxiety and sleep problems in childhood, then mood swings in adolescence, with depressive episodes predating mania by several years.

Dr. Chang said while prepubertal mania has been described, it is likely less common than postpubertal mania, “and harder to diagnose given the natural neurodevelopmental propensity of young children to rapidly cycle with their moods.”

Many experts have called for an evaluation of what symptoms constitute a diagnosis of bipolar disorder in children, rather than trying to shade adult-oriented symptoms to fit children. A precise definition would tailor subjects enrolled in clinical trials so that findings would be meaningful and applicable to the children seen in clinical practice, hopefully pointing the way to an evidence-based approach to pharmacotherapy.

In the meantime, treatment guidelines developed by an expert consensus panel that included Dr. Carlson and Dr. Chang offer diagnostic support and provide algorithms for treatment of bipolar I disorder with or without psychosis in children and adolescents (J. Amer. Acad. Child Adolesc. Psychiatry 2005;44:213–35).

A practice parameter with 11 specific recommendations also offers comprehensive guidance to clinicians (J. Am. Acad. Child Adolesc. Psychiatry 2007; 46:107–25).

Dr. Carlson and Dr. Chang describe personal prescribing patterns that conform to these guidelines, most often selecting lithium or another mood stabilizer or an atypical antipsychotic as first line monotherapy, but sometimes recommending combination therapy.

Lithium, valproate, aripiprazole, and quetiapine all figure prominently in his initial treatment strategies, with quetiapine edging out the others if sleep regulation is a particular problem.

A child presenting with rather classic euphoric mania might make Dr. Chang prescribe lithium first, whereas a more chronic picture of predominantly irritable mania or a mixed state would make him lean toward an atypical antipsychotic.

Depression remains a challenge in youthful populations as well as in adults, and Dr. Chang is generally reluctant to prescribe selective serotonin reuptake inhibitors if there is a reasonable suspicion that the child has bipolar disorder.

“We stay away from them if at all possible,” concerned that they may precipitate a manic episode.

He might consider lamotrigine for a child who is already overweight, dosing it very cautiously at first, especially in smaller children, and being cognizant of the risk of a severe rash. He also now considers adding metformin to the regimen of any child or adolescent who gains considerable weight on the atypicals.

Dr. Carlson cited the same sorts of considerations. Atypical antipsychotics, for example, might be her treatment of choice for a child whose most concerning symptoms are aggression and emotional lability, because these drugs tend to ameliorate these symptoms regardless of whether the ultimate diagnosis is bipolar disorder.

Most children with bipolar disorder end up requiring combination therapy for their symptoms, plus occasional agents to manage side effects.

As the regimens grow more complex, the already limited evidence base shrinks to nearly nil, Dr. Chang said. Side effect patterns in children are also poorly understood. “Cognitive side effects have not really been studied at all. We don't have much evidence to guide us, and compared with adults, the cognitive piece is really important,” he said.

When the adult literature suggests a problematic cognitive picture, as in the case of topiramate, Dr. Chang tends to avoid prescribing that drug.

Both clinicians emphasized the need to address the child's environment within the context of his or her symptoms, incorporating psychotherapeutic and educational interventions in any treatment strategy. “Medication in the absence of the others [interventions] is rarely successful,” Dr. Chang said.

Dr. Carlson reported that she is a consultant for many of the pharmaceutical companies conducting research into bipolar disorder and ADHD and is currently participating in a study of lamotrigine (GlaxoSmithKline). Dr. Chang said he has received research or grant support from, or served on the speakers bureau for, AstraZeneca Pharmaceuticals, Bristol-Myers Squibb, Eli Lilly & Co., Otsuka America Pharmaceutical Inc., and GlaxoSmithKline.

By Betsy Bates. Share your thoughts and suggestions at [email protected]

Few data support the use of 'powerful, fat-making antipsychotics' for the rest of the child's life.

Source DR. CARLSON

Even the experts say it's a tough call to diagnose a child–particularly a young child–with bipolar disorder, making for enigmatic medication decisions in the pediatric population.

“It's always difficult, and the diagnosis is the most important thing before beginning treatment,” said Dr. Kiki Chang, founder and director of the Pediatric Bipolar Disorders Program at Stanford (Calif.) University.

“It's a diagnosis I've been looking at for the better part of 35 years, and I still find it very hard,” agreed Dr. Gabrielle Carlson, professor of psychiatry and behavioral science at the State University of New York at Stony Brook. When it comes to very young children–under the age of 10–“you get into really dicey territory.”

The problem is that diagnostic criteria for bipolar I, bipolar II, and bipolar disorder not otherwise specified in the DSM-IV were developed based on research in adults and may be exceedingly difficult to apply to children.

It's been said that all normal 4-year-olds look a bit bipolar, with wild mood swings, euphoria, racing thoughts, grandiosity, periods of extreme creative and physical energy, reports of monsters under their beds, and a seemingly reduced need for sleep (by parental report).

Clinical experience and many longitudinal studies do point to profoundly troubled behavior in some children that does have a flavor of bipolar disorder, and many of these children do go on to have unequivocal bipolar disorder in adulthood.

In the most recently published report from Dr. Barbara Geller's group at Washington University, St. Louis, 44% of young adults identified in childhood with bipolar I disorder symptoms had a manic episode after the age of 18, a rate 13–44 times higher than in the general population (Arch. Gen. Psychiatry 2008;65:1125–33).

However, community diagnoses are notoriously fallible, illustrated by the fact that half of the children referred to the Pediatric Bipolar Disorders Program at Stanford do not have the disease. Often, they prove to have unipolar depression marked by irritability. Or pervasive developmental disorder. Or autism, Dr. Chang said.

Significant language impairment and developmental delays complicated the diagnosis of one of Dr. Carlson's patients who, at age 5, nearly got killed running alongside cars because he thought he could run faster than anyone else. He jumped out of a tree, and displayed other examples of “clearly grandiose” behavior. When he was 7, she asked him about chasing traffic and he said, “I was little at the time.” The tree? “I never did that again,” he said. Later, he boasted he could swim across Long Island Sound–a claim he later traced to his grandfather's musing that he could “swim like a fish.”

By age 10, it was clear that child's diagnosis was autism. “He always had interesting ways of putting the world together. But he wasn't delusional when pressed,” said Dr. Carlson.

Being precise about a diagnosis in children with unusual, shocking, and/or harmful behaviors would make little difference if medication management was the same whether a child has bipolar disorder or one of the many differential diagnoses masquerading as bipolar disorder, such as depression, attention-deficit/hyperactivity disorder (ADHD), pervasive developmental disorder, anxiety disorders, Tourette syndrome, or the autism spectrum disorders. But it's not.

“The question of diagnosis makes a big difference,” Dr. Carlson said. In the case of “diagnostic ambiguity” between severe ADHD and bipolar disorder, she chooses to treat the ADHD first, unless there are clear signs of mania.

One advantage of treating ADHD with stimulants is their quick action, sometimes providing rapid evidence of improvement. Plus, their use over many years in multiple clinical trials in children provides reassurance of their safety and guidance about dosing.

It can be difficult to start on a conservative course of action in the face of extreme behavior and symptoms, but Dr. Carlson remembers the lesson she learned from an adolescent who had been unsuccessfully treated with anticonvulsants and atypical antipsychotics for 5 years.

So frightening were the child's early meltdowns that the mother and a community psychiatrist feared that stimulant medication would be contraindicated, with the potential of making a “nightmare” situation worse. But after years of treatment, the youth's symptoms worsened and he was hospitalized. She decided to taper his medications and try traditional stimulants for ADHD, along with time-outs and consistent behavior-modification strategies. “He responded very nicely,” she said. “What was heartwarming was how proud he was that he had control of himself. The mother told me, 'I was able to be a regular mom.'”

Dr. Chang also favors treating ADHD when the diagnosis tends to lean that way (and doesn't include frank mania). He starts with standard doses of short-acting methylphenidate, even when one or more parents has a history of bipolar disorder.

Whereas experts once believed that stimulants would “tip” most children with undiagnosed bipolar disorder into manic episodes, the consensus now is that this is a rare occurrence and fairly easily managed, he said. “Just stop the stimulants.”

An alternative therapy for ADHD symptoms might be atomoxetine (Strattera), a hydrochloride salt, which Dr. Chang considers if stimulants aggravate hyperactive behavior.

If a traditional therapy for ADHD reduces symptoms, both specialists said they feel comfortable in closely monitoring a child through adolescence, when more typical symptoms of bipolar disorder may emerge.

In looking at studies of patients under the age of 10, Dr. Carlson today sees few data to support the use of “powerful, fat-making antipsychotics” for the rest of the child's life (assuming the child proves to have bipolar disorder). She believes there is support in the literature for the short-term use of atypical antipsychotics for management of aggression associated with many diagnoses, however.

Of note, an international review of five longitudinal studies of the children of parents with bipolar disorder found little evidence of classically defined mania in prepubertal children (J. Can. Acad. Child Adoles. Psychiatry 2009;18:200–5).

In the study by Dr. Anne Duffy of Dalhousie University in Halifax, Nova Scotia, children who went on to develop mood disorders seemed to follow a fairly predictable course leading to a first activated episode in adolescence or early adulthood–nonspecific anxiety and sleep problems in childhood, then mood swings in adolescence, with depressive episodes predating mania by several years.

Dr. Chang said while prepubertal mania has been described, it is likely less common than postpubertal mania, “and harder to diagnose given the natural neurodevelopmental propensity of young children to rapidly cycle with their moods.”

Many experts have called for an evaluation of what symptoms constitute a diagnosis of bipolar disorder in children, rather than trying to shade adult-oriented symptoms to fit children. A precise definition would tailor subjects enrolled in clinical trials so that findings would be meaningful and applicable to the children seen in clinical practice, hopefully pointing the way to an evidence-based approach to pharmacotherapy.

In the meantime, treatment guidelines developed by an expert consensus panel that included Dr. Carlson and Dr. Chang offer diagnostic support and provide algorithms for treatment of bipolar I disorder with or without psychosis in children and adolescents (J. Amer. Acad. Child Adolesc. Psychiatry 2005;44:213–35).

A practice parameter with 11 specific recommendations also offers comprehensive guidance to clinicians (J. Am. Acad. Child Adolesc. Psychiatry 2007; 46:107–25).

Dr. Carlson and Dr. Chang describe personal prescribing patterns that conform to these guidelines, most often selecting lithium or another mood stabilizer or an atypical antipsychotic as first line monotherapy, but sometimes recommending combination therapy.

Lithium, valproate, aripiprazole, and quetiapine all figure prominently in his initial treatment strategies, with quetiapine edging out the others if sleep regulation is a particular problem.

A child presenting with rather classic euphoric mania might make Dr. Chang prescribe lithium first, whereas a more chronic picture of predominantly irritable mania or a mixed state would make him lean toward an atypical antipsychotic.

Depression remains a challenge in youthful populations as well as in adults, and Dr. Chang is generally reluctant to prescribe selective serotonin reuptake inhibitors if there is a reasonable suspicion that the child has bipolar disorder.

“We stay away from them if at all possible,” concerned that they may precipitate a manic episode.

He might consider lamotrigine for a child who is already overweight, dosing it very cautiously at first, especially in smaller children, and being cognizant of the risk of a severe rash. He also now considers adding metformin to the regimen of any child or adolescent who gains considerable weight on the atypicals.

Dr. Carlson cited the same sorts of considerations. Atypical antipsychotics, for example, might be her treatment of choice for a child whose most concerning symptoms are aggression and emotional lability, because these drugs tend to ameliorate these symptoms regardless of whether the ultimate diagnosis is bipolar disorder.

Most children with bipolar disorder end up requiring combination therapy for their symptoms, plus occasional agents to manage side effects.

As the regimens grow more complex, the already limited evidence base shrinks to nearly nil, Dr. Chang said. Side effect patterns in children are also poorly understood. “Cognitive side effects have not really been studied at all. We don't have much evidence to guide us, and compared with adults, the cognitive piece is really important,” he said.

When the adult literature suggests a problematic cognitive picture, as in the case of topiramate, Dr. Chang tends to avoid prescribing that drug.

Both clinicians emphasized the need to address the child's environment within the context of his or her symptoms, incorporating psychotherapeutic and educational interventions in any treatment strategy. “Medication in the absence of the others [interventions] is rarely successful,” Dr. Chang said.

Dr. Carlson reported that she is a consultant for many of the pharmaceutical companies conducting research into bipolar disorder and ADHD and is currently participating in a study of lamotrigine (GlaxoSmithKline). Dr. Chang said he has received research or grant support from, or served on the speakers bureau for, AstraZeneca Pharmaceuticals, Bristol-Myers Squibb, Eli Lilly & Co., Otsuka America Pharmaceutical Inc., and GlaxoSmithKline.

By Betsy Bates. Share your thoughts and suggestions at [email protected]

Few data support the use of 'powerful, fat-making antipsychotics' for the rest of the child's life.

Source DR. CARLSON

ISTANBUL, TURKEY – Flexibly dosed ziprasidone displayed favorable safety and efficacy in children and adolescents with bipolar I disorder in a double-blind, placebo-controlled, randomized clinical trial.

The study involved 238 bipolar I patients aged 6–17 years with a manic or mixed episode who were randomized 2:1 to ziprasidone (Geodon) at 60–160 mg/day or placebo at 36 U.S. centers. Sixty-five percent of patients in the ziprasidone arm and 58% assigned to placebo completed the 4-week trial, Dr. Robert L. Findling reported at the annual congress of the European College of Neuropsychopharmacology.

The primary study end point was change in the Young Mania Rating Scale total score over the course of 4 weeks. The ziprasidone group had a mean 13.8-point drop, significantly greater than the 8.6-point decrease with placebo, according to Dr. Findling, professor of psychiatry and pediatrics at Case Western Reserve University, Cleveland.

The secondary end point was change over time in the Clinical Global Impression of Severity score: a mean reduction of 1.43 points from baseline in the ziprasidone group, compared with a 0.74-point decrease in controls.

The efficacy curves began separating within the first week, while ziprasidone was still being titrated toward a target dose of 60–80 mg/day in children weighing less than 45 kg, or 120–160 mg in those weighing more. The second-generation antipsychotic was given twice daily with food.

Side effects of ziprasidone were similar to those encountered in adult therapy. Sedation occurred in one-third of patients; somnolence in one-quarter; and nausea, fatigue, and dizziness each in 11%–13% of patients.

Weight gain occurred in one patient in each study arm. Prolongation of the QT interval on ECG was noted in a single patient in the ziprasidone arm, whose peak was 478 milliseconds (msec). The mean increase in QT interval in the ziprasidone group at 4 weeks was 8.3 msec, compared with a mean 2.9 msec decrease in the placebo arm.

This is an important study because of the limited safety and efficacy data available on the use of antipsychotic agents among pediatric patients, along with the documented importance of initiating treatment as early in the disease course as possible to achieve the best possible outcomes, according to the psychiatrist.

The trial was supported by Pfizer Inc., manufacturer of ziprasidone. Dr. Findling disclosed having received research grants and/or serving as a consultant to or on the speakers bureau for Pfizer and roughly a dozen other pharmaceutical companies.

With ziprasidone, the mean drop in the score was 13.8 points, compared with 8.6 in the placebo group.

Source DR. FINDLING

ISTANBUL, TURKEY – Flexibly dosed ziprasidone displayed favorable safety and efficacy in children and adolescents with bipolar I disorder in a double-blind, placebo-controlled, randomized clinical trial.

The study involved 238 bipolar I patients aged 6–17 years with a manic or mixed episode who were randomized 2:1 to ziprasidone (Geodon) at 60–160 mg/day or placebo at 36 U.S. centers. Sixty-five percent of patients in the ziprasidone arm and 58% assigned to placebo completed the 4-week trial, Dr. Robert L. Findling reported at the annual congress of the European College of Neuropsychopharmacology.

The primary study end point was change in the Young Mania Rating Scale total score over the course of 4 weeks. The ziprasidone group had a mean 13.8-point drop, significantly greater than the 8.6-point decrease with placebo, according to Dr. Findling, professor of psychiatry and pediatrics at Case Western Reserve University, Cleveland.

The secondary end point was change over time in the Clinical Global Impression of Severity score: a mean reduction of 1.43 points from baseline in the ziprasidone group, compared with a 0.74-point decrease in controls.

The efficacy curves began separating within the first week, while ziprasidone was still being titrated toward a target dose of 60–80 mg/day in children weighing less than 45 kg, or 120–160 mg in those weighing more. The second-generation antipsychotic was given twice daily with food.

Side effects of ziprasidone were similar to those encountered in adult therapy. Sedation occurred in one-third of patients; somnolence in one-quarter; and nausea, fatigue, and dizziness each in 11%–13% of patients.

Weight gain occurred in one patient in each study arm. Prolongation of the QT interval on ECG was noted in a single patient in the ziprasidone arm, whose peak was 478 milliseconds (msec). The mean increase in QT interval in the ziprasidone group at 4 weeks was 8.3 msec, compared with a mean 2.9 msec decrease in the placebo arm.

This is an important study because of the limited safety and efficacy data available on the use of antipsychotic agents among pediatric patients, along with the documented importance of initiating treatment as early in the disease course as possible to achieve the best possible outcomes, according to the psychiatrist.

The trial was supported by Pfizer Inc., manufacturer of ziprasidone. Dr. Findling disclosed having received research grants and/or serving as a consultant to or on the speakers bureau for Pfizer and roughly a dozen other pharmaceutical companies.

With ziprasidone, the mean drop in the score was 13.8 points, compared with 8.6 in the placebo group.

Source DR. FINDLING

ISTANBUL, TURKEY – Flexibly dosed ziprasidone displayed favorable safety and efficacy in children and adolescents with bipolar I disorder in a double-blind, placebo-controlled, randomized clinical trial.

The study involved 238 bipolar I patients aged 6–17 years with a manic or mixed episode who were randomized 2:1 to ziprasidone (Geodon) at 60–160 mg/day or placebo at 36 U.S. centers. Sixty-five percent of patients in the ziprasidone arm and 58% assigned to placebo completed the 4-week trial, Dr. Robert L. Findling reported at the annual congress of the European College of Neuropsychopharmacology.

The primary study end point was change in the Young Mania Rating Scale total score over the course of 4 weeks. The ziprasidone group had a mean 13.8-point drop, significantly greater than the 8.6-point decrease with placebo, according to Dr. Findling, professor of psychiatry and pediatrics at Case Western Reserve University, Cleveland.

The secondary end point was change over time in the Clinical Global Impression of Severity score: a mean reduction of 1.43 points from baseline in the ziprasidone group, compared with a 0.74-point decrease in controls.

The efficacy curves began separating within the first week, while ziprasidone was still being titrated toward a target dose of 60–80 mg/day in children weighing less than 45 kg, or 120–160 mg in those weighing more. The second-generation antipsychotic was given twice daily with food.

Side effects of ziprasidone were similar to those encountered in adult therapy. Sedation occurred in one-third of patients; somnolence in one-quarter; and nausea, fatigue, and dizziness each in 11%–13% of patients.

Weight gain occurred in one patient in each study arm. Prolongation of the QT interval on ECG was noted in a single patient in the ziprasidone arm, whose peak was 478 milliseconds (msec). The mean increase in QT interval in the ziprasidone group at 4 weeks was 8.3 msec, compared with a mean 2.9 msec decrease in the placebo arm.

This is an important study because of the limited safety and efficacy data available on the use of antipsychotic agents among pediatric patients, along with the documented importance of initiating treatment as early in the disease course as possible to achieve the best possible outcomes, according to the psychiatrist.

The trial was supported by Pfizer Inc., manufacturer of ziprasidone. Dr. Findling disclosed having received research grants and/or serving as a consultant to or on the speakers bureau for Pfizer and roughly a dozen other pharmaceutical companies.

With ziprasidone, the mean drop in the score was 13.8 points, compared with 8.6 in the placebo group.

Source DR. FINDLING

In August 2009, the FDA approved asenapine for treating acute exacerbation of schizophrenia and acute manic or mixed episodes of bipolar disorder with or without psychosis in adults (Table 1). Asenapine is the first psychotropic to obtain simultaneous FDA approval for schizophrenia and bipolar disorder. The drug’s unique receptor binding profile shows promise in treatment of positive and negative symptoms of schizophrenia with a low risk of extrapyramidal and anticholinergic side effects.

Table 1

Asenapine: Fast facts

How it works

Asenapine is an atypical antipsychotic. Although the exact mechanism of these medications’ efficacy is unknown, their antipsychotic and antimanic activity is thought to be the result of antagonism of central dopamine receptors. According to dopamine theory proposed in the 1960s:

• dopaminergic hyperactivity in mesolimbic dopaminergic pathways contributes to positive symptoms of schizophrenia—hallucinations, delusions, disorganized thoughts and behaviors, and catatonia
• dopaminergic hypoactivity in mesocortical dopaminergic pathways (prefrontal cortex) contributes to negative symptoms of schizophrenia—alogia, avolition, anhedonia, autism, social withdrawal, attention problems, blunted affect, and abstract thinking difficulty.

Asenapine has high affinity for multiple dopamine, serotonin, noradrenergic α1 and α2, and histamine H1 receptors, where it works as an antagonist. Asenapine’s affinity for several serotonin, noradrenergic, and dopaminergic D3 and D4 receptors is higher than its affinity for D2 receptors (Table 2),¹ which distinguishes asenapine from other atypical antipsychotics except clozapine.

Blockade of 5-HT2A and 5-HT2C receptors in prefrontal cortex increases dopamine release in this area; theoretically, this effect should improve negative symptoms. Another mechanism that possibly improves cognition and negative symptoms is asenapine’s antagonism at central α2 noradrenergic receptors. Central α1 noradrenergic receptor antagonism also might be helpful in improving positive symptoms of schizophrenia.¹

Asenapine’s affinity for the muscarinic-1 cholinergic receptors is quite low, and adverse effects associated with antagonism at these receptors—dry mouth, blurred vision, constipation, and urinary retention—are minimal.²

Table 2

Asenapine’s binding affinity for receptor subtypes*

Pharmacokinetics

Absorption of asenapine after oral (swallowed) administration is 2%. To increase total bioavailability to 35%, the drug is manufactured as sublingual dissolvable tablets. After sublingual administration, asenapine is readily absorbed and achieves peak plasma concentration in approximately 1 hour. After absorption, 95% of asenapine binds to transport proteins albumin and α1 acid glycoprotein. The half-life of the medication is approximately 24 hours, and steady state usually is achieved in 3 days.

Metabolism creates about 40 metabolites via multiple metabolic pathways; the main ones are glucuronidation by UGT1A4 and oxidative metabolism by cytochrome P450 (CYP)1A2. Asenapine is a weak inhibitor of CYP2D6, so coadministration of asenapine with other drugs that are substrates or inhibitors of CYP1A2 (eg, fluvoxamine) or CYP2D6 (eg, paroxetine, fluoxetine) should be done cautiously. Because asenapine elimination is biphasic, twice-daily dosing is recommended.³

Efficacy in clinical trials

Schizophrenia. Asenapine’s efficacy for treating schizophrenia was evaluated in 3 fixed-dose, 6-week, randomized, double-blind, placebo- and active- (haloperidol, olanzapine, and risperidone) controlled clinical trials in adults.^3-5 Subjects in these studies met DSM-IV criteria for schizophrenia and had acute exacerbation of their illness, with Positive and Negative Syndrome Scale (PANSS) total scores ≥60. Symptom improvement was measured after 6 weeks by PANSS total score, PANSS positive subscale, and Clinical Global Impression scale (CGI).

The first trial (n=174) compared asenapine, 5 mg twice daily, to placebo and risperidone, 3 mg twice daily.^3-5 Asenapine was superior to placebo as demonstrated by symptom improvement on all 3 scales. Risperidone showed statistically significant symptom improvement on PANSS positive subscale and CGI but not on PANSS total score.

In the second trial (n=448), 2 fixed doses of asenapine (5 mg twice daily and 10 mg twice daily) and olanzapine, 15 mg/d, were compared with placebo.^3,5 The only statistically significant symptom improvement in the asenapine group compared with placebo was on the PANSS positive subscale among subjects receiving 5 mg twice daily. Improvements measured by CGI and PANSS total score were not statistically significant.

Olanzapine showed statistically significant symptom improvement on all 3 scales compared with placebo. This study is a negative trial for asenapine; asenapine failed to separate from placebo, whereas olanzapine—the active comparator—did.

The third trial (n=448) compared asenapine, 5 mg twice daily and 10 mg twice daily, with placebo and haloperidol, 4 mg twice daily.^3,5 Compared with placebo, asenapine at both doses and haloperidol improved symptoms on all 3 scales. The 10-mg twice-daily dosage did not provide any additional benefits compared with the 5 mg twice-daily dosage.

Bipolar disorder. Asenapine’s efficacy for bipolar disorder was established in two 3-week, randomized, double-blind, placebo- and olanzapine-controlled studies in adults with acute manic or mixed episodes with or without psychosis.^3,6-9 Symptoms were assessed using the Young Mania Rating Scale (YMRS) and Clinical Global Impression-Bipolar (CGI-BP) scale.

In both studies, subjects were randomly assigned to receive asenapine, 10 mg twice daily; olanzapine, 5 to 20 mg/d; or placebo. Depending on efficacy and tolerability, the asenapine dose could be adjusted within the dosing range of 5 mg to 10 mg twice daily starting on day 2. Ninety percent of subjects stayed on the 10 mg twice-daily dose. In both studies, asenapine and olanzapine were statistically superior to placebo on YMRS and CGI-BP severity of illness scores.

Currently no evidence supports asenapine’s efficacy for maintenance treatment of schizophrenia or bipolar disorder. American Psychiatric Association practice guidelines recommend continuing treatment for a minimum of 6 months after stabilization of acute episodes of schizophrenia or bipolar disorder to prevent recurrence.¹⁰

Tolerability in clinical trials

Tolerability information provided in this article was obtained from a Clinical Trial Database consisting of 3,350 subjects:¹¹

• 1,953 patients participated in multiple dose effectiveness trials (1,480 with schizophrenia and 473 with bipolar disorder manic/mixed episodes)
• 486 subjects were treated for at least 24 weeks
• 293 subjects were treated for at least 52 weeks.

Overall, asenapine was well tolerated (Table 3).¹¹ The most common adverse effects in schizophrenia trials were akathisia, oral hypoesthesia, and somnolence. The discontinuation rate due to adverse effects in schizophrenia trials was 9% in the asenapine group vs 10% in the placebo group.

Among patients with bipolar disorder, the most common side effects were somnolence, dizziness, extrapyramidal symptoms other than akathisia, and increased weight. The discontinuation rate for subjects treated with asenapine was 10% vs 6% with placebo. The most common adverse reactions associated with discontinuation were anxiety and oral hypoesthesia. Oral hypoesthesia did not occur in the placebo group, and akathisia was the only dose-dependent adverse reaction.

Dizziness and weight gain. Clinically important adverse effects of asenapine include dizziness and weight gain. Dizziness is possibly related to orthostatic hypotension caused by the drug’s activity at the α1 receptor (antagonist). To prevent ischemic events or falls with subsequent injuries, use asenapine with caution in hypotensive patients and those with cardiovascular or cerebrovascular problems.

In clinical trials investigating asenapine’s efficacy, mean weight gain was greater in patients receiving asenapine than those receiving placebo. In short-term studies, mean weight gain in patients treated with asenapine was 1.1 kg for subjects with schizophrenia and 1.3 kg for subjects with bipolar mania.³ Mean weight gain in patients treated with placebo was 0.1 kg for subjects with schizophrenia and 0.2 kg for those with bipolar mania.

In a 52-week comparator study of patients with schizophrenia and schizoaffective disorder, mean weight gain was 0.9 kg in the asenapine group vs 4.2 kg in the olanzapine group.³ In both groups, the greatest weight increase occurred in subjects with body mass index <23.

There were no clinically relevant mean changes in serum fasting glucose, serum fasting triglycerides, fasting cholesterol, transaminases, and prolactin. Thrombocytopenia, anemia, tachycardia, temporary bundle branch block, visual accommodation disorder, oral paresthesia, glossodynia, swollen tongue, hyponatremia, and dysarthria occurred in 1 in 100 to 1 in 1,000 patients.

Table 3

Percentages of clinical trial patients who experienced adverse effects with asenapine vs placebo

Contraindications

There are no absolute contraindications to asenapine use; however, the medication is not recommended for treating:

• women who are pregnant if the risks of treatment outweigh the benefits (pregnancy risk C)
• breast-feeding mothers
• patients with severe hepatic impairment (Child-Pugh C).

Asenapine carries the same class warnings and precautions as other antipsychotic medications, including a “black box” warning of increased mortality risk in elderly patients with dementia-related psychosis. Other class warnings include an increased risk of transient ischemic attack and cerebrovascular accidents in elderly patients with dementia-related psychosis; neuroleptic malignant syndrome; tardive dyskinesia; glycemia/diabetes mellitus; hyperprolactinemia; leukopenia; neutropenia; and agranulocytosis.

Because asenapine is associated with QT prolongation, do not administer it with other QT-prolonging agents, such as procainamide, sotalol, quinidine, erythromycin, clarithromycin, methadone, or other antipsychotics.

Dosing

Asenapine is manufactured as 5-mg and 10-mg sublingual tablets. Advise patients to avoid eating or drinking for 10 minutes after taking asenapine.

The recommended starting and target dosage for patients with schizophrenia is 5 mg twice daily. The recommended starting dosage for patients with an acute mixed or manic episode of bipolar I disorder is 10 mg twice daily; however, this can be reduced to 5 mg twice daily if the patient experiences intolerable side effects.

Related resource

• Asenapine (Saphris) prescribing information. www.spfiles.com/pisaphrisv1.pdf.

Drug brand names

• Asenapine • Saphris
• Clarithromycin • Biaxin
• Clozapine • Clozaril
• Erythromycin • ERY-C, Ery-Tab
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Haloperidol • Haldol
• Methadone • Dolophine, Methadose
• Olanzapine • Zyprexa
• Paroxetine • Paxil
• Procainamide • Procanbid
• Quinidine • Quinidine
• Risperidone • Risperdal
• Sotalol • Betapace, Sorine

Disclosures

Dr. Lincoln reports no financial relationship with any company whose products are mentioned in this article, or with manufacturers of competing products.

Dr. Preskorn receives grant/research support from AstraZeneca, Biovail, Boehringer-Ingleheim, Cyberonics, Eli Lilly and Company, EnVivo, GlaxoSmithKline, UNC Chapel Hill, and Wyeth. He is a consultant to Allergan, Covidien, Eli Lilly and Company, Evotec, Lundbeck/Takeda, Transcept, and Wyeth.

In August 2009, the FDA approved asenapine for treating acute exacerbation of schizophrenia and acute manic or mixed episodes of bipolar disorder with or without psychosis in adults (Table 1). Asenapine is the first psychotropic to obtain simultaneous FDA approval for schizophrenia and bipolar disorder. The drug’s unique receptor binding profile shows promise in treatment of positive and negative symptoms of schizophrenia with a low risk of extrapyramidal and anticholinergic side effects.

Table 1

Asenapine: Fast facts

How it works

Asenapine is an atypical antipsychotic. Although the exact mechanism of these medications’ efficacy is unknown, their antipsychotic and antimanic activity is thought to be the result of antagonism of central dopamine receptors. According to dopamine theory proposed in the 1960s:

• dopaminergic hyperactivity in mesolimbic dopaminergic pathways contributes to positive symptoms of schizophrenia—hallucinations, delusions, disorganized thoughts and behaviors, and catatonia
• dopaminergic hypoactivity in mesocortical dopaminergic pathways (prefrontal cortex) contributes to negative symptoms of schizophrenia—alogia, avolition, anhedonia, autism, social withdrawal, attention problems, blunted affect, and abstract thinking difficulty.

Asenapine has high affinity for multiple dopamine, serotonin, noradrenergic α1 and α2, and histamine H1 receptors, where it works as an antagonist. Asenapine’s affinity for several serotonin, noradrenergic, and dopaminergic D3 and D4 receptors is higher than its affinity for D2 receptors (Table 2),¹ which distinguishes asenapine from other atypical antipsychotics except clozapine.

Blockade of 5-HT2A and 5-HT2C receptors in prefrontal cortex increases dopamine release in this area; theoretically, this effect should improve negative symptoms. Another mechanism that possibly improves cognition and negative symptoms is asenapine’s antagonism at central α2 noradrenergic receptors. Central α1 noradrenergic receptor antagonism also might be helpful in improving positive symptoms of schizophrenia.¹

Asenapine’s affinity for the muscarinic-1 cholinergic receptors is quite low, and adverse effects associated with antagonism at these receptors—dry mouth, blurred vision, constipation, and urinary retention—are minimal.²

Table 2

Asenapine’s binding affinity for receptor subtypes*

Pharmacokinetics

Absorption of asenapine after oral (swallowed) administration is 2%. To increase total bioavailability to 35%, the drug is manufactured as sublingual dissolvable tablets. After sublingual administration, asenapine is readily absorbed and achieves peak plasma concentration in approximately 1 hour. After absorption, 95% of asenapine binds to transport proteins albumin and α1 acid glycoprotein. The half-life of the medication is approximately 24 hours, and steady state usually is achieved in 3 days.

Metabolism creates about 40 metabolites via multiple metabolic pathways; the main ones are glucuronidation by UGT1A4 and oxidative metabolism by cytochrome P450 (CYP)1A2. Asenapine is a weak inhibitor of CYP2D6, so coadministration of asenapine with other drugs that are substrates or inhibitors of CYP1A2 (eg, fluvoxamine) or CYP2D6 (eg, paroxetine, fluoxetine) should be done cautiously. Because asenapine elimination is biphasic, twice-daily dosing is recommended.³

Efficacy in clinical trials

Schizophrenia. Asenapine’s efficacy for treating schizophrenia was evaluated in 3 fixed-dose, 6-week, randomized, double-blind, placebo- and active- (haloperidol, olanzapine, and risperidone) controlled clinical trials in adults.^3-5 Subjects in these studies met DSM-IV criteria for schizophrenia and had acute exacerbation of their illness, with Positive and Negative Syndrome Scale (PANSS) total scores ≥60. Symptom improvement was measured after 6 weeks by PANSS total score, PANSS positive subscale, and Clinical Global Impression scale (CGI).

The first trial (n=174) compared asenapine, 5 mg twice daily, to placebo and risperidone, 3 mg twice daily.^3-5 Asenapine was superior to placebo as demonstrated by symptom improvement on all 3 scales. Risperidone showed statistically significant symptom improvement on PANSS positive subscale and CGI but not on PANSS total score.

In the second trial (n=448), 2 fixed doses of asenapine (5 mg twice daily and 10 mg twice daily) and olanzapine, 15 mg/d, were compared with placebo.^3,5 The only statistically significant symptom improvement in the asenapine group compared with placebo was on the PANSS positive subscale among subjects receiving 5 mg twice daily. Improvements measured by CGI and PANSS total score were not statistically significant.

Olanzapine showed statistically significant symptom improvement on all 3 scales compared with placebo. This study is a negative trial for asenapine; asenapine failed to separate from placebo, whereas olanzapine—the active comparator—did.

The third trial (n=448) compared asenapine, 5 mg twice daily and 10 mg twice daily, with placebo and haloperidol, 4 mg twice daily.^3,5 Compared with placebo, asenapine at both doses and haloperidol improved symptoms on all 3 scales. The 10-mg twice-daily dosage did not provide any additional benefits compared with the 5 mg twice-daily dosage.

Bipolar disorder. Asenapine’s efficacy for bipolar disorder was established in two 3-week, randomized, double-blind, placebo- and olanzapine-controlled studies in adults with acute manic or mixed episodes with or without psychosis.^3,6-9 Symptoms were assessed using the Young Mania Rating Scale (YMRS) and Clinical Global Impression-Bipolar (CGI-BP) scale.

In both studies, subjects were randomly assigned to receive asenapine, 10 mg twice daily; olanzapine, 5 to 20 mg/d; or placebo. Depending on efficacy and tolerability, the asenapine dose could be adjusted within the dosing range of 5 mg to 10 mg twice daily starting on day 2. Ninety percent of subjects stayed on the 10 mg twice-daily dose. In both studies, asenapine and olanzapine were statistically superior to placebo on YMRS and CGI-BP severity of illness scores.

Currently no evidence supports asenapine’s efficacy for maintenance treatment of schizophrenia or bipolar disorder. American Psychiatric Association practice guidelines recommend continuing treatment for a minimum of 6 months after stabilization of acute episodes of schizophrenia or bipolar disorder to prevent recurrence.¹⁰

Tolerability in clinical trials

Tolerability information provided in this article was obtained from a Clinical Trial Database consisting of 3,350 subjects:¹¹

• 1,953 patients participated in multiple dose effectiveness trials (1,480 with schizophrenia and 473 with bipolar disorder manic/mixed episodes)
• 486 subjects were treated for at least 24 weeks
• 293 subjects were treated for at least 52 weeks.

Overall, asenapine was well tolerated (Table 3).¹¹ The most common adverse effects in schizophrenia trials were akathisia, oral hypoesthesia, and somnolence. The discontinuation rate due to adverse effects in schizophrenia trials was 9% in the asenapine group vs 10% in the placebo group.

Among patients with bipolar disorder, the most common side effects were somnolence, dizziness, extrapyramidal symptoms other than akathisia, and increased weight. The discontinuation rate for subjects treated with asenapine was 10% vs 6% with placebo. The most common adverse reactions associated with discontinuation were anxiety and oral hypoesthesia. Oral hypoesthesia did not occur in the placebo group, and akathisia was the only dose-dependent adverse reaction.

Dizziness and weight gain. Clinically important adverse effects of asenapine include dizziness and weight gain. Dizziness is possibly related to orthostatic hypotension caused by the drug’s activity at the α1 receptor (antagonist). To prevent ischemic events or falls with subsequent injuries, use asenapine with caution in hypotensive patients and those with cardiovascular or cerebrovascular problems.

In clinical trials investigating asenapine’s efficacy, mean weight gain was greater in patients receiving asenapine than those receiving placebo. In short-term studies, mean weight gain in patients treated with asenapine was 1.1 kg for subjects with schizophrenia and 1.3 kg for subjects with bipolar mania.³ Mean weight gain in patients treated with placebo was 0.1 kg for subjects with schizophrenia and 0.2 kg for those with bipolar mania.

In a 52-week comparator study of patients with schizophrenia and schizoaffective disorder, mean weight gain was 0.9 kg in the asenapine group vs 4.2 kg in the olanzapine group.³ In both groups, the greatest weight increase occurred in subjects with body mass index <23.

There were no clinically relevant mean changes in serum fasting glucose, serum fasting triglycerides, fasting cholesterol, transaminases, and prolactin. Thrombocytopenia, anemia, tachycardia, temporary bundle branch block, visual accommodation disorder, oral paresthesia, glossodynia, swollen tongue, hyponatremia, and dysarthria occurred in 1 in 100 to 1 in 1,000 patients.

Table 3

Percentages of clinical trial patients who experienced adverse effects with asenapine vs placebo

Contraindications

There are no absolute contraindications to asenapine use; however, the medication is not recommended for treating:

• women who are pregnant if the risks of treatment outweigh the benefits (pregnancy risk C)
• breast-feeding mothers
• patients with severe hepatic impairment (Child-Pugh C).

Asenapine carries the same class warnings and precautions as other antipsychotic medications, including a “black box” warning of increased mortality risk in elderly patients with dementia-related psychosis. Other class warnings include an increased risk of transient ischemic attack and cerebrovascular accidents in elderly patients with dementia-related psychosis; neuroleptic malignant syndrome; tardive dyskinesia; glycemia/diabetes mellitus; hyperprolactinemia; leukopenia; neutropenia; and agranulocytosis.

Because asenapine is associated with QT prolongation, do not administer it with other QT-prolonging agents, such as procainamide, sotalol, quinidine, erythromycin, clarithromycin, methadone, or other antipsychotics.

Dosing

Asenapine is manufactured as 5-mg and 10-mg sublingual tablets. Advise patients to avoid eating or drinking for 10 minutes after taking asenapine.

The recommended starting and target dosage for patients with schizophrenia is 5 mg twice daily. The recommended starting dosage for patients with an acute mixed or manic episode of bipolar I disorder is 10 mg twice daily; however, this can be reduced to 5 mg twice daily if the patient experiences intolerable side effects.

Related resource

• Asenapine (Saphris) prescribing information. www.spfiles.com/pisaphrisv1.pdf.

Drug brand names

• Asenapine • Saphris
• Clarithromycin • Biaxin
• Clozapine • Clozaril
• Erythromycin • ERY-C, Ery-Tab
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Haloperidol • Haldol
• Methadone • Dolophine, Methadose
• Olanzapine • Zyprexa
• Paroxetine • Paxil
• Procainamide • Procanbid
• Quinidine • Quinidine
• Risperidone • Risperdal
• Sotalol • Betapace, Sorine

Disclosures

Dr. Lincoln reports no financial relationship with any company whose products are mentioned in this article, or with manufacturers of competing products.

Dr. Preskorn receives grant/research support from AstraZeneca, Biovail, Boehringer-Ingleheim, Cyberonics, Eli Lilly and Company, EnVivo, GlaxoSmithKline, UNC Chapel Hill, and Wyeth. He is a consultant to Allergan, Covidien, Eli Lilly and Company, Evotec, Lundbeck/Takeda, Transcept, and Wyeth.

In August 2009, the FDA approved asenapine for treating acute exacerbation of schizophrenia and acute manic or mixed episodes of bipolar disorder with or without psychosis in adults (Table 1). Asenapine is the first psychotropic to obtain simultaneous FDA approval for schizophrenia and bipolar disorder. The drug’s unique receptor binding profile shows promise in treatment of positive and negative symptoms of schizophrenia with a low risk of extrapyramidal and anticholinergic side effects.

Table 1

Asenapine: Fast facts

How it works

Asenapine is an atypical antipsychotic. Although the exact mechanism of these medications’ efficacy is unknown, their antipsychotic and antimanic activity is thought to be the result of antagonism of central dopamine receptors. According to dopamine theory proposed in the 1960s:

• dopaminergic hyperactivity in mesolimbic dopaminergic pathways contributes to positive symptoms of schizophrenia—hallucinations, delusions, disorganized thoughts and behaviors, and catatonia
• dopaminergic hypoactivity in mesocortical dopaminergic pathways (prefrontal cortex) contributes to negative symptoms of schizophrenia—alogia, avolition, anhedonia, autism, social withdrawal, attention problems, blunted affect, and abstract thinking difficulty.

Asenapine has high affinity for multiple dopamine, serotonin, noradrenergic α1 and α2, and histamine H1 receptors, where it works as an antagonist. Asenapine’s affinity for several serotonin, noradrenergic, and dopaminergic D3 and D4 receptors is higher than its affinity for D2 receptors (Table 2),¹ which distinguishes asenapine from other atypical antipsychotics except clozapine.

Blockade of 5-HT2A and 5-HT2C receptors in prefrontal cortex increases dopamine release in this area; theoretically, this effect should improve negative symptoms. Another mechanism that possibly improves cognition and negative symptoms is asenapine’s antagonism at central α2 noradrenergic receptors. Central α1 noradrenergic receptor antagonism also might be helpful in improving positive symptoms of schizophrenia.¹

Asenapine’s affinity for the muscarinic-1 cholinergic receptors is quite low, and adverse effects associated with antagonism at these receptors—dry mouth, blurred vision, constipation, and urinary retention—are minimal.²

Table 2

Asenapine’s binding affinity for receptor subtypes*

Pharmacokinetics

Absorption of asenapine after oral (swallowed) administration is 2%. To increase total bioavailability to 35%, the drug is manufactured as sublingual dissolvable tablets. After sublingual administration, asenapine is readily absorbed and achieves peak plasma concentration in approximately 1 hour. After absorption, 95% of asenapine binds to transport proteins albumin and α1 acid glycoprotein. The half-life of the medication is approximately 24 hours, and steady state usually is achieved in 3 days.

Metabolism creates about 40 metabolites via multiple metabolic pathways; the main ones are glucuronidation by UGT1A4 and oxidative metabolism by cytochrome P450 (CYP)1A2. Asenapine is a weak inhibitor of CYP2D6, so coadministration of asenapine with other drugs that are substrates or inhibitors of CYP1A2 (eg, fluvoxamine) or CYP2D6 (eg, paroxetine, fluoxetine) should be done cautiously. Because asenapine elimination is biphasic, twice-daily dosing is recommended.³

Efficacy in clinical trials

Schizophrenia. Asenapine’s efficacy for treating schizophrenia was evaluated in 3 fixed-dose, 6-week, randomized, double-blind, placebo- and active- (haloperidol, olanzapine, and risperidone) controlled clinical trials in adults.^3-5 Subjects in these studies met DSM-IV criteria for schizophrenia and had acute exacerbation of their illness, with Positive and Negative Syndrome Scale (PANSS) total scores ≥60. Symptom improvement was measured after 6 weeks by PANSS total score, PANSS positive subscale, and Clinical Global Impression scale (CGI).

The first trial (n=174) compared asenapine, 5 mg twice daily, to placebo and risperidone, 3 mg twice daily.^3-5 Asenapine was superior to placebo as demonstrated by symptom improvement on all 3 scales. Risperidone showed statistically significant symptom improvement on PANSS positive subscale and CGI but not on PANSS total score.

In the second trial (n=448), 2 fixed doses of asenapine (5 mg twice daily and 10 mg twice daily) and olanzapine, 15 mg/d, were compared with placebo.^3,5 The only statistically significant symptom improvement in the asenapine group compared with placebo was on the PANSS positive subscale among subjects receiving 5 mg twice daily. Improvements measured by CGI and PANSS total score were not statistically significant.

Olanzapine showed statistically significant symptom improvement on all 3 scales compared with placebo. This study is a negative trial for asenapine; asenapine failed to separate from placebo, whereas olanzapine—the active comparator—did.

The third trial (n=448) compared asenapine, 5 mg twice daily and 10 mg twice daily, with placebo and haloperidol, 4 mg twice daily.^3,5 Compared with placebo, asenapine at both doses and haloperidol improved symptoms on all 3 scales. The 10-mg twice-daily dosage did not provide any additional benefits compared with the 5 mg twice-daily dosage.

Bipolar disorder. Asenapine’s efficacy for bipolar disorder was established in two 3-week, randomized, double-blind, placebo- and olanzapine-controlled studies in adults with acute manic or mixed episodes with or without psychosis.^3,6-9 Symptoms were assessed using the Young Mania Rating Scale (YMRS) and Clinical Global Impression-Bipolar (CGI-BP) scale.

In both studies, subjects were randomly assigned to receive asenapine, 10 mg twice daily; olanzapine, 5 to 20 mg/d; or placebo. Depending on efficacy and tolerability, the asenapine dose could be adjusted within the dosing range of 5 mg to 10 mg twice daily starting on day 2. Ninety percent of subjects stayed on the 10 mg twice-daily dose. In both studies, asenapine and olanzapine were statistically superior to placebo on YMRS and CGI-BP severity of illness scores.

Currently no evidence supports asenapine’s efficacy for maintenance treatment of schizophrenia or bipolar disorder. American Psychiatric Association practice guidelines recommend continuing treatment for a minimum of 6 months after stabilization of acute episodes of schizophrenia or bipolar disorder to prevent recurrence.¹⁰

Tolerability in clinical trials

Tolerability information provided in this article was obtained from a Clinical Trial Database consisting of 3,350 subjects:¹¹

• 1,953 patients participated in multiple dose effectiveness trials (1,480 with schizophrenia and 473 with bipolar disorder manic/mixed episodes)
• 486 subjects were treated for at least 24 weeks
• 293 subjects were treated for at least 52 weeks.

Overall, asenapine was well tolerated (Table 3).¹¹ The most common adverse effects in schizophrenia trials were akathisia, oral hypoesthesia, and somnolence. The discontinuation rate due to adverse effects in schizophrenia trials was 9% in the asenapine group vs 10% in the placebo group.

Among patients with bipolar disorder, the most common side effects were somnolence, dizziness, extrapyramidal symptoms other than akathisia, and increased weight. The discontinuation rate for subjects treated with asenapine was 10% vs 6% with placebo. The most common adverse reactions associated with discontinuation were anxiety and oral hypoesthesia. Oral hypoesthesia did not occur in the placebo group, and akathisia was the only dose-dependent adverse reaction.

Dizziness and weight gain. Clinically important adverse effects of asenapine include dizziness and weight gain. Dizziness is possibly related to orthostatic hypotension caused by the drug’s activity at the α1 receptor (antagonist). To prevent ischemic events or falls with subsequent injuries, use asenapine with caution in hypotensive patients and those with cardiovascular or cerebrovascular problems.

In clinical trials investigating asenapine’s efficacy, mean weight gain was greater in patients receiving asenapine than those receiving placebo. In short-term studies, mean weight gain in patients treated with asenapine was 1.1 kg for subjects with schizophrenia and 1.3 kg for subjects with bipolar mania.³ Mean weight gain in patients treated with placebo was 0.1 kg for subjects with schizophrenia and 0.2 kg for those with bipolar mania.

In a 52-week comparator study of patients with schizophrenia and schizoaffective disorder, mean weight gain was 0.9 kg in the asenapine group vs 4.2 kg in the olanzapine group.³ In both groups, the greatest weight increase occurred in subjects with body mass index <23.

There were no clinically relevant mean changes in serum fasting glucose, serum fasting triglycerides, fasting cholesterol, transaminases, and prolactin. Thrombocytopenia, anemia, tachycardia, temporary bundle branch block, visual accommodation disorder, oral paresthesia, glossodynia, swollen tongue, hyponatremia, and dysarthria occurred in 1 in 100 to 1 in 1,000 patients.

Table 3

Percentages of clinical trial patients who experienced adverse effects with asenapine vs placebo

Contraindications

There are no absolute contraindications to asenapine use; however, the medication is not recommended for treating:

• women who are pregnant if the risks of treatment outweigh the benefits (pregnancy risk C)
• breast-feeding mothers
• patients with severe hepatic impairment (Child-Pugh C).

Asenapine carries the same class warnings and precautions as other antipsychotic medications, including a “black box” warning of increased mortality risk in elderly patients with dementia-related psychosis. Other class warnings include an increased risk of transient ischemic attack and cerebrovascular accidents in elderly patients with dementia-related psychosis; neuroleptic malignant syndrome; tardive dyskinesia; glycemia/diabetes mellitus; hyperprolactinemia; leukopenia; neutropenia; and agranulocytosis.

Because asenapine is associated with QT prolongation, do not administer it with other QT-prolonging agents, such as procainamide, sotalol, quinidine, erythromycin, clarithromycin, methadone, or other antipsychotics.

Dosing

Asenapine is manufactured as 5-mg and 10-mg sublingual tablets. Advise patients to avoid eating or drinking for 10 minutes after taking asenapine.

The recommended starting and target dosage for patients with schizophrenia is 5 mg twice daily. The recommended starting dosage for patients with an acute mixed or manic episode of bipolar I disorder is 10 mg twice daily; however, this can be reduced to 5 mg twice daily if the patient experiences intolerable side effects.

Related resource

• Asenapine (Saphris) prescribing information. www.spfiles.com/pisaphrisv1.pdf.

Drug brand names

• Asenapine • Saphris
• Clarithromycin • Biaxin
• Clozapine • Clozaril
• Erythromycin • ERY-C, Ery-Tab
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Haloperidol • Haldol
• Methadone • Dolophine, Methadose
• Olanzapine • Zyprexa
• Paroxetine • Paxil
• Procainamide • Procanbid
• Quinidine • Quinidine
• Risperidone • Risperdal
• Sotalol • Betapace, Sorine

Disclosures

Dr. Lincoln reports no financial relationship with any company whose products are mentioned in this article, or with manufacturers of competing products.

Dr. Preskorn receives grant/research support from AstraZeneca, Biovail, Boehringer-Ingleheim, Cyberonics, Eli Lilly and Company, EnVivo, GlaxoSmithKline, UNC Chapel Hill, and Wyeth. He is a consultant to Allergan, Covidien, Eli Lilly and Company, Evotec, Lundbeck/Takeda, Transcept, and Wyeth.

Comment on this article

Mrs. S, age 34, worked as an office manager with responsibilities for more than 40 employees for 5 years. Starting in her mid 20s she had repeated periods of depression, binge drinking, and risk-taking that were treated ineffectively with antidepressants. Ultimately, she was fired from her job.

Eventually Mrs. S was diagnosed as bipolar and over time responded well to a mood-stabilizing regimen. She now desires to return to work, both for financial reasons and for the sense of accomplishment that comes from working. Initially, personnel managers review her résumé and tell her she would be bored by the routine nature of entry-level positions, or they offer her jobs with major responsibilities. She accepts a high-level position but soon leaves, feeling overwhelmed by the stress.

Bipolar disorder’s long-term course presents a therapeutic challenge when patients desire to remain employed, seek temporary or permanent disability status, or—most commonly—attempt to return to employment after a period of inability to work. As the experience of Mrs. S illustrates, previous capabilities that appear higher than the person’s present or recent work experience are a key issue to address in interpersonal therapy.

Evidence-based research is informative, but ultimately you must apply judgment and flexibility in setting and revising goals with the bipolar individual. Attention to the disorder’s core characteristics can help you equip patients for work that contributes to their pursuit of health.

Obstacles to employment

Role function. Bipolar disorder impairs family and social function in approximately one-half of persons with this diagnosis, a higher impairment rate than in persons with major depression.¹

Cognitive function. Bipolar disorder patients have subtle sustained impairments in cognitive function, particularly working memory.^2,3 These deficits—although generally much less severe than in persons with schizophrenia—contribute to workplace and educational difficulties.

Unstable mood. Some symptoms associated with elevated mood contribute to functional impairment. These are not limited to mania or hypomania but also can be prominent in mixed states and depression.

A study from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) found that two-thirds of 1,380 depressed bipolar I and II patients had ?1 concomitant symptoms principally associated with manic states. The most prominent were distractibility, pressured speech and thoughts, risky behavior, and agitation.⁴ Each of these—or, more often, all of these—can interfere with work responsibilities.

Circadian rhythm pattern. Sleep disturbances in bipolar disorder differ from those associated with other medical conditions. Bipolar patients’ tendency to increase their activity and interests in the evening may keep them awake into the early morning hours. Insufficient sleep and impaired daytime cognition and alertness related to idio syncratic circadian rhythms can interfere with job requirements.⁵ The structure of employment can help many bipolar patients maintain effective sleep patterns as well as waking activities (Box 1).

Some individuals recognize their disturbed activity pattern, but many view it simply as the way they approach a day. For the latter group, a sustained treatment effort is needed to help them recognize the adverse consequences of the pattern and develop a more effective daily routine.

Adverse treatment effects. Although important, this core medical issue is not central to the interpersonal focus of this article. The simple tolerability objective in prescribing medications—and less frequently therapies such as electroconvulsive treatment—is to avoid dosages that impair concentration, alertness, or motor speed and accuracy. Similarly, avoid medications that can cause physical changes noticeable to others—such as tremor, sleepiness, or significant weight gain—or adjust dosages to eliminate these side effects.

Box 1

Bipolar symptom domains

Anxiety is recognized as a separate and major domain in bipolar psychopathology,⁶ contributing strongly to poor outcomes. Although anxiety is somewhat more predominant in depression and mixed states, it is common in manic and recovered bipolar states as well.

Social anxiety and panic states appear to be most specifically associated with bipolar disorder.⁷ Because these types of anxiety entail excessive fearful responses, psychotherapeutic techniques including extinction approaches can be helpful.

Depression in bipolar disorder tends to manifest as slowed motor and cognitive function, which is likely to be evident in work situations. Additionally, loss of social interests—one of the most common and severe aspects of depression in bipolar disorders—is likely to be evident to coworkers and to negatively impact work effectiveness.

Irritability occurs most frequently in mixed bipolar states but also is characteristic of—though generally less intense in—depressed and manic clinical states. Even when strictly internal and subjective, irritability can reduce an individual’s confidence and work effectiveness. Expressed irritability, from minor annoyances to explosive outbursts, can have serious employment consequences, including termination.

Manic symptoms. The impulsivity that is common in bipolar mania can interfere with work. Acting without considering consequences, taking undue risks, or reaching conclusions on inadequate information can cause problems, including physical harm to self or coworkers. Excessive talking—usually associated with internally recognized racing thoughts—can be a nuisance when mild or problematic if it interferes with customer or coworker interactions.

Hyperactivity and increased energy may be perceived as behaviors that facilitate productivity at work (Box 2).^8-10 The adaptive characteristics of many hypomanic states are infrequent or absent in depressive, manic, and mixed manic clinical states, however.

Psychosis is principally associated with manic episodes, but it can be a component of any symptomatic clinical state. Delusional ideas or persecutory thoughts are rarely compatible with a work environment, in part because of potential risks to others.

Box 2

Componential treatment

Bipolar disorder’s multiple symptom domains suggest a componential approach to treatment. It may be useful to convey this concept metaphorically to the patient. When working on a jigsaw puzzle, a section that has been put together can be largely left intact and attention turned to other sections of the puzzle. Similarly, once a particular bipolar component is well managed—whether via medication, lifestyle, attitudes, or combinations of these—that symptom is likely to remain stable, barring a new insult/stressor (such as a medical condition requiring drugs that interfere with the bipolar regimen).

If mood stabilizers control risky behavior, impulsivity, and affective lability, the regimen generally will remain effective. If residual or new problems develop in another area (such as anxiety, sleep cycle, or irritability), choose drug regimens and psychoeducation approaches that are compatible with the mood-stabilizing plan. This attitude toward treatment:

• is reassuring to most patients, who come to see a new or recurring problem in one domain as not inherently a harbinger of complete relapse
• can reduce patient- or clinician-initiated deletions and additions of medications in a regimen that has been established as effective.

Autobiographical accounts of persons with bipolar disorders can be useful in educating patients about the considerations presented here. Actress Patty Duke made these observations in describing the gradual development of an effective treatment for her severe bipolar disorder:

I work at not flying off the handle…and I’m much better at it. My general medical bills dropped by $50,000 a year since my bipolar diagnosis and treatment. Until then, I was always in the hospital for some phantom illness. I was there with real symptoms born of depression. I haven’t been in the hospital since I was diagnosed.

My recovery from manic-depression has been an evolution, not a sudden miracle. For someone who spent 50% of her life screaming and yelling about something, I am now down to, say, 5%.¹¹

Psychosocial factors to consider

Stigma in the workplace. Although most coworkers are tolerant of and fair-minded about the functional difficulties common in symptomatic bipolar disorder, some will have biased, inaccurate views about psychiatric conditions. Advise bipolar individuals to make case-by-case decisions about whether to provide personal information to other employees and, if so, how much.

As with most medical conditions, the default choice will be to not discuss personal information in the workplace. Some coworkers, however, might appreciate learning of the bipolar condition (for example, a supervisor who seems empathic to an employee’s seeming stressed state).

Realistic expectations. Most clinicians recognize that relief from a syndromal bipolar state is achieved more quickly than a sustained recovered status in which symptoms are minimal. Attaining functional capacity in a normal range also lags, both in time and in the proportion of persons who ever achieve sustained good function.¹² Patients, their families, and often employers may have unrealistic expectations about early resumption of work after a depressive or manic episode resolves.

Ethnic considerations. Some literature suggests ethnic differences in the initial presentation of bipolar disorder, with more severe manifestations in some populations particularly if psychosis is a component symptom.¹³ Additionally, some cultural views about stigma from illness can add to patients’ or family members’ reluctance to re-enter the workplace.

Socioeconomic status. Sometimes bipolar illness puts out of reach the occupational activities that an individual has previously undertaken or that are characteristic of the family’s experience and expectations. Resistance to a change in self-concept can add to the difficulty in successfully moving a patient to consider employment that is more routinized and less intellectual or decisional in nature (Box 3).¹⁴

Divergence in education vs work status. Persons with bipolar disorders often have substantial divergence between high educational attainment and lower work performance. When this is the case, all or most of the factors reviewed in this article probably have contributed. Mrs. S’s experience illustrates this aspect of our care for persons with bipolar disorders.

Box 3

CASE CONTINUED: Finding a new balance

After leaving the stressful high-level job, Mrs. S next resolved to limit her search to half-time positions and took a job with limited responsibilities in a bookstore. Her work productivity was outstanding, but she became easily flustered when asked to assume additional responsibilities. Some of these required quick learning of new skills in inventory re-supply or interacting with dissatisfied customers.

As she became more confident and less fearful of being fired, Mrs. S talked with 2 supervisors about her illness management. This halted their well-intentioned efforts to promote her, based on their perception of her as talented and engaging.

Attention to these workplace issues took up approximately half of the time in her regular psychiatric appointments for more than 1 year. Through this process, Mrs. S developed increasingly effective insight into the complex mix of her accomplishments and resilience on one hand and her fluctuating social and vocational impairment on the other. She also recognized that subsyndromal symptoms continued at times, despite her overall good functional state. These insights and her greater self-confidence helped Mrs. S resolve and manage the divergences in her own and others’ perceptions of her capabilities and potential.

Related Resource

• Coping with depression or bipolar disorder at your job (patient information). Depression and Bipolar Support Alliance. www.dbsalliance.org/site/PageServer?pagename=Employment_Information.

Disclosure

Dr. Bowden reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Comment on this article

Mrs. S, age 34, worked as an office manager with responsibilities for more than 40 employees for 5 years. Starting in her mid 20s she had repeated periods of depression, binge drinking, and risk-taking that were treated ineffectively with antidepressants. Ultimately, she was fired from her job.

Eventually Mrs. S was diagnosed as bipolar and over time responded well to a mood-stabilizing regimen. She now desires to return to work, both for financial reasons and for the sense of accomplishment that comes from working. Initially, personnel managers review her résumé and tell her she would be bored by the routine nature of entry-level positions, or they offer her jobs with major responsibilities. She accepts a high-level position but soon leaves, feeling overwhelmed by the stress.

Bipolar disorder’s long-term course presents a therapeutic challenge when patients desire to remain employed, seek temporary or permanent disability status, or—most commonly—attempt to return to employment after a period of inability to work. As the experience of Mrs. S illustrates, previous capabilities that appear higher than the person’s present or recent work experience are a key issue to address in interpersonal therapy.

Evidence-based research is informative, but ultimately you must apply judgment and flexibility in setting and revising goals with the bipolar individual. Attention to the disorder’s core characteristics can help you equip patients for work that contributes to their pursuit of health.

Obstacles to employment

Role function. Bipolar disorder impairs family and social function in approximately one-half of persons with this diagnosis, a higher impairment rate than in persons with major depression.¹

Cognitive function. Bipolar disorder patients have subtle sustained impairments in cognitive function, particularly working memory.^2,3 These deficits—although generally much less severe than in persons with schizophrenia—contribute to workplace and educational difficulties.

Unstable mood. Some symptoms associated with elevated mood contribute to functional impairment. These are not limited to mania or hypomania but also can be prominent in mixed states and depression.

A study from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) found that two-thirds of 1,380 depressed bipolar I and II patients had ?1 concomitant symptoms principally associated with manic states. The most prominent were distractibility, pressured speech and thoughts, risky behavior, and agitation.⁴ Each of these—or, more often, all of these—can interfere with work responsibilities.

Circadian rhythm pattern. Sleep disturbances in bipolar disorder differ from those associated with other medical conditions. Bipolar patients’ tendency to increase their activity and interests in the evening may keep them awake into the early morning hours. Insufficient sleep and impaired daytime cognition and alertness related to idio syncratic circadian rhythms can interfere with job requirements.⁵ The structure of employment can help many bipolar patients maintain effective sleep patterns as well as waking activities (Box 1).

Some individuals recognize their disturbed activity pattern, but many view it simply as the way they approach a day. For the latter group, a sustained treatment effort is needed to help them recognize the adverse consequences of the pattern and develop a more effective daily routine.

Adverse treatment effects. Although important, this core medical issue is not central to the interpersonal focus of this article. The simple tolerability objective in prescribing medications—and less frequently therapies such as electroconvulsive treatment—is to avoid dosages that impair concentration, alertness, or motor speed and accuracy. Similarly, avoid medications that can cause physical changes noticeable to others—such as tremor, sleepiness, or significant weight gain—or adjust dosages to eliminate these side effects.

Box 1

Bipolar symptom domains

Anxiety is recognized as a separate and major domain in bipolar psychopathology,⁶ contributing strongly to poor outcomes. Although anxiety is somewhat more predominant in depression and mixed states, it is common in manic and recovered bipolar states as well.

Social anxiety and panic states appear to be most specifically associated with bipolar disorder.⁷ Because these types of anxiety entail excessive fearful responses, psychotherapeutic techniques including extinction approaches can be helpful.

Depression in bipolar disorder tends to manifest as slowed motor and cognitive function, which is likely to be evident in work situations. Additionally, loss of social interests—one of the most common and severe aspects of depression in bipolar disorders—is likely to be evident to coworkers and to negatively impact work effectiveness.

Irritability occurs most frequently in mixed bipolar states but also is characteristic of—though generally less intense in—depressed and manic clinical states. Even when strictly internal and subjective, irritability can reduce an individual’s confidence and work effectiveness. Expressed irritability, from minor annoyances to explosive outbursts, can have serious employment consequences, including termination.

Manic symptoms. The impulsivity that is common in bipolar mania can interfere with work. Acting without considering consequences, taking undue risks, or reaching conclusions on inadequate information can cause problems, including physical harm to self or coworkers. Excessive talking—usually associated with internally recognized racing thoughts—can be a nuisance when mild or problematic if it interferes with customer or coworker interactions.

Hyperactivity and increased energy may be perceived as behaviors that facilitate productivity at work (Box 2).^8-10 The adaptive characteristics of many hypomanic states are infrequent or absent in depressive, manic, and mixed manic clinical states, however.

Psychosis is principally associated with manic episodes, but it can be a component of any symptomatic clinical state. Delusional ideas or persecutory thoughts are rarely compatible with a work environment, in part because of potential risks to others.

Box 2

Componential treatment

Bipolar disorder’s multiple symptom domains suggest a componential approach to treatment. It may be useful to convey this concept metaphorically to the patient. When working on a jigsaw puzzle, a section that has been put together can be largely left intact and attention turned to other sections of the puzzle. Similarly, once a particular bipolar component is well managed—whether via medication, lifestyle, attitudes, or combinations of these—that symptom is likely to remain stable, barring a new insult/stressor (such as a medical condition requiring drugs that interfere with the bipolar regimen).

If mood stabilizers control risky behavior, impulsivity, and affective lability, the regimen generally will remain effective. If residual or new problems develop in another area (such as anxiety, sleep cycle, or irritability), choose drug regimens and psychoeducation approaches that are compatible with the mood-stabilizing plan. This attitude toward treatment:

• is reassuring to most patients, who come to see a new or recurring problem in one domain as not inherently a harbinger of complete relapse
• can reduce patient- or clinician-initiated deletions and additions of medications in a regimen that has been established as effective.

Autobiographical accounts of persons with bipolar disorders can be useful in educating patients about the considerations presented here. Actress Patty Duke made these observations in describing the gradual development of an effective treatment for her severe bipolar disorder:

I work at not flying off the handle…and I’m much better at it. My general medical bills dropped by $50,000 a year since my bipolar diagnosis and treatment. Until then, I was always in the hospital for some phantom illness. I was there with real symptoms born of depression. I haven’t been in the hospital since I was diagnosed.

My recovery from manic-depression has been an evolution, not a sudden miracle. For someone who spent 50% of her life screaming and yelling about something, I am now down to, say, 5%.¹¹

Psychosocial factors to consider

Stigma in the workplace. Although most coworkers are tolerant of and fair-minded about the functional difficulties common in symptomatic bipolar disorder, some will have biased, inaccurate views about psychiatric conditions. Advise bipolar individuals to make case-by-case decisions about whether to provide personal information to other employees and, if so, how much.

As with most medical conditions, the default choice will be to not discuss personal information in the workplace. Some coworkers, however, might appreciate learning of the bipolar condition (for example, a supervisor who seems empathic to an employee’s seeming stressed state).

Realistic expectations. Most clinicians recognize that relief from a syndromal bipolar state is achieved more quickly than a sustained recovered status in which symptoms are minimal. Attaining functional capacity in a normal range also lags, both in time and in the proportion of persons who ever achieve sustained good function.¹² Patients, their families, and often employers may have unrealistic expectations about early resumption of work after a depressive or manic episode resolves.

Ethnic considerations. Some literature suggests ethnic differences in the initial presentation of bipolar disorder, with more severe manifestations in some populations particularly if psychosis is a component symptom.¹³ Additionally, some cultural views about stigma from illness can add to patients’ or family members’ reluctance to re-enter the workplace.

Socioeconomic status. Sometimes bipolar illness puts out of reach the occupational activities that an individual has previously undertaken or that are characteristic of the family’s experience and expectations. Resistance to a change in self-concept can add to the difficulty in successfully moving a patient to consider employment that is more routinized and less intellectual or decisional in nature (Box 3).¹⁴

Divergence in education vs work status. Persons with bipolar disorders often have substantial divergence between high educational attainment and lower work performance. When this is the case, all or most of the factors reviewed in this article probably have contributed. Mrs. S’s experience illustrates this aspect of our care for persons with bipolar disorders.

Box 3

CASE CONTINUED: Finding a new balance

After leaving the stressful high-level job, Mrs. S next resolved to limit her search to half-time positions and took a job with limited responsibilities in a bookstore. Her work productivity was outstanding, but she became easily flustered when asked to assume additional responsibilities. Some of these required quick learning of new skills in inventory re-supply or interacting with dissatisfied customers.

As she became more confident and less fearful of being fired, Mrs. S talked with 2 supervisors about her illness management. This halted their well-intentioned efforts to promote her, based on their perception of her as talented and engaging.

Attention to these workplace issues took up approximately half of the time in her regular psychiatric appointments for more than 1 year. Through this process, Mrs. S developed increasingly effective insight into the complex mix of her accomplishments and resilience on one hand and her fluctuating social and vocational impairment on the other. She also recognized that subsyndromal symptoms continued at times, despite her overall good functional state. These insights and her greater self-confidence helped Mrs. S resolve and manage the divergences in her own and others’ perceptions of her capabilities and potential.

Related Resource

• Coping with depression or bipolar disorder at your job (patient information). Depression and Bipolar Support Alliance. www.dbsalliance.org/site/PageServer?pagename=Employment_Information.

Disclosure

Dr. Bowden reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Comment on this article

Mrs. S, age 34, worked as an office manager with responsibilities for more than 40 employees for 5 years. Starting in her mid 20s she had repeated periods of depression, binge drinking, and risk-taking that were treated ineffectively with antidepressants. Ultimately, she was fired from her job.

Eventually Mrs. S was diagnosed as bipolar and over time responded well to a mood-stabilizing regimen. She now desires to return to work, both for financial reasons and for the sense of accomplishment that comes from working. Initially, personnel managers review her résumé and tell her she would be bored by the routine nature of entry-level positions, or they offer her jobs with major responsibilities. She accepts a high-level position but soon leaves, feeling overwhelmed by the stress.

Bipolar disorder’s long-term course presents a therapeutic challenge when patients desire to remain employed, seek temporary or permanent disability status, or—most commonly—attempt to return to employment after a period of inability to work. As the experience of Mrs. S illustrates, previous capabilities that appear higher than the person’s present or recent work experience are a key issue to address in interpersonal therapy.

Evidence-based research is informative, but ultimately you must apply judgment and flexibility in setting and revising goals with the bipolar individual. Attention to the disorder’s core characteristics can help you equip patients for work that contributes to their pursuit of health.

Obstacles to employment

Role function. Bipolar disorder impairs family and social function in approximately one-half of persons with this diagnosis, a higher impairment rate than in persons with major depression.¹

Cognitive function. Bipolar disorder patients have subtle sustained impairments in cognitive function, particularly working memory.^2,3 These deficits—although generally much less severe than in persons with schizophrenia—contribute to workplace and educational difficulties.

Unstable mood. Some symptoms associated with elevated mood contribute to functional impairment. These are not limited to mania or hypomania but also can be prominent in mixed states and depression.

A study from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) found that two-thirds of 1,380 depressed bipolar I and II patients had ?1 concomitant symptoms principally associated with manic states. The most prominent were distractibility, pressured speech and thoughts, risky behavior, and agitation.⁴ Each of these—or, more often, all of these—can interfere with work responsibilities.

Circadian rhythm pattern. Sleep disturbances in bipolar disorder differ from those associated with other medical conditions. Bipolar patients’ tendency to increase their activity and interests in the evening may keep them awake into the early morning hours. Insufficient sleep and impaired daytime cognition and alertness related to idio syncratic circadian rhythms can interfere with job requirements.⁵ The structure of employment can help many bipolar patients maintain effective sleep patterns as well as waking activities (Box 1).

Some individuals recognize their disturbed activity pattern, but many view it simply as the way they approach a day. For the latter group, a sustained treatment effort is needed to help them recognize the adverse consequences of the pattern and develop a more effective daily routine.

Adverse treatment effects. Although important, this core medical issue is not central to the interpersonal focus of this article. The simple tolerability objective in prescribing medications—and less frequently therapies such as electroconvulsive treatment—is to avoid dosages that impair concentration, alertness, or motor speed and accuracy. Similarly, avoid medications that can cause physical changes noticeable to others—such as tremor, sleepiness, or significant weight gain—or adjust dosages to eliminate these side effects.

Box 1

Bipolar symptom domains

Anxiety is recognized as a separate and major domain in bipolar psychopathology,⁶ contributing strongly to poor outcomes. Although anxiety is somewhat more predominant in depression and mixed states, it is common in manic and recovered bipolar states as well.

Social anxiety and panic states appear to be most specifically associated with bipolar disorder.⁷ Because these types of anxiety entail excessive fearful responses, psychotherapeutic techniques including extinction approaches can be helpful.

Depression in bipolar disorder tends to manifest as slowed motor and cognitive function, which is likely to be evident in work situations. Additionally, loss of social interests—one of the most common and severe aspects of depression in bipolar disorders—is likely to be evident to coworkers and to negatively impact work effectiveness.

Irritability occurs most frequently in mixed bipolar states but also is characteristic of—though generally less intense in—depressed and manic clinical states. Even when strictly internal and subjective, irritability can reduce an individual’s confidence and work effectiveness. Expressed irritability, from minor annoyances to explosive outbursts, can have serious employment consequences, including termination.

Manic symptoms. The impulsivity that is common in bipolar mania can interfere with work. Acting without considering consequences, taking undue risks, or reaching conclusions on inadequate information can cause problems, including physical harm to self or coworkers. Excessive talking—usually associated with internally recognized racing thoughts—can be a nuisance when mild or problematic if it interferes with customer or coworker interactions.

Hyperactivity and increased energy may be perceived as behaviors that facilitate productivity at work (Box 2).^8-10 The adaptive characteristics of many hypomanic states are infrequent or absent in depressive, manic, and mixed manic clinical states, however.

Psychosis is principally associated with manic episodes, but it can be a component of any symptomatic clinical state. Delusional ideas or persecutory thoughts are rarely compatible with a work environment, in part because of potential risks to others.

Box 2

Componential treatment

Bipolar disorder’s multiple symptom domains suggest a componential approach to treatment. It may be useful to convey this concept metaphorically to the patient. When working on a jigsaw puzzle, a section that has been put together can be largely left intact and attention turned to other sections of the puzzle. Similarly, once a particular bipolar component is well managed—whether via medication, lifestyle, attitudes, or combinations of these—that symptom is likely to remain stable, barring a new insult/stressor (such as a medical condition requiring drugs that interfere with the bipolar regimen).

If mood stabilizers control risky behavior, impulsivity, and affective lability, the regimen generally will remain effective. If residual or new problems develop in another area (such as anxiety, sleep cycle, or irritability), choose drug regimens and psychoeducation approaches that are compatible with the mood-stabilizing plan. This attitude toward treatment:

• is reassuring to most patients, who come to see a new or recurring problem in one domain as not inherently a harbinger of complete relapse
• can reduce patient- or clinician-initiated deletions and additions of medications in a regimen that has been established as effective.

Autobiographical accounts of persons with bipolar disorders can be useful in educating patients about the considerations presented here. Actress Patty Duke made these observations in describing the gradual development of an effective treatment for her severe bipolar disorder:

I work at not flying off the handle…and I’m much better at it. My general medical bills dropped by $50,000 a year since my bipolar diagnosis and treatment. Until then, I was always in the hospital for some phantom illness. I was there with real symptoms born of depression. I haven’t been in the hospital since I was diagnosed.

My recovery from manic-depression has been an evolution, not a sudden miracle. For someone who spent 50% of her life screaming and yelling about something, I am now down to, say, 5%.¹¹

Psychosocial factors to consider

Stigma in the workplace. Although most coworkers are tolerant of and fair-minded about the functional difficulties common in symptomatic bipolar disorder, some will have biased, inaccurate views about psychiatric conditions. Advise bipolar individuals to make case-by-case decisions about whether to provide personal information to other employees and, if so, how much.

As with most medical conditions, the default choice will be to not discuss personal information in the workplace. Some coworkers, however, might appreciate learning of the bipolar condition (for example, a supervisor who seems empathic to an employee’s seeming stressed state).

Realistic expectations. Most clinicians recognize that relief from a syndromal bipolar state is achieved more quickly than a sustained recovered status in which symptoms are minimal. Attaining functional capacity in a normal range also lags, both in time and in the proportion of persons who ever achieve sustained good function.¹² Patients, their families, and often employers may have unrealistic expectations about early resumption of work after a depressive or manic episode resolves.

Ethnic considerations. Some literature suggests ethnic differences in the initial presentation of bipolar disorder, with more severe manifestations in some populations particularly if psychosis is a component symptom.¹³ Additionally, some cultural views about stigma from illness can add to patients’ or family members’ reluctance to re-enter the workplace.

Socioeconomic status. Sometimes bipolar illness puts out of reach the occupational activities that an individual has previously undertaken or that are characteristic of the family’s experience and expectations. Resistance to a change in self-concept can add to the difficulty in successfully moving a patient to consider employment that is more routinized and less intellectual or decisional in nature (Box 3).¹⁴

Divergence in education vs work status. Persons with bipolar disorders often have substantial divergence between high educational attainment and lower work performance. When this is the case, all or most of the factors reviewed in this article probably have contributed. Mrs. S’s experience illustrates this aspect of our care for persons with bipolar disorders.

Box 3

CASE CONTINUED: Finding a new balance

After leaving the stressful high-level job, Mrs. S next resolved to limit her search to half-time positions and took a job with limited responsibilities in a bookstore. Her work productivity was outstanding, but she became easily flustered when asked to assume additional responsibilities. Some of these required quick learning of new skills in inventory re-supply or interacting with dissatisfied customers.

As she became more confident and less fearful of being fired, Mrs. S talked with 2 supervisors about her illness management. This halted their well-intentioned efforts to promote her, based on their perception of her as talented and engaging.

Attention to these workplace issues took up approximately half of the time in her regular psychiatric appointments for more than 1 year. Through this process, Mrs. S developed increasingly effective insight into the complex mix of her accomplishments and resilience on one hand and her fluctuating social and vocational impairment on the other. She also recognized that subsyndromal symptoms continued at times, despite her overall good functional state. These insights and her greater self-confidence helped Mrs. S resolve and manage the divergences in her own and others’ perceptions of her capabilities and potential.

Related Resource

• Coping with depression or bipolar disorder at your job (patient information). Depression and Bipolar Support Alliance. www.dbsalliance.org/site/PageServer?pagename=Employment_Information.

Disclosure

Dr. Bowden reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Today’s buzzword in health care is evidence-based medicine. Most clinicians would agree that evidence from clinical research should guide decisions about treating bipolar disorder. In theory, randomized controlled trials should tell us how to manage bipolar patients and achieve therapeutic success. ^{page 40.)}

We rarely have encountered a patient with postpartum depression or psychosis who does not have a history of (often undiagnosed and untreated) recurrent mood episodes. For most of these patients, a mood stabilizer may be a better choice than an antidepressant.

The role of thyroid hormones

Adding a thyroid hormone—usually liothyronine—to an antidepressant has been demonstrated to accelerate, ^{page 47.)}

Atypical depression and the bipolar spectrum

Depressive episodes are considered either “typical” (a category that includes melancholic depression—in DSM-IV-TR, major depression with melancholic features) or “atypical” (in DSM-IV-TR, major depression with atypical features). Atypical features were originally associated with response to monoamine oxidase inhibitor antidepressants, whereas non atypical depression was thought more likely to respond to tricyclic antidepressants.³⁴ The depression of bipolar disorder is usually atypical ( Box 4 ), especially in patients with softer variants of the illness.³⁵

We believe that depressed patients with atypical symptoms aggregate into groups according to the presence, severity, and character of interdepressive manic or hypomanic episodes. Some patients experience recurrent depressive episodes with intervening euthymia (recurrent major depression), whereas others experience depressive episodes punctuated by brief subthreshold hypomanic episodes. Patients in these groups occasionally tolerate or even benefit from cautiously managed antidepressant monotherapy. Patients with atypical depressive episodes alternating with frank hypomanic, manic, mixed, or manic-psychotic episodes usually require a mood stabilizer and may benefit from cotreatment with an atypical antipsychotic.

Akiskol and Benazzi³⁵ suggest that atypical depression may be a subtype of the bipolar spectrum. Our experience suggests that the bipolar spectrum is a continuum of degrees of risk for mood instability in persons with recurrent atypical depression.

Box 4

Related resources

• Lieber AL. Bipolar spectrum disorder: an overview of the soft bipolar spectrum. www.psycom.net/depression.central.lieber.html.
• Phelps J. Why am I still depressed? Recognizing and managing the ups and downs of bipolar II and soft bipolar disorder. www.psycheducation.org.
• Maier T. Evidence-based psychiatry: understanding the limitations of a method. J Eval Clin Pract. 2006;12(3):325.

Drug brand names

• Liothyronine • Cytomel
• Sertraline • Zoloft

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Today’s buzzword in health care is evidence-based medicine. Most clinicians would agree that evidence from clinical research should guide decisions about treating bipolar disorder. In theory, randomized controlled trials should tell us how to manage bipolar patients and achieve therapeutic success. ^{page 40.)}

We rarely have encountered a patient with postpartum depression or psychosis who does not have a history of (often undiagnosed and untreated) recurrent mood episodes. For most of these patients, a mood stabilizer may be a better choice than an antidepressant.

The role of thyroid hormones

Adding a thyroid hormone—usually liothyronine—to an antidepressant has been demonstrated to accelerate, ^{page 47.)}

Atypical depression and the bipolar spectrum

Depressive episodes are considered either “typical” (a category that includes melancholic depression—in DSM-IV-TR, major depression with melancholic features) or “atypical” (in DSM-IV-TR, major depression with atypical features). Atypical features were originally associated with response to monoamine oxidase inhibitor antidepressants, whereas non atypical depression was thought more likely to respond to tricyclic antidepressants.³⁴ The depression of bipolar disorder is usually atypical ( Box 4 ), especially in patients with softer variants of the illness.³⁵

We believe that depressed patients with atypical symptoms aggregate into groups according to the presence, severity, and character of interdepressive manic or hypomanic episodes. Some patients experience recurrent depressive episodes with intervening euthymia (recurrent major depression), whereas others experience depressive episodes punctuated by brief subthreshold hypomanic episodes. Patients in these groups occasionally tolerate or even benefit from cautiously managed antidepressant monotherapy. Patients with atypical depressive episodes alternating with frank hypomanic, manic, mixed, or manic-psychotic episodes usually require a mood stabilizer and may benefit from cotreatment with an atypical antipsychotic.

Akiskol and Benazzi³⁵ suggest that atypical depression may be a subtype of the bipolar spectrum. Our experience suggests that the bipolar spectrum is a continuum of degrees of risk for mood instability in persons with recurrent atypical depression.

Box 4

Related resources

• Lieber AL. Bipolar spectrum disorder: an overview of the soft bipolar spectrum. www.psycom.net/depression.central.lieber.html.
• Phelps J. Why am I still depressed? Recognizing and managing the ups and downs of bipolar II and soft bipolar disorder. www.psycheducation.org.
• Maier T. Evidence-based psychiatry: understanding the limitations of a method. J Eval Clin Pract. 2006;12(3):325.

Drug brand names

• Liothyronine • Cytomel
• Sertraline • Zoloft

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Today’s buzzword in health care is evidence-based medicine. Most clinicians would agree that evidence from clinical research should guide decisions about treating bipolar disorder. In theory, randomized controlled trials should tell us how to manage bipolar patients and achieve therapeutic success. ^{page 40.)}

We rarely have encountered a patient with postpartum depression or psychosis who does not have a history of (often undiagnosed and untreated) recurrent mood episodes. For most of these patients, a mood stabilizer may be a better choice than an antidepressant.

The role of thyroid hormones

Adding a thyroid hormone—usually liothyronine—to an antidepressant has been demonstrated to accelerate, ^{page 47.)}

Atypical depression and the bipolar spectrum

Depressive episodes are considered either “typical” (a category that includes melancholic depression—in DSM-IV-TR, major depression with melancholic features) or “atypical” (in DSM-IV-TR, major depression with atypical features). Atypical features were originally associated with response to monoamine oxidase inhibitor antidepressants, whereas non atypical depression was thought more likely to respond to tricyclic antidepressants.³⁴ The depression of bipolar disorder is usually atypical ( Box 4 ), especially in patients with softer variants of the illness.³⁵

We believe that depressed patients with atypical symptoms aggregate into groups according to the presence, severity, and character of interdepressive manic or hypomanic episodes. Some patients experience recurrent depressive episodes with intervening euthymia (recurrent major depression), whereas others experience depressive episodes punctuated by brief subthreshold hypomanic episodes. Patients in these groups occasionally tolerate or even benefit from cautiously managed antidepressant monotherapy. Patients with atypical depressive episodes alternating with frank hypomanic, manic, mixed, or manic-psychotic episodes usually require a mood stabilizer and may benefit from cotreatment with an atypical antipsychotic.

Akiskol and Benazzi³⁵ suggest that atypical depression may be a subtype of the bipolar spectrum. Our experience suggests that the bipolar spectrum is a continuum of degrees of risk for mood instability in persons with recurrent atypical depression.

Box 4

Related resources

• Lieber AL. Bipolar spectrum disorder: an overview of the soft bipolar spectrum. www.psycom.net/depression.central.lieber.html.
• Phelps J. Why am I still depressed? Recognizing and managing the ups and downs of bipolar II and soft bipolar disorder. www.psycheducation.org.
• Maier T. Evidence-based psychiatry: understanding the limitations of a method. J Eval Clin Pract. 2006;12(3):325.

Drug brand names

• Liothyronine • Cytomel
• Sertraline • Zoloft

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Can knowing a patient’s environmental stressors and family history help us more quickly diagnose bipolar mania?

Kessing et al¹ studied patients who were diagnosed as having mania or a mixed episode during their first psychiatric hospitalization. They found that certain life events were associated with these diagnoses, reinforcing the belief that environment to some extent influences psychiatric illness.

Although more research is needed, this finding may help psychiatrists reach a diagnosis of bipolar mania when the clinical course is unclear. Life events that may contribute to bipolar mania are remembered with the mnemonic MANIAS:

• Marital status change. The patient recently was married, divorced, or lost a significant other to death.
• Family Admission. The patient’s mother, father, or sibling was hospitalized at some point for a psychiatric disorder. It does not seem to matter whether the patient remembers the family member’s hospitalization.
• No work. The patient is unemployed.
• Inability to work. The patient is disabled or collects disability benefits.
• Abstaining from relationships. The patient does not have a significant other.
• Suicide was completed by the patient’s mother, father, or sibling. It does not matter how long ago or at what point in the patient’s life the suicide happened.

Can knowing a patient’s environmental stressors and family history help us more quickly diagnose bipolar mania?

Kessing et al¹ studied patients who were diagnosed as having mania or a mixed episode during their first psychiatric hospitalization. They found that certain life events were associated with these diagnoses, reinforcing the belief that environment to some extent influences psychiatric illness.

Although more research is needed, this finding may help psychiatrists reach a diagnosis of bipolar mania when the clinical course is unclear. Life events that may contribute to bipolar mania are remembered with the mnemonic MANIAS:

• Marital status change. The patient recently was married, divorced, or lost a significant other to death.
• Family Admission. The patient’s mother, father, or sibling was hospitalized at some point for a psychiatric disorder. It does not seem to matter whether the patient remembers the family member’s hospitalization.
• No work. The patient is unemployed.
• Inability to work. The patient is disabled or collects disability benefits.
• Abstaining from relationships. The patient does not have a significant other.
• Suicide was completed by the patient’s mother, father, or sibling. It does not matter how long ago or at what point in the patient’s life the suicide happened.

Can knowing a patient’s environmental stressors and family history help us more quickly diagnose bipolar mania?

Kessing et al¹ studied patients who were diagnosed as having mania or a mixed episode during their first psychiatric hospitalization. They found that certain life events were associated with these diagnoses, reinforcing the belief that environment to some extent influences psychiatric illness.

Although more research is needed, this finding may help psychiatrists reach a diagnosis of bipolar mania when the clinical course is unclear. Life events that may contribute to bipolar mania are remembered with the mnemonic MANIAS:

• Marital status change. The patient recently was married, divorced, or lost a significant other to death.
• Family Admission. The patient’s mother, father, or sibling was hospitalized at some point for a psychiatric disorder. It does not seem to matter whether the patient remembers the family member’s hospitalization.
• No work. The patient is unemployed.
• Inability to work. The patient is disabled or collects disability benefits.
• Abstaining from relationships. The patient does not have a significant other.
• Suicide was completed by the patient’s mother, father, or sibling. It does not matter how long ago or at what point in the patient’s life the suicide happened.