Ram J. Bishnoi, MD

Bipolar disorder is a prevalent disorder in the primary care setting.^1,2 Primary care providers therefore commonly encounter bipolar depression (BD; a major depressive episode in the context of bipolar disorder), which might be (1) an emerging depressive episode in previously undiagnosed bipolar disorder or (2) a recurrent episode during the course of chronic bipolar illness.^3,4

A primary care–based collaborative model has been identified as a potential strategy for effective management of chronic mental health conditions such as bipolar disorder.^5,6 However, this collaborative treatment model isn’t widely available; many patients with bipolar disorder are, in fact, treated solely by their primary care provider.

Two years ago in this journal,⁷ we addressed how to precisely identify an episode of BD and differentiate it from major depressive disorder (MDD; also known as unipolar depression). In this review, in addition to advancing clinical knowledge of BD, we provide:

• an overview of treatment options for BD (in contrast to the treatment of unipolar depression)
• the pharmacotherapeutic know-how to initiate and maintain treatment for uncomplicated episodes of BD.

We do not discuss management of manic, hypomanic, and mixed episodes of bipolar disorder.

How to identify bipolar depression

Understanding the (sometimes) unclear distinction between bipolar I and bipolar II disorders in an individual patient is key to formulating a therapeutic regimen for BD.

Bipolar I disorder consists of manic episodes, alternating (more often than not) with depressive episodes. Bipolar I usually manifests first with a depressive episode.

Bipolar II disorder manifests with depressive episodes and hypomanic episodes (but never manic episodes).

Continue to: Depressive episodes in the bipolar disorders

Depressive episodes in the bipolar disorders. Bipolar depression can be seen in the settings of both bipolar I and II disorders. When a patient presents with a manic episode, a history of depressive episodes is common (although not essential) to diagnose bipolar I; alternatively, a history of hypomania (but no prior mania) and depression is needed to make the diagnosis of bipolar II. The natural history of the bipolar disorders is therefore alternating manic and almost always depressive episodes (bipolar I) and alternating hypomanic and always depressive episodes (bipolar II).⁸

Failure to adequately treat bipolar depressive episodes can have serious consequences, including a worsening course of illness, alcohol and substance use disorder, and suicide.

Symptoms of hypomanic episodes are similar to what are seen in manic episodes, but are of shorter duration (≥ 4 days [episodes of mania are at least of 1 week’s duration]), lower intensity (no psychotic symptoms), and not associated with significant functional impairment or hospitalization. Table 1⁷ further describes the differentiating features of bipolar I and bipolar II. A history of an unequivocal manic or hypomanic episode makes the diagnosis of BD relatively easy. However, an unclear history of manic or hypomanic symptoms or episodes frequently leads to misdiagnosis or underdiagnosis of BD.

In both bipolar I and II, it is depressive symptoms and episodes that place the greatest burden on patients across the lifespan: They are the most commonly experienced features of the bipolar disorders^9,10 and lead to significant distress and functional impairment¹¹; in fact, patients with bipolar disorder spend 3 (or more) times as long in depressive episodes as in manic or hypomanic episodes.^12,13 In addition, subthreshold depressive symptoms occur commonly between major mood episodes.

Failure to identify and adequately treat depressive episodes of the bipolar disorders can have serious consequences: Patients are at risk of a worsening course of illness, alcohol use disorder, substance use disorder, chronic disability, mixed states, rapid cycling of mood episodes, and suicide.

Guidelines for treating bipolar depression

Despite the similarity in presenting symptoms and signs of depressive episodes in bipolar disorders and MDD, treating episodes of BD is significantly different than treating MDD. Antidepressant monotherapy, a mainstay of treatment for MDD, has limited utility in BD (especially depressive episodes of bipolar I) because of its limited efficacy and potential to destabilize mood, lead to rapid cycling, and induce mania or hypomania. Treatment options for BD include pharmacotherapy (the primary modality), psychological intervention (a useful adjunct, described later), and electroconvulsive therapy (ECT; highly worth considering in severe or treatment-resistant cases).

Continue to: For this article...

For this article, we searched PubMed and Google Scholar for guidelines for the management of bipolar disorders in adults that were published between July 2013 (when the US Food and Drug Administration [FDA] approved lurasidone for the treatment of BD) and March 2019. Related guideline-­referenced articles and clinical trials were also reviewed.

Our search identified 6 guidelines issued during the search period, developed by the:

• Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD),¹⁴
• British Association for Psychopharmacology (BAP),¹⁵
• Japanese Society of Mood Disorders (JSMD),¹⁶
• National Institute for Health and Care Excellence (NICE),¹⁷
• International College of Neuropsychopharmacology (CINP),¹⁸ and
• Royal Australian and New Zealand College of Psychiatrists.¹⁹

How to manage an episode of bipolar depression

First-line pharmacotherapeutic agents for the management of BD in acute bipolar I are listed and described in Table 2.^4-19 Compared to the number of studies and reports on the management of BD in bipolar I, few studies have been conducted that specifically examine the treatment of BD in acute bipolar II. In practice, evidence from the treatment of BD in bipolar I has been extrapolated to the treatment of bipolar II depression. CANMAT–ISBD guidelines recommend quetiapine as the only first-line therapy for BD in bipolar II; JSMD, CINP, and NICE guidelines do not make distinct recommendations for treating BD in bipolar II.

Top recommended medications for bipolar depression are lithium, quetiapine, olanzapine, lamotrigine, and combined olanzapine/ fluoxetine.

Patients who have BD can present de novo (ie, not taking any medication for bipolar disorder) or with a breakthrough episode while on maintenance medication(s). In either case, monotherapy for BD is preferred, although combinations of medications (Table 2^14-19) can be more effective in some cases. Treatment guidelines overlap to a high degree, especially in regard to first-line treatments, but there is variation, especially beyond first-line therapeutics.²⁰

The top recommended medications for BD are lithium, quetiapine, olanzapine, lamotrigine, and combined olanzapine/fluoxetine. FDA-approved agents for treating acute BD specifically include quetiapine, lurasidone, and combined olanzapine/fluoxetine. Guidelines generally recommend a first step of adjusting the dosage of medications in any established regimen before changing or adding other agents. If clinical improvement is not seen using any recommended medications, psychiatric referral is recommended. See Table 3^21,22 for dosing and titration guidance and highlights of both common and rare but serious adverse effects.

Continue to: Recommendations, best options for acute bipolar depression

Start with lithium, lamotrigine, quetiapine, or lurasidone as the first-line medication at the dosages given in Table 3.^21,22 Olanzapine alone, or in combination with fluoxetine, can be used when it has been determined that the medications listed above are ineffective.

Note that lithium requires regular blood monitoring (Table 3^21,22). However, lithium has the advantage of strong supporting evidence of benefit in all mood episodes of bipolar disorders (depressive, manic, hypomanic), as well as maintenance, prevention of recurrence, and anti-suicidal properties.

Also of note: Lurasidone is much more costly than other recommended medications because it is available only by brand name in the United States; the other agents are available as generics. Consider generic equivalents of the recommended agents when cost is an important factor, in part because of the impact that cost has on medication adherence for some patients.

Last, olanzapine should be used later in the treatment algorithm, unless rapid control of symptoms is needed or other first-line medications are ineffective or not tolerated—given the higher propensity of the drug to produce weight gain and cause metabolic problems, including obesity and hyperglycemia.

The importance of maintenance therapy

Almost all patients with BD require maintenance treatment to prevent subsequent episodes, reduce residual symptoms, and restore functioning and quality of life. Maintenance therapy is formulated on the basis of efficacy and tolerability in the individual patient.

Continue to: As a general rule...

Lithium has strong supporting evidence of benefit in mood episodes of all bipolar disorders.

As a general rule, the strongest evidence for preventing recurrent BD episodes favors lithium—and most guidelines therefore support lithium as first-line maintenance therapy. It is important to note, however, that if a medication (or medications) successfully aborted an acute BD episode in a given patient, that agent (or agents) should be continued for maintenance purposes to prevent or minimize future episodes—generally, at the same dosage. First-line pharmacotherapeutic agents for the maintenance of bipolar disorder, and thus to prevent subsequent episodes of BD, are listed in Table 4.^14-19

℞ antidepressantsin bipolar depression?

The use of antidepressants to treat BD remains a topic of ongoing deliberation. Antidepressant treatment of BD has historically raised concern for depressive relapse due to ineffectiveness and the ability of antidepressants to increase (1) the frequency of manic and hypomanic episodes²³ and (2) mood instability in the form of induction of mixed states or rapid cycling. Among most authorities, the recommendation against using antidepressants for BD in both bipolar I and II is the same; however, limited evidence allows the use of antidepressant monotherapy in select cases of BD episodes in bipolar II,^24,25 although not bipolar I.

The consensus in the field is that medications with mood-stabilizing effects should be considered as monotherapy before adding an antidepressant (if an antidepressant is to be added) to treat BD in bipolar II.²⁶ In other words, if an antidepressant is to be used at all, it should be combined with a mood stabilizer or atypical antipsychotic^15,27 and should probably not be used long term. The efficacy of antidepressants in treating BD in bipolar II should be assessed periodically at follow-up.

Nonpharmaceutical treatment options

Although pharmacotherapy is the mainstay of treatment of BD, adjunctive psychotherapy can be useful for treating acute BD episodes that occur during the maintenance phase of the disorder. Psychoeducation (ie, education on psychiatric illness and the importance of medication adherence), alone or in combination with interpersonal and social rhythm therapy (IPSRT), family-focused therapy (FFT), and cognitive behavioral therapy (CBT) can add to the overall efficacy of pharmacotherapy by lowering the risk of relapse and enhancing psychosocial functioning.²⁸

IPSRT is supported by what is known as the instability model, which specifies that 3 interconnected pathways trigger recurrences of a bipolar episode: stressful life events, medication nonadherence, and social-rhythm disruption. IPSRT also uses principles of interpersonal psychotherapy that are applied in treating MDD, “arguing that improvement in interpersonal relationships can ameliorate affective symptoms and prevent their return.”^29,30

Continue to: FFT

FFT focuses on communication styles between patients and their spouses and families. The goal is to improve relationship functioning. FFT is delivered to the patient and the family.

Attention to social factors. For psychotherapy to provide adequate results as an adjunct to pharmacotherapy, social stressors (eg, homelessness and financial concerns) might also need to be considered and addressed through social services or a social work consult.

NICE guidelines recommend psychological intervention (in particular, with CBT and FFT) for acute BD. CANMAT–ISBD guidelines recommend either adjunctive psychoeducation, CBT, or FFT during the maintenance phase. Again, medication is the mainstay of treatment for BD in bipolar disorders; psychotherapy has an adjunctive role—unlike the approach to treatment of MDD, in which psychotherapy can be used alone in cases of mild, or even moderate, severity.

Referral for specialty care

In the primary care setting, providers might choose to manage BD by initiating first-line pharmacotherapeutic agents or continuing established treatment regimens with necessary dosage adjustments. These patients should be monitored closely until symptoms remit.

However, it is important for the primary care provider to identify patients who need psychiatric referral. Complex presentations, severe symptoms, and poor treatment response might warrant evaluation and management by a psychiatrist. Furthermore, patients with comorbid psychotic features, catatonia, or severely debilitating depression (with or without suicidality) need referral to the emergency department.

Continue to: Electroconvulsive therapy (ECT)

Electroconvulsive therapy (ECT). Patients might also need referral to Psychiatry for ECT, which is recommended by ­CANMAT–ISBD and JSMD guidelines as a second-line option; by the Royal Australian and New Zealand College of Psychiatrists as a third-line option; and by BAP for cases that are resistant to conventional treatment, with or without a high risk of suicide; in pregnancy; and in life-threatening situations.^15,31,32

Telemedicine. There is a considerable shortage of mental health care professionals.^33,34 The fact that nearly all (96%) counties in the United States have an unmet need for prescribers of mental health services (mainly psychiatrists) makes it crucial that primary care physicians be knowledgeable and prepared to manage BD—often with infrequent psychiatry consultation or, even, without psychiatry consultation. For primary care facilities that lack access to psychiatric services, telemedicine can be used as a consultative resource.

Limited evidence allows the use of antidepressant monotherapy in select cases of bipolar depressive episodes in bipolar II, although not in bipolar I.

Psychiatric consultation using telemedicine technologies has provided significant cost savings for medical centers and decreased the likelihood of hospital admission,³⁵ thereby alleviating health care costs and improving care, as shown in a rural Kansas county study.³⁶ Furthermore, the burden on emergency departments in several states has been significantly reduced with psychiatric consultations via interactive telemedicine technologies.³⁷

ACKNOWLEDGEMENT
Mark Yassa, BS, provided editing assistance.

CORRESPONDENCE
Nagy Youssef, MD, PhD, Medical College of Georgia at Augusta University, Department of Psychiatry and Health Behavior, 997 St. Sebastian Way, Augusta, GA 30912; [email protected].

Bipolar disorder is a prevalent disorder in the primary care setting.^1,2 Primary care providers therefore commonly encounter bipolar depression (BD; a major depressive episode in the context of bipolar disorder), which might be (1) an emerging depressive episode in previously undiagnosed bipolar disorder or (2) a recurrent episode during the course of chronic bipolar illness.^3,4

A primary care–based collaborative model has been identified as a potential strategy for effective management of chronic mental health conditions such as bipolar disorder.^5,6 However, this collaborative treatment model isn’t widely available; many patients with bipolar disorder are, in fact, treated solely by their primary care provider.

Two years ago in this journal,⁷ we addressed how to precisely identify an episode of BD and differentiate it from major depressive disorder (MDD; also known as unipolar depression). In this review, in addition to advancing clinical knowledge of BD, we provide:

• an overview of treatment options for BD (in contrast to the treatment of unipolar depression)
• the pharmacotherapeutic know-how to initiate and maintain treatment for uncomplicated episodes of BD.

We do not discuss management of manic, hypomanic, and mixed episodes of bipolar disorder.

How to identify bipolar depression

Understanding the (sometimes) unclear distinction between bipolar I and bipolar II disorders in an individual patient is key to formulating a therapeutic regimen for BD.

Bipolar I disorder consists of manic episodes, alternating (more often than not) with depressive episodes. Bipolar I usually manifests first with a depressive episode.

Bipolar II disorder manifests with depressive episodes and hypomanic episodes (but never manic episodes).

Continue to: Depressive episodes in the bipolar disorders

Depressive episodes in the bipolar disorders. Bipolar depression can be seen in the settings of both bipolar I and II disorders. When a patient presents with a manic episode, a history of depressive episodes is common (although not essential) to diagnose bipolar I; alternatively, a history of hypomania (but no prior mania) and depression is needed to make the diagnosis of bipolar II. The natural history of the bipolar disorders is therefore alternating manic and almost always depressive episodes (bipolar I) and alternating hypomanic and always depressive episodes (bipolar II).⁸

Failure to adequately treat bipolar depressive episodes can have serious consequences, including a worsening course of illness, alcohol and substance use disorder, and suicide.

Symptoms of hypomanic episodes are similar to what are seen in manic episodes, but are of shorter duration (≥ 4 days [episodes of mania are at least of 1 week’s duration]), lower intensity (no psychotic symptoms), and not associated with significant functional impairment or hospitalization. Table 1⁷ further describes the differentiating features of bipolar I and bipolar II. A history of an unequivocal manic or hypomanic episode makes the diagnosis of BD relatively easy. However, an unclear history of manic or hypomanic symptoms or episodes frequently leads to misdiagnosis or underdiagnosis of BD.

In both bipolar I and II, it is depressive symptoms and episodes that place the greatest burden on patients across the lifespan: They are the most commonly experienced features of the bipolar disorders^9,10 and lead to significant distress and functional impairment¹¹; in fact, patients with bipolar disorder spend 3 (or more) times as long in depressive episodes as in manic or hypomanic episodes.^12,13 In addition, subthreshold depressive symptoms occur commonly between major mood episodes.

Failure to identify and adequately treat depressive episodes of the bipolar disorders can have serious consequences: Patients are at risk of a worsening course of illness, alcohol use disorder, substance use disorder, chronic disability, mixed states, rapid cycling of mood episodes, and suicide.

Guidelines for treating bipolar depression

Despite the similarity in presenting symptoms and signs of depressive episodes in bipolar disorders and MDD, treating episodes of BD is significantly different than treating MDD. Antidepressant monotherapy, a mainstay of treatment for MDD, has limited utility in BD (especially depressive episodes of bipolar I) because of its limited efficacy and potential to destabilize mood, lead to rapid cycling, and induce mania or hypomania. Treatment options for BD include pharmacotherapy (the primary modality), psychological intervention (a useful adjunct, described later), and electroconvulsive therapy (ECT; highly worth considering in severe or treatment-resistant cases).

Continue to: For this article...

For this article, we searched PubMed and Google Scholar for guidelines for the management of bipolar disorders in adults that were published between July 2013 (when the US Food and Drug Administration [FDA] approved lurasidone for the treatment of BD) and March 2019. Related guideline-­referenced articles and clinical trials were also reviewed.

Our search identified 6 guidelines issued during the search period, developed by the:

• Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD),¹⁴
• British Association for Psychopharmacology (BAP),¹⁵
• Japanese Society of Mood Disorders (JSMD),¹⁶
• National Institute for Health and Care Excellence (NICE),¹⁷
• International College of Neuropsychopharmacology (CINP),¹⁸ and
• Royal Australian and New Zealand College of Psychiatrists.¹⁹

How to manage an episode of bipolar depression

First-line pharmacotherapeutic agents for the management of BD in acute bipolar I are listed and described in Table 2.^4-19 Compared to the number of studies and reports on the management of BD in bipolar I, few studies have been conducted that specifically examine the treatment of BD in acute bipolar II. In practice, evidence from the treatment of BD in bipolar I has been extrapolated to the treatment of bipolar II depression. CANMAT–ISBD guidelines recommend quetiapine as the only first-line therapy for BD in bipolar II; JSMD, CINP, and NICE guidelines do not make distinct recommendations for treating BD in bipolar II.

Top recommended medications for bipolar depression are lithium, quetiapine, olanzapine, lamotrigine, and combined olanzapine/ fluoxetine.

Patients who have BD can present de novo (ie, not taking any medication for bipolar disorder) or with a breakthrough episode while on maintenance medication(s). In either case, monotherapy for BD is preferred, although combinations of medications (Table 2^14-19) can be more effective in some cases. Treatment guidelines overlap to a high degree, especially in regard to first-line treatments, but there is variation, especially beyond first-line therapeutics.²⁰

The top recommended medications for BD are lithium, quetiapine, olanzapine, lamotrigine, and combined olanzapine/fluoxetine. FDA-approved agents for treating acute BD specifically include quetiapine, lurasidone, and combined olanzapine/fluoxetine. Guidelines generally recommend a first step of adjusting the dosage of medications in any established regimen before changing or adding other agents. If clinical improvement is not seen using any recommended medications, psychiatric referral is recommended. See Table 3^21,22 for dosing and titration guidance and highlights of both common and rare but serious adverse effects.

Continue to: Recommendations, best options for acute bipolar depression

Start with lithium, lamotrigine, quetiapine, or lurasidone as the first-line medication at the dosages given in Table 3.^21,22 Olanzapine alone, or in combination with fluoxetine, can be used when it has been determined that the medications listed above are ineffective.

Note that lithium requires regular blood monitoring (Table 3^21,22). However, lithium has the advantage of strong supporting evidence of benefit in all mood episodes of bipolar disorders (depressive, manic, hypomanic), as well as maintenance, prevention of recurrence, and anti-suicidal properties.

Also of note: Lurasidone is much more costly than other recommended medications because it is available only by brand name in the United States; the other agents are available as generics. Consider generic equivalents of the recommended agents when cost is an important factor, in part because of the impact that cost has on medication adherence for some patients.

Last, olanzapine should be used later in the treatment algorithm, unless rapid control of symptoms is needed or other first-line medications are ineffective or not tolerated—given the higher propensity of the drug to produce weight gain and cause metabolic problems, including obesity and hyperglycemia.

The importance of maintenance therapy

Almost all patients with BD require maintenance treatment to prevent subsequent episodes, reduce residual symptoms, and restore functioning and quality of life. Maintenance therapy is formulated on the basis of efficacy and tolerability in the individual patient.

Continue to: As a general rule...

Lithium has strong supporting evidence of benefit in mood episodes of all bipolar disorders.

As a general rule, the strongest evidence for preventing recurrent BD episodes favors lithium—and most guidelines therefore support lithium as first-line maintenance therapy. It is important to note, however, that if a medication (or medications) successfully aborted an acute BD episode in a given patient, that agent (or agents) should be continued for maintenance purposes to prevent or minimize future episodes—generally, at the same dosage. First-line pharmacotherapeutic agents for the maintenance of bipolar disorder, and thus to prevent subsequent episodes of BD, are listed in Table 4.^14-19

℞ antidepressantsin bipolar depression?

The use of antidepressants to treat BD remains a topic of ongoing deliberation. Antidepressant treatment of BD has historically raised concern for depressive relapse due to ineffectiveness and the ability of antidepressants to increase (1) the frequency of manic and hypomanic episodes²³ and (2) mood instability in the form of induction of mixed states or rapid cycling. Among most authorities, the recommendation against using antidepressants for BD in both bipolar I and II is the same; however, limited evidence allows the use of antidepressant monotherapy in select cases of BD episodes in bipolar II,^24,25 although not bipolar I.

The consensus in the field is that medications with mood-stabilizing effects should be considered as monotherapy before adding an antidepressant (if an antidepressant is to be added) to treat BD in bipolar II.²⁶ In other words, if an antidepressant is to be used at all, it should be combined with a mood stabilizer or atypical antipsychotic^15,27 and should probably not be used long term. The efficacy of antidepressants in treating BD in bipolar II should be assessed periodically at follow-up.

Nonpharmaceutical treatment options

Although pharmacotherapy is the mainstay of treatment of BD, adjunctive psychotherapy can be useful for treating acute BD episodes that occur during the maintenance phase of the disorder. Psychoeducation (ie, education on psychiatric illness and the importance of medication adherence), alone or in combination with interpersonal and social rhythm therapy (IPSRT), family-focused therapy (FFT), and cognitive behavioral therapy (CBT) can add to the overall efficacy of pharmacotherapy by lowering the risk of relapse and enhancing psychosocial functioning.²⁸

IPSRT is supported by what is known as the instability model, which specifies that 3 interconnected pathways trigger recurrences of a bipolar episode: stressful life events, medication nonadherence, and social-rhythm disruption. IPSRT also uses principles of interpersonal psychotherapy that are applied in treating MDD, “arguing that improvement in interpersonal relationships can ameliorate affective symptoms and prevent their return.”^29,30

Continue to: FFT

FFT focuses on communication styles between patients and their spouses and families. The goal is to improve relationship functioning. FFT is delivered to the patient and the family.

Attention to social factors. For psychotherapy to provide adequate results as an adjunct to pharmacotherapy, social stressors (eg, homelessness and financial concerns) might also need to be considered and addressed through social services or a social work consult.

NICE guidelines recommend psychological intervention (in particular, with CBT and FFT) for acute BD. CANMAT–ISBD guidelines recommend either adjunctive psychoeducation, CBT, or FFT during the maintenance phase. Again, medication is the mainstay of treatment for BD in bipolar disorders; psychotherapy has an adjunctive role—unlike the approach to treatment of MDD, in which psychotherapy can be used alone in cases of mild, or even moderate, severity.

Referral for specialty care

In the primary care setting, providers might choose to manage BD by initiating first-line pharmacotherapeutic agents or continuing established treatment regimens with necessary dosage adjustments. These patients should be monitored closely until symptoms remit.

However, it is important for the primary care provider to identify patients who need psychiatric referral. Complex presentations, severe symptoms, and poor treatment response might warrant evaluation and management by a psychiatrist. Furthermore, patients with comorbid psychotic features, catatonia, or severely debilitating depression (with or without suicidality) need referral to the emergency department.

Continue to: Electroconvulsive therapy (ECT)

Electroconvulsive therapy (ECT). Patients might also need referral to Psychiatry for ECT, which is recommended by ­CANMAT–ISBD and JSMD guidelines as a second-line option; by the Royal Australian and New Zealand College of Psychiatrists as a third-line option; and by BAP for cases that are resistant to conventional treatment, with or without a high risk of suicide; in pregnancy; and in life-threatening situations.^15,31,32

Telemedicine. There is a considerable shortage of mental health care professionals.^33,34 The fact that nearly all (96%) counties in the United States have an unmet need for prescribers of mental health services (mainly psychiatrists) makes it crucial that primary care physicians be knowledgeable and prepared to manage BD—often with infrequent psychiatry consultation or, even, without psychiatry consultation. For primary care facilities that lack access to psychiatric services, telemedicine can be used as a consultative resource.

Limited evidence allows the use of antidepressant monotherapy in select cases of bipolar depressive episodes in bipolar II, although not in bipolar I.

Psychiatric consultation using telemedicine technologies has provided significant cost savings for medical centers and decreased the likelihood of hospital admission,³⁵ thereby alleviating health care costs and improving care, as shown in a rural Kansas county study.³⁶ Furthermore, the burden on emergency departments in several states has been significantly reduced with psychiatric consultations via interactive telemedicine technologies.³⁷

ACKNOWLEDGEMENT
Mark Yassa, BS, provided editing assistance.

CORRESPONDENCE
Nagy Youssef, MD, PhD, Medical College of Georgia at Augusta University, Department of Psychiatry and Health Behavior, 997 St. Sebastian Way, Augusta, GA 30912; [email protected].

Bipolar disorder is a prevalent disorder in the primary care setting.^1,2 Primary care providers therefore commonly encounter bipolar depression (BD; a major depressive episode in the context of bipolar disorder), which might be (1) an emerging depressive episode in previously undiagnosed bipolar disorder or (2) a recurrent episode during the course of chronic bipolar illness.^3,4

A primary care–based collaborative model has been identified as a potential strategy for effective management of chronic mental health conditions such as bipolar disorder.^5,6 However, this collaborative treatment model isn’t widely available; many patients with bipolar disorder are, in fact, treated solely by their primary care provider.

Two years ago in this journal,⁷ we addressed how to precisely identify an episode of BD and differentiate it from major depressive disorder (MDD; also known as unipolar depression). In this review, in addition to advancing clinical knowledge of BD, we provide:

• an overview of treatment options for BD (in contrast to the treatment of unipolar depression)
• the pharmacotherapeutic know-how to initiate and maintain treatment for uncomplicated episodes of BD.

We do not discuss management of manic, hypomanic, and mixed episodes of bipolar disorder.

How to identify bipolar depression

Understanding the (sometimes) unclear distinction between bipolar I and bipolar II disorders in an individual patient is key to formulating a therapeutic regimen for BD.

Bipolar I disorder consists of manic episodes, alternating (more often than not) with depressive episodes. Bipolar I usually manifests first with a depressive episode.

Bipolar II disorder manifests with depressive episodes and hypomanic episodes (but never manic episodes).

Continue to: Depressive episodes in the bipolar disorders

Depressive episodes in the bipolar disorders. Bipolar depression can be seen in the settings of both bipolar I and II disorders. When a patient presents with a manic episode, a history of depressive episodes is common (although not essential) to diagnose bipolar I; alternatively, a history of hypomania (but no prior mania) and depression is needed to make the diagnosis of bipolar II. The natural history of the bipolar disorders is therefore alternating manic and almost always depressive episodes (bipolar I) and alternating hypomanic and always depressive episodes (bipolar II).⁸

Failure to adequately treat bipolar depressive episodes can have serious consequences, including a worsening course of illness, alcohol and substance use disorder, and suicide.

Symptoms of hypomanic episodes are similar to what are seen in manic episodes, but are of shorter duration (≥ 4 days [episodes of mania are at least of 1 week’s duration]), lower intensity (no psychotic symptoms), and not associated with significant functional impairment or hospitalization. Table 1⁷ further describes the differentiating features of bipolar I and bipolar II. A history of an unequivocal manic or hypomanic episode makes the diagnosis of BD relatively easy. However, an unclear history of manic or hypomanic symptoms or episodes frequently leads to misdiagnosis or underdiagnosis of BD.

In both bipolar I and II, it is depressive symptoms and episodes that place the greatest burden on patients across the lifespan: They are the most commonly experienced features of the bipolar disorders^9,10 and lead to significant distress and functional impairment¹¹; in fact, patients with bipolar disorder spend 3 (or more) times as long in depressive episodes as in manic or hypomanic episodes.^12,13 In addition, subthreshold depressive symptoms occur commonly between major mood episodes.

Failure to identify and adequately treat depressive episodes of the bipolar disorders can have serious consequences: Patients are at risk of a worsening course of illness, alcohol use disorder, substance use disorder, chronic disability, mixed states, rapid cycling of mood episodes, and suicide.

Guidelines for treating bipolar depression

Despite the similarity in presenting symptoms and signs of depressive episodes in bipolar disorders and MDD, treating episodes of BD is significantly different than treating MDD. Antidepressant monotherapy, a mainstay of treatment for MDD, has limited utility in BD (especially depressive episodes of bipolar I) because of its limited efficacy and potential to destabilize mood, lead to rapid cycling, and induce mania or hypomania. Treatment options for BD include pharmacotherapy (the primary modality), psychological intervention (a useful adjunct, described later), and electroconvulsive therapy (ECT; highly worth considering in severe or treatment-resistant cases).

Continue to: For this article...

For this article, we searched PubMed and Google Scholar for guidelines for the management of bipolar disorders in adults that were published between July 2013 (when the US Food and Drug Administration [FDA] approved lurasidone for the treatment of BD) and March 2019. Related guideline-­referenced articles and clinical trials were also reviewed.

Our search identified 6 guidelines issued during the search period, developed by the:

• Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD),¹⁴
• British Association for Psychopharmacology (BAP),¹⁵
• Japanese Society of Mood Disorders (JSMD),¹⁶
• National Institute for Health and Care Excellence (NICE),¹⁷
• International College of Neuropsychopharmacology (CINP),¹⁸ and
• Royal Australian and New Zealand College of Psychiatrists.¹⁹

How to manage an episode of bipolar depression

First-line pharmacotherapeutic agents for the management of BD in acute bipolar I are listed and described in Table 2.^4-19 Compared to the number of studies and reports on the management of BD in bipolar I, few studies have been conducted that specifically examine the treatment of BD in acute bipolar II. In practice, evidence from the treatment of BD in bipolar I has been extrapolated to the treatment of bipolar II depression. CANMAT–ISBD guidelines recommend quetiapine as the only first-line therapy for BD in bipolar II; JSMD, CINP, and NICE guidelines do not make distinct recommendations for treating BD in bipolar II.

Top recommended medications for bipolar depression are lithium, quetiapine, olanzapine, lamotrigine, and combined olanzapine/ fluoxetine.

Patients who have BD can present de novo (ie, not taking any medication for bipolar disorder) or with a breakthrough episode while on maintenance medication(s). In either case, monotherapy for BD is preferred, although combinations of medications (Table 2^14-19) can be more effective in some cases. Treatment guidelines overlap to a high degree, especially in regard to first-line treatments, but there is variation, especially beyond first-line therapeutics.²⁰

The top recommended medications for BD are lithium, quetiapine, olanzapine, lamotrigine, and combined olanzapine/fluoxetine. FDA-approved agents for treating acute BD specifically include quetiapine, lurasidone, and combined olanzapine/fluoxetine. Guidelines generally recommend a first step of adjusting the dosage of medications in any established regimen before changing or adding other agents. If clinical improvement is not seen using any recommended medications, psychiatric referral is recommended. See Table 3^21,22 for dosing and titration guidance and highlights of both common and rare but serious adverse effects.

Continue to: Recommendations, best options for acute bipolar depression

Start with lithium, lamotrigine, quetiapine, or lurasidone as the first-line medication at the dosages given in Table 3.^21,22 Olanzapine alone, or in combination with fluoxetine, can be used when it has been determined that the medications listed above are ineffective.

Note that lithium requires regular blood monitoring (Table 3^21,22). However, lithium has the advantage of strong supporting evidence of benefit in all mood episodes of bipolar disorders (depressive, manic, hypomanic), as well as maintenance, prevention of recurrence, and anti-suicidal properties.

Also of note: Lurasidone is much more costly than other recommended medications because it is available only by brand name in the United States; the other agents are available as generics. Consider generic equivalents of the recommended agents when cost is an important factor, in part because of the impact that cost has on medication adherence for some patients.

Last, olanzapine should be used later in the treatment algorithm, unless rapid control of symptoms is needed or other first-line medications are ineffective or not tolerated—given the higher propensity of the drug to produce weight gain and cause metabolic problems, including obesity and hyperglycemia.

The importance of maintenance therapy

Almost all patients with BD require maintenance treatment to prevent subsequent episodes, reduce residual symptoms, and restore functioning and quality of life. Maintenance therapy is formulated on the basis of efficacy and tolerability in the individual patient.

Continue to: As a general rule...

Lithium has strong supporting evidence of benefit in mood episodes of all bipolar disorders.

As a general rule, the strongest evidence for preventing recurrent BD episodes favors lithium—and most guidelines therefore support lithium as first-line maintenance therapy. It is important to note, however, that if a medication (or medications) successfully aborted an acute BD episode in a given patient, that agent (or agents) should be continued for maintenance purposes to prevent or minimize future episodes—generally, at the same dosage. First-line pharmacotherapeutic agents for the maintenance of bipolar disorder, and thus to prevent subsequent episodes of BD, are listed in Table 4.^14-19

℞ antidepressantsin bipolar depression?

The use of antidepressants to treat BD remains a topic of ongoing deliberation. Antidepressant treatment of BD has historically raised concern for depressive relapse due to ineffectiveness and the ability of antidepressants to increase (1) the frequency of manic and hypomanic episodes²³ and (2) mood instability in the form of induction of mixed states or rapid cycling. Among most authorities, the recommendation against using antidepressants for BD in both bipolar I and II is the same; however, limited evidence allows the use of antidepressant monotherapy in select cases of BD episodes in bipolar II,^24,25 although not bipolar I.

The consensus in the field is that medications with mood-stabilizing effects should be considered as monotherapy before adding an antidepressant (if an antidepressant is to be added) to treat BD in bipolar II.²⁶ In other words, if an antidepressant is to be used at all, it should be combined with a mood stabilizer or atypical antipsychotic^15,27 and should probably not be used long term. The efficacy of antidepressants in treating BD in bipolar II should be assessed periodically at follow-up.

Nonpharmaceutical treatment options

Although pharmacotherapy is the mainstay of treatment of BD, adjunctive psychotherapy can be useful for treating acute BD episodes that occur during the maintenance phase of the disorder. Psychoeducation (ie, education on psychiatric illness and the importance of medication adherence), alone or in combination with interpersonal and social rhythm therapy (IPSRT), family-focused therapy (FFT), and cognitive behavioral therapy (CBT) can add to the overall efficacy of pharmacotherapy by lowering the risk of relapse and enhancing psychosocial functioning.²⁸

IPSRT is supported by what is known as the instability model, which specifies that 3 interconnected pathways trigger recurrences of a bipolar episode: stressful life events, medication nonadherence, and social-rhythm disruption. IPSRT also uses principles of interpersonal psychotherapy that are applied in treating MDD, “arguing that improvement in interpersonal relationships can ameliorate affective symptoms and prevent their return.”^29,30

Continue to: FFT

FFT focuses on communication styles between patients and their spouses and families. The goal is to improve relationship functioning. FFT is delivered to the patient and the family.

Attention to social factors. For psychotherapy to provide adequate results as an adjunct to pharmacotherapy, social stressors (eg, homelessness and financial concerns) might also need to be considered and addressed through social services or a social work consult.

NICE guidelines recommend psychological intervention (in particular, with CBT and FFT) for acute BD. CANMAT–ISBD guidelines recommend either adjunctive psychoeducation, CBT, or FFT during the maintenance phase. Again, medication is the mainstay of treatment for BD in bipolar disorders; psychotherapy has an adjunctive role—unlike the approach to treatment of MDD, in which psychotherapy can be used alone in cases of mild, or even moderate, severity.

Referral for specialty care

In the primary care setting, providers might choose to manage BD by initiating first-line pharmacotherapeutic agents or continuing established treatment regimens with necessary dosage adjustments. These patients should be monitored closely until symptoms remit.

However, it is important for the primary care provider to identify patients who need psychiatric referral. Complex presentations, severe symptoms, and poor treatment response might warrant evaluation and management by a psychiatrist. Furthermore, patients with comorbid psychotic features, catatonia, or severely debilitating depression (with or without suicidality) need referral to the emergency department.

Continue to: Electroconvulsive therapy (ECT)

Electroconvulsive therapy (ECT). Patients might also need referral to Psychiatry for ECT, which is recommended by ­CANMAT–ISBD and JSMD guidelines as a second-line option; by the Royal Australian and New Zealand College of Psychiatrists as a third-line option; and by BAP for cases that are resistant to conventional treatment, with or without a high risk of suicide; in pregnancy; and in life-threatening situations.^15,31,32

Telemedicine. There is a considerable shortage of mental health care professionals.^33,34 The fact that nearly all (96%) counties in the United States have an unmet need for prescribers of mental health services (mainly psychiatrists) makes it crucial that primary care physicians be knowledgeable and prepared to manage BD—often with infrequent psychiatry consultation or, even, without psychiatry consultation. For primary care facilities that lack access to psychiatric services, telemedicine can be used as a consultative resource.

Limited evidence allows the use of antidepressant monotherapy in select cases of bipolar depressive episodes in bipolar II, although not in bipolar I.

Psychiatric consultation using telemedicine technologies has provided significant cost savings for medical centers and decreased the likelihood of hospital admission,³⁵ thereby alleviating health care costs and improving care, as shown in a rural Kansas county study.³⁶ Furthermore, the burden on emergency departments in several states has been significantly reduced with psychiatric consultations via interactive telemedicine technologies.³⁷

ACKNOWLEDGEMENT
Mark Yassa, BS, provided editing assistance.

CORRESPONDENCE
Nagy Youssef, MD, PhD, Medical College of Georgia at Augusta University, Department of Psychiatry and Health Behavior, 997 St. Sebastian Way, Augusta, GA 30912; [email protected].

Discuss this article at www.facebook.com/CurrentPsychiatry

Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB) are the first and second most common causes of neurodegenerative dementia, respectively.^{“New Alzheimer’s disease guidelines: Implications for clinicians,” Current Psychiatry, March 2012, p. 15-20; http://bit.ly/UNYikk.}

The 2005 report of the DLB Consortium⁵ recognizes central, core, suggestive, and supportive features of DLB (Table 1).^5,10 These features are considered in the context of other confounding clinical conditions and the timing of cognitive and motor symptoms. The revised DLB criteria⁵ require a central feature of progressive cognitive decline. “Probable DLB” is when a patient presents with 2 core features or 1 core feature and ≥1 suggestive features. A diagnosis of “possible DLB” requires 1 core feature or 1 suggestive feature in the presence of progressive cognitive decline.

Table 1

Diagnostic criteria for AD and DLB

Biomarkers for AD, but not DLB

The 2011 diagnostic criteria for AD incorporate biomarkers that can be measured in vivo and reflect speci?c features of disease-related pathophysiologic processes. Biomarkers for AD are divided into 2 categories:¹¹

• amyloid-beta (Aβ) accumulation: abnormal tracer retention on amyloid positron emission topography (PET) imaging and low cerebrospinal fluid (CSF) Aβ42
• neuronal degeneration or injury: elevated CSF tau (total and phosphorylated tau), decreased ?uorodeoxyglucose uptake on PET in temporo-parietal cortices, and atrophy on structural MRI in the hippocampal and temporo-parietal regions.

No clinically applicable genotypic or CSF markers exist to support a DLB diagnosis, but there are many promising candidates, including elevated levels of CSF p-tau 181, CSF levels of alpha- and beta-synuclein,¹² and CSF beta-glucocerebrosidase levels.¹³ PET mapping of brain acetylcholinesterase activity,¹⁴ 123I-2β-carbomethoxy-3β- (4-iodophenyl)-N-(3-fluoropropyl)nortropane single photon emission computed tomography (SPECT) dopamine transporter (DaT) imaging¹⁵ and metaiodobenzylguanidine (MIBG) scintigraphy also are promising methods. DaT scan SPECT is FDA-approved for detecting loss of functional dopaminergic neuron terminals in the striatum and can differentiate between AD and DLB with a sensitivity and specificity of 78% to 88% and 94% to 100%, respectively.¹⁶ This test is covered by Medicare for differentiating AD and DLB.

Differences in presentation

Cognitive impairment. Contrary to the early memory impairment that characterizes AD, memory deficits in DLB usually appear later in the disease course.⁵ Patients with DLB manifest greater attentional, visuospatial, and executive impairments than those with AD, whereas AD causes more profound episodic (declarative) memory impairment than DLB. DLB patients show more preserved consolidation and storage of verbal information than AD patients because of less neuroanatomical and cholinergic compromise in the medial temporal lobe. There is no evidence of significant differences in remote memory, semantic memory, and language (naming and fluency).

Compromised attention in DLB may be the basis for fluctuating cognition, a characteristic of the disease. The greater attentional impairment and reaction time variability in DLB compared with AD is evident during complex tasks for attention and may be a function of the executive and visuospatial demands of the tasks.¹⁷

Executive functions critical to adaptive, goal-directed behavior are more impaired in DLB than AD. DLB patients are more susceptible to distraction and have difficulty engaging in a task and shifting from 1 task to another. This, together with a tendency for confabulation and perseveration, are signs of executive dysfunction.

Neuropsychiatric features. DLB patients are more likely than AD patients to exhibit psychiatric symptoms and have more functional impairment.¹⁸ In an analysis of autopsy-confirmed cases, hallucinations and delusions were more frequent with Lewy body pathology (75%) than AD (21%) at initial clinical evaluation.¹⁸ By the end stages of both illnesses, the degree of psychotic symptoms is comparable.¹⁹ Depression is common in DLB; whether base rates of depressed mood and major depression differ between DLB and AD is uncertain.²⁰

Psychosis in AD can be induced by medication or delirium, or triggered by poor sensory perceptions. Psychotic symptoms occur more frequently during the moderate and advanced stages of AD, when patients present with visual hallucinations, delusions, or delusional misidentifications. As many as 10% to 20% of patients with AD experience hallucinations, typically visual. Delusions occur in 30% to 50% of AD patients, usually in the later stages of the disease. The most common delusional themes are infidelity, theft, and paranoia. Female sex is a risk factor for psychosis in AD. Delusions co-occur with aggression, anxiety, and aberrant motor behavior.

Visual hallucinations—mostly vivid, well-formed, false perceptions of insects, animals, or people—are the defining feature of DLB.²¹ Many patients recognize that they are experiencing visual hallucinations and can ignore them. DLB patients also may experience visual illusions, such as misperceiving household objects as living beings. Delusions—typically paranoid—are common among DLB patients, as are depression and anxiety.¹ Agitation or aggressive behavior tends to occur late in the illness, if at all.

The causes of psychotic symptoms in DLB are not fully understood, but dopamine dysfunction likely is involved in hallucinations, delusions, and agitation, and serotonin dysfunction may be associated with depression and anxiety. Rapid eye movement (REM) sleep/wakefulness dysregulation, in which the dream imagery of REM sleep may occur during wakefulness, also has been proposed as a mechanism for visual hallucinations in DLB.²² In DLB, psychotic symptoms occur early and are a hallmark of this illness, whereas in AD they usually occur in the middle to late stages of the disease.

Motor symptoms. In AD, extrapyramidal symptoms (EPS) are common later in the disease, are strongly correlated with disease severity, and are a strong, independent predictor of depression severity.²³ EPS are more common in DLB than in AD²⁴ and DLB patients are at higher risk of developing EPS even with low doses of typical antipsychotics, compared with AD patients.²⁵

Other symptoms. REM sleep behavior disorder (RBD) is characterized by enacting dreams—often violent—during REM sleep. RBD is common in DLB and many patients also have excessive daytime somnolence. Other sleep disorders in DLB include insomnia, obstructive sleep apnea, central sleep apnea, restless legs syndrome, and periodic limb movements during sleep.

In AD patients, common sleep behaviors include confusion in the early evening (“sundowning”) and frequent nighttime awakenings, often accompanied by wandering.²⁶ Orthostatic hypotension, impotence, urinary incontinence, and constipation are common in DLB. Lack of insight concerning personal cognitive, mood, and behavioral state is highly prevalent in AD patients and more common than in DLB.

Diagnostic evaluation

Because there are no definitive clinical markers for DLB, diagnosis is based on a detailed clinical and family history from the patient and a reliable informant, as well as a physical, neurologic, and mental status examination that looks for associated noncognitive symptoms, and neuropsychological evaluation. Reasons DLB may be misdiagnosed include:

• Some “core” clinical features of DLB may not appear or may overlap with AD.
• Presence and severity of concurrent AD pathology in DLB may modify the clinical presentation, with decreased rates of hallucinations and parkinsonism and increased neurofibrillary tangles.
• Failure to reliably identify fluctuations—variations in cognition and arousal, such as periods of unresponsiveness while awake (“zoning out”), excessive daytime somnolence, and disorganized speech.²⁷

Detecting and characterizing cognitive deficits in dementia patients using neuropsychological testing is important in establishing a clinical diagnosis, determining baseline levels of impairment, forming a prognosis, and initiating disease-specific treatments. Differences in neuropsychological findings in AD and DLB are outlined in Table 2.^16,28-33 Several studies have suggested using these measures to differentiate patients with DLB from those with AD.²⁰

Table 2

Diagnostic testing for Alzheimer’s disease and dementia with Lewy bodies

Evidence is insufficient to support using electroencephalographic and polysomnographic studies when initially evaluating patients with dementia. Brain CT or MRI are recommended as part of the initial evaluation of dementia patients to exclude treatable causes of dementia and help clarify the differential diagnosis. Occipital hypometabolism and hypoperfusion demonstrated on PET and SPECT imaging have high sensitivity and specificity for differentiating AD from DLB.

To diagnose DLB more consistently, look for core features of the disease, RBD, antipsychotic hypersensitivity, and decreased striatal binding at presynaptic DaT sites.¹⁵ Abnormal (low binding) DaT activity is the most reliable diagnostic marker for DLB.³⁴ Myocardial scintigraphy with MIBG is sensitive to pathologic changes of DLB before clinical expression and could overcome the difficulties of using clinical criteria alone to identify patients with DLB.³⁵ MIBG scintigraphy may be preferred to DaT scan because it is less expensive and its sensitivity and specificity to DLB are independent of the presence of parkinsonism.³⁵

For an overview of pharmacotherapy options for patients with AD or DLB, see Box 2.

Box 2

Related Resources

• Hanyu H, Sato T, Hirao K, et al. Differences in clinical course between dementia with Lewy bodies and Alzheimer’s disease. Eur J Neurol. 2009;16(2):212-217.
• Walker Z, McKeith I, Rodda J, et al. Comparison of cognitive decline between dementia with Lewy bodies and Alzheimer’s disease: a cohort study. BMJ Open. 2012;2:e000380.

Drug Brand Names

• Aripiprazole • Abilify
• Clonazepam • Klonopin
• Donepezil • Aricept
• Galantamine • Razadyne, Reminyl
• Levodopa • Dopar, Larodopa
• Memantine • Namenda
• Quetiapine • Seroquel
• Rivastigmine • Exelon

Disclosure

Drs. Bishnoi and Manepalli report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Grossberg serves as a consultant to Forest, Janssen, Novartis, and Pfizer. His department receives research funding from Novartis, Janssen, and Pfizer.

Discuss this article at www.facebook.com/CurrentPsychiatry

Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB) are the first and second most common causes of neurodegenerative dementia, respectively.^{“New Alzheimer’s disease guidelines: Implications for clinicians,” Current Psychiatry, March 2012, p. 15-20; http://bit.ly/UNYikk.}

The 2005 report of the DLB Consortium⁵ recognizes central, core, suggestive, and supportive features of DLB (Table 1).^5,10 These features are considered in the context of other confounding clinical conditions and the timing of cognitive and motor symptoms. The revised DLB criteria⁵ require a central feature of progressive cognitive decline. “Probable DLB” is when a patient presents with 2 core features or 1 core feature and ≥1 suggestive features. A diagnosis of “possible DLB” requires 1 core feature or 1 suggestive feature in the presence of progressive cognitive decline.

Table 1

Diagnostic criteria for AD and DLB

Biomarkers for AD, but not DLB

The 2011 diagnostic criteria for AD incorporate biomarkers that can be measured in vivo and reflect speci?c features of disease-related pathophysiologic processes. Biomarkers for AD are divided into 2 categories:¹¹

• amyloid-beta (Aβ) accumulation: abnormal tracer retention on amyloid positron emission topography (PET) imaging and low cerebrospinal fluid (CSF) Aβ42
• neuronal degeneration or injury: elevated CSF tau (total and phosphorylated tau), decreased ?uorodeoxyglucose uptake on PET in temporo-parietal cortices, and atrophy on structural MRI in the hippocampal and temporo-parietal regions.

No clinically applicable genotypic or CSF markers exist to support a DLB diagnosis, but there are many promising candidates, including elevated levels of CSF p-tau 181, CSF levels of alpha- and beta-synuclein,¹² and CSF beta-glucocerebrosidase levels.¹³ PET mapping of brain acetylcholinesterase activity,¹⁴ 123I-2β-carbomethoxy-3β- (4-iodophenyl)-N-(3-fluoropropyl)nortropane single photon emission computed tomography (SPECT) dopamine transporter (DaT) imaging¹⁵ and metaiodobenzylguanidine (MIBG) scintigraphy also are promising methods. DaT scan SPECT is FDA-approved for detecting loss of functional dopaminergic neuron terminals in the striatum and can differentiate between AD and DLB with a sensitivity and specificity of 78% to 88% and 94% to 100%, respectively.¹⁶ This test is covered by Medicare for differentiating AD and DLB.

Differences in presentation

Cognitive impairment. Contrary to the early memory impairment that characterizes AD, memory deficits in DLB usually appear later in the disease course.⁵ Patients with DLB manifest greater attentional, visuospatial, and executive impairments than those with AD, whereas AD causes more profound episodic (declarative) memory impairment than DLB. DLB patients show more preserved consolidation and storage of verbal information than AD patients because of less neuroanatomical and cholinergic compromise in the medial temporal lobe. There is no evidence of significant differences in remote memory, semantic memory, and language (naming and fluency).

Compromised attention in DLB may be the basis for fluctuating cognition, a characteristic of the disease. The greater attentional impairment and reaction time variability in DLB compared with AD is evident during complex tasks for attention and may be a function of the executive and visuospatial demands of the tasks.¹⁷

Executive functions critical to adaptive, goal-directed behavior are more impaired in DLB than AD. DLB patients are more susceptible to distraction and have difficulty engaging in a task and shifting from 1 task to another. This, together with a tendency for confabulation and perseveration, are signs of executive dysfunction.

Neuropsychiatric features. DLB patients are more likely than AD patients to exhibit psychiatric symptoms and have more functional impairment.¹⁸ In an analysis of autopsy-confirmed cases, hallucinations and delusions were more frequent with Lewy body pathology (75%) than AD (21%) at initial clinical evaluation.¹⁸ By the end stages of both illnesses, the degree of psychotic symptoms is comparable.¹⁹ Depression is common in DLB; whether base rates of depressed mood and major depression differ between DLB and AD is uncertain.²⁰

Psychosis in AD can be induced by medication or delirium, or triggered by poor sensory perceptions. Psychotic symptoms occur more frequently during the moderate and advanced stages of AD, when patients present with visual hallucinations, delusions, or delusional misidentifications. As many as 10% to 20% of patients with AD experience hallucinations, typically visual. Delusions occur in 30% to 50% of AD patients, usually in the later stages of the disease. The most common delusional themes are infidelity, theft, and paranoia. Female sex is a risk factor for psychosis in AD. Delusions co-occur with aggression, anxiety, and aberrant motor behavior.

Visual hallucinations—mostly vivid, well-formed, false perceptions of insects, animals, or people—are the defining feature of DLB.²¹ Many patients recognize that they are experiencing visual hallucinations and can ignore them. DLB patients also may experience visual illusions, such as misperceiving household objects as living beings. Delusions—typically paranoid—are common among DLB patients, as are depression and anxiety.¹ Agitation or aggressive behavior tends to occur late in the illness, if at all.

The causes of psychotic symptoms in DLB are not fully understood, but dopamine dysfunction likely is involved in hallucinations, delusions, and agitation, and serotonin dysfunction may be associated with depression and anxiety. Rapid eye movement (REM) sleep/wakefulness dysregulation, in which the dream imagery of REM sleep may occur during wakefulness, also has been proposed as a mechanism for visual hallucinations in DLB.²² In DLB, psychotic symptoms occur early and are a hallmark of this illness, whereas in AD they usually occur in the middle to late stages of the disease.

Motor symptoms. In AD, extrapyramidal symptoms (EPS) are common later in the disease, are strongly correlated with disease severity, and are a strong, independent predictor of depression severity.²³ EPS are more common in DLB than in AD²⁴ and DLB patients are at higher risk of developing EPS even with low doses of typical antipsychotics, compared with AD patients.²⁵

Other symptoms. REM sleep behavior disorder (RBD) is characterized by enacting dreams—often violent—during REM sleep. RBD is common in DLB and many patients also have excessive daytime somnolence. Other sleep disorders in DLB include insomnia, obstructive sleep apnea, central sleep apnea, restless legs syndrome, and periodic limb movements during sleep.

In AD patients, common sleep behaviors include confusion in the early evening (“sundowning”) and frequent nighttime awakenings, often accompanied by wandering.²⁶ Orthostatic hypotension, impotence, urinary incontinence, and constipation are common in DLB. Lack of insight concerning personal cognitive, mood, and behavioral state is highly prevalent in AD patients and more common than in DLB.

Diagnostic evaluation

Because there are no definitive clinical markers for DLB, diagnosis is based on a detailed clinical and family history from the patient and a reliable informant, as well as a physical, neurologic, and mental status examination that looks for associated noncognitive symptoms, and neuropsychological evaluation. Reasons DLB may be misdiagnosed include:

• Some “core” clinical features of DLB may not appear or may overlap with AD.
• Presence and severity of concurrent AD pathology in DLB may modify the clinical presentation, with decreased rates of hallucinations and parkinsonism and increased neurofibrillary tangles.
• Failure to reliably identify fluctuations—variations in cognition and arousal, such as periods of unresponsiveness while awake (“zoning out”), excessive daytime somnolence, and disorganized speech.²⁷

Detecting and characterizing cognitive deficits in dementia patients using neuropsychological testing is important in establishing a clinical diagnosis, determining baseline levels of impairment, forming a prognosis, and initiating disease-specific treatments. Differences in neuropsychological findings in AD and DLB are outlined in Table 2.^16,28-33 Several studies have suggested using these measures to differentiate patients with DLB from those with AD.²⁰

Table 2

Diagnostic testing for Alzheimer’s disease and dementia with Lewy bodies

Evidence is insufficient to support using electroencephalographic and polysomnographic studies when initially evaluating patients with dementia. Brain CT or MRI are recommended as part of the initial evaluation of dementia patients to exclude treatable causes of dementia and help clarify the differential diagnosis. Occipital hypometabolism and hypoperfusion demonstrated on PET and SPECT imaging have high sensitivity and specificity for differentiating AD from DLB.

To diagnose DLB more consistently, look for core features of the disease, RBD, antipsychotic hypersensitivity, and decreased striatal binding at presynaptic DaT sites.¹⁵ Abnormal (low binding) DaT activity is the most reliable diagnostic marker for DLB.³⁴ Myocardial scintigraphy with MIBG is sensitive to pathologic changes of DLB before clinical expression and could overcome the difficulties of using clinical criteria alone to identify patients with DLB.³⁵ MIBG scintigraphy may be preferred to DaT scan because it is less expensive and its sensitivity and specificity to DLB are independent of the presence of parkinsonism.³⁵

For an overview of pharmacotherapy options for patients with AD or DLB, see Box 2.

Box 2

Related Resources

• Hanyu H, Sato T, Hirao K, et al. Differences in clinical course between dementia with Lewy bodies and Alzheimer’s disease. Eur J Neurol. 2009;16(2):212-217.
• Walker Z, McKeith I, Rodda J, et al. Comparison of cognitive decline between dementia with Lewy bodies and Alzheimer’s disease: a cohort study. BMJ Open. 2012;2:e000380.

Drug Brand Names

• Aripiprazole • Abilify
• Clonazepam • Klonopin
• Donepezil • Aricept
• Galantamine • Razadyne, Reminyl
• Levodopa • Dopar, Larodopa
• Memantine • Namenda
• Quetiapine • Seroquel
• Rivastigmine • Exelon

Disclosure

Drs. Bishnoi and Manepalli report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Grossberg serves as a consultant to Forest, Janssen, Novartis, and Pfizer. His department receives research funding from Novartis, Janssen, and Pfizer.

Discuss this article at www.facebook.com/CurrentPsychiatry

Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB) are the first and second most common causes of neurodegenerative dementia, respectively.^{“New Alzheimer’s disease guidelines: Implications for clinicians,” Current Psychiatry, March 2012, p. 15-20; http://bit.ly/UNYikk.}

The 2005 report of the DLB Consortium⁵ recognizes central, core, suggestive, and supportive features of DLB (Table 1).^5,10 These features are considered in the context of other confounding clinical conditions and the timing of cognitive and motor symptoms. The revised DLB criteria⁵ require a central feature of progressive cognitive decline. “Probable DLB” is when a patient presents with 2 core features or 1 core feature and ≥1 suggestive features. A diagnosis of “possible DLB” requires 1 core feature or 1 suggestive feature in the presence of progressive cognitive decline.

Table 1

Diagnostic criteria for AD and DLB

Biomarkers for AD, but not DLB

The 2011 diagnostic criteria for AD incorporate biomarkers that can be measured in vivo and reflect speci?c features of disease-related pathophysiologic processes. Biomarkers for AD are divided into 2 categories:¹¹

• amyloid-beta (Aβ) accumulation: abnormal tracer retention on amyloid positron emission topography (PET) imaging and low cerebrospinal fluid (CSF) Aβ42
• neuronal degeneration or injury: elevated CSF tau (total and phosphorylated tau), decreased ?uorodeoxyglucose uptake on PET in temporo-parietal cortices, and atrophy on structural MRI in the hippocampal and temporo-parietal regions.

No clinically applicable genotypic or CSF markers exist to support a DLB diagnosis, but there are many promising candidates, including elevated levels of CSF p-tau 181, CSF levels of alpha- and beta-synuclein,¹² and CSF beta-glucocerebrosidase levels.¹³ PET mapping of brain acetylcholinesterase activity,¹⁴ 123I-2β-carbomethoxy-3β- (4-iodophenyl)-N-(3-fluoropropyl)nortropane single photon emission computed tomography (SPECT) dopamine transporter (DaT) imaging¹⁵ and metaiodobenzylguanidine (MIBG) scintigraphy also are promising methods. DaT scan SPECT is FDA-approved for detecting loss of functional dopaminergic neuron terminals in the striatum and can differentiate between AD and DLB with a sensitivity and specificity of 78% to 88% and 94% to 100%, respectively.¹⁶ This test is covered by Medicare for differentiating AD and DLB.

Differences in presentation

Cognitive impairment. Contrary to the early memory impairment that characterizes AD, memory deficits in DLB usually appear later in the disease course.⁵ Patients with DLB manifest greater attentional, visuospatial, and executive impairments than those with AD, whereas AD causes more profound episodic (declarative) memory impairment than DLB. DLB patients show more preserved consolidation and storage of verbal information than AD patients because of less neuroanatomical and cholinergic compromise in the medial temporal lobe. There is no evidence of significant differences in remote memory, semantic memory, and language (naming and fluency).

Compromised attention in DLB may be the basis for fluctuating cognition, a characteristic of the disease. The greater attentional impairment and reaction time variability in DLB compared with AD is evident during complex tasks for attention and may be a function of the executive and visuospatial demands of the tasks.¹⁷

Executive functions critical to adaptive, goal-directed behavior are more impaired in DLB than AD. DLB patients are more susceptible to distraction and have difficulty engaging in a task and shifting from 1 task to another. This, together with a tendency for confabulation and perseveration, are signs of executive dysfunction.

Neuropsychiatric features. DLB patients are more likely than AD patients to exhibit psychiatric symptoms and have more functional impairment.¹⁸ In an analysis of autopsy-confirmed cases, hallucinations and delusions were more frequent with Lewy body pathology (75%) than AD (21%) at initial clinical evaluation.¹⁸ By the end stages of both illnesses, the degree of psychotic symptoms is comparable.¹⁹ Depression is common in DLB; whether base rates of depressed mood and major depression differ between DLB and AD is uncertain.²⁰

Psychosis in AD can be induced by medication or delirium, or triggered by poor sensory perceptions. Psychotic symptoms occur more frequently during the moderate and advanced stages of AD, when patients present with visual hallucinations, delusions, or delusional misidentifications. As many as 10% to 20% of patients with AD experience hallucinations, typically visual. Delusions occur in 30% to 50% of AD patients, usually in the later stages of the disease. The most common delusional themes are infidelity, theft, and paranoia. Female sex is a risk factor for psychosis in AD. Delusions co-occur with aggression, anxiety, and aberrant motor behavior.

Visual hallucinations—mostly vivid, well-formed, false perceptions of insects, animals, or people—are the defining feature of DLB.²¹ Many patients recognize that they are experiencing visual hallucinations and can ignore them. DLB patients also may experience visual illusions, such as misperceiving household objects as living beings. Delusions—typically paranoid—are common among DLB patients, as are depression and anxiety.¹ Agitation or aggressive behavior tends to occur late in the illness, if at all.

The causes of psychotic symptoms in DLB are not fully understood, but dopamine dysfunction likely is involved in hallucinations, delusions, and agitation, and serotonin dysfunction may be associated with depression and anxiety. Rapid eye movement (REM) sleep/wakefulness dysregulation, in which the dream imagery of REM sleep may occur during wakefulness, also has been proposed as a mechanism for visual hallucinations in DLB.²² In DLB, psychotic symptoms occur early and are a hallmark of this illness, whereas in AD they usually occur in the middle to late stages of the disease.

Motor symptoms. In AD, extrapyramidal symptoms (EPS) are common later in the disease, are strongly correlated with disease severity, and are a strong, independent predictor of depression severity.²³ EPS are more common in DLB than in AD²⁴ and DLB patients are at higher risk of developing EPS even with low doses of typical antipsychotics, compared with AD patients.²⁵

Other symptoms. REM sleep behavior disorder (RBD) is characterized by enacting dreams—often violent—during REM sleep. RBD is common in DLB and many patients also have excessive daytime somnolence. Other sleep disorders in DLB include insomnia, obstructive sleep apnea, central sleep apnea, restless legs syndrome, and periodic limb movements during sleep.

In AD patients, common sleep behaviors include confusion in the early evening (“sundowning”) and frequent nighttime awakenings, often accompanied by wandering.²⁶ Orthostatic hypotension, impotence, urinary incontinence, and constipation are common in DLB. Lack of insight concerning personal cognitive, mood, and behavioral state is highly prevalent in AD patients and more common than in DLB.

Diagnostic evaluation

Because there are no definitive clinical markers for DLB, diagnosis is based on a detailed clinical and family history from the patient and a reliable informant, as well as a physical, neurologic, and mental status examination that looks for associated noncognitive symptoms, and neuropsychological evaluation. Reasons DLB may be misdiagnosed include:

• Some “core” clinical features of DLB may not appear or may overlap with AD.
• Presence and severity of concurrent AD pathology in DLB may modify the clinical presentation, with decreased rates of hallucinations and parkinsonism and increased neurofibrillary tangles.
• Failure to reliably identify fluctuations—variations in cognition and arousal, such as periods of unresponsiveness while awake (“zoning out”), excessive daytime somnolence, and disorganized speech.²⁷

Detecting and characterizing cognitive deficits in dementia patients using neuropsychological testing is important in establishing a clinical diagnosis, determining baseline levels of impairment, forming a prognosis, and initiating disease-specific treatments. Differences in neuropsychological findings in AD and DLB are outlined in Table 2.^16,28-33 Several studies have suggested using these measures to differentiate patients with DLB from those with AD.²⁰

Table 2

Diagnostic testing for Alzheimer’s disease and dementia with Lewy bodies

Evidence is insufficient to support using electroencephalographic and polysomnographic studies when initially evaluating patients with dementia. Brain CT or MRI are recommended as part of the initial evaluation of dementia patients to exclude treatable causes of dementia and help clarify the differential diagnosis. Occipital hypometabolism and hypoperfusion demonstrated on PET and SPECT imaging have high sensitivity and specificity for differentiating AD from DLB.

To diagnose DLB more consistently, look for core features of the disease, RBD, antipsychotic hypersensitivity, and decreased striatal binding at presynaptic DaT sites.¹⁵ Abnormal (low binding) DaT activity is the most reliable diagnostic marker for DLB.³⁴ Myocardial scintigraphy with MIBG is sensitive to pathologic changes of DLB before clinical expression and could overcome the difficulties of using clinical criteria alone to identify patients with DLB.³⁵ MIBG scintigraphy may be preferred to DaT scan because it is less expensive and its sensitivity and specificity to DLB are independent of the presence of parkinsonism.³⁵

For an overview of pharmacotherapy options for patients with AD or DLB, see Box 2.

Box 2

Related Resources

• Hanyu H, Sato T, Hirao K, et al. Differences in clinical course between dementia with Lewy bodies and Alzheimer’s disease. Eur J Neurol. 2009;16(2):212-217.
• Walker Z, McKeith I, Rodda J, et al. Comparison of cognitive decline between dementia with Lewy bodies and Alzheimer’s disease: a cohort study. BMJ Open. 2012;2:e000380.

Drug Brand Names

• Aripiprazole • Abilify
• Clonazepam • Klonopin
• Donepezil • Aricept
• Galantamine • Razadyne, Reminyl
• Levodopa • Dopar, Larodopa
• Memantine • Namenda
• Quetiapine • Seroquel
• Rivastigmine • Exelon

Disclosure

Drs. Bishnoi and Manepalli report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Grossberg serves as a consultant to Forest, Janssen, Novartis, and Pfizer. His department receives research funding from Novartis, Janssen, and Pfizer.