Bipolar Disorder

After testing positive for cocaine on a recent court-mandated urine drug screen, Mr. M, age 49, is referred by his parole officer for psychiatric and substance abuse treatment. Mr. M has bipolar I disorder and alcohol, cocaine, and opioid dependence. He says he has been hospitalized or incarcerated at least once each year for the past 22 years. Mr. M has seen numerous psychiatrists as an outpatient, but rarely for more than 2 to 3 months and has not taken any psychotropics for more than 5 months.

Approximately 1 week before his recent urine drug screen, Mr. M became euphoric, stopped sleeping for several days, and spent $2,000 on cocaine and “escorts.” He reports that each day he smokes 30 cigarettes and drinks 1 pint of liquor and prefers to use cocaine and opiates by IV injection. Several years ago Mr. M was diagnosed with hepatitis C virus (HCV) but received no further workup or treatment. Although he denies manic or psychotic symptoms, Mr. M is observed speaking to unseen others in the waiting room and has difficulty remaining still during his interview. His chief concern is insomnia, stating, “Doc, I just need something to help me sleep.”

The high prevalence of substance use disorders (SUDs) in persons with bipolar disorder (BD) is well documented.^1,2 Up to 60% of bipolar patients develop an SUD at some point in their lives.^3-5 Alcohol use disorders are particularly common among BD patients, with a lifetime prevalence of roughly 50%.^2-5 Recent epidemiologic data indicate that 38% of persons with bipolar I disorder and 19% of those with bipolar II disorder meet criteria for alcohol dependence.⁵ Comorbid SUDs in patients with BD are associated with:

• poor treatment compliance
• longer and more frequent mood episodes
• more mixed episodes
• more hospitalizations
• more frequent suicide attempts.^1,2

The impact of co-occurring SUDs on suicidality is particularly high among those with bipolar I disorder.⁶

Frequently referred to as “dual diagnosis” conditions, co-occurring BD and SUDs may be more accurately envisioned as multi-morbid, rather than comorbid, illnesses. Data from the Stanley Foundation Bipolar Network suggest that 42% of BD patients have a lifetime history of ≥2 comorbid axis I disorders.⁷ Rates of generalized anxiety disorder, panic disorder, and posttraumatic stress disorder are particularly high in BD patients with co-occurring SUDs.^8,9 In addition, the presence of 1 SUD may mark the presence of other SUDs; for example, alcohol dependence is strongly associated with polysubstance abuse, especially in females with BD.⁸ Furthermore, medical comorbidities that impact treatment decisions also are highly prevalent in BD patients with comorbid SUDs.¹⁰ In particular, HCV rates are higher in persons with BD compared with the general population,¹¹ and are >5 times as likely in bipolar patients with co-occurring SUDs.¹²

Unfortunately, limited treatment research guides clinical management of comorbid BD and SUDs.^2,13,14 Clinical trials of medications for BD traditionally have excluded patients with SUDs, and persons with serious mental illness usually are ineligible for SUD treatment studies.¹³ Furthermore, the few randomized controlled trials (RCTs) conducted in persons with both illnesses have been constrained by relatively small sample sizes and low retention rates. In the absence of a definitive consensus for optimal treatment, this article outlines general clinical considerations and an integrated approach to assessing and managing this complex patient population.

Birds of a feather

Multiple hypotheses try to account for the high rate of SUDs in patients with BD (Table 1), but none fully explain the complex interaction observed clinically.^14,15 Substance dependence and BD are chronic remitting/relapsing disorders with heterogeneous presentations and highly variable natural histories. As with SUDs, BD may go undiagnosed and untreated for years, coming to clinical attention only after substantial disease progression.¹⁶

The fluctuating illness course in BD and SUDs makes diagnosis and treatment difficult. Symptomatic periods often are interrupted by spontaneous remissions and longer—although usually temporary—periods of perceived control. Both BD and SUDs may be associated with profound mood instability, increased impulsivity, altered responsiveness to reward, and impaired executive function.¹⁷ Finally, the high degree of heritability in BD¹⁸ and many SUDs¹⁹ may make treatment engagement more difficult if either disorder is present in multiple family members because of:

• potential for greater clinical severity
• reduced psychosocial resources
• altered familial behavioral norms that may impede the patient’s recognition of illness.

Denial of illness is a critical symptom that may fluctuate with disease course in both disorders. Persons with BD or SUDs may be least likely to recognize that they are ill during periods of highest symptom severity. Accordingly, treatment adherence in patients with either disorder may be limited at baseline and decline further when the 2 illnesses co-occur.²⁰

Involvement in the criminal justice system and medical comorbidities, particularly HCV, also complicate diagnosis and treatment of BD patients with SUDs. For more information about these topics, see Box1 and Box2.

Table 1

Why is substance abuse so prevalent among bipolar patients?

Integrated clinical management

Assessment. Although not intended to be comprehensive, suggestions for routine assessment of patients with suspected SUDs and/or BD are listed in Table 2. Because clinicians may encounter dual diagnosis patients in general psychiatric clinics or specialty (addiction or mood disorder) clinics, it is useful to obtain a thorough substance use history in all patients with known or suspected BD as well as a thorough history of hypomania/mania and depression in all patients with addictive disorders. BD diagnoses by self-report or chart history in patients with SUDs should be considered cautiously because BD often is overdiagnosed in persons engaged in active substance abuse or experiencing withdrawal.²¹ If past or present mood symptoms and substance use have co-occurred, further focused assessment of mood symptoms before alcohol and drug use or during extended periods of abstinence are necessary to make the diagnosis of bipolar disorder with confidence. Family history of SUDs and/or BD are neither necessary nor sufficient for either diagnosis; however, collateral information from family or significant others could help make the diagnosis and may identify aids and obstacles to treatment planning and engagement.

When a patient’s clinical history strongly supports the diagnoses of BD and co-occurring SUDs, more detailed inquiry is warranted. Determining the patient’s age at onset of each disorder may have prognostic value because onset of mania before SUDs developed, especially in adolescence, may predict a more severe course of both illnesses.²² A complete alcohol use history should include routine questioning about past withdrawal. Previous withdrawal seizures in an actively drinking BD patient may tip the balance toward adding an anticonvulsant for mood stabilization. A thorough SUD history should elicit information about polysubstance abuse or dependence and include screening for injection drug use and other risk factors for HCV and human immunodeficiency virus (HIV), such as hypersexuality during manic or hypomanic episodes. Document the date of the last screening for HCV/ HIV in BD patients at high risk of infection. The U.S. Centers for Disease Control and Prevention recommends that all patients at high risk for HIV consider voluntary screening at least annually.²³

Assess your patient’s historical and ongoing alcohol and other drug abuse at the initial visit, and continue to monitor substance use at all subsequent visits, especially in patients with HCV. When feasible, order urine drug screening and laboratory testing for alcohol use biomarkers such as carbohydrate-deficient transferrin and gamma-glutamyltransferase to supplement self-report data, especially in patients with poor insight or low motivation. Assess suicidal ideation and any changes in suicide risk factors at every visit.

Treatment. No biologic therapies have been FDA-approved for treating patients with co-occurring BD and SUDs. Comorbid SUDs in BD patients—as well as rapid cycling and mixed mood episodes, both of which are more common in patients with comorbid SUDs—predict poor response to lithium.¹⁷ However, the evidence base for optimal pharmacotherapy remains extremely limited. Published double-blind, placebo-controlled RCTs in persons with BD and co-morbid SUDs are limited to only 1 trial each of lithium, carbamazepine, quetiapine, and naltrexone, and 2 comparisons of lithium plus divalproex vs lithium alone (Table 3).^24-29

Salloum et al²⁴ reported that bipolar I disorder patients with alcohol dependence who received divalproex plus lithium as maintenance treatment had fewer heavy drinking days and fewer drinks per heavy drinking day than those receiving lithium plus placebo. However, the addition of divalproex did not improve manic or depressive symptoms, and depression remission rates remained relatively low in both groups. A recent 6-month study comparing lithium vs lithium plus divalproex in patients with SUDs and rapid-cycling BD found no additional benefit of divalproex over lithium monotherapy in retention, mood, or substance use outcomes.²⁸ However, modest evidence that anticonvulsants such as valproic acid and carbamazepine may help treat acute alcohol withdrawal² could support their preferential use as mood stabilizers over lithium in actively drinking BD patients.

Research underscores the difficulty in keeping dual diagnosis patients in treatment. Salloum et al²⁴ reported that only one-third of randomized subjects completed the 24-week study. In the Kemp study,²⁸ 79% of 149 recruited subjects failed to complete the lead-in stabilization phase. Of the 31 remaining subjects who were randomized to lithium or lithium/divalproex combination, only 8 (26% of those randomized, 5% of those recruited) completed the 6-month trial.

Substance abuse is associated with significantly decreased treatment adherence in persons with BD²⁰ and may affect medication choice. For example, caution may be warranted in the use of lamotrigine in substance-abusing patients with poor adherence because re-titration from the starting dose is recommended if the medicine has been missed for a consecutive period exceeding 5 half-lives of the drug.³⁰

Notable progress has been made in developing psychosocial treatments for comorbid SUDs and BD. Integrated group therapy has been designed to address the 2 disorders simultaneously by emphasizing the relationship between the disorders and highlighting similarities in cognitive and behavioral change that promote recovery in both.³¹ In a recent well-controlled RCT, this approach reduced alcohol and other drug use to approximately one-half the levels observed in those who received only group drug counseling.³¹

Research suggests that an integrated approach that encompasses psychiatric, medical, psychosocial, and legal dimensions simultaneously may be most effective. For patients such as Mr. M, this would include aggressively treating mood symptoms while employing motivational interviewing techniques to improve engagement in substance dependence treatment. If possible, involving family members, parole officials, housing agencies, and other public assistance workers in the treatment plan may increase treatment adherence and reduce loss of contact during illness exacerbations. Stabilization of substance use and psychiatric morbidity should be accompanied by timely evaluation of HCV and other medical comorbidities in order to improve long-term prognosis.

Table 2

Assessing patients you suspect have comorbid BD and SUDs

Table 3

Pharmacotherapy for bipolar disorder and co-occurring SUDs

Related Resources

• International Society for Bipolar Disorders. www.isbd.org.
• National Institute on Alcohol Abuse and Alcoholism. www.niaaa.nih.gov.
• National Institute on Drug Abuse. www.nida.nih.gov.

Drug Brand Names

• Carbamazepine • Tegretol
• Divalproex/valproic acid • Depakote
• Lamotrigine • Lamictal
• Lithium • Lithobid
• Naltrexone • ReVia
• Quetiapine • Seroquel

Disclosure

Dr. Tolliver receives research grant funding from Forest Laboratories and the National Institute on Alcohol Abuse and Alcoholism. Neither source influenced the content or submission of this manuscript.

Box 1

Box 2

After testing positive for cocaine on a recent court-mandated urine drug screen, Mr. M, age 49, is referred by his parole officer for psychiatric and substance abuse treatment. Mr. M has bipolar I disorder and alcohol, cocaine, and opioid dependence. He says he has been hospitalized or incarcerated at least once each year for the past 22 years. Mr. M has seen numerous psychiatrists as an outpatient, but rarely for more than 2 to 3 months and has not taken any psychotropics for more than 5 months.

Approximately 1 week before his recent urine drug screen, Mr. M became euphoric, stopped sleeping for several days, and spent $2,000 on cocaine and “escorts.” He reports that each day he smokes 30 cigarettes and drinks 1 pint of liquor and prefers to use cocaine and opiates by IV injection. Several years ago Mr. M was diagnosed with hepatitis C virus (HCV) but received no further workup or treatment. Although he denies manic or psychotic symptoms, Mr. M is observed speaking to unseen others in the waiting room and has difficulty remaining still during his interview. His chief concern is insomnia, stating, “Doc, I just need something to help me sleep.”

The high prevalence of substance use disorders (SUDs) in persons with bipolar disorder (BD) is well documented.^1,2 Up to 60% of bipolar patients develop an SUD at some point in their lives.^3-5 Alcohol use disorders are particularly common among BD patients, with a lifetime prevalence of roughly 50%.^2-5 Recent epidemiologic data indicate that 38% of persons with bipolar I disorder and 19% of those with bipolar II disorder meet criteria for alcohol dependence.⁵ Comorbid SUDs in patients with BD are associated with:

• poor treatment compliance
• longer and more frequent mood episodes
• more mixed episodes
• more hospitalizations
• more frequent suicide attempts.^1,2

The impact of co-occurring SUDs on suicidality is particularly high among those with bipolar I disorder.⁶

Frequently referred to as “dual diagnosis” conditions, co-occurring BD and SUDs may be more accurately envisioned as multi-morbid, rather than comorbid, illnesses. Data from the Stanley Foundation Bipolar Network suggest that 42% of BD patients have a lifetime history of ≥2 comorbid axis I disorders.⁷ Rates of generalized anxiety disorder, panic disorder, and posttraumatic stress disorder are particularly high in BD patients with co-occurring SUDs.^8,9 In addition, the presence of 1 SUD may mark the presence of other SUDs; for example, alcohol dependence is strongly associated with polysubstance abuse, especially in females with BD.⁸ Furthermore, medical comorbidities that impact treatment decisions also are highly prevalent in BD patients with comorbid SUDs.¹⁰ In particular, HCV rates are higher in persons with BD compared with the general population,¹¹ and are >5 times as likely in bipolar patients with co-occurring SUDs.¹²

Unfortunately, limited treatment research guides clinical management of comorbid BD and SUDs.^2,13,14 Clinical trials of medications for BD traditionally have excluded patients with SUDs, and persons with serious mental illness usually are ineligible for SUD treatment studies.¹³ Furthermore, the few randomized controlled trials (RCTs) conducted in persons with both illnesses have been constrained by relatively small sample sizes and low retention rates. In the absence of a definitive consensus for optimal treatment, this article outlines general clinical considerations and an integrated approach to assessing and managing this complex patient population.

Birds of a feather

Multiple hypotheses try to account for the high rate of SUDs in patients with BD (Table 1), but none fully explain the complex interaction observed clinically.^14,15 Substance dependence and BD are chronic remitting/relapsing disorders with heterogeneous presentations and highly variable natural histories. As with SUDs, BD may go undiagnosed and untreated for years, coming to clinical attention only after substantial disease progression.¹⁶

The fluctuating illness course in BD and SUDs makes diagnosis and treatment difficult. Symptomatic periods often are interrupted by spontaneous remissions and longer—although usually temporary—periods of perceived control. Both BD and SUDs may be associated with profound mood instability, increased impulsivity, altered responsiveness to reward, and impaired executive function.¹⁷ Finally, the high degree of heritability in BD¹⁸ and many SUDs¹⁹ may make treatment engagement more difficult if either disorder is present in multiple family members because of:

• potential for greater clinical severity
• reduced psychosocial resources
• altered familial behavioral norms that may impede the patient’s recognition of illness.

Denial of illness is a critical symptom that may fluctuate with disease course in both disorders. Persons with BD or SUDs may be least likely to recognize that they are ill during periods of highest symptom severity. Accordingly, treatment adherence in patients with either disorder may be limited at baseline and decline further when the 2 illnesses co-occur.²⁰

Involvement in the criminal justice system and medical comorbidities, particularly HCV, also complicate diagnosis and treatment of BD patients with SUDs. For more information about these topics, see Box1 and Box2.

Table 1

Why is substance abuse so prevalent among bipolar patients?

Integrated clinical management

Assessment. Although not intended to be comprehensive, suggestions for routine assessment of patients with suspected SUDs and/or BD are listed in Table 2. Because clinicians may encounter dual diagnosis patients in general psychiatric clinics or specialty (addiction or mood disorder) clinics, it is useful to obtain a thorough substance use history in all patients with known or suspected BD as well as a thorough history of hypomania/mania and depression in all patients with addictive disorders. BD diagnoses by self-report or chart history in patients with SUDs should be considered cautiously because BD often is overdiagnosed in persons engaged in active substance abuse or experiencing withdrawal.²¹ If past or present mood symptoms and substance use have co-occurred, further focused assessment of mood symptoms before alcohol and drug use or during extended periods of abstinence are necessary to make the diagnosis of bipolar disorder with confidence. Family history of SUDs and/or BD are neither necessary nor sufficient for either diagnosis; however, collateral information from family or significant others could help make the diagnosis and may identify aids and obstacles to treatment planning and engagement.

When a patient’s clinical history strongly supports the diagnoses of BD and co-occurring SUDs, more detailed inquiry is warranted. Determining the patient’s age at onset of each disorder may have prognostic value because onset of mania before SUDs developed, especially in adolescence, may predict a more severe course of both illnesses.²² A complete alcohol use history should include routine questioning about past withdrawal. Previous withdrawal seizures in an actively drinking BD patient may tip the balance toward adding an anticonvulsant for mood stabilization. A thorough SUD history should elicit information about polysubstance abuse or dependence and include screening for injection drug use and other risk factors for HCV and human immunodeficiency virus (HIV), such as hypersexuality during manic or hypomanic episodes. Document the date of the last screening for HCV/ HIV in BD patients at high risk of infection. The U.S. Centers for Disease Control and Prevention recommends that all patients at high risk for HIV consider voluntary screening at least annually.²³

Assess your patient’s historical and ongoing alcohol and other drug abuse at the initial visit, and continue to monitor substance use at all subsequent visits, especially in patients with HCV. When feasible, order urine drug screening and laboratory testing for alcohol use biomarkers such as carbohydrate-deficient transferrin and gamma-glutamyltransferase to supplement self-report data, especially in patients with poor insight or low motivation. Assess suicidal ideation and any changes in suicide risk factors at every visit.

Treatment. No biologic therapies have been FDA-approved for treating patients with co-occurring BD and SUDs. Comorbid SUDs in BD patients—as well as rapid cycling and mixed mood episodes, both of which are more common in patients with comorbid SUDs—predict poor response to lithium.¹⁷ However, the evidence base for optimal pharmacotherapy remains extremely limited. Published double-blind, placebo-controlled RCTs in persons with BD and co-morbid SUDs are limited to only 1 trial each of lithium, carbamazepine, quetiapine, and naltrexone, and 2 comparisons of lithium plus divalproex vs lithium alone (Table 3).^24-29

Salloum et al²⁴ reported that bipolar I disorder patients with alcohol dependence who received divalproex plus lithium as maintenance treatment had fewer heavy drinking days and fewer drinks per heavy drinking day than those receiving lithium plus placebo. However, the addition of divalproex did not improve manic or depressive symptoms, and depression remission rates remained relatively low in both groups. A recent 6-month study comparing lithium vs lithium plus divalproex in patients with SUDs and rapid-cycling BD found no additional benefit of divalproex over lithium monotherapy in retention, mood, or substance use outcomes.²⁸ However, modest evidence that anticonvulsants such as valproic acid and carbamazepine may help treat acute alcohol withdrawal² could support their preferential use as mood stabilizers over lithium in actively drinking BD patients.

Research underscores the difficulty in keeping dual diagnosis patients in treatment. Salloum et al²⁴ reported that only one-third of randomized subjects completed the 24-week study. In the Kemp study,²⁸ 79% of 149 recruited subjects failed to complete the lead-in stabilization phase. Of the 31 remaining subjects who were randomized to lithium or lithium/divalproex combination, only 8 (26% of those randomized, 5% of those recruited) completed the 6-month trial.

Substance abuse is associated with significantly decreased treatment adherence in persons with BD²⁰ and may affect medication choice. For example, caution may be warranted in the use of lamotrigine in substance-abusing patients with poor adherence because re-titration from the starting dose is recommended if the medicine has been missed for a consecutive period exceeding 5 half-lives of the drug.³⁰

Notable progress has been made in developing psychosocial treatments for comorbid SUDs and BD. Integrated group therapy has been designed to address the 2 disorders simultaneously by emphasizing the relationship between the disorders and highlighting similarities in cognitive and behavioral change that promote recovery in both.³¹ In a recent well-controlled RCT, this approach reduced alcohol and other drug use to approximately one-half the levels observed in those who received only group drug counseling.³¹

Research suggests that an integrated approach that encompasses psychiatric, medical, psychosocial, and legal dimensions simultaneously may be most effective. For patients such as Mr. M, this would include aggressively treating mood symptoms while employing motivational interviewing techniques to improve engagement in substance dependence treatment. If possible, involving family members, parole officials, housing agencies, and other public assistance workers in the treatment plan may increase treatment adherence and reduce loss of contact during illness exacerbations. Stabilization of substance use and psychiatric morbidity should be accompanied by timely evaluation of HCV and other medical comorbidities in order to improve long-term prognosis.

Table 2

Assessing patients you suspect have comorbid BD and SUDs

Table 3

Pharmacotherapy for bipolar disorder and co-occurring SUDs

Related Resources

• International Society for Bipolar Disorders. www.isbd.org.
• National Institute on Alcohol Abuse and Alcoholism. www.niaaa.nih.gov.
• National Institute on Drug Abuse. www.nida.nih.gov.

Drug Brand Names

• Carbamazepine • Tegretol
• Divalproex/valproic acid • Depakote
• Lamotrigine • Lamictal
• Lithium • Lithobid
• Naltrexone • ReVia
• Quetiapine • Seroquel

Disclosure

Dr. Tolliver receives research grant funding from Forest Laboratories and the National Institute on Alcohol Abuse and Alcoholism. Neither source influenced the content or submission of this manuscript.

Box 1

Box 2

After testing positive for cocaine on a recent court-mandated urine drug screen, Mr. M, age 49, is referred by his parole officer for psychiatric and substance abuse treatment. Mr. M has bipolar I disorder and alcohol, cocaine, and opioid dependence. He says he has been hospitalized or incarcerated at least once each year for the past 22 years. Mr. M has seen numerous psychiatrists as an outpatient, but rarely for more than 2 to 3 months and has not taken any psychotropics for more than 5 months.

Approximately 1 week before his recent urine drug screen, Mr. M became euphoric, stopped sleeping for several days, and spent $2,000 on cocaine and “escorts.” He reports that each day he smokes 30 cigarettes and drinks 1 pint of liquor and prefers to use cocaine and opiates by IV injection. Several years ago Mr. M was diagnosed with hepatitis C virus (HCV) but received no further workup or treatment. Although he denies manic or psychotic symptoms, Mr. M is observed speaking to unseen others in the waiting room and has difficulty remaining still during his interview. His chief concern is insomnia, stating, “Doc, I just need something to help me sleep.”

The high prevalence of substance use disorders (SUDs) in persons with bipolar disorder (BD) is well documented.^1,2 Up to 60% of bipolar patients develop an SUD at some point in their lives.^3-5 Alcohol use disorders are particularly common among BD patients, with a lifetime prevalence of roughly 50%.^2-5 Recent epidemiologic data indicate that 38% of persons with bipolar I disorder and 19% of those with bipolar II disorder meet criteria for alcohol dependence.⁵ Comorbid SUDs in patients with BD are associated with:

• poor treatment compliance
• longer and more frequent mood episodes
• more mixed episodes
• more hospitalizations
• more frequent suicide attempts.^1,2

The impact of co-occurring SUDs on suicidality is particularly high among those with bipolar I disorder.⁶

Frequently referred to as “dual diagnosis” conditions, co-occurring BD and SUDs may be more accurately envisioned as multi-morbid, rather than comorbid, illnesses. Data from the Stanley Foundation Bipolar Network suggest that 42% of BD patients have a lifetime history of ≥2 comorbid axis I disorders.⁷ Rates of generalized anxiety disorder, panic disorder, and posttraumatic stress disorder are particularly high in BD patients with co-occurring SUDs.^8,9 In addition, the presence of 1 SUD may mark the presence of other SUDs; for example, alcohol dependence is strongly associated with polysubstance abuse, especially in females with BD.⁸ Furthermore, medical comorbidities that impact treatment decisions also are highly prevalent in BD patients with comorbid SUDs.¹⁰ In particular, HCV rates are higher in persons with BD compared with the general population,¹¹ and are >5 times as likely in bipolar patients with co-occurring SUDs.¹²

Unfortunately, limited treatment research guides clinical management of comorbid BD and SUDs.^2,13,14 Clinical trials of medications for BD traditionally have excluded patients with SUDs, and persons with serious mental illness usually are ineligible for SUD treatment studies.¹³ Furthermore, the few randomized controlled trials (RCTs) conducted in persons with both illnesses have been constrained by relatively small sample sizes and low retention rates. In the absence of a definitive consensus for optimal treatment, this article outlines general clinical considerations and an integrated approach to assessing and managing this complex patient population.

Birds of a feather

Multiple hypotheses try to account for the high rate of SUDs in patients with BD (Table 1), but none fully explain the complex interaction observed clinically.^14,15 Substance dependence and BD are chronic remitting/relapsing disorders with heterogeneous presentations and highly variable natural histories. As with SUDs, BD may go undiagnosed and untreated for years, coming to clinical attention only after substantial disease progression.¹⁶

The fluctuating illness course in BD and SUDs makes diagnosis and treatment difficult. Symptomatic periods often are interrupted by spontaneous remissions and longer—although usually temporary—periods of perceived control. Both BD and SUDs may be associated with profound mood instability, increased impulsivity, altered responsiveness to reward, and impaired executive function.¹⁷ Finally, the high degree of heritability in BD¹⁸ and many SUDs¹⁹ may make treatment engagement more difficult if either disorder is present in multiple family members because of:

• potential for greater clinical severity
• reduced psychosocial resources
• altered familial behavioral norms that may impede the patient’s recognition of illness.

Denial of illness is a critical symptom that may fluctuate with disease course in both disorders. Persons with BD or SUDs may be least likely to recognize that they are ill during periods of highest symptom severity. Accordingly, treatment adherence in patients with either disorder may be limited at baseline and decline further when the 2 illnesses co-occur.²⁰

Involvement in the criminal justice system and medical comorbidities, particularly HCV, also complicate diagnosis and treatment of BD patients with SUDs. For more information about these topics, see Box1 and Box2.

Table 1

Why is substance abuse so prevalent among bipolar patients?

Integrated clinical management

Assessment. Although not intended to be comprehensive, suggestions for routine assessment of patients with suspected SUDs and/or BD are listed in Table 2. Because clinicians may encounter dual diagnosis patients in general psychiatric clinics or specialty (addiction or mood disorder) clinics, it is useful to obtain a thorough substance use history in all patients with known or suspected BD as well as a thorough history of hypomania/mania and depression in all patients with addictive disorders. BD diagnoses by self-report or chart history in patients with SUDs should be considered cautiously because BD often is overdiagnosed in persons engaged in active substance abuse or experiencing withdrawal.²¹ If past or present mood symptoms and substance use have co-occurred, further focused assessment of mood symptoms before alcohol and drug use or during extended periods of abstinence are necessary to make the diagnosis of bipolar disorder with confidence. Family history of SUDs and/or BD are neither necessary nor sufficient for either diagnosis; however, collateral information from family or significant others could help make the diagnosis and may identify aids and obstacles to treatment planning and engagement.

When a patient’s clinical history strongly supports the diagnoses of BD and co-occurring SUDs, more detailed inquiry is warranted. Determining the patient’s age at onset of each disorder may have prognostic value because onset of mania before SUDs developed, especially in adolescence, may predict a more severe course of both illnesses.²² A complete alcohol use history should include routine questioning about past withdrawal. Previous withdrawal seizures in an actively drinking BD patient may tip the balance toward adding an anticonvulsant for mood stabilization. A thorough SUD history should elicit information about polysubstance abuse or dependence and include screening for injection drug use and other risk factors for HCV and human immunodeficiency virus (HIV), such as hypersexuality during manic or hypomanic episodes. Document the date of the last screening for HCV/ HIV in BD patients at high risk of infection. The U.S. Centers for Disease Control and Prevention recommends that all patients at high risk for HIV consider voluntary screening at least annually.²³

Assess your patient’s historical and ongoing alcohol and other drug abuse at the initial visit, and continue to monitor substance use at all subsequent visits, especially in patients with HCV. When feasible, order urine drug screening and laboratory testing for alcohol use biomarkers such as carbohydrate-deficient transferrin and gamma-glutamyltransferase to supplement self-report data, especially in patients with poor insight or low motivation. Assess suicidal ideation and any changes in suicide risk factors at every visit.

Treatment. No biologic therapies have been FDA-approved for treating patients with co-occurring BD and SUDs. Comorbid SUDs in BD patients—as well as rapid cycling and mixed mood episodes, both of which are more common in patients with comorbid SUDs—predict poor response to lithium.¹⁷ However, the evidence base for optimal pharmacotherapy remains extremely limited. Published double-blind, placebo-controlled RCTs in persons with BD and co-morbid SUDs are limited to only 1 trial each of lithium, carbamazepine, quetiapine, and naltrexone, and 2 comparisons of lithium plus divalproex vs lithium alone (Table 3).^24-29

Salloum et al²⁴ reported that bipolar I disorder patients with alcohol dependence who received divalproex plus lithium as maintenance treatment had fewer heavy drinking days and fewer drinks per heavy drinking day than those receiving lithium plus placebo. However, the addition of divalproex did not improve manic or depressive symptoms, and depression remission rates remained relatively low in both groups. A recent 6-month study comparing lithium vs lithium plus divalproex in patients with SUDs and rapid-cycling BD found no additional benefit of divalproex over lithium monotherapy in retention, mood, or substance use outcomes.²⁸ However, modest evidence that anticonvulsants such as valproic acid and carbamazepine may help treat acute alcohol withdrawal² could support their preferential use as mood stabilizers over lithium in actively drinking BD patients.

Research underscores the difficulty in keeping dual diagnosis patients in treatment. Salloum et al²⁴ reported that only one-third of randomized subjects completed the 24-week study. In the Kemp study,²⁸ 79% of 149 recruited subjects failed to complete the lead-in stabilization phase. Of the 31 remaining subjects who were randomized to lithium or lithium/divalproex combination, only 8 (26% of those randomized, 5% of those recruited) completed the 6-month trial.

Substance abuse is associated with significantly decreased treatment adherence in persons with BD²⁰ and may affect medication choice. For example, caution may be warranted in the use of lamotrigine in substance-abusing patients with poor adherence because re-titration from the starting dose is recommended if the medicine has been missed for a consecutive period exceeding 5 half-lives of the drug.³⁰

Notable progress has been made in developing psychosocial treatments for comorbid SUDs and BD. Integrated group therapy has been designed to address the 2 disorders simultaneously by emphasizing the relationship between the disorders and highlighting similarities in cognitive and behavioral change that promote recovery in both.³¹ In a recent well-controlled RCT, this approach reduced alcohol and other drug use to approximately one-half the levels observed in those who received only group drug counseling.³¹

Research suggests that an integrated approach that encompasses psychiatric, medical, psychosocial, and legal dimensions simultaneously may be most effective. For patients such as Mr. M, this would include aggressively treating mood symptoms while employing motivational interviewing techniques to improve engagement in substance dependence treatment. If possible, involving family members, parole officials, housing agencies, and other public assistance workers in the treatment plan may increase treatment adherence and reduce loss of contact during illness exacerbations. Stabilization of substance use and psychiatric morbidity should be accompanied by timely evaluation of HCV and other medical comorbidities in order to improve long-term prognosis.

Table 2

Assessing patients you suspect have comorbid BD and SUDs

Table 3

Pharmacotherapy for bipolar disorder and co-occurring SUDs

Related Resources

• International Society for Bipolar Disorders. www.isbd.org.
• National Institute on Alcohol Abuse and Alcoholism. www.niaaa.nih.gov.
• National Institute on Drug Abuse. www.nida.nih.gov.

Drug Brand Names

• Carbamazepine • Tegretol
• Divalproex/valproic acid • Depakote
• Lamotrigine • Lamictal
• Lithium • Lithobid
• Naltrexone • ReVia
• Quetiapine • Seroquel

Disclosure

Dr. Tolliver receives research grant funding from Forest Laboratories and the National Institute on Alcohol Abuse and Alcoholism. Neither source influenced the content or submission of this manuscript.

Box 1

Box 2

Consider the neuroendocrinology of menopause when evaluating midlife women for new or worsening mood symptoms. The risk of depression increases during perimenopause, even in women with no history of depression.¹ Fluctuating estrogen levels can cause vasomotor symptoms (VMS) and depression, presenting diagnostic and treatment challenges. In addition to conducting a comprehensive psychiatric evaluation, our collaborative rotation between the UCLA-Kern Psychiatry Residency Program and the department of obstetrics and gynecology uses the following approach for women age >40.

Obtain a menstrual history

Ask your patient when her last menstrual period was and if her periods are irregular, heavy, light, or missing. Menopausal transition begins when the length of the menstrual cycle varies and ends with the final menstrual period. Perimenopause begins early in the transition and ends 12 months after the last menses. During this time VMS and mood instability may worsen.

Ask about menopausal symptoms

Hot flashes typically begin as a sudden sensation of heat centered in the upper chest and face that rapidly generalizes. Flashes last 2 to 4 minutes and often are accompanied by profuse perspiration and occasional palpitations. VMS can occur several times during the day and night. Hot flashes—the most common symptom associated with menopausal transition—peak during the 12 months surrounding the last period and can commonly persist up to 5 years or more. Hot flashes affect a woman’s sense of well-being and often are the reason women seek medical attention during midlife.

Insomnia. Sleep disturbance during the menopausal transition is common, sometimes severe, and may be related to nocturnal hot flashes and night sweats. Hot flashes and awakenings are sometimes followed by chills, shivering, anxiety, or panic.

Mood instability. Dysregulation of monoaminergic neurotransmitter systems caused by fluctuating estrogen levels may cause both depression and VMS.² Perimenopausal women with VMS are more likely to be depressed than those who do not have VMS. VMS may signal the onset or recurrence of major depression.

Sexual changes. Estrogen deficiency may lead to vaginal dryness and urogenital atrophy, resulting in infection, painful intercourse, or decreased sexual desire.

Body aches. Many perimenopausal women complain of stiffness, joint pain, breast pain, menstrual migraines, bladder discomfort, and impaired balance.

Memory changes. Complaints of forgetfulness may reflect aging and effects of sleep disturbance.³

Diagnostic workup

Perimenopause can be diagnosed before clinical symptoms appear if the follicle stimulating hormone (FSH) level is >25 IU/L and estrogen is <40 pg/mL during the early follicular phase (day 3 of the menstrual cycle).³ In women age <45 with irregular bleeding and menopause symptoms, check serum beta human chorionic gonadotropin (to rule out pregnancy), prolactin, thyroid-stimulating hormone, and FSH.

Women of any age with estrogen deficiency—such as those undergoing chemotherapy for breast cancer, treatment with gonadotropin-releasing hormone agonists for endometriosis or in-vitro fertilization, premature ovarian failure, or who have undergone oophorectomy—might experience VMS and other perimenopausal symptoms.

Women age >45 with 12 months of amenorrhea may be diagnosed with menopause clinically without further testing.

Treatment strategies

Fewer women are choosing hormone replacement therapy (HRT) (estrogen alone or estrogen and progesterone) after the landmark Women’s Health Initiative (WHI) study in 2002.⁴ Reports that HRT may increase the risk of breast cancer and offers no cardiac protection prompted many women to forego or discontinue HRT use. Subsequent interpretation of the WHI data has reduced many of these concerns.⁵ As a result, estrogen alone currently is the most effective and only FDA-approved treatment for VMS.⁵ Because of overlap between VMS and depression, treatment for these 2 conditions could be combined. Theoretically, treating VMS could prevent a major depressive episode in vulnerable women and may improve the chance of full remission of depression.¹

Although results of studies of HRT for depression are mixed, estrogen alone may be effective for mild depression during perimenopause but not postmenopause. Estrogen also may be appropriate during perimenopause if a depressive disorder represents a first-onset episode of mild to moderate severity.⁶ Estrogen is not FDA-approved for treating perimenopausal depression. As with all medications, counsel patients on the risks and benefits and administer the medication at the lowest dose and for the shortest time period to effectively treat symptoms.

Consider antidepressants when HRT is contraindicated or declined. Selective norepinephrine reuptake inhibitors such as venlafaxine, desvenlafaxine, and duloxetine have demonstrated efficacy for VMS and depression.² Selective serotonin reuptake inhibitors (SSRIs) are effective in women age <40 but show inconsistent efficacy for VMS and depression in women age >50. SSRIs combined with estrogen therapy may be useful in postmenopausal women.²

Biopsychosocial factors

Psychosocial attitudes about aging, sexual attractiveness, and children leaving home may contribute to depression during perimenopause. However, many women welcome the freedom from menstrual periods and pregnancy worries.

Some women may not be aware of the impact of menopausal changes on mood. Educating patients with a mood disorder about what to expect and identifying and treating disabling hormonal dysregulation symptoms is an ideal opportunity to enhance the quality of life for patients during menopause and beyond.

Consider the neuroendocrinology of menopause when evaluating midlife women for new or worsening mood symptoms. The risk of depression increases during perimenopause, even in women with no history of depression.¹ Fluctuating estrogen levels can cause vasomotor symptoms (VMS) and depression, presenting diagnostic and treatment challenges. In addition to conducting a comprehensive psychiatric evaluation, our collaborative rotation between the UCLA-Kern Psychiatry Residency Program and the department of obstetrics and gynecology uses the following approach for women age >40.

Obtain a menstrual history

Ask your patient when her last menstrual period was and if her periods are irregular, heavy, light, or missing. Menopausal transition begins when the length of the menstrual cycle varies and ends with the final menstrual period. Perimenopause begins early in the transition and ends 12 months after the last menses. During this time VMS and mood instability may worsen.

Ask about menopausal symptoms

Hot flashes typically begin as a sudden sensation of heat centered in the upper chest and face that rapidly generalizes. Flashes last 2 to 4 minutes and often are accompanied by profuse perspiration and occasional palpitations. VMS can occur several times during the day and night. Hot flashes—the most common symptom associated with menopausal transition—peak during the 12 months surrounding the last period and can commonly persist up to 5 years or more. Hot flashes affect a woman’s sense of well-being and often are the reason women seek medical attention during midlife.

Insomnia. Sleep disturbance during the menopausal transition is common, sometimes severe, and may be related to nocturnal hot flashes and night sweats. Hot flashes and awakenings are sometimes followed by chills, shivering, anxiety, or panic.

Mood instability. Dysregulation of monoaminergic neurotransmitter systems caused by fluctuating estrogen levels may cause both depression and VMS.² Perimenopausal women with VMS are more likely to be depressed than those who do not have VMS. VMS may signal the onset or recurrence of major depression.

Sexual changes. Estrogen deficiency may lead to vaginal dryness and urogenital atrophy, resulting in infection, painful intercourse, or decreased sexual desire.

Body aches. Many perimenopausal women complain of stiffness, joint pain, breast pain, menstrual migraines, bladder discomfort, and impaired balance.

Memory changes. Complaints of forgetfulness may reflect aging and effects of sleep disturbance.³

Diagnostic workup

Perimenopause can be diagnosed before clinical symptoms appear if the follicle stimulating hormone (FSH) level is >25 IU/L and estrogen is <40 pg/mL during the early follicular phase (day 3 of the menstrual cycle).³ In women age <45 with irregular bleeding and menopause symptoms, check serum beta human chorionic gonadotropin (to rule out pregnancy), prolactin, thyroid-stimulating hormone, and FSH.

Women of any age with estrogen deficiency—such as those undergoing chemotherapy for breast cancer, treatment with gonadotropin-releasing hormone agonists for endometriosis or in-vitro fertilization, premature ovarian failure, or who have undergone oophorectomy—might experience VMS and other perimenopausal symptoms.

Women age >45 with 12 months of amenorrhea may be diagnosed with menopause clinically without further testing.

Treatment strategies

Fewer women are choosing hormone replacement therapy (HRT) (estrogen alone or estrogen and progesterone) after the landmark Women’s Health Initiative (WHI) study in 2002.⁴ Reports that HRT may increase the risk of breast cancer and offers no cardiac protection prompted many women to forego or discontinue HRT use. Subsequent interpretation of the WHI data has reduced many of these concerns.⁵ As a result, estrogen alone currently is the most effective and only FDA-approved treatment for VMS.⁵ Because of overlap between VMS and depression, treatment for these 2 conditions could be combined. Theoretically, treating VMS could prevent a major depressive episode in vulnerable women and may improve the chance of full remission of depression.¹

Although results of studies of HRT for depression are mixed, estrogen alone may be effective for mild depression during perimenopause but not postmenopause. Estrogen also may be appropriate during perimenopause if a depressive disorder represents a first-onset episode of mild to moderate severity.⁶ Estrogen is not FDA-approved for treating perimenopausal depression. As with all medications, counsel patients on the risks and benefits and administer the medication at the lowest dose and for the shortest time period to effectively treat symptoms.

Consider antidepressants when HRT is contraindicated or declined. Selective norepinephrine reuptake inhibitors such as venlafaxine, desvenlafaxine, and duloxetine have demonstrated efficacy for VMS and depression.² Selective serotonin reuptake inhibitors (SSRIs) are effective in women age <40 but show inconsistent efficacy for VMS and depression in women age >50. SSRIs combined with estrogen therapy may be useful in postmenopausal women.²

Biopsychosocial factors

Psychosocial attitudes about aging, sexual attractiveness, and children leaving home may contribute to depression during perimenopause. However, many women welcome the freedom from menstrual periods and pregnancy worries.

Some women may not be aware of the impact of menopausal changes on mood. Educating patients with a mood disorder about what to expect and identifying and treating disabling hormonal dysregulation symptoms is an ideal opportunity to enhance the quality of life for patients during menopause and beyond.

Consider the neuroendocrinology of menopause when evaluating midlife women for new or worsening mood symptoms. The risk of depression increases during perimenopause, even in women with no history of depression.¹ Fluctuating estrogen levels can cause vasomotor symptoms (VMS) and depression, presenting diagnostic and treatment challenges. In addition to conducting a comprehensive psychiatric evaluation, our collaborative rotation between the UCLA-Kern Psychiatry Residency Program and the department of obstetrics and gynecology uses the following approach for women age >40.

Obtain a menstrual history

Ask your patient when her last menstrual period was and if her periods are irregular, heavy, light, or missing. Menopausal transition begins when the length of the menstrual cycle varies and ends with the final menstrual period. Perimenopause begins early in the transition and ends 12 months after the last menses. During this time VMS and mood instability may worsen.

Ask about menopausal symptoms

Hot flashes typically begin as a sudden sensation of heat centered in the upper chest and face that rapidly generalizes. Flashes last 2 to 4 minutes and often are accompanied by profuse perspiration and occasional palpitations. VMS can occur several times during the day and night. Hot flashes—the most common symptom associated with menopausal transition—peak during the 12 months surrounding the last period and can commonly persist up to 5 years or more. Hot flashes affect a woman’s sense of well-being and often are the reason women seek medical attention during midlife.

Insomnia. Sleep disturbance during the menopausal transition is common, sometimes severe, and may be related to nocturnal hot flashes and night sweats. Hot flashes and awakenings are sometimes followed by chills, shivering, anxiety, or panic.

Mood instability. Dysregulation of monoaminergic neurotransmitter systems caused by fluctuating estrogen levels may cause both depression and VMS.² Perimenopausal women with VMS are more likely to be depressed than those who do not have VMS. VMS may signal the onset or recurrence of major depression.

Sexual changes. Estrogen deficiency may lead to vaginal dryness and urogenital atrophy, resulting in infection, painful intercourse, or decreased sexual desire.

Body aches. Many perimenopausal women complain of stiffness, joint pain, breast pain, menstrual migraines, bladder discomfort, and impaired balance.

Memory changes. Complaints of forgetfulness may reflect aging and effects of sleep disturbance.³

Diagnostic workup

Perimenopause can be diagnosed before clinical symptoms appear if the follicle stimulating hormone (FSH) level is >25 IU/L and estrogen is <40 pg/mL during the early follicular phase (day 3 of the menstrual cycle).³ In women age <45 with irregular bleeding and menopause symptoms, check serum beta human chorionic gonadotropin (to rule out pregnancy), prolactin, thyroid-stimulating hormone, and FSH.

Women of any age with estrogen deficiency—such as those undergoing chemotherapy for breast cancer, treatment with gonadotropin-releasing hormone agonists for endometriosis or in-vitro fertilization, premature ovarian failure, or who have undergone oophorectomy—might experience VMS and other perimenopausal symptoms.

Women age >45 with 12 months of amenorrhea may be diagnosed with menopause clinically without further testing.

Treatment strategies

Fewer women are choosing hormone replacement therapy (HRT) (estrogen alone or estrogen and progesterone) after the landmark Women’s Health Initiative (WHI) study in 2002.⁴ Reports that HRT may increase the risk of breast cancer and offers no cardiac protection prompted many women to forego or discontinue HRT use. Subsequent interpretation of the WHI data has reduced many of these concerns.⁵ As a result, estrogen alone currently is the most effective and only FDA-approved treatment for VMS.⁵ Because of overlap between VMS and depression, treatment for these 2 conditions could be combined. Theoretically, treating VMS could prevent a major depressive episode in vulnerable women and may improve the chance of full remission of depression.¹

Although results of studies of HRT for depression are mixed, estrogen alone may be effective for mild depression during perimenopause but not postmenopause. Estrogen also may be appropriate during perimenopause if a depressive disorder represents a first-onset episode of mild to moderate severity.⁶ Estrogen is not FDA-approved for treating perimenopausal depression. As with all medications, counsel patients on the risks and benefits and administer the medication at the lowest dose and for the shortest time period to effectively treat symptoms.

Consider antidepressants when HRT is contraindicated or declined. Selective norepinephrine reuptake inhibitors such as venlafaxine, desvenlafaxine, and duloxetine have demonstrated efficacy for VMS and depression.² Selective serotonin reuptake inhibitors (SSRIs) are effective in women age <40 but show inconsistent efficacy for VMS and depression in women age >50. SSRIs combined with estrogen therapy may be useful in postmenopausal women.²

Biopsychosocial factors

Psychosocial attitudes about aging, sexual attractiveness, and children leaving home may contribute to depression during perimenopause. However, many women welcome the freedom from menstrual periods and pregnancy worries.

Some women may not be aware of the impact of menopausal changes on mood. Educating patients with a mood disorder about what to expect and identifying and treating disabling hormonal dysregulation symptoms is an ideal opportunity to enhance the quality of life for patients during menopause and beyond.

Few topics are as controversial as the role of antidepressants for patients with bipolar disorder. Although depression usually is the predominant, most enduring mood state in bipolar disorder, clinicians often face uncertainty about using antidepressants because of concerns about safety and efficacy. Whether and when to use antidepressants for bipolar depression hinges on complex parameters that preclude any single, simple rule.

Rather than asking if antidepressants are useful or detrimental for depressed patients with bipolar disorder, a more practical question might be: Under what circumstances are antidepressants likely to be beneficial, deleterious, or ineffective for an individual patient? Because “real world” patients often have idiosyncrasies that defy practice guidelines’ generic treatment recommendations, clinicians who practice in the proverbial trenches need strategies to tailor treatments to each patient that are informed—but not dictated—by evidence-based research.

Early suspicions

Concerns that antidepressants might precipitate mania were first described with tricyclic antidepressant (TCA) use in Europe in the 1960s. After bupropion and selective serotonin reuptake inhibitors (SSRIs) emerged, some clinicians believed they posed a lesser risk for this phenomenon compared with TCAs^1,2 or monoamine oxidase inhibitors (MAOIs).³

Antidepressants’ potential to induce short-term mania/hypomania following acute exposure has been weighed against the longer-term risk for worsening illness course by increasing frequency of subsequent episodes (so-called cycle acceleration). In the 1980s, some researchers suggested that rapid cycling might—at least in some instances—represent an iatrogenic phenomenon caused by long-term antidepressant use. These issues remain controversial, but more than 20 years of research suggest that antidepressants induce mania or accelerate cycling in a smaller minority of bipolar disorder patients than was once thought.

Table 1 and Table 2 summarize findings from randomized controlled studies that have examined antidepressants’ efficacy for acute bipolar depression. Except for a study of fluoxetine plus olanzapine,⁴ no large-scale placebo-controlled trial has demonstrated superior antidepressant response to a mood stabilizer plus antidepressant compared with a mood stabilizer alone.

Table 1

Antidepressants for bipolar depression: SSRIs and SNRIs*

Table 2

Antidepressants for bipolar depression: MAOIs, TCAs, and bupropion*

MYTH 1: Antidepressant-induced mania is a highly prevalent, widespread problem.

Reality: Although some might argue that the precise relative risk of antidepressant-induced mania or hypomania is unknown (eg, considering intervening factors such as the natural illness course), recent literature suggests that the emergence of mania or hypomania can be reasonably attributed to antidepressant use in no more than 10% to 25% of patients with bipolar disorder.^5,6 Part of the difficulty in estimating the true prevalence of antidepressant-induced mania involves variability and inconsistency in defining mania induction.

A recent consensus statement proposed a graduated series of definitions for treatment-emergent affective switch:⁷

• “Definite” switch involves fulfilling DSM-IV syndromic criteria for a manic, hypomanic, or mixed episode for at least 2 days, within 8 weeks of antidepressant introduction.
• “Likely” switches call for at least 2 DSM-IV mania or hypomania symptoms plus a Young Mania Rating Scale (YMRS) score >12, occurring for at least 2 days, within 12 weeks of antidepressant introduction.
• “Possible” switches require a “clear change” in mood or energy with a YMRS score >8, persisting ≥4 hours over 2 days, occurring within 12 weeks of antidepressant initiation.

Adverse effects such as agitation typically diminish or remit with dosage reductions or drug cessation, whereas true antidepressant-induced polarity switches persist even after the medication is discontinued. Moreover, it is often difficult—if not impossible—to know with certainty when a polarity switch results from treatment effects vs the natural illness course. In my experience, true manic or hypomanic syndromes soon after antidepressant exposure are less common than heterogeneous, nonspecific symptoms such as agitation, anxiety, insomnia, or worsening depression (ie, lack of efficacy).

MYTH 2: Antidepressant response rates are lower in bipolar depression.

Reality: It is difficult to draw broad conclusions about antidepressant response rates in unipolar vs bipolar depression because:

• few direct comparisons have been reported
• all relevant studies are retrospective
• small sample sizes in most studies may not have satisfactorily controlled for factors that could predispose to mood destabilization (Table 3).

Table 3

What increases risk of antidepressant-induced mania?

A retrospective review of bipolar (n=41) and unipolar (n=37) depressed patients by Ghaemi et al⁸ found no significant difference in acute nonresponse rates between the groups. Similarly, Bottlender et al⁹ found no differences in treatment response when comparing naturalistic antidepressant outcomes for 50 unipolar and 50 bipolar patients matched for age, sex, and illness duration. Comparable antidepressant response outcomes also were reported in a retrospective study of 2,032 unipolar and bipolar inpatients conducted by Möller et al,¹⁰ and between unipolar (n=31) vs bipolar II (n=17) depressed patients receiving venlafaxine monotherapy for 6 weeks.¹¹

Antidepressant response may depend on factors such as episode chronicity or the number of failed medication trials within a given episode, regardless of illness polarity. This was suggested by the remarkably low response rates after 2 failed initial antidepressant treatments in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) unipolar depression trials. In my experience, antidepressant efficacy is more often a function of factors in addition to polarity, including:

• illness severity
• chronicity
• psychiatric, medical, or substance use comorbidity
• psychosocial skills, such as the capacity to tolerate distress, utilize effective coping techniques, and maintain appropriate relationships with others.

MYTH 3: Most antidepressants have been systematically studied for treatment of depression in bipolar disorder.

Reality: Only paroxetine,^12,13 bupropion,¹² and imipramine¹³ have been studied in randomized, large-scale, adequately powered placebo-controlled trials. Studies of other antidepressants suffer from small sample sizes (inadequate statistical power), lack of placebo controls, or failure to control for possible confounding factors, such as lack of stratification for bipolar I vs II subtype or presence vs absence of rapid cycling.

One large randomized trial showed comparable antidepressant efficacy with a mood stabilizer plus adjunctive venlafaxine (43%) vs sertraline (55%) vs bupropion (49%) over 10 weeks,¹⁴ but the lack of a mood stabilizer monotherapy comparison group limits the ability to anticipate whether adjunctive antidepressants increase response or remission rates more than mood stabilizers alone. Adjunctive imipramine,¹³ paroxetine,^12,13,15 and bupropion¹² yield no greater improvement in depressive symptoms than is seen with optimally dosed mood stabilizers alone.

Mirtazapine, a serotonergic/noradrenergic antidepressant that is sometimes prescribed off-label as a sleep aid, has not been systematically studied for safety or efficacy in bipolar depression. In case reports, mirtazapine has induced mania in patients with unipolar depression.^16-18 Using mirtazapine to counteract insomnia may be safer in patients with unipolar depression than in those with bipolar disorder. Because poor sleep is a core feature of mania, be certain to differentiate complaints that reflect simple insomnia from a loss of need for sleep:

• daytime fatigue is more common in insomnia than loss of need for sleep
• nocturnal hyperactivity is more often associated with loss of need for sleep.

Using an antidepressant to treat sleep problems that may derive from emerging mania or hypomania runs counter to basic pharmacodynamic principles and may pose greater risk than benefit.

Generally, using a medication that has been studied for treating a specific clinical entity such as bipolar depression is preferable to using one that has not. Avoid medications that have multiple negative placebo-controlled trials—such as paroxetine—unless you have evidence of efficacy in an individual patient.

MYTH 4: Risk for inducing mania is higher with noradrenergic antidepressants.

Reality: This popular belief arose from a unifying hypothesis offered by Sachs et al¹ and Leverich et al¹⁴ to explain higher rates of mania following treatment with desipramine than bupropion,¹ SSRIs compared with TCAs,² or venlafaxine compared with bupropion or sertraline.¹⁴ However, while plausible, this hypothesis does not fully account for the putative noradrenergic properties of bupropion—presumably via increased pre-synaptic norepinephrine outflow, rather than noradrenergic reuptake inhibition¹⁹—which reportedly has a lower risk of switching than desipramine1 or venlafaxine.¹⁴

The risk for venlafaxine monotherapy to induce mania or hypomania in patients with bipolar II depression has been reported to be nonexistent¹¹ or no higher than seen with lithium.²⁰ Also, some noradrenergic agents, such as duloxetine, have not been shown to induce mania in major depression,²¹ although duloxetine’s potential to destabilize mood is unknown because of the absence of data in bipolar disorder. Finally, although large-scale clinical trials have not examined the safety and efficacy of the noradrenergic reuptake inhibitor atomoxetine, several case reports have suggested its potential for inducing mania or hypomania.^22,23

Likely, all-or-none admonitions against using noradrenergic antidepressants are oversimplifications.

MYTH 5: Coadministering an antimanic mood stabilizer reliably prevents antidepressant-induced mania.

Reality: Most practice guidelines advise administering antimanic mood stabilizers before initiating an antidepressant. Clinicians widely interpret this recommendation as reinforcing the assumption that a mood stabilizer will diminish mania risk when introducing an antidepressant. (Less often, clinicians interpret it as meaning that a mood stabilizer itself may provide antidepressant efficacy.) In fact, whether (and which) antimanic agents mitigate the risk for antidepressant-induced mania has received little empirical study. The largest dataset on this topic—the randomized controlled data from Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD)¹²—found that the risk for treatment-emergent manic switch with paroxetine or bupropion was almost identical (about 10%) with or without an FDA-approved antimanic agent.

In a retrospective study, Henry et al⁶ found that cotherapy with lithium but not divalproex or carbamazepine protects against antidepressant-induced mania, and that switch rates to mania were the same whether or not an antidepressant was taken with an anticonvulsant. In a naturalistic retrospective study (n=158), Bottlender et al²⁴ revealed that mood stabilizers (lithium, carbamazepine, or divalproex) prevented switches from depression to mania during treatment with TCAs but not SSRIs or MAOIs.

I favor incorporating lithium or other antimanic agents in the regimens of patients with bipolar depression not primarily to guard against antidepressant-induced mania but more for pharmacodynamic synergy—complementary mechanisms of action that collectively may produce more substantial antidepressant effects—especially when the patient’s illness course has included manic or hypomanic features in the preceding year.

MYTH 6: Antidepressants cause or worsen rapid cycling.

Reality: Wehr et al²⁵ reported that antidepressants may accelerate cycling frequency (ie, inter-episode durations become shorter) in a small subgroup (N=10) of patients. By contrast, use of TCAs was not more likely in the weeks preceding shifts from depression to mania or hypomania in a 14-year follow-up study of bipolar rapid cycling from the NIMH Collaborative Depression Study.²⁶ In fact, rapid-cycling patients spent more weeks depressed when taking lithium without a TCA than with 1.

Findings from STEP-BD indicate that prospectively observed rapid cycling, as defined by DSM-IV criteria, is relatively rare, although subjects taking antidepressants often had multiple episodes per year.²⁷ These naturalistic data could suggest that antidepressant use leads to more depressive episodes, or that more depressive episodes lead to more antidepressant use. Causal relationships cannot be inferred from the nonrandomized study design. Nevertheless, antidepressant use was not associated with reduced depressive episodes over 1 year.

I believe that, in general, antidepressants are unlikely to improve a truly rapid-cycling illness course. In this scenario, a more “panoramic” understanding of the need to treat multiple relapses and polarity changes over time likely warrants using multiple anti-cycling agents. Rapid cycling is treated over the course of 1 year, rather than 1 episode.

MYTH 7: Antidepressants should never be used without a mood stabilizer for bipolar depression.

Reality: This admonition is widely cited as a general recommendation from modern practice guidelines; however, it mainly pertains to depression treatment in patients with bipolar I disorder, for whom most controlled trial data exist. For example, relatively high rates of treatment-emergent mania have been reported with TCA or MAOI monotherapy in bipolar I disorder patients (Table 2). Yet for bipolar II disorder, controlled trials demonstrate superior outcomes with venlafaxine monotherapy compared with lithium monotherapy, with no increase in mood destabilization.²⁰

Neither the safety nor the efficacy of antidepressants with vs without mood stabilizers has been studied systematically in cyclothymic or mood disorder patients who may fall within the so-called bipolar spectrum but have never met DSM-IV criteria for a lifetime manic or hypomanic episode (ie, bipolar disorder not otherwise specified). Extrapolation from findings based on bipolar I disorder patients may not be valid for all bipolar subtypes.

Clinical strategies

In constructing a rationale-based approach to bipolar depression, consider these steps:

Step 1: Assess candidacy for antidepressant use. A number of key features can help you delineate the current illness state and context in which depressive symptoms arise—features that may influence you patient’s vulnerability to mood destabilization, and therefore are pertinent for gauging the likelihood that antidepressants may help or harm (Table 4).

Step 2: Consider mood stabilizers with antidepressant properties. Determine whether your patient is taking any mood stabilizers that possess robust antidepressant properties, or whether it may be beneficial to introduce one of these agents before initiating adjunctive antidepressants. Mood stabilizers with antidepressant efficacy are compelling options for patients presenting with any of the features listed in the right-hand column of Table 4, as well as those with:

• psychotic features
• marked agitation
• multiple prior antidepressant nonresponses
• high depression recurrence rates regardless of episode duration (ie, cyclicity, irrespective of ≥4 discrete episodes per year).

Table 4

Assessing antidepressant candidacy in bipolar depression

Prospective mood charting may help to establish the latter, in which case recurrence (rather than polarity) may cause waxing and waning depressed mood states.

Psychotropic agents or combinations that have shown to be effective for bipolar depression (supported by at least 1 randomized controlled trial) without destabilizing mood include quetiapine, olanzapine, olanzapine-fluoxetine combination, lamotrigine, and lithium plus lamotrigine. Those with some—but less robustly demonstrated—antidepressant action include lithium, divalproex, and carbamazepine. Other than quetiapine and olanzapine, second-generation antipsychotics have not demonstrated antidepressant effects in bipolar depression.

In general, optimize therapy with 1 or more mood stabilizers with antidepressant properties before deciding it is necessary to add antidepressants.

Step 3: Use antidepressants in suitable patients. For patients with no risk factors for mood destabilization from antidepressants (Table 3), these drugs may be worth incorporating, keeping in mind the following guiding principles:

• In patients with bipolar I depression, it is preferable to add an antidepressant to an antimanic mood stabilizer (ie, lithium, divalproex, carbamazepine, or an antipsychotic) rather than prescribing antidepressant monotherapy. There is greater diversity of opinion about the safety of antidepressant monotherapy for bipolar II depression.
• Consider using antidepressants that have at least 1 positive randomized controlled trial in bipolar disorder and low risk for mood destabilization (bupropion,^12,14 sertraline,¹⁴ fluoxetine,^4,5 tranylcypromine,^3,28 or venlafaxine in bipolar II depression²⁰) before using those with reported increased risk for inducing mania or hypomania (TCAs^1,2 or venlafaxine in bipolar I depression¹⁴), multiple negative controlled trials (paroxetine^12,13), or no controlled data in bipolar depression (citalopram, escitalopram, fluvoxamine, mirtazapine, duloxetine, desvenlafaxine, nefazodone, and selegiline transdermal). Combinations of antidepressants have not been adequately studied in bipolar depression.

• The optimal duration of antidepressant therapy is unknown. However, longer-term treatment may be worthwhile in patients who show robust acute antidepressant response and experience infrequent mania or hypomania. Long-term antidepressant use is less compelling in patients with a poor initial response²⁹ or rapid cycling.³⁰ Abrupt antidepressant cessation also may induce mania, potentially by disrupting homeostasis.³¹ In the absence of rapid cycling, manic/hypomanic features, or worsening suicidal features, and in the presence of an unequivocal acute response and a greater predisposition to depression than mania, it is reasonable to continue an antidepressant indefinitely until new signs of mania or hypomania emerge.
• Emerging signs of mania or hypomania should signal the need to discontinue the antidepressant. Dosage reductions alone may not diminish emerging manic or hypomanic symptoms, and “counterbalancing” maneuvers (ie, adding antimanic agents while continuing an antidepressant) may not effectively stabilize mood.

Step 4: Consider novel strategies. In the absence of a response to the strategy outlined above—particularly among poor candidates for continued antidepressant therapy—other novel strategies have support from at least 1 randomized controlled trial, including pramipexole,^32,33 modafinil,³⁴ riluzole,³⁵ and n-acetyl cysteine.³⁶ Other interventions worth considering include:

• adjunctive thyroid hormone
• cognitive therapy
• light therapy (if a seasonal component is evident)
• electroconvulsive therapy.

Related resources

• Goldberg JF. Treating depression in bipolar disorder. http://thedoctorschannel.com/video/3077.html.
• Goldberg JF. Pharmacologic treatment of acute mania.http://thedoctorschannel.com/video/3032.html.

Drug brand names

• Atomoxetine • Strattera
• Bupropion • Wellbutrin
• Carbamazepine • Tegretol, Equetro
• Citalopram • Celexa
• Desipramine • Norpramin
• Desvenlafaxine • Pristiq
• Divalproex • Depakote, Depakene
• Duloxetine • Cymbalta
• Escitalopram • Lexapro
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Imipramine • Tofranil
• Isocarboxazid • Marplan
• Lamotrigine • Lamictal
• Lithium • Lithobid, Eskalith
• Milnacipran • Ixel, Savella
• Mirtazapine • Remeron
• Moclobemide • Aurorix, Manerix
• Modafinil • Provigil
• Nefazodone • Serzone
• Olanzapine • Zyprexa
• Olanzapine-fluoxetine • Symbyax
• Paroxetine • Paxil
• Phenelzine • Nardil
• Pramipexole • Mirapex
• Quetiapine • Seroquel
• Riluzole • Rilutek
• Selegiline transdermal • EMSAM
• Sertraline • Zoloft
• Tranylcypromine • Parnate
• Venlafaxine • Effexor

Disclosures

Dr. Goldberg is a consultant to Eli Lilly and Company and a speaker for AstraZeneca, Eli Lilly and Company, GlaxoSmithKline, Merck, and Pfizer Inc., and has received speaking honoraria from Janssen-Cilag.

Few topics are as controversial as the role of antidepressants for patients with bipolar disorder. Although depression usually is the predominant, most enduring mood state in bipolar disorder, clinicians often face uncertainty about using antidepressants because of concerns about safety and efficacy. Whether and when to use antidepressants for bipolar depression hinges on complex parameters that preclude any single, simple rule.

Rather than asking if antidepressants are useful or detrimental for depressed patients with bipolar disorder, a more practical question might be: Under what circumstances are antidepressants likely to be beneficial, deleterious, or ineffective for an individual patient? Because “real world” patients often have idiosyncrasies that defy practice guidelines’ generic treatment recommendations, clinicians who practice in the proverbial trenches need strategies to tailor treatments to each patient that are informed—but not dictated—by evidence-based research.

Early suspicions

Concerns that antidepressants might precipitate mania were first described with tricyclic antidepressant (TCA) use in Europe in the 1960s. After bupropion and selective serotonin reuptake inhibitors (SSRIs) emerged, some clinicians believed they posed a lesser risk for this phenomenon compared with TCAs^1,2 or monoamine oxidase inhibitors (MAOIs).³

Antidepressants’ potential to induce short-term mania/hypomania following acute exposure has been weighed against the longer-term risk for worsening illness course by increasing frequency of subsequent episodes (so-called cycle acceleration). In the 1980s, some researchers suggested that rapid cycling might—at least in some instances—represent an iatrogenic phenomenon caused by long-term antidepressant use. These issues remain controversial, but more than 20 years of research suggest that antidepressants induce mania or accelerate cycling in a smaller minority of bipolar disorder patients than was once thought.

Table 1 and Table 2 summarize findings from randomized controlled studies that have examined antidepressants’ efficacy for acute bipolar depression. Except for a study of fluoxetine plus olanzapine,⁴ no large-scale placebo-controlled trial has demonstrated superior antidepressant response to a mood stabilizer plus antidepressant compared with a mood stabilizer alone.

Table 1

Antidepressants for bipolar depression: SSRIs and SNRIs*

Table 2

Antidepressants for bipolar depression: MAOIs, TCAs, and bupropion*

MYTH 1: Antidepressant-induced mania is a highly prevalent, widespread problem.

Reality: Although some might argue that the precise relative risk of antidepressant-induced mania or hypomania is unknown (eg, considering intervening factors such as the natural illness course), recent literature suggests that the emergence of mania or hypomania can be reasonably attributed to antidepressant use in no more than 10% to 25% of patients with bipolar disorder.^5,6 Part of the difficulty in estimating the true prevalence of antidepressant-induced mania involves variability and inconsistency in defining mania induction.

A recent consensus statement proposed a graduated series of definitions for treatment-emergent affective switch:⁷

• “Definite” switch involves fulfilling DSM-IV syndromic criteria for a manic, hypomanic, or mixed episode for at least 2 days, within 8 weeks of antidepressant introduction.
• “Likely” switches call for at least 2 DSM-IV mania or hypomania symptoms plus a Young Mania Rating Scale (YMRS) score >12, occurring for at least 2 days, within 12 weeks of antidepressant introduction.
• “Possible” switches require a “clear change” in mood or energy with a YMRS score >8, persisting ≥4 hours over 2 days, occurring within 12 weeks of antidepressant initiation.

Adverse effects such as agitation typically diminish or remit with dosage reductions or drug cessation, whereas true antidepressant-induced polarity switches persist even after the medication is discontinued. Moreover, it is often difficult—if not impossible—to know with certainty when a polarity switch results from treatment effects vs the natural illness course. In my experience, true manic or hypomanic syndromes soon after antidepressant exposure are less common than heterogeneous, nonspecific symptoms such as agitation, anxiety, insomnia, or worsening depression (ie, lack of efficacy).

MYTH 2: Antidepressant response rates are lower in bipolar depression.

Reality: It is difficult to draw broad conclusions about antidepressant response rates in unipolar vs bipolar depression because:

• few direct comparisons have been reported
• all relevant studies are retrospective
• small sample sizes in most studies may not have satisfactorily controlled for factors that could predispose to mood destabilization (Table 3).

Table 3

What increases risk of antidepressant-induced mania?

A retrospective review of bipolar (n=41) and unipolar (n=37) depressed patients by Ghaemi et al⁸ found no significant difference in acute nonresponse rates between the groups. Similarly, Bottlender et al⁹ found no differences in treatment response when comparing naturalistic antidepressant outcomes for 50 unipolar and 50 bipolar patients matched for age, sex, and illness duration. Comparable antidepressant response outcomes also were reported in a retrospective study of 2,032 unipolar and bipolar inpatients conducted by Möller et al,¹⁰ and between unipolar (n=31) vs bipolar II (n=17) depressed patients receiving venlafaxine monotherapy for 6 weeks.¹¹

Antidepressant response may depend on factors such as episode chronicity or the number of failed medication trials within a given episode, regardless of illness polarity. This was suggested by the remarkably low response rates after 2 failed initial antidepressant treatments in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) unipolar depression trials. In my experience, antidepressant efficacy is more often a function of factors in addition to polarity, including:

• illness severity
• chronicity
• psychiatric, medical, or substance use comorbidity
• psychosocial skills, such as the capacity to tolerate distress, utilize effective coping techniques, and maintain appropriate relationships with others.

MYTH 3: Most antidepressants have been systematically studied for treatment of depression in bipolar disorder.

Reality: Only paroxetine,^12,13 bupropion,¹² and imipramine¹³ have been studied in randomized, large-scale, adequately powered placebo-controlled trials. Studies of other antidepressants suffer from small sample sizes (inadequate statistical power), lack of placebo controls, or failure to control for possible confounding factors, such as lack of stratification for bipolar I vs II subtype or presence vs absence of rapid cycling.

One large randomized trial showed comparable antidepressant efficacy with a mood stabilizer plus adjunctive venlafaxine (43%) vs sertraline (55%) vs bupropion (49%) over 10 weeks,¹⁴ but the lack of a mood stabilizer monotherapy comparison group limits the ability to anticipate whether adjunctive antidepressants increase response or remission rates more than mood stabilizers alone. Adjunctive imipramine,¹³ paroxetine,^12,13,15 and bupropion¹² yield no greater improvement in depressive symptoms than is seen with optimally dosed mood stabilizers alone.

Mirtazapine, a serotonergic/noradrenergic antidepressant that is sometimes prescribed off-label as a sleep aid, has not been systematically studied for safety or efficacy in bipolar depression. In case reports, mirtazapine has induced mania in patients with unipolar depression.^16-18 Using mirtazapine to counteract insomnia may be safer in patients with unipolar depression than in those with bipolar disorder. Because poor sleep is a core feature of mania, be certain to differentiate complaints that reflect simple insomnia from a loss of need for sleep:

• daytime fatigue is more common in insomnia than loss of need for sleep
• nocturnal hyperactivity is more often associated with loss of need for sleep.

Using an antidepressant to treat sleep problems that may derive from emerging mania or hypomania runs counter to basic pharmacodynamic principles and may pose greater risk than benefit.

Generally, using a medication that has been studied for treating a specific clinical entity such as bipolar depression is preferable to using one that has not. Avoid medications that have multiple negative placebo-controlled trials—such as paroxetine—unless you have evidence of efficacy in an individual patient.

MYTH 4: Risk for inducing mania is higher with noradrenergic antidepressants.

Reality: This popular belief arose from a unifying hypothesis offered by Sachs et al¹ and Leverich et al¹⁴ to explain higher rates of mania following treatment with desipramine than bupropion,¹ SSRIs compared with TCAs,² or venlafaxine compared with bupropion or sertraline.¹⁴ However, while plausible, this hypothesis does not fully account for the putative noradrenergic properties of bupropion—presumably via increased pre-synaptic norepinephrine outflow, rather than noradrenergic reuptake inhibition¹⁹—which reportedly has a lower risk of switching than desipramine1 or venlafaxine.¹⁴

The risk for venlafaxine monotherapy to induce mania or hypomania in patients with bipolar II depression has been reported to be nonexistent¹¹ or no higher than seen with lithium.²⁰ Also, some noradrenergic agents, such as duloxetine, have not been shown to induce mania in major depression,²¹ although duloxetine’s potential to destabilize mood is unknown because of the absence of data in bipolar disorder. Finally, although large-scale clinical trials have not examined the safety and efficacy of the noradrenergic reuptake inhibitor atomoxetine, several case reports have suggested its potential for inducing mania or hypomania.^22,23

Likely, all-or-none admonitions against using noradrenergic antidepressants are oversimplifications.

MYTH 5: Coadministering an antimanic mood stabilizer reliably prevents antidepressant-induced mania.

Reality: Most practice guidelines advise administering antimanic mood stabilizers before initiating an antidepressant. Clinicians widely interpret this recommendation as reinforcing the assumption that a mood stabilizer will diminish mania risk when introducing an antidepressant. (Less often, clinicians interpret it as meaning that a mood stabilizer itself may provide antidepressant efficacy.) In fact, whether (and which) antimanic agents mitigate the risk for antidepressant-induced mania has received little empirical study. The largest dataset on this topic—the randomized controlled data from Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD)¹²—found that the risk for treatment-emergent manic switch with paroxetine or bupropion was almost identical (about 10%) with or without an FDA-approved antimanic agent.

In a retrospective study, Henry et al⁶ found that cotherapy with lithium but not divalproex or carbamazepine protects against antidepressant-induced mania, and that switch rates to mania were the same whether or not an antidepressant was taken with an anticonvulsant. In a naturalistic retrospective study (n=158), Bottlender et al²⁴ revealed that mood stabilizers (lithium, carbamazepine, or divalproex) prevented switches from depression to mania during treatment with TCAs but not SSRIs or MAOIs.

I favor incorporating lithium or other antimanic agents in the regimens of patients with bipolar depression not primarily to guard against antidepressant-induced mania but more for pharmacodynamic synergy—complementary mechanisms of action that collectively may produce more substantial antidepressant effects—especially when the patient’s illness course has included manic or hypomanic features in the preceding year.

MYTH 6: Antidepressants cause or worsen rapid cycling.

Reality: Wehr et al²⁵ reported that antidepressants may accelerate cycling frequency (ie, inter-episode durations become shorter) in a small subgroup (N=10) of patients. By contrast, use of TCAs was not more likely in the weeks preceding shifts from depression to mania or hypomania in a 14-year follow-up study of bipolar rapid cycling from the NIMH Collaborative Depression Study.²⁶ In fact, rapid-cycling patients spent more weeks depressed when taking lithium without a TCA than with 1.

Findings from STEP-BD indicate that prospectively observed rapid cycling, as defined by DSM-IV criteria, is relatively rare, although subjects taking antidepressants often had multiple episodes per year.²⁷ These naturalistic data could suggest that antidepressant use leads to more depressive episodes, or that more depressive episodes lead to more antidepressant use. Causal relationships cannot be inferred from the nonrandomized study design. Nevertheless, antidepressant use was not associated with reduced depressive episodes over 1 year.

I believe that, in general, antidepressants are unlikely to improve a truly rapid-cycling illness course. In this scenario, a more “panoramic” understanding of the need to treat multiple relapses and polarity changes over time likely warrants using multiple anti-cycling agents. Rapid cycling is treated over the course of 1 year, rather than 1 episode.

MYTH 7: Antidepressants should never be used without a mood stabilizer for bipolar depression.

Reality: This admonition is widely cited as a general recommendation from modern practice guidelines; however, it mainly pertains to depression treatment in patients with bipolar I disorder, for whom most controlled trial data exist. For example, relatively high rates of treatment-emergent mania have been reported with TCA or MAOI monotherapy in bipolar I disorder patients (Table 2). Yet for bipolar II disorder, controlled trials demonstrate superior outcomes with venlafaxine monotherapy compared with lithium monotherapy, with no increase in mood destabilization.²⁰

Neither the safety nor the efficacy of antidepressants with vs without mood stabilizers has been studied systematically in cyclothymic or mood disorder patients who may fall within the so-called bipolar spectrum but have never met DSM-IV criteria for a lifetime manic or hypomanic episode (ie, bipolar disorder not otherwise specified). Extrapolation from findings based on bipolar I disorder patients may not be valid for all bipolar subtypes.

Clinical strategies

In constructing a rationale-based approach to bipolar depression, consider these steps:

Step 1: Assess candidacy for antidepressant use. A number of key features can help you delineate the current illness state and context in which depressive symptoms arise—features that may influence you patient’s vulnerability to mood destabilization, and therefore are pertinent for gauging the likelihood that antidepressants may help or harm (Table 4).

Step 2: Consider mood stabilizers with antidepressant properties. Determine whether your patient is taking any mood stabilizers that possess robust antidepressant properties, or whether it may be beneficial to introduce one of these agents before initiating adjunctive antidepressants. Mood stabilizers with antidepressant efficacy are compelling options for patients presenting with any of the features listed in the right-hand column of Table 4, as well as those with:

• psychotic features
• marked agitation
• multiple prior antidepressant nonresponses
• high depression recurrence rates regardless of episode duration (ie, cyclicity, irrespective of ≥4 discrete episodes per year).

Table 4

Assessing antidepressant candidacy in bipolar depression

Prospective mood charting may help to establish the latter, in which case recurrence (rather than polarity) may cause waxing and waning depressed mood states.

Psychotropic agents or combinations that have shown to be effective for bipolar depression (supported by at least 1 randomized controlled trial) without destabilizing mood include quetiapine, olanzapine, olanzapine-fluoxetine combination, lamotrigine, and lithium plus lamotrigine. Those with some—but less robustly demonstrated—antidepressant action include lithium, divalproex, and carbamazepine. Other than quetiapine and olanzapine, second-generation antipsychotics have not demonstrated antidepressant effects in bipolar depression.

In general, optimize therapy with 1 or more mood stabilizers with antidepressant properties before deciding it is necessary to add antidepressants.

Step 3: Use antidepressants in suitable patients. For patients with no risk factors for mood destabilization from antidepressants (Table 3), these drugs may be worth incorporating, keeping in mind the following guiding principles:

• In patients with bipolar I depression, it is preferable to add an antidepressant to an antimanic mood stabilizer (ie, lithium, divalproex, carbamazepine, or an antipsychotic) rather than prescribing antidepressant monotherapy. There is greater diversity of opinion about the safety of antidepressant monotherapy for bipolar II depression.
• Consider using antidepressants that have at least 1 positive randomized controlled trial in bipolar disorder and low risk for mood destabilization (bupropion,^12,14 sertraline,¹⁴ fluoxetine,^4,5 tranylcypromine,^3,28 or venlafaxine in bipolar II depression²⁰) before using those with reported increased risk for inducing mania or hypomania (TCAs^1,2 or venlafaxine in bipolar I depression¹⁴), multiple negative controlled trials (paroxetine^12,13), or no controlled data in bipolar depression (citalopram, escitalopram, fluvoxamine, mirtazapine, duloxetine, desvenlafaxine, nefazodone, and selegiline transdermal). Combinations of antidepressants have not been adequately studied in bipolar depression.

• The optimal duration of antidepressant therapy is unknown. However, longer-term treatment may be worthwhile in patients who show robust acute antidepressant response and experience infrequent mania or hypomania. Long-term antidepressant use is less compelling in patients with a poor initial response²⁹ or rapid cycling.³⁰ Abrupt antidepressant cessation also may induce mania, potentially by disrupting homeostasis.³¹ In the absence of rapid cycling, manic/hypomanic features, or worsening suicidal features, and in the presence of an unequivocal acute response and a greater predisposition to depression than mania, it is reasonable to continue an antidepressant indefinitely until new signs of mania or hypomania emerge.
• Emerging signs of mania or hypomania should signal the need to discontinue the antidepressant. Dosage reductions alone may not diminish emerging manic or hypomanic symptoms, and “counterbalancing” maneuvers (ie, adding antimanic agents while continuing an antidepressant) may not effectively stabilize mood.

Step 4: Consider novel strategies. In the absence of a response to the strategy outlined above—particularly among poor candidates for continued antidepressant therapy—other novel strategies have support from at least 1 randomized controlled trial, including pramipexole,^32,33 modafinil,³⁴ riluzole,³⁵ and n-acetyl cysteine.³⁶ Other interventions worth considering include:

• adjunctive thyroid hormone
• cognitive therapy
• light therapy (if a seasonal component is evident)
• electroconvulsive therapy.

Related resources

• Goldberg JF. Treating depression in bipolar disorder. http://thedoctorschannel.com/video/3077.html.
• Goldberg JF. Pharmacologic treatment of acute mania.http://thedoctorschannel.com/video/3032.html.

Drug brand names

• Atomoxetine • Strattera
• Bupropion • Wellbutrin
• Carbamazepine • Tegretol, Equetro
• Citalopram • Celexa
• Desipramine • Norpramin
• Desvenlafaxine • Pristiq
• Divalproex • Depakote, Depakene
• Duloxetine • Cymbalta
• Escitalopram • Lexapro
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Imipramine • Tofranil
• Isocarboxazid • Marplan
• Lamotrigine • Lamictal
• Lithium • Lithobid, Eskalith
• Milnacipran • Ixel, Savella
• Mirtazapine • Remeron
• Moclobemide • Aurorix, Manerix
• Modafinil • Provigil
• Nefazodone • Serzone
• Olanzapine • Zyprexa
• Olanzapine-fluoxetine • Symbyax
• Paroxetine • Paxil
• Phenelzine • Nardil
• Pramipexole • Mirapex
• Quetiapine • Seroquel
• Riluzole • Rilutek
• Selegiline transdermal • EMSAM
• Sertraline • Zoloft
• Tranylcypromine • Parnate
• Venlafaxine • Effexor

Disclosures

Dr. Goldberg is a consultant to Eli Lilly and Company and a speaker for AstraZeneca, Eli Lilly and Company, GlaxoSmithKline, Merck, and Pfizer Inc., and has received speaking honoraria from Janssen-Cilag.

Few topics are as controversial as the role of antidepressants for patients with bipolar disorder. Although depression usually is the predominant, most enduring mood state in bipolar disorder, clinicians often face uncertainty about using antidepressants because of concerns about safety and efficacy. Whether and when to use antidepressants for bipolar depression hinges on complex parameters that preclude any single, simple rule.

Rather than asking if antidepressants are useful or detrimental for depressed patients with bipolar disorder, a more practical question might be: Under what circumstances are antidepressants likely to be beneficial, deleterious, or ineffective for an individual patient? Because “real world” patients often have idiosyncrasies that defy practice guidelines’ generic treatment recommendations, clinicians who practice in the proverbial trenches need strategies to tailor treatments to each patient that are informed—but not dictated—by evidence-based research.

Early suspicions

Concerns that antidepressants might precipitate mania were first described with tricyclic antidepressant (TCA) use in Europe in the 1960s. After bupropion and selective serotonin reuptake inhibitors (SSRIs) emerged, some clinicians believed they posed a lesser risk for this phenomenon compared with TCAs^1,2 or monoamine oxidase inhibitors (MAOIs).³

Antidepressants’ potential to induce short-term mania/hypomania following acute exposure has been weighed against the longer-term risk for worsening illness course by increasing frequency of subsequent episodes (so-called cycle acceleration). In the 1980s, some researchers suggested that rapid cycling might—at least in some instances—represent an iatrogenic phenomenon caused by long-term antidepressant use. These issues remain controversial, but more than 20 years of research suggest that antidepressants induce mania or accelerate cycling in a smaller minority of bipolar disorder patients than was once thought.

Table 1 and Table 2 summarize findings from randomized controlled studies that have examined antidepressants’ efficacy for acute bipolar depression. Except for a study of fluoxetine plus olanzapine,⁴ no large-scale placebo-controlled trial has demonstrated superior antidepressant response to a mood stabilizer plus antidepressant compared with a mood stabilizer alone.

Table 1

Antidepressants for bipolar depression: SSRIs and SNRIs*

Table 2

Antidepressants for bipolar depression: MAOIs, TCAs, and bupropion*

MYTH 1: Antidepressant-induced mania is a highly prevalent, widespread problem.

Reality: Although some might argue that the precise relative risk of antidepressant-induced mania or hypomania is unknown (eg, considering intervening factors such as the natural illness course), recent literature suggests that the emergence of mania or hypomania can be reasonably attributed to antidepressant use in no more than 10% to 25% of patients with bipolar disorder.^5,6 Part of the difficulty in estimating the true prevalence of antidepressant-induced mania involves variability and inconsistency in defining mania induction.

A recent consensus statement proposed a graduated series of definitions for treatment-emergent affective switch:⁷

• “Definite” switch involves fulfilling DSM-IV syndromic criteria for a manic, hypomanic, or mixed episode for at least 2 days, within 8 weeks of antidepressant introduction.
• “Likely” switches call for at least 2 DSM-IV mania or hypomania symptoms plus a Young Mania Rating Scale (YMRS) score >12, occurring for at least 2 days, within 12 weeks of antidepressant introduction.
• “Possible” switches require a “clear change” in mood or energy with a YMRS score >8, persisting ≥4 hours over 2 days, occurring within 12 weeks of antidepressant initiation.

Adverse effects such as agitation typically diminish or remit with dosage reductions or drug cessation, whereas true antidepressant-induced polarity switches persist even after the medication is discontinued. Moreover, it is often difficult—if not impossible—to know with certainty when a polarity switch results from treatment effects vs the natural illness course. In my experience, true manic or hypomanic syndromes soon after antidepressant exposure are less common than heterogeneous, nonspecific symptoms such as agitation, anxiety, insomnia, or worsening depression (ie, lack of efficacy).

MYTH 2: Antidepressant response rates are lower in bipolar depression.

Reality: It is difficult to draw broad conclusions about antidepressant response rates in unipolar vs bipolar depression because:

• few direct comparisons have been reported
• all relevant studies are retrospective
• small sample sizes in most studies may not have satisfactorily controlled for factors that could predispose to mood destabilization (Table 3).

Table 3

What increases risk of antidepressant-induced mania?

A retrospective review of bipolar (n=41) and unipolar (n=37) depressed patients by Ghaemi et al⁸ found no significant difference in acute nonresponse rates between the groups. Similarly, Bottlender et al⁹ found no differences in treatment response when comparing naturalistic antidepressant outcomes for 50 unipolar and 50 bipolar patients matched for age, sex, and illness duration. Comparable antidepressant response outcomes also were reported in a retrospective study of 2,032 unipolar and bipolar inpatients conducted by Möller et al,¹⁰ and between unipolar (n=31) vs bipolar II (n=17) depressed patients receiving venlafaxine monotherapy for 6 weeks.¹¹

Antidepressant response may depend on factors such as episode chronicity or the number of failed medication trials within a given episode, regardless of illness polarity. This was suggested by the remarkably low response rates after 2 failed initial antidepressant treatments in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) unipolar depression trials. In my experience, antidepressant efficacy is more often a function of factors in addition to polarity, including:

• illness severity
• chronicity
• psychiatric, medical, or substance use comorbidity
• psychosocial skills, such as the capacity to tolerate distress, utilize effective coping techniques, and maintain appropriate relationships with others.

MYTH 3: Most antidepressants have been systematically studied for treatment of depression in bipolar disorder.

Reality: Only paroxetine,^12,13 bupropion,¹² and imipramine¹³ have been studied in randomized, large-scale, adequately powered placebo-controlled trials. Studies of other antidepressants suffer from small sample sizes (inadequate statistical power), lack of placebo controls, or failure to control for possible confounding factors, such as lack of stratification for bipolar I vs II subtype or presence vs absence of rapid cycling.

One large randomized trial showed comparable antidepressant efficacy with a mood stabilizer plus adjunctive venlafaxine (43%) vs sertraline (55%) vs bupropion (49%) over 10 weeks,¹⁴ but the lack of a mood stabilizer monotherapy comparison group limits the ability to anticipate whether adjunctive antidepressants increase response or remission rates more than mood stabilizers alone. Adjunctive imipramine,¹³ paroxetine,^12,13,15 and bupropion¹² yield no greater improvement in depressive symptoms than is seen with optimally dosed mood stabilizers alone.

Mirtazapine, a serotonergic/noradrenergic antidepressant that is sometimes prescribed off-label as a sleep aid, has not been systematically studied for safety or efficacy in bipolar depression. In case reports, mirtazapine has induced mania in patients with unipolar depression.^16-18 Using mirtazapine to counteract insomnia may be safer in patients with unipolar depression than in those with bipolar disorder. Because poor sleep is a core feature of mania, be certain to differentiate complaints that reflect simple insomnia from a loss of need for sleep:

• daytime fatigue is more common in insomnia than loss of need for sleep
• nocturnal hyperactivity is more often associated with loss of need for sleep.

Using an antidepressant to treat sleep problems that may derive from emerging mania or hypomania runs counter to basic pharmacodynamic principles and may pose greater risk than benefit.

Generally, using a medication that has been studied for treating a specific clinical entity such as bipolar depression is preferable to using one that has not. Avoid medications that have multiple negative placebo-controlled trials—such as paroxetine—unless you have evidence of efficacy in an individual patient.

MYTH 4: Risk for inducing mania is higher with noradrenergic antidepressants.

Reality: This popular belief arose from a unifying hypothesis offered by Sachs et al¹ and Leverich et al¹⁴ to explain higher rates of mania following treatment with desipramine than bupropion,¹ SSRIs compared with TCAs,² or venlafaxine compared with bupropion or sertraline.¹⁴ However, while plausible, this hypothesis does not fully account for the putative noradrenergic properties of bupropion—presumably via increased pre-synaptic norepinephrine outflow, rather than noradrenergic reuptake inhibition¹⁹—which reportedly has a lower risk of switching than desipramine1 or venlafaxine.¹⁴

The risk for venlafaxine monotherapy to induce mania or hypomania in patients with bipolar II depression has been reported to be nonexistent¹¹ or no higher than seen with lithium.²⁰ Also, some noradrenergic agents, such as duloxetine, have not been shown to induce mania in major depression,²¹ although duloxetine’s potential to destabilize mood is unknown because of the absence of data in bipolar disorder. Finally, although large-scale clinical trials have not examined the safety and efficacy of the noradrenergic reuptake inhibitor atomoxetine, several case reports have suggested its potential for inducing mania or hypomania.^22,23

Likely, all-or-none admonitions against using noradrenergic antidepressants are oversimplifications.

MYTH 5: Coadministering an antimanic mood stabilizer reliably prevents antidepressant-induced mania.

Reality: Most practice guidelines advise administering antimanic mood stabilizers before initiating an antidepressant. Clinicians widely interpret this recommendation as reinforcing the assumption that a mood stabilizer will diminish mania risk when introducing an antidepressant. (Less often, clinicians interpret it as meaning that a mood stabilizer itself may provide antidepressant efficacy.) In fact, whether (and which) antimanic agents mitigate the risk for antidepressant-induced mania has received little empirical study. The largest dataset on this topic—the randomized controlled data from Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD)¹²—found that the risk for treatment-emergent manic switch with paroxetine or bupropion was almost identical (about 10%) with or without an FDA-approved antimanic agent.

In a retrospective study, Henry et al⁶ found that cotherapy with lithium but not divalproex or carbamazepine protects against antidepressant-induced mania, and that switch rates to mania were the same whether or not an antidepressant was taken with an anticonvulsant. In a naturalistic retrospective study (n=158), Bottlender et al²⁴ revealed that mood stabilizers (lithium, carbamazepine, or divalproex) prevented switches from depression to mania during treatment with TCAs but not SSRIs or MAOIs.

I favor incorporating lithium or other antimanic agents in the regimens of patients with bipolar depression not primarily to guard against antidepressant-induced mania but more for pharmacodynamic synergy—complementary mechanisms of action that collectively may produce more substantial antidepressant effects—especially when the patient’s illness course has included manic or hypomanic features in the preceding year.

MYTH 6: Antidepressants cause or worsen rapid cycling.

Reality: Wehr et al²⁵ reported that antidepressants may accelerate cycling frequency (ie, inter-episode durations become shorter) in a small subgroup (N=10) of patients. By contrast, use of TCAs was not more likely in the weeks preceding shifts from depression to mania or hypomania in a 14-year follow-up study of bipolar rapid cycling from the NIMH Collaborative Depression Study.²⁶ In fact, rapid-cycling patients spent more weeks depressed when taking lithium without a TCA than with 1.

Findings from STEP-BD indicate that prospectively observed rapid cycling, as defined by DSM-IV criteria, is relatively rare, although subjects taking antidepressants often had multiple episodes per year.²⁷ These naturalistic data could suggest that antidepressant use leads to more depressive episodes, or that more depressive episodes lead to more antidepressant use. Causal relationships cannot be inferred from the nonrandomized study design. Nevertheless, antidepressant use was not associated with reduced depressive episodes over 1 year.

I believe that, in general, antidepressants are unlikely to improve a truly rapid-cycling illness course. In this scenario, a more “panoramic” understanding of the need to treat multiple relapses and polarity changes over time likely warrants using multiple anti-cycling agents. Rapid cycling is treated over the course of 1 year, rather than 1 episode.

MYTH 7: Antidepressants should never be used without a mood stabilizer for bipolar depression.

Reality: This admonition is widely cited as a general recommendation from modern practice guidelines; however, it mainly pertains to depression treatment in patients with bipolar I disorder, for whom most controlled trial data exist. For example, relatively high rates of treatment-emergent mania have been reported with TCA or MAOI monotherapy in bipolar I disorder patients (Table 2). Yet for bipolar II disorder, controlled trials demonstrate superior outcomes with venlafaxine monotherapy compared with lithium monotherapy, with no increase in mood destabilization.²⁰

Neither the safety nor the efficacy of antidepressants with vs without mood stabilizers has been studied systematically in cyclothymic or mood disorder patients who may fall within the so-called bipolar spectrum but have never met DSM-IV criteria for a lifetime manic or hypomanic episode (ie, bipolar disorder not otherwise specified). Extrapolation from findings based on bipolar I disorder patients may not be valid for all bipolar subtypes.

Clinical strategies

In constructing a rationale-based approach to bipolar depression, consider these steps:

Step 1: Assess candidacy for antidepressant use. A number of key features can help you delineate the current illness state and context in which depressive symptoms arise—features that may influence you patient’s vulnerability to mood destabilization, and therefore are pertinent for gauging the likelihood that antidepressants may help or harm (Table 4).

Step 2: Consider mood stabilizers with antidepressant properties. Determine whether your patient is taking any mood stabilizers that possess robust antidepressant properties, or whether it may be beneficial to introduce one of these agents before initiating adjunctive antidepressants. Mood stabilizers with antidepressant efficacy are compelling options for patients presenting with any of the features listed in the right-hand column of Table 4, as well as those with:

• psychotic features
• marked agitation
• multiple prior antidepressant nonresponses
• high depression recurrence rates regardless of episode duration (ie, cyclicity, irrespective of ≥4 discrete episodes per year).

Table 4

Assessing antidepressant candidacy in bipolar depression

Prospective mood charting may help to establish the latter, in which case recurrence (rather than polarity) may cause waxing and waning depressed mood states.

Psychotropic agents or combinations that have shown to be effective for bipolar depression (supported by at least 1 randomized controlled trial) without destabilizing mood include quetiapine, olanzapine, olanzapine-fluoxetine combination, lamotrigine, and lithium plus lamotrigine. Those with some—but less robustly demonstrated—antidepressant action include lithium, divalproex, and carbamazepine. Other than quetiapine and olanzapine, second-generation antipsychotics have not demonstrated antidepressant effects in bipolar depression.

In general, optimize therapy with 1 or more mood stabilizers with antidepressant properties before deciding it is necessary to add antidepressants.

Step 3: Use antidepressants in suitable patients. For patients with no risk factors for mood destabilization from antidepressants (Table 3), these drugs may be worth incorporating, keeping in mind the following guiding principles:

• In patients with bipolar I depression, it is preferable to add an antidepressant to an antimanic mood stabilizer (ie, lithium, divalproex, carbamazepine, or an antipsychotic) rather than prescribing antidepressant monotherapy. There is greater diversity of opinion about the safety of antidepressant monotherapy for bipolar II depression.
• Consider using antidepressants that have at least 1 positive randomized controlled trial in bipolar disorder and low risk for mood destabilization (bupropion,^12,14 sertraline,¹⁴ fluoxetine,^4,5 tranylcypromine,^3,28 or venlafaxine in bipolar II depression²⁰) before using those with reported increased risk for inducing mania or hypomania (TCAs^1,2 or venlafaxine in bipolar I depression¹⁴), multiple negative controlled trials (paroxetine^12,13), or no controlled data in bipolar depression (citalopram, escitalopram, fluvoxamine, mirtazapine, duloxetine, desvenlafaxine, nefazodone, and selegiline transdermal). Combinations of antidepressants have not been adequately studied in bipolar depression.

• The optimal duration of antidepressant therapy is unknown. However, longer-term treatment may be worthwhile in patients who show robust acute antidepressant response and experience infrequent mania or hypomania. Long-term antidepressant use is less compelling in patients with a poor initial response²⁹ or rapid cycling.³⁰ Abrupt antidepressant cessation also may induce mania, potentially by disrupting homeostasis.³¹ In the absence of rapid cycling, manic/hypomanic features, or worsening suicidal features, and in the presence of an unequivocal acute response and a greater predisposition to depression than mania, it is reasonable to continue an antidepressant indefinitely until new signs of mania or hypomania emerge.
• Emerging signs of mania or hypomania should signal the need to discontinue the antidepressant. Dosage reductions alone may not diminish emerging manic or hypomanic symptoms, and “counterbalancing” maneuvers (ie, adding antimanic agents while continuing an antidepressant) may not effectively stabilize mood.

Step 4: Consider novel strategies. In the absence of a response to the strategy outlined above—particularly among poor candidates for continued antidepressant therapy—other novel strategies have support from at least 1 randomized controlled trial, including pramipexole,^32,33 modafinil,³⁴ riluzole,³⁵ and n-acetyl cysteine.³⁶ Other interventions worth considering include:

• adjunctive thyroid hormone
• cognitive therapy
• light therapy (if a seasonal component is evident)
• electroconvulsive therapy.

Related resources

• Goldberg JF. Treating depression in bipolar disorder. http://thedoctorschannel.com/video/3077.html.
• Goldberg JF. Pharmacologic treatment of acute mania.http://thedoctorschannel.com/video/3032.html.

Drug brand names

• Atomoxetine • Strattera
• Bupropion • Wellbutrin
• Carbamazepine • Tegretol, Equetro
• Citalopram • Celexa
• Desipramine • Norpramin
• Desvenlafaxine • Pristiq
• Divalproex • Depakote, Depakene
• Duloxetine • Cymbalta
• Escitalopram • Lexapro
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Imipramine • Tofranil
• Isocarboxazid • Marplan
• Lamotrigine • Lamictal
• Lithium • Lithobid, Eskalith
• Milnacipran • Ixel, Savella
• Mirtazapine • Remeron
• Moclobemide • Aurorix, Manerix
• Modafinil • Provigil
• Nefazodone • Serzone
• Olanzapine • Zyprexa
• Olanzapine-fluoxetine • Symbyax
• Paroxetine • Paxil
• Phenelzine • Nardil
• Pramipexole • Mirapex
• Quetiapine • Seroquel
• Riluzole • Rilutek
• Selegiline transdermal • EMSAM
• Sertraline • Zoloft
• Tranylcypromine • Parnate
• Venlafaxine • Effexor

Disclosures

Dr. Goldberg is a consultant to Eli Lilly and Company and a speaker for AstraZeneca, Eli Lilly and Company, GlaxoSmithKline, Merck, and Pfizer Inc., and has received speaking honoraria from Janssen-Cilag.

Dr. I, a 48-year-old university professor, is brought to the ER by her husband because she has developed an irrational fear of being chased by Nazis. The fears have become increasingly bizarre, her husband reports. She believes her Nazi persecutors are bandaging their arms and using wheelchairs to pretend to be disabled. When out with her husband, Dr. I points to people in wheelchairs, convinced they are after her, will kill her, and are incensed because she left Germany—her country of birth. Her hus­band brought her to the ER when she started to hear her persecutors addressing her in German at night.

Psychoses of unknown cause usually begin in late ado­lescence or early adulthood. Less frequently the onset occurs in later adulthood (age ≥40). Late-onset psycho­sis is much more prevalent in women than in men for reasons that are imperfectly understood.

When you are evaluating a midlife woman with first onset of psychosis, don’t assume an illness of unknown cause (bipolar disorder or schizophrenia) until after you have done a comprehensive search for triggers of her psychotic symptoms. After age 40, women are more likely than men to develop psychosis because of gender-specific medical and psychological precipitants.

Predisposing factors for psychosis
Psychosis is an emergent quality of structural and chemical changes in the brain. As such, it can be ex­pected to surface during:
   • brain reorganization or transition (adolescence, senescence, brain trauma, stroke, starvation, inflammation, or brain tumor)
   • change in brain chemistry (flux in go­nadal, thyroid, or adrenal hormone levels; electrolyte imbalance; fever; exposure to chemical substances; immune response).

Psychological stress impacting the brain via stress hormones also can predispose a person to psychosis.

Because some individuals are more prone than others to develop psycho­sis during brain alteration, chemical and structural changes in the brain are as­sumed to interact with genetic propensi­ties to influence gene expression. Once a psychotic event has occurred, it is thought to sensitize the brain so that subsequent events emerge more readily.¹

Schizophrenia—though not the only ill­ness in which psychosis plays a role—is a prototype for psychotic illness, and sev­eral reported sex differences in this dis­order are worth noting.² The incidence of schizophrenia is approximately the same in both sexes, but women show a later age of onset—a paradox in that the brain de­velops at a faster pace in females and theo­retically should reach the threshold for the first appearance of schizophrenia earlier. Women also require lower doses of anti­psychotic medication to recover from an acute psychotic episode and to maintain remission, at least before menopause.^3,4 Both of these differences can be explained as an effect of estrogen on a) gene expres­sion⁵ and b) liver enzymes that metabolize antipsychotics.⁶

The estrogen hypothesis. Women show a tendency toward premenstrual and post­partum exacerbation of symptoms when estrogen levels are relatively low. These clinical observations, confirmed by some but not all studies, have led to the hypoth­esis that estrogens are neuroprotective⁷ and also protect against psychosis.⁸

Estrogen withdrawal in specific brain cells may release a cascade of events that over time can increase the severity of psy­chotic and cognitive symptoms. The reason for suspecting such effects is based on what we know about estrogenic effects on neurotransmitter, cognitive, and stress-induction pathways, and—more fundamentally—on neuronal growth and atrophy.

According to the estrogen hypothesis, women are—to some degree—protected against schizophrenia by their relatively high gonadal estrogen production between puberty and and menopause. Women lose this protection with the onset of perimeno­pausal estrogen fluctuation and decline, accounting for their second peak of illness onset after age 45.

Epidemiologic studies showing a second peak of schizophrenia onset in women (but not men) around the age of menopause sup­port this hypothesis.^9,10 Longitudinal out­comes for schizophrenia—which are better in women than in men during late adolescence or early adulthood11—gradually even out after the first 15 years of illness, suggest­ing that women’s advantage is lost at a time approximating menopause (Box 1).

The question, then, becomes: Is it only because of estrogen loss after age 40 that women become more prone to develop a psychotic illness? Other differences be­tween the sexes that may play roles include immune function, low iron stores, sleep suf­ficiency, thyroid function, exposure to toxic substances (including therapeutic drugs), societal pressures to be slim while aging (Table), and the experience of stress.¹²

CASE CONTINUED
Exhausted and confused
Dr. I is a well-groomed, handsome woman, but she hardly speaks when interviewed, looking frightened and somewhat bewildered. She has never had a mental health problem, nor has anyone in her family. She agrees to stay in the hospital but is not sure why. She has slept no more than 1 or 2 hours in the last several days.

Her early history is unremarkable. She did well in school. After earning a PhD at the Univer­sity of Leipzig, she and her husband immigrated to Canada. Both are university professors. They never decided not to have children, but children hadn’t come. Her menstrual periods stopped 2 years before admission. The question about children is the only 1 that elicits emotion in Dr. I. When I ask about it, tears come to her eyes as she shakes her head.

Her husband reports that she has not been eating well and has, in the last year, started to drink more alcohol than usual—3 to 4 drinks of whiskey a night. She does not smoke cigarettes, and her health generally is good. She uses no medications. Her hus­band describes their marital relationship as very close, although it has become strained in recent weeks because of her unreasonable fears. He admits that their work is always stressful; competition is fierce, with more and more deadlines and less and less leisure time. The couple has few friends and no hobbies.

Late-onset psychosis symptoms
In late-onset psychosis (after age 45), men appear to suffer substantially milder symp­toms and spend less time hospitalized than women.¹³ Women with late-onset schizophrenia have more severe positive symptoms than men and fewer negative symptoms.^14,15 Overall, patients with late-onset schizophrenia have a lower prevalence of looseness of associations and negative symptoms than those with earlier onset.^16,17

In addition, individuals with schizo­phrenia who become ill in middle age have been reported to:
   • show better neuropsychological per­formance (particularly in learning and ab­straction/cognitive flexibility) than those with early onset
   • possibly have larger thalamic volumes
   • respond to lower antipsychotic doses.¹⁸

Auditory and visual hallucinations frequently are observed in patients with comorbid late-onset schizophrenia and auditory and visual impairment.¹⁶ Palmer et al¹⁸ reported no difference in family his­tory of schizophrenia between early and late onset, but this is controversial. Con­vert et al¹⁶ note that most studies reveal a lower lifetime risk of schizophrenia in first-degree relatives of patients with late-onset than early-onset schizophrenia.

CASE CONTINUED
Medical workup
Dr. I’s physical exam is unremarkable. Her thy­roid is not enlarged; there are no breast lumps. On mental status exam, her mood is flat. She is preoccupied with fears of the Nazis. Routine blood tests show slight anemia; fasting glu­cose levels are within normal range.

I give Dr. I zopiclone, 7.5 mg, to help her sleep. The next day she keeps to herself, eats very little, and appears disinterested in her surroundings. Nursing staff report that she often seems frightened. Dr. I asks to use the ward phone to call Germany but is told that she cannot make long distance calls from that phone. This seems to disturb her.

Differential diagnosis
Sensory impairment, substance abuse, and metabolic changes have been implicated in the appearance of psychosis in later life. More specific to women than men, howev­er, are medical and psychiatric precipitants. These include autoimmune disease (and its treatment) and psychiatric disorders, as well as thyroid dysfunction, self-induced starvation (anorexia nervosa) and diet aids, substance use and abuse, insomnia, and iron deficiency (Table).

Autoimmune disease and treatment. Nearly 80% of patients with autoimmune disease are women, and these disorders (as well as their treatment) can manifest as psychosis. Corticosteroids have a well-documented history of triggering psy­chotic symptoms, which are twice as likely in women than in men. The incidence of severe psychosis while taking oral predni­sone ranges from 1.6% to 50% and averages 5.7%. The average daily dose of corticoste­roids for patients who develop psychosis is 59.5 mg/d.

Corticosteroid creams absorbed through skin as well as inhaled and intranasal cor­ticosteroids in their more potent formula­tions can have systemic effects, including psychosis. Nonsteroidal anti-inflammatory drugs such as ibuprofen also can trigger psychosis.¹⁹

Psychiatric disorders. Posttraumatic stress disorder with psychotic symptoms may overlap with categories such as psy­chogenic psychoses, hysterical psychoses, nonaffective remitting psychoses, acute brief psychoses, reactive psychoses, acute and transient psychoses, and bouffées dé­lirantes (in France, the name for transient psychotic reactions).²⁰ Consider these female-predominant conditions in the differential diagnosis, along with micro­psychotic episodes in borderline personal­ity disorder, in which the predominance of women is 3:1.

Medical treatment for depression and anxiety also can lead to psychotic symp­toms through individual susceptibility to the action of specific drugs or through withdrawal effects.

Clinical assessment
Question all women presenting with psy­chosis about eating habits and diet pills, and check for hypokalemia and hypocal­cemia to rule out starvation effects and reactions to stimulants. Also ask about in­halants, and examine for anemia and thy­roid dysfunction. Consider all medications as having the potential to trigger psychotic symptoms.

A family history of illness is important, with a focus on autoimmune disorder and its treatment. A thorough psychiatric history is crucial and needs to include assess­ment of sleep, mood, and relationships with attachment figures. Do not assume ill­nesses of unknown cause (bipolar disorder or schizophrenia) until after a comprehen­sive search for precipitants of psychotic symptoms.

CASE CONTINUED
Guilty feelings
To address her delusions, I start Dr. I on ris­peridone, 2 mg at bedtime. She goes home for the weekend, and her husband reports that she slept throughout the visit. When she returns, she spends a lot of time in bed but is more communicative.

When I ask Dr. I whether she has called Germany, she says she called her recently widowed father. Dr. I begins to cry when talk­ing of her mother, and tells the nurse she feels guilty for not visiting for the last few years. When her mother died 6 months ago, Dr. I had not seen her in 4 years.

Her fears remit with risperidone, main­tained at 2 mg/d, but Dr. I remains depressed and responds slowly to treatment with cital­opram, 20 mg/d, and supportive therapy. Her final diagnosis is mood disorder with psy­chotic features.

Treatment
When treating women with late-onset psy­chosis, remove all potential triggers and address underlying illness. Cognitive ther­apy targeting specific symptoms is useful; antipsychotics probably will be necessary. Age-related physiologic changes make older persons more sensitive to the thera­peutic and toxic effects of antipsychotics.

Estrogen therapy? Women suffering from schizophrenia show significantly lower es­trogen levels than the general population of women, and they experience first-onset or recurrence of a psychotic episode signif­icantly more often in low estrogen phases of the cycle. Estrogens have therefore been postulated to constitute a protective factor against psychosis, which means perimeno­pause is an at-risk period.²¹ Although evi­dence is limited, preliminary studies have found beneficial effects from short-term, off-label use of estrogen therapy in women with psychotic illness (Box 2).

Because continuous use of estrogen plus progestin has been associated with an in­creased risk of adverse effects,²² off-label use of selective estrogen receptor modula­tors (SERMs) also is being investigated in women with schizophrenia. SERMs act as tissue-specific estrogen agonists and an­tagonists because they can either inhibit or enhance estrogen-induced activation of estrogen response element-containing genes.²³

Wong et al²⁴ used a crossover design to compare the SERM raloxifene with place­bo as adjunctive treatment for 6 postmeno­pausal women with schizophrenia. Each woman received 8 weeks of raloxifene, 60 mg/d, and 8 weeks of placebo. Three be­gan with placebo and 3 with raloxifene.

Verbal memory was measured weekly with the California Verbal Learning Test, using 5 memory trials, free and cued short-delay recall, and long-delay recall. At baseline, the participants had lower scores than older adults in the general popula­tion. Eight weeks of placebo improved scores somewhat, suggesting a practice effect. Eight weeks of raloxifene improved cognitive scores to a level similar to that of schizophrenia-free subjects. After 16 weeks, however, cognitive scores in the 2 groups were indistinguishable.

At present I do not recommend estrogen for women with late-onset schizophrenia because the risk is too high and raloxifene does not enter the brain sufficiently to be a valuable cognitive enhancer. Novel SERMs with more specific efficacy for improving cognitive function may prove useful in the future,²⁵ however, as may phytoestro­gens. Adjunctive hormone modulation is a promising area of gender-specific treat­ment for serious mental illness.²⁶

CASE CONCLUSION
Gradually improving
Dr. I’s depression was triggered by her moth­er’s death and regrets about not visiting and not being a mother. The content of her de­lusions was related to her guilt about not having returned to Germany; the delusions were probably triggered by depression, al­cohol intake, her relative hypoestrogenic state, stress at work, lack of social supports, and dependence on her husband.

Over the next few years, Dr. I is maintained on a low dose of risperidone (reduced from 2 mg/d to 1 mg/d) and citalopram (reduced from 20 mg/d to 10 mg/d). She becomes increas­ingly engaged in supportive dynamic therapy, and her symptoms gradually improve.

BOTTOM LINE
Psychosis onset in midlife is mostly a female phenomenon because a perimenopausal estrogen decline increases women’s susceptibility. Seek specific triggers such as medical illness or response to a drug before assuming an illness of unknown cause such as bipolar disorder or schizophrenia. Cognitive therapy targeting specific symptoms is useful; antipsychotics probably will be necessary.

Related Resources
• Women and psychosis: A guide for women and their families. Centre for Addiction and Mental Health. University of Toronto. www.camh.net/About_Addiction_Mental_ Health/Mental_Health_Information/Women_Psychosis.
• Seeman MV. Women and psychosis. www.medscape.com/ viewarticle/408912.
• Chattopadhyay S. Estrogen and schizophrenia: Any link? The Internet Journal of Mental Health. 2004;2(1). www.ispub. com/journal/the_internet_journal_of_mental_health.html.

Drug Brand Names
Citalopram • Celexa                         Prednisone • Deltasone,
Estradiol • Estrace,                                    Orasone, others
   Estrofem, others                           Raloxifene • Evista
Estradiol transdermal •                     Risperidone • Risperdal
   Estraderm , Climara, others
Methylphenidate • Concerta,
   Ritalin, others

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

Dr. I, a 48-year-old university professor, is brought to the ER by her husband because she has developed an irrational fear of being chased by Nazis. The fears have become increasingly bizarre, her husband reports. She believes her Nazi persecutors are bandaging their arms and using wheelchairs to pretend to be disabled. When out with her husband, Dr. I points to people in wheelchairs, convinced they are after her, will kill her, and are incensed because she left Germany—her country of birth. Her hus­band brought her to the ER when she started to hear her persecutors addressing her in German at night.

Psychoses of unknown cause usually begin in late ado­lescence or early adulthood. Less frequently the onset occurs in later adulthood (age ≥40). Late-onset psycho­sis is much more prevalent in women than in men for reasons that are imperfectly understood.

When you are evaluating a midlife woman with first onset of psychosis, don’t assume an illness of unknown cause (bipolar disorder or schizophrenia) until after you have done a comprehensive search for triggers of her psychotic symptoms. After age 40, women are more likely than men to develop psychosis because of gender-specific medical and psychological precipitants.

Predisposing factors for psychosis
Psychosis is an emergent quality of structural and chemical changes in the brain. As such, it can be ex­pected to surface during:
   • brain reorganization or transition (adolescence, senescence, brain trauma, stroke, starvation, inflammation, or brain tumor)
   • change in brain chemistry (flux in go­nadal, thyroid, or adrenal hormone levels; electrolyte imbalance; fever; exposure to chemical substances; immune response).

Psychological stress impacting the brain via stress hormones also can predispose a person to psychosis.

Because some individuals are more prone than others to develop psycho­sis during brain alteration, chemical and structural changes in the brain are as­sumed to interact with genetic propensi­ties to influence gene expression. Once a psychotic event has occurred, it is thought to sensitize the brain so that subsequent events emerge more readily.¹

Schizophrenia—though not the only ill­ness in which psychosis plays a role—is a prototype for psychotic illness, and sev­eral reported sex differences in this dis­order are worth noting.² The incidence of schizophrenia is approximately the same in both sexes, but women show a later age of onset—a paradox in that the brain de­velops at a faster pace in females and theo­retically should reach the threshold for the first appearance of schizophrenia earlier. Women also require lower doses of anti­psychotic medication to recover from an acute psychotic episode and to maintain remission, at least before menopause.^3,4 Both of these differences can be explained as an effect of estrogen on a) gene expres­sion⁵ and b) liver enzymes that metabolize antipsychotics.⁶

The estrogen hypothesis. Women show a tendency toward premenstrual and post­partum exacerbation of symptoms when estrogen levels are relatively low. These clinical observations, confirmed by some but not all studies, have led to the hypoth­esis that estrogens are neuroprotective⁷ and also protect against psychosis.⁸

Estrogen withdrawal in specific brain cells may release a cascade of events that over time can increase the severity of psy­chotic and cognitive symptoms. The reason for suspecting such effects is based on what we know about estrogenic effects on neurotransmitter, cognitive, and stress-induction pathways, and—more fundamentally—on neuronal growth and atrophy.

According to the estrogen hypothesis, women are—to some degree—protected against schizophrenia by their relatively high gonadal estrogen production between puberty and and menopause. Women lose this protection with the onset of perimeno­pausal estrogen fluctuation and decline, accounting for their second peak of illness onset after age 45.

Epidemiologic studies showing a second peak of schizophrenia onset in women (but not men) around the age of menopause sup­port this hypothesis.^9,10 Longitudinal out­comes for schizophrenia—which are better in women than in men during late adolescence or early adulthood11—gradually even out after the first 15 years of illness, suggest­ing that women’s advantage is lost at a time approximating menopause (Box 1).

The question, then, becomes: Is it only because of estrogen loss after age 40 that women become more prone to develop a psychotic illness? Other differences be­tween the sexes that may play roles include immune function, low iron stores, sleep suf­ficiency, thyroid function, exposure to toxic substances (including therapeutic drugs), societal pressures to be slim while aging (Table), and the experience of stress.¹²

CASE CONTINUED
Exhausted and confused
Dr. I is a well-groomed, handsome woman, but she hardly speaks when interviewed, looking frightened and somewhat bewildered. She has never had a mental health problem, nor has anyone in her family. She agrees to stay in the hospital but is not sure why. She has slept no more than 1 or 2 hours in the last several days.

Her early history is unremarkable. She did well in school. After earning a PhD at the Univer­sity of Leipzig, she and her husband immigrated to Canada. Both are university professors. They never decided not to have children, but children hadn’t come. Her menstrual periods stopped 2 years before admission. The question about children is the only 1 that elicits emotion in Dr. I. When I ask about it, tears come to her eyes as she shakes her head.

Her husband reports that she has not been eating well and has, in the last year, started to drink more alcohol than usual—3 to 4 drinks of whiskey a night. She does not smoke cigarettes, and her health generally is good. She uses no medications. Her hus­band describes their marital relationship as very close, although it has become strained in recent weeks because of her unreasonable fears. He admits that their work is always stressful; competition is fierce, with more and more deadlines and less and less leisure time. The couple has few friends and no hobbies.

Late-onset psychosis symptoms
In late-onset psychosis (after age 45), men appear to suffer substantially milder symp­toms and spend less time hospitalized than women.¹³ Women with late-onset schizophrenia have more severe positive symptoms than men and fewer negative symptoms.^14,15 Overall, patients with late-onset schizophrenia have a lower prevalence of looseness of associations and negative symptoms than those with earlier onset.^16,17

In addition, individuals with schizo­phrenia who become ill in middle age have been reported to:
   • show better neuropsychological per­formance (particularly in learning and ab­straction/cognitive flexibility) than those with early onset
   • possibly have larger thalamic volumes
   • respond to lower antipsychotic doses.¹⁸

Auditory and visual hallucinations frequently are observed in patients with comorbid late-onset schizophrenia and auditory and visual impairment.¹⁶ Palmer et al¹⁸ reported no difference in family his­tory of schizophrenia between early and late onset, but this is controversial. Con­vert et al¹⁶ note that most studies reveal a lower lifetime risk of schizophrenia in first-degree relatives of patients with late-onset than early-onset schizophrenia.

CASE CONTINUED
Medical workup
Dr. I’s physical exam is unremarkable. Her thy­roid is not enlarged; there are no breast lumps. On mental status exam, her mood is flat. She is preoccupied with fears of the Nazis. Routine blood tests show slight anemia; fasting glu­cose levels are within normal range.

I give Dr. I zopiclone, 7.5 mg, to help her sleep. The next day she keeps to herself, eats very little, and appears disinterested in her surroundings. Nursing staff report that she often seems frightened. Dr. I asks to use the ward phone to call Germany but is told that she cannot make long distance calls from that phone. This seems to disturb her.

Differential diagnosis
Sensory impairment, substance abuse, and metabolic changes have been implicated in the appearance of psychosis in later life. More specific to women than men, howev­er, are medical and psychiatric precipitants. These include autoimmune disease (and its treatment) and psychiatric disorders, as well as thyroid dysfunction, self-induced starvation (anorexia nervosa) and diet aids, substance use and abuse, insomnia, and iron deficiency (Table).

Autoimmune disease and treatment. Nearly 80% of patients with autoimmune disease are women, and these disorders (as well as their treatment) can manifest as psychosis. Corticosteroids have a well-documented history of triggering psy­chotic symptoms, which are twice as likely in women than in men. The incidence of severe psychosis while taking oral predni­sone ranges from 1.6% to 50% and averages 5.7%. The average daily dose of corticoste­roids for patients who develop psychosis is 59.5 mg/d.

Corticosteroid creams absorbed through skin as well as inhaled and intranasal cor­ticosteroids in their more potent formula­tions can have systemic effects, including psychosis. Nonsteroidal anti-inflammatory drugs such as ibuprofen also can trigger psychosis.¹⁹

Psychiatric disorders. Posttraumatic stress disorder with psychotic symptoms may overlap with categories such as psy­chogenic psychoses, hysterical psychoses, nonaffective remitting psychoses, acute brief psychoses, reactive psychoses, acute and transient psychoses, and bouffées dé­lirantes (in France, the name for transient psychotic reactions).²⁰ Consider these female-predominant conditions in the differential diagnosis, along with micro­psychotic episodes in borderline personal­ity disorder, in which the predominance of women is 3:1.

Medical treatment for depression and anxiety also can lead to psychotic symp­toms through individual susceptibility to the action of specific drugs or through withdrawal effects.

Clinical assessment
Question all women presenting with psy­chosis about eating habits and diet pills, and check for hypokalemia and hypocal­cemia to rule out starvation effects and reactions to stimulants. Also ask about in­halants, and examine for anemia and thy­roid dysfunction. Consider all medications as having the potential to trigger psychotic symptoms.

A family history of illness is important, with a focus on autoimmune disorder and its treatment. A thorough psychiatric history is crucial and needs to include assess­ment of sleep, mood, and relationships with attachment figures. Do not assume ill­nesses of unknown cause (bipolar disorder or schizophrenia) until after a comprehen­sive search for precipitants of psychotic symptoms.

CASE CONTINUED
Guilty feelings
To address her delusions, I start Dr. I on ris­peridone, 2 mg at bedtime. She goes home for the weekend, and her husband reports that she slept throughout the visit. When she returns, she spends a lot of time in bed but is more communicative.

When I ask Dr. I whether she has called Germany, she says she called her recently widowed father. Dr. I begins to cry when talk­ing of her mother, and tells the nurse she feels guilty for not visiting for the last few years. When her mother died 6 months ago, Dr. I had not seen her in 4 years.

Her fears remit with risperidone, main­tained at 2 mg/d, but Dr. I remains depressed and responds slowly to treatment with cital­opram, 20 mg/d, and supportive therapy. Her final diagnosis is mood disorder with psy­chotic features.

Treatment
When treating women with late-onset psy­chosis, remove all potential triggers and address underlying illness. Cognitive ther­apy targeting specific symptoms is useful; antipsychotics probably will be necessary. Age-related physiologic changes make older persons more sensitive to the thera­peutic and toxic effects of antipsychotics.

Estrogen therapy? Women suffering from schizophrenia show significantly lower es­trogen levels than the general population of women, and they experience first-onset or recurrence of a psychotic episode signif­icantly more often in low estrogen phases of the cycle. Estrogens have therefore been postulated to constitute a protective factor against psychosis, which means perimeno­pause is an at-risk period.²¹ Although evi­dence is limited, preliminary studies have found beneficial effects from short-term, off-label use of estrogen therapy in women with psychotic illness (Box 2).

Because continuous use of estrogen plus progestin has been associated with an in­creased risk of adverse effects,²² off-label use of selective estrogen receptor modula­tors (SERMs) also is being investigated in women with schizophrenia. SERMs act as tissue-specific estrogen agonists and an­tagonists because they can either inhibit or enhance estrogen-induced activation of estrogen response element-containing genes.²³

Wong et al²⁴ used a crossover design to compare the SERM raloxifene with place­bo as adjunctive treatment for 6 postmeno­pausal women with schizophrenia. Each woman received 8 weeks of raloxifene, 60 mg/d, and 8 weeks of placebo. Three be­gan with placebo and 3 with raloxifene.

Verbal memory was measured weekly with the California Verbal Learning Test, using 5 memory trials, free and cued short-delay recall, and long-delay recall. At baseline, the participants had lower scores than older adults in the general popula­tion. Eight weeks of placebo improved scores somewhat, suggesting a practice effect. Eight weeks of raloxifene improved cognitive scores to a level similar to that of schizophrenia-free subjects. After 16 weeks, however, cognitive scores in the 2 groups were indistinguishable.

At present I do not recommend estrogen for women with late-onset schizophrenia because the risk is too high and raloxifene does not enter the brain sufficiently to be a valuable cognitive enhancer. Novel SERMs with more specific efficacy for improving cognitive function may prove useful in the future,²⁵ however, as may phytoestro­gens. Adjunctive hormone modulation is a promising area of gender-specific treat­ment for serious mental illness.²⁶

CASE CONCLUSION
Gradually improving
Dr. I’s depression was triggered by her moth­er’s death and regrets about not visiting and not being a mother. The content of her de­lusions was related to her guilt about not having returned to Germany; the delusions were probably triggered by depression, al­cohol intake, her relative hypoestrogenic state, stress at work, lack of social supports, and dependence on her husband.

Over the next few years, Dr. I is maintained on a low dose of risperidone (reduced from 2 mg/d to 1 mg/d) and citalopram (reduced from 20 mg/d to 10 mg/d). She becomes increas­ingly engaged in supportive dynamic therapy, and her symptoms gradually improve.

BOTTOM LINE
Psychosis onset in midlife is mostly a female phenomenon because a perimenopausal estrogen decline increases women’s susceptibility. Seek specific triggers such as medical illness or response to a drug before assuming an illness of unknown cause such as bipolar disorder or schizophrenia. Cognitive therapy targeting specific symptoms is useful; antipsychotics probably will be necessary.

Related Resources
• Women and psychosis: A guide for women and their families. Centre for Addiction and Mental Health. University of Toronto. www.camh.net/About_Addiction_Mental_ Health/Mental_Health_Information/Women_Psychosis.
• Seeman MV. Women and psychosis. www.medscape.com/ viewarticle/408912.
• Chattopadhyay S. Estrogen and schizophrenia: Any link? The Internet Journal of Mental Health. 2004;2(1). www.ispub. com/journal/the_internet_journal_of_mental_health.html.

Drug Brand Names
Citalopram • Celexa                         Prednisone • Deltasone,
Estradiol • Estrace,                                    Orasone, others
   Estrofem, others                           Raloxifene • Evista
Estradiol transdermal •                     Risperidone • Risperdal
   Estraderm , Climara, others
Methylphenidate • Concerta,
   Ritalin, others

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

Dr. I, a 48-year-old university professor, is brought to the ER by her husband because she has developed an irrational fear of being chased by Nazis. The fears have become increasingly bizarre, her husband reports. She believes her Nazi persecutors are bandaging their arms and using wheelchairs to pretend to be disabled. When out with her husband, Dr. I points to people in wheelchairs, convinced they are after her, will kill her, and are incensed because she left Germany—her country of birth. Her hus­band brought her to the ER when she started to hear her persecutors addressing her in German at night.

Psychoses of unknown cause usually begin in late ado­lescence or early adulthood. Less frequently the onset occurs in later adulthood (age ≥40). Late-onset psycho­sis is much more prevalent in women than in men for reasons that are imperfectly understood.

When you are evaluating a midlife woman with first onset of psychosis, don’t assume an illness of unknown cause (bipolar disorder or schizophrenia) until after you have done a comprehensive search for triggers of her psychotic symptoms. After age 40, women are more likely than men to develop psychosis because of gender-specific medical and psychological precipitants.

Predisposing factors for psychosis
Psychosis is an emergent quality of structural and chemical changes in the brain. As such, it can be ex­pected to surface during:
   • brain reorganization or transition (adolescence, senescence, brain trauma, stroke, starvation, inflammation, or brain tumor)
   • change in brain chemistry (flux in go­nadal, thyroid, or adrenal hormone levels; electrolyte imbalance; fever; exposure to chemical substances; immune response).

Psychological stress impacting the brain via stress hormones also can predispose a person to psychosis.

Because some individuals are more prone than others to develop psycho­sis during brain alteration, chemical and structural changes in the brain are as­sumed to interact with genetic propensi­ties to influence gene expression. Once a psychotic event has occurred, it is thought to sensitize the brain so that subsequent events emerge more readily.¹

Schizophrenia—though not the only ill­ness in which psychosis plays a role—is a prototype for psychotic illness, and sev­eral reported sex differences in this dis­order are worth noting.² The incidence of schizophrenia is approximately the same in both sexes, but women show a later age of onset—a paradox in that the brain de­velops at a faster pace in females and theo­retically should reach the threshold for the first appearance of schizophrenia earlier. Women also require lower doses of anti­psychotic medication to recover from an acute psychotic episode and to maintain remission, at least before menopause.^3,4 Both of these differences can be explained as an effect of estrogen on a) gene expres­sion⁵ and b) liver enzymes that metabolize antipsychotics.⁶

The estrogen hypothesis. Women show a tendency toward premenstrual and post­partum exacerbation of symptoms when estrogen levels are relatively low. These clinical observations, confirmed by some but not all studies, have led to the hypoth­esis that estrogens are neuroprotective⁷ and also protect against psychosis.⁸

Estrogen withdrawal in specific brain cells may release a cascade of events that over time can increase the severity of psy­chotic and cognitive symptoms. The reason for suspecting such effects is based on what we know about estrogenic effects on neurotransmitter, cognitive, and stress-induction pathways, and—more fundamentally—on neuronal growth and atrophy.

According to the estrogen hypothesis, women are—to some degree—protected against schizophrenia by their relatively high gonadal estrogen production between puberty and and menopause. Women lose this protection with the onset of perimeno­pausal estrogen fluctuation and decline, accounting for their second peak of illness onset after age 45.

Epidemiologic studies showing a second peak of schizophrenia onset in women (but not men) around the age of menopause sup­port this hypothesis.^9,10 Longitudinal out­comes for schizophrenia—which are better in women than in men during late adolescence or early adulthood11—gradually even out after the first 15 years of illness, suggest­ing that women’s advantage is lost at a time approximating menopause (Box 1).

The question, then, becomes: Is it only because of estrogen loss after age 40 that women become more prone to develop a psychotic illness? Other differences be­tween the sexes that may play roles include immune function, low iron stores, sleep suf­ficiency, thyroid function, exposure to toxic substances (including therapeutic drugs), societal pressures to be slim while aging (Table), and the experience of stress.¹²

CASE CONTINUED
Exhausted and confused
Dr. I is a well-groomed, handsome woman, but she hardly speaks when interviewed, looking frightened and somewhat bewildered. She has never had a mental health problem, nor has anyone in her family. She agrees to stay in the hospital but is not sure why. She has slept no more than 1 or 2 hours in the last several days.

Her early history is unremarkable. She did well in school. After earning a PhD at the Univer­sity of Leipzig, she and her husband immigrated to Canada. Both are university professors. They never decided not to have children, but children hadn’t come. Her menstrual periods stopped 2 years before admission. The question about children is the only 1 that elicits emotion in Dr. I. When I ask about it, tears come to her eyes as she shakes her head.

Her husband reports that she has not been eating well and has, in the last year, started to drink more alcohol than usual—3 to 4 drinks of whiskey a night. She does not smoke cigarettes, and her health generally is good. She uses no medications. Her hus­band describes their marital relationship as very close, although it has become strained in recent weeks because of her unreasonable fears. He admits that their work is always stressful; competition is fierce, with more and more deadlines and less and less leisure time. The couple has few friends and no hobbies.

Late-onset psychosis symptoms
In late-onset psychosis (after age 45), men appear to suffer substantially milder symp­toms and spend less time hospitalized than women.¹³ Women with late-onset schizophrenia have more severe positive symptoms than men and fewer negative symptoms.^14,15 Overall, patients with late-onset schizophrenia have a lower prevalence of looseness of associations and negative symptoms than those with earlier onset.^16,17

In addition, individuals with schizo­phrenia who become ill in middle age have been reported to:
   • show better neuropsychological per­formance (particularly in learning and ab­straction/cognitive flexibility) than those with early onset
   • possibly have larger thalamic volumes
   • respond to lower antipsychotic doses.¹⁸

Auditory and visual hallucinations frequently are observed in patients with comorbid late-onset schizophrenia and auditory and visual impairment.¹⁶ Palmer et al¹⁸ reported no difference in family his­tory of schizophrenia between early and late onset, but this is controversial. Con­vert et al¹⁶ note that most studies reveal a lower lifetime risk of schizophrenia in first-degree relatives of patients with late-onset than early-onset schizophrenia.

CASE CONTINUED
Medical workup
Dr. I’s physical exam is unremarkable. Her thy­roid is not enlarged; there are no breast lumps. On mental status exam, her mood is flat. She is preoccupied with fears of the Nazis. Routine blood tests show slight anemia; fasting glu­cose levels are within normal range.

I give Dr. I zopiclone, 7.5 mg, to help her sleep. The next day she keeps to herself, eats very little, and appears disinterested in her surroundings. Nursing staff report that she often seems frightened. Dr. I asks to use the ward phone to call Germany but is told that she cannot make long distance calls from that phone. This seems to disturb her.

Differential diagnosis
Sensory impairment, substance abuse, and metabolic changes have been implicated in the appearance of psychosis in later life. More specific to women than men, howev­er, are medical and psychiatric precipitants. These include autoimmune disease (and its treatment) and psychiatric disorders, as well as thyroid dysfunction, self-induced starvation (anorexia nervosa) and diet aids, substance use and abuse, insomnia, and iron deficiency (Table).

Autoimmune disease and treatment. Nearly 80% of patients with autoimmune disease are women, and these disorders (as well as their treatment) can manifest as psychosis. Corticosteroids have a well-documented history of triggering psy­chotic symptoms, which are twice as likely in women than in men. The incidence of severe psychosis while taking oral predni­sone ranges from 1.6% to 50% and averages 5.7%. The average daily dose of corticoste­roids for patients who develop psychosis is 59.5 mg/d.

Corticosteroid creams absorbed through skin as well as inhaled and intranasal cor­ticosteroids in their more potent formula­tions can have systemic effects, including psychosis. Nonsteroidal anti-inflammatory drugs such as ibuprofen also can trigger psychosis.¹⁹

Psychiatric disorders. Posttraumatic stress disorder with psychotic symptoms may overlap with categories such as psy­chogenic psychoses, hysterical psychoses, nonaffective remitting psychoses, acute brief psychoses, reactive psychoses, acute and transient psychoses, and bouffées dé­lirantes (in France, the name for transient psychotic reactions).²⁰ Consider these female-predominant conditions in the differential diagnosis, along with micro­psychotic episodes in borderline personal­ity disorder, in which the predominance of women is 3:1.

Medical treatment for depression and anxiety also can lead to psychotic symp­toms through individual susceptibility to the action of specific drugs or through withdrawal effects.

Clinical assessment
Question all women presenting with psy­chosis about eating habits and diet pills, and check for hypokalemia and hypocal­cemia to rule out starvation effects and reactions to stimulants. Also ask about in­halants, and examine for anemia and thy­roid dysfunction. Consider all medications as having the potential to trigger psychotic symptoms.

A family history of illness is important, with a focus on autoimmune disorder and its treatment. A thorough psychiatric history is crucial and needs to include assess­ment of sleep, mood, and relationships with attachment figures. Do not assume ill­nesses of unknown cause (bipolar disorder or schizophrenia) until after a comprehen­sive search for precipitants of psychotic symptoms.

CASE CONTINUED
Guilty feelings
To address her delusions, I start Dr. I on ris­peridone, 2 mg at bedtime. She goes home for the weekend, and her husband reports that she slept throughout the visit. When she returns, she spends a lot of time in bed but is more communicative.

When I ask Dr. I whether she has called Germany, she says she called her recently widowed father. Dr. I begins to cry when talk­ing of her mother, and tells the nurse she feels guilty for not visiting for the last few years. When her mother died 6 months ago, Dr. I had not seen her in 4 years.

Her fears remit with risperidone, main­tained at 2 mg/d, but Dr. I remains depressed and responds slowly to treatment with cital­opram, 20 mg/d, and supportive therapy. Her final diagnosis is mood disorder with psy­chotic features.

Treatment
When treating women with late-onset psy­chosis, remove all potential triggers and address underlying illness. Cognitive ther­apy targeting specific symptoms is useful; antipsychotics probably will be necessary. Age-related physiologic changes make older persons more sensitive to the thera­peutic and toxic effects of antipsychotics.

Estrogen therapy? Women suffering from schizophrenia show significantly lower es­trogen levels than the general population of women, and they experience first-onset or recurrence of a psychotic episode signif­icantly more often in low estrogen phases of the cycle. Estrogens have therefore been postulated to constitute a protective factor against psychosis, which means perimeno­pause is an at-risk period.²¹ Although evi­dence is limited, preliminary studies have found beneficial effects from short-term, off-label use of estrogen therapy in women with psychotic illness (Box 2).

Because continuous use of estrogen plus progestin has been associated with an in­creased risk of adverse effects,²² off-label use of selective estrogen receptor modula­tors (SERMs) also is being investigated in women with schizophrenia. SERMs act as tissue-specific estrogen agonists and an­tagonists because they can either inhibit or enhance estrogen-induced activation of estrogen response element-containing genes.²³

Wong et al²⁴ used a crossover design to compare the SERM raloxifene with place­bo as adjunctive treatment for 6 postmeno­pausal women with schizophrenia. Each woman received 8 weeks of raloxifene, 60 mg/d, and 8 weeks of placebo. Three be­gan with placebo and 3 with raloxifene.

Verbal memory was measured weekly with the California Verbal Learning Test, using 5 memory trials, free and cued short-delay recall, and long-delay recall. At baseline, the participants had lower scores than older adults in the general popula­tion. Eight weeks of placebo improved scores somewhat, suggesting a practice effect. Eight weeks of raloxifene improved cognitive scores to a level similar to that of schizophrenia-free subjects. After 16 weeks, however, cognitive scores in the 2 groups were indistinguishable.

At present I do not recommend estrogen for women with late-onset schizophrenia because the risk is too high and raloxifene does not enter the brain sufficiently to be a valuable cognitive enhancer. Novel SERMs with more specific efficacy for improving cognitive function may prove useful in the future,²⁵ however, as may phytoestro­gens. Adjunctive hormone modulation is a promising area of gender-specific treat­ment for serious mental illness.²⁶

CASE CONCLUSION
Gradually improving
Dr. I’s depression was triggered by her moth­er’s death and regrets about not visiting and not being a mother. The content of her de­lusions was related to her guilt about not having returned to Germany; the delusions were probably triggered by depression, al­cohol intake, her relative hypoestrogenic state, stress at work, lack of social supports, and dependence on her husband.

Over the next few years, Dr. I is maintained on a low dose of risperidone (reduced from 2 mg/d to 1 mg/d) and citalopram (reduced from 20 mg/d to 10 mg/d). She becomes increas­ingly engaged in supportive dynamic therapy, and her symptoms gradually improve.

BOTTOM LINE
Psychosis onset in midlife is mostly a female phenomenon because a perimenopausal estrogen decline increases women’s susceptibility. Seek specific triggers such as medical illness or response to a drug before assuming an illness of unknown cause such as bipolar disorder or schizophrenia. Cognitive therapy targeting specific symptoms is useful; antipsychotics probably will be necessary.

Related Resources
• Women and psychosis: A guide for women and their families. Centre for Addiction and Mental Health. University of Toronto. www.camh.net/About_Addiction_Mental_ Health/Mental_Health_Information/Women_Psychosis.
• Seeman MV. Women and psychosis. www.medscape.com/ viewarticle/408912.
• Chattopadhyay S. Estrogen and schizophrenia: Any link? The Internet Journal of Mental Health. 2004;2(1). www.ispub. com/journal/the_internet_journal_of_mental_health.html.

Drug Brand Names
Citalopram • Celexa                         Prednisone • Deltasone,
Estradiol • Estrace,                                    Orasone, others
   Estrofem, others                           Raloxifene • Evista
Estradiol transdermal •                     Risperidone • Risperdal
   Estraderm , Climara, others
Methylphenidate • Concerta,
   Ritalin, others

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

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.